Posts Tagged ‘breast cancer’

Prognostic biomarker for NSCLC and Cancer Metastasis

Posted in Cancer and Current Therapeutics, Immunodiagnostics, Lung and pulmonology, tagged 4MiR‐515‐5p, breast cancer, CD24, immunohistochemistry, liquid biopsy, MARK4, Membranous CD24 expression, microRNAs, Microtubule Affinity‐Regulating Kinase, monoclonal antibody SWA11, Non-small cell lung cancer, NSCLC, Prognostic marker on March 24, 2016| Leave a Comment »

Prognostic biomarker for NSCLC and Cancer Metastasis

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Membranous CD24 expression as detected by the monoclonal antibody SWA11 is a prognostic marker in non-small cell lung cancer patients

Michael Majores, Anne Schindler, Angela Fuchs, Johannes Stein, Lukas Heukamp, Peter Altevogt and Glen Kristiansen

BMC Clinical Pathology201515:19   http://dx.doi.org:/10.1186/s12907-015-0019-z

Background    Lung cancer is one of the most common malignant neoplasms worldwide and has a high mortality rate. To enable individualized therapy regimens, a better understanding of the molecular tumor biology has still to be elucidated. The expression of the cell surface protein CD24 has already been claimed to be associated with shorter patient survival in non-small cell lung cancer (NSCLC), however, the prognostic value and applicability of CD24 immunostaining in paraffin embedded tissue specimens has been questioned due to the recent acknowledgement of restricted epitope specificity of the commonly used antibody SN3b.   Methods    A cohort of 137 primary NSCLC cases was immunostained with a novel CD24 antibody (clone SWA11), which specifically recognizes the CD24 protein core and the resulting expression data were compared with expression profiles based on the monoclonal antibody SN3b. Furthermore, expression data were correlated to clinico-pathological parameters. Univariate and multivariate survival analyses were conducted with Kaplan Meier estimates and Cox regression, respectively. Results    CD24 positivity was found in 34 % resp. 21 % (SN3b) of NSCLC with a membranous and/or cytoplasmic staining pattern. Kaplan-Meier analyses revealed that membranous, but not cytoplasmic CD24 expression (clone SWA11) was associated with lympho-nodular spread and shorter overall survival times (both p < 0.05). CD24 expression established by SN3b antibodies did not reveal significant clinicopathological correlations with overall survival, neither for cytoplasmic nor membranous CD24 staining.  Conclusions    Membranous CD24 immunoreactivity, as detected with antibody clone SWA11 may serve as a prognostic factor for lymphonodular spread and poorer overall survival. Furthermore, these results corroborate the importance of a careful distinction between membranous and cytoplasmic localisation, if CD24 is to be considered as a potential prognostic biomarker.

 

Lung cancer is a major cause of carcinoma related death, being responsible for 17.8 % of all cancer deaths and accounting for more than a million deaths worldwide per year [1]. Despite intense studies to improve therapy options, its prognosis has remained poor with a 5-year overall survival rate of less than 15 % [2].

In the past decade, the largest subgroup of lung cancer, i.e. non-small cell lung cancer (NSCLC), has been subjected to exerted research for a better understanding of the underlying molecular biology of lung cancer. More than ten years ago, CD24 has already been suggested as a novel and promising biomarker for carcinoma progression in NSCLC [3] and several groups have confirmed this finding on protein and transcript level [2, 4]. CD24 is a highly glycosylated protein, that binds to the cell surface through a GPI (glycosyl-phosphatidylinositol)-anchor and functions as a cell adhesion molecule and is involved in cell-cell-interaction via its P-selectin binding site [5]. CD24 has been found to be expressed by pre-B-lymphocytes [5]. It is assumed that CD24-positive cells can attach more easily to platelets and activated endothelial cells [6, 7]. Notably, CD24 has also been observed in many human carcinomas, such as ovarian cancer, renal cell cancer, breast cancer and NSCLC [3, 8–12]. In epithelial ovarian cancer high scores of cytoplasmic CD24 were highly predictive of shorter patient survival times (mean 97.8 vs. 36.5 months), whereas membranous CD24 expression seemed to have no influence on survival times. Interestingly, CD24 positivity (membranous or cytoplasmic) of prostate cancer samples was significantly associated to younger patient age and higher pT stages and a higher 3-year prostate-specific antigen (PSA) relapse rate compared with CD24-negative tumours.

In patients with gallbladder carcinoma, tumors with up-regulation of CD24 revealed lymph node metastasis and lymphovascular invasion more frequently. Moreover, up-regulation of CD24 tended to show deeper invasion depth and higher TNM stage [13]. Together, these findings support CD24 as a prognostic marker for carcinoma progression and poorer survival.

Despite these intriguing findings, major concerns regarding a lack of epitope specificity of the commonly used monoclonal antibody SN3b have been raised [14]. Recent findings indicate that the mAb (monoclonal antibody) SN3b does not bind to the protein core itself, but binds to a glycan structure that decorates the CD24 molecule. On the one hand, this motif is not present on all forms of CD24 and—on the other hand—it can be present in other epitopes irrespective of CD24 [14]. These limitations underline the need for more specific CD24 antibodies, such as the mAb SWA11 antibody that has been suggested to be more specific as it binds to the protein core [14].

As CD24 is a promising biomarker for the risk assessment of disease progression, the goal of the present study was to investigate CD24 expression in NSCLC using the novel, more specific monoclonal antibody (mAb) SWA11. Special emphasis was put on the comparison of SN3b- and SWA11-mediated CD24 detection regarding a) the subcellular distribution of CD24 expression (i.e. membranous versus cytoplasmic expression) and b) its correlation with various clinicopathological features including patient survival times.

Table 1

Clinicopathological characteristics of the NSCLC cohort

		AC	SCC
		N (%)	N (%)
Tumour stage (pT)
	1	29 (21.2 %)	5 (3.6)
	2	51 (37.2 %)	23 (16.8 %)
	3	6 (4.4 %)	6 (4.4 %)
	4	1 (0.7 %)	0 (0 %)
Nodal Status (pN)	0	37 (27.0 %)	15 (10.9 %)
	1	15 (10.9 %)	9 (6.6 %)
	2	14 (10.2 %)	3 (2.2 %)
	3	1 (0.7 %)	0 (0.0 %)
Grading (G)	1	5 (3.6 %)	0 (0.0 %)
	2	41 (29.9 %)	16 (11.6 %)
	3	44 (32.1 %)	17 (12.4 %)
Mean age at surgery		64,2	64,56
(median age)		(65)	(67)
Sex (m:w)		68:34	30:5
Median OS (months)		52	24
(SD; 95 % CI [months])		(±23.7; 5.5– 98.5)	(± 12.8;0.0– 49.0)

 

Immunohistochemical detection of CD24 expression using clone SWA11 and SN3b

Using the mAb SWA11, 47 of 137 (34.3 %) NSCLC revealed CD24 expression (either cytoplasmic or membranous) (Table 2). CD24 expression was observed more frequently in adenocarcinomas (AC) than in squamous cell carcinomas (SCC). In AC cytoplasmic expression was observed more frequently than membranous expression. In SCC, both cyptoplasmic and membranous expression was rare. Normal lung parenchyma (i.e. alveolar surface cells) showed no expression of CD24. Bronchial epithelium showed a strong membranous and cytoplasmic staining of the brush border (Fig. 1).

Table 2

Cytoplasmic and membranous expression of CD24

SWA11 (mAb clone)			SN3b (mAB clone)
	AC	SCC		AC	SCC
Cytoplasmic	N (%)	N (%)	Cytoplasmic	N (%)	N (%)
0	45 (32.6 %)	19 (13.8 %)	0	76 (55.1 %)	31 (22.5 %)
1	22 (15.9 %)	8 (5.8 %)	1	12 (8.7 %)	1 (0.7 %)
2	17 (12.3 %)	4 (2.9 %)	2	7 (5.1 %)	2 (1.4 %)
3	18 (13.0 %)	4 (2.9 %)	3	1 (0.7 %)	0 (0 %)
	AC	SCC		AC	SCC
Membranous	N (%)	N (%)	Membranous	N (%)	N (%)
0	68 (49.3 %)	21 (15.2 %)	0	64 (46.4 %)	30 (21.7 %)
1	21 (15.2 %)	5 (3.6 %)	1	10 (7.2 %)	2 (1.4 %)
2	8 (5.8 %)	4 (2.9 %)	2	12 (8.7 %)	2 1.4 %)
3	5 (3.6 %)	5 (3.6 %)	3	10 (7.2 %)	0 (0 %)

Staining intensities are determined as follows:

0: negative or equivocal, 1: weak, 2: moderate and 3: strong CD24 staining

 

Fig 1

The immunohistochemical characterization reveals membranous and/or cytoplasmic CD24 (mAb SWA11) expression. Strong cytoplasmic CD24 expression is found in a proportion of both AC (a) and SCC (b, d) specimens. Membranous CD24 expression can be pronounced with only scant or even absent cytoplasmic staining as shown in the AC (c). Also, both membranous and cytoplasmic CD24 detection can be found in some instances (d), the insert is showing the corresponding squamous carcinoma in-situ with membranous staining. Simultaneous membranous and cytoplasmic CD24 expression is also found in AC specimens (e, f). In normal tissue, alveolar epithelial cells do not express CD24 (g), whereas CD24 staining is found at the apical cell membrane of bronchial respiratory epithelia (h)

Using the mAb SN3b, 29 of 137 (21.2 %) NSCLC revealed CD24 expression (either cytoplasmic or membranous) (Table 2). As above, CD24 expression was observed more frequently in adenocarcinomas (AC) than in squamous cell carcinomas (SCC). However, in contrast to mAb SWA11 cytoplasmic expression was observed less frequently than membranous expression in AC. In SCC, both cytoplasmic and membranous expression was rare. Normal lung parenchyma (i.e. alveolar surface cells) showed a distinct membranous immunoreactivity. Bronchial epithelium revealed both membranous and cytoplasmic staining of CD24.

Correlation between SWA11 and SN3b: As SWA11 and SN3b detect different epitopes, we evaluated the correlation of the immunohistochemical staining patterns. Of 132 NSCLC specimens with matched expression data, only 9 specimens (6.8 %) revealed a concordant CD24 expression. Of these cases, 4 cases revealed a concordant cytoplasmic staining and another 5 cases revealed a concordant membranous CD24 expression. Statistically, no significant correlation between the two mAb could be observed (cc = −0.63, p = 0.470; Fisher’s exact test p = 0.665). The correlation of cytoplasmic and membranous expression (for each antibody) was as follows: cc = 0.475 (p < 0.05) for SWA11 (n = 108) and cc = 0.140 (p = 0.11) for SN3b (n = 103).

Survival analyses

Recent studies indicate that CD24 expression is associated with tumor progression and poorer survival rates. Therefore, we performed follow up analyses with a special emphasis on 1) the prognostic value of mAb SWA11 in dependence on subcellular staining characteristics and 2) the prognostic values of different clinicopathological parameters:

Prognostic value of CD24 in Kaplan Meier Analyses

Only membranous CD24 (SWA11) staining revealed significantly poorer survival rates (median overall survival 21 vs. 52 months; p = 0.005) as illustrated in Fig. 2. In contrast, cytoplasmic CD24 (SWA11) staining did not affect the survival rates (median OS 34 vs. 35 months; p = 0.884) (Table 3). When stratifying the cohort into SCC (n = 35) and AC (n = 102) in Kaplan Meier analyses, membranous CD24 (SWA11) expression did not affect patients’ survival, neither in SCC (p = 0.243) nor AC (p = 0.135) (Table 3), probably due to the small number of observations (Fisher exact test: p > 0.05). After stratification for AC subtypes, membranous CD24 expression (SWA11) showed a tendency towards an association with poorer survival in acinar subtype AC, but failed significance (p = 0.328).

Fig 2

Survival analysis. Kaplan-Meier curves according to SWA11 expression. Cases with moderate to strong expression were bundled in a ‘high expression’ and cases with negative or weak expression in a ‘low expression’ group. Membranous expression of CD24 detected by SWA11 proved to be an independent marker for shorter survival times in NSCLC (p = 0.005)

Table 3

Univariate survival analysis

SWA11	No. of cases	Mean survival time	Median survival time	p-value
		(months +/− s.e.)	(months +/− s.e.)
Mem CD24
Negative	76	84.833 +/− 10.395	52.000 +/− 27.030	0.005
Positive	16	27.925 +/− 6.379	21.000 +/− 4.000
Cyto CD24
Negative	66	75.209 +/− 10.577	35.000 +/− 12.422	0.884
Positive	26	60.540 +/− 11.551	34.000 +/− 12.196
Total CD24
Negative	64	76.972 +/− 10.841	35.000 +/− 13.726	0.633
Positive	28	57.535 +/− 10.895	34.000 +/− 9.303
SCC
Mem CD24 negative	16	52.063 +/− 14.668	16.000 +/− 16.000	0.243
Mem CD24 positive	7	21.571 +/− 7.201	24.000 +/− 23.568
AC
Mem CD24 negative	59	88.953 +/− 11.631	56.000 +/− 22.885	0.135
Mem CD24 positive	8	39.167 +/− 11.674	21.000 +/− 8.485
pN0	31	103.641 +/− 14.940	93.000 +/− 28.224	0.012
pN1+	30	54.911 +/− 10.646	26.000 +/− 0.983

 

…..

Univariate survival analysis according to the Cox regression model (mAb SWA11)

	Beta	HR (hazard ratio)	95 % CI of HR	P-value
SWA11 mem all	0.856	2.353	1.268–4.364	0.007
pN	0.963	2.620	1.389–4.943	0.003
pT	0.844	2.325	1.279–4.224	0.006
Tumour type	0.975	2.651	1.999–3.517	0.000

Table 5

Multivariate survival analysis according to the Cox regression model (mAb SWA11)

	Beta	HR (hazard ratio)	95 % CI of HR	P-value
SWA11 mem all	0.944	2.571	1.211–5.458	0.014
pN	0.737	2.091	1.087–4.021	0.027
pT	0.587	1.799	0.755–4.283	0.185

 

…..

In the present study, we have analyzed immunohistochemical staining characteristics and the prognostic value of CD24 expression in NSCLC with a special emphasis on the comparison of the CD24 antibodies SWA11 and SN3b. The most important result of our study is that the prognostic relevance of CD24 is critically dependent on the careful consideration of sub-cellular compartments and the epitope specificity of the antibody used.

Overall, about one third of the NSCLC cohort revealed a significant CD24 expression (either cytoplasmic or membranous). These results are in line with the findings of other studies. In another NSCLC cohort, CD24 (SN3b) expression was found in 33 % of the samples (87 of 267 cases) [2]. Consistent with those results, we have found similar rates of high CD24 expression levels (35 % of the cases) for SWA11. Originally, we would have expected lower rates than those found by Lee et al, as they used the antibody SN3b, that also recognizes yet unidentified other glycoproteins next to CD24. Furthermore, they used whole mount sections instead of tissue microarrays. A possible explanation for rather equal detection rates would be the fact that it has been demonstrated that the epitope recognized by SN3b is indeed present in CD24, but is not found in all glycoforms of CD24 [14]. In contrast to the commonly used mAb SN3b, mAb SWA11 binds to the protein core of CD24 and does not depict other glycan moieties next to CD24. The protein core of CD24 is linear, consisting of the amino acid sequence leucine-proline-alanine (LAP) next to a glycosyl-phosphatidylinositol anchor [15].

CD24 expression has been associated with disease progression and cancer-related death in the majority of malignant tumors [2, 3, 16, 17], although a caveat to these data is that most of these studies are based on the supposedly less specific CD24 clone SN3b. Lee et al demonstrated a significant association between CD24-high expression (SN3b) and shorter patient survival times. Furthermore, Lee and colleagues and ourselves in former studies referred the results to cytoplasmic CD24 expression [2, 3].

Switching Off Cancers’ Ability to Spread

http://www.technologynetworks.com/rnai/news.aspx?ID=189704

A key molecule in breast and lung cancer cells can help switch off the cancers’ ability to spread around the body.

The findings by researchers at Imperial College London, published in the journal EMBO Reports, may help scientists develop treatments that prevent cancer travelling around the body – or produce some kind of test that allows doctors to gauge how likely a cancer is to spread. During tumour growth, cancer cells can break off and travel in the bloodstream or lymph system to other parts of the body, in a process called metastasis.

Patients whose cancers spread tend to have a worse prognosis, explains Professor Justin Stebbing, senior author of the study from the Department of Surgery and Cancer at Imperial: “The ability of a cancer to spread around the body has a large impact on a patient’s survival. However, at the moment we are still in the dark about why some cancers spread around the body – while others stay in one place. This study has given important insights into this process.”

The researchers were looking at breast and lung cancer cells and they found that a protein called MARK4 enables the cells to break free and move around to other parts of the body, such as the brain and liver. Although scientist are still unsure how it does this, one theory is it affects the cell’s internal scaffolding, enabling it to move more easily around the body. The team found that a molecule called miR-515-5p helps to silence, or switch off, the gene that produces MARK4.

In the study, the team used human breast cancer and lung cancer cells to show that the miR-515-5p molecule silences the gene MARK4. They then confirmed this in mouse models, which showed that increasing the amount of miR-515-5p prevents the spread of cancer cells. The findings also revealed that the silencer molecule was found in lower levels in human tumours that had spread around the body. The team then also established that patients with breast and lung cancers whose tumours had low amounts of these silencer molecules – or high amounts of MARK4 – had lower survival rates.

Researchers are now investigating whether either the MARK4 gene or the silencer molecule could be targeted with drugs. They are also investigating whether these molecules could be used to develop a test to indicate whether a patient’s cancer is likely to spread. Professor Stebbing said: “In our work we have shown that this silencer molecule is important in the spread of cancer. This is very early stage research, so we now need more studies to find out more about this molecule, and if it is present in other types of cancer.”

Dr Olivier Pardo, lead author of the paper, also from the Department of Surgery and Cancer at Imperial, added: “Our work also identified that MARK4 enables breast and lung cancer cells to both divide and invade other parts of the body. These findings could have profound implications for treating breast and lung cancers, two of the biggest cancer killers worldwide.” The study was supported by the NIHR Imperial Biomedical Research Centre, the Medical Research Council, Action Against Cancer and the Cancer Treatment and Research Trust.

 

‘Silencer molecules’ switch off cancer’s ability to spread around body

by Kate Wighton

Scientists have revealed that a key molecule in breast and lung cancer cells can help switch off the cancers’ ability to spread around the body

The findings by researchers at Imperial College London, published in the journal EMBO Reports, may help scientists develop treatments that prevent cancer travelling around the body – or produce some kind of test that allows doctors to gauge how likely a cancer is to spread.

During tumour growth, cancer cells can break off and travel in the bloodstream or lymph system to other parts of the body, in a process called metastasis.

Patients whose cancers spread tend to have a worse prognosis, explains Professor Justin Stebbing, senior author of the study from the Department of Surgery and Cancer at Imperial: “The ability of a cancer to spread around the body has a large impact on a patient’s survival. However, at the moment we are still in the dark about why some cancers spread around the body – while others stay in one place. This study has given important insights into this process.”

The researchers were looking at breast and lung cancer cells and they found that a protein called MARK4 enables the cells to break free and move around to other parts of the body, such as the brain and liver. Although scientist are still unsure how it does this, one theory is it affects the cell’s internal scaffolding, enabling it to move more easily around the body.

 

miR‐515‐5p controls cancer cell migration through MARK4 regulation

Olivier E Pardo, Leandro Castellano, Catriona E Munro, Yili Hu, Francesco Mauri,Jonathan Krell, Romain Lara, Filipa G Pinho, Thameenah Choudhury, Adam EFrampton, Loredana Pellegrino, Dmitry Pshezhetskiy, Yulan Wang, JonathanWaxman, Michael J Seckl, Justin Stebbing    

EMBO reports (2016) embr.201540970   http://embor.embopress.org/content/early/2016/02/10/embr.201540970     http://dx.doi.org:/10.15252/embr.201540970| Published online 10.02.2016

Here, we show that miR‐515‐5p inhibits cancer cell migration and metastasis. RNA‐seq analyses of both oestrogen receptor receptor‐positive and receptor‐negative breast cancer cells overexpressing miR‐515‐5p reveal down‐regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR‐515‐5p inhibits MARK4 directly 3′ UTR interaction and that MARK4 knock‐down mimics the effect of miR‐515‐5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR‐515‐5p, suggesting miR‐515‐5p mediates this process through MARK4 down‐regulation. Furthermore, miR‐515‐5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR‐515‐5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR‐515‐5p and low MARK4 expression correlate with increased breast and lung cancer patients’ survival, respectively. Taken together, these data demonstrate the importance of miR‐515‐5p/MARK4 regulation in cell migration and metastasis across two common cancers.

miR‐515‐5p inhibits cancer progression, cell migration and metastasis through its direct target MARK4, a regulator of the cytoskeleton and cell motility. Moreover, reduced miR‐515‐5p and increased MARK4 levels in metastatic lung and breast cancer correlate with poor patient prognosis.

• MARK4 down‐regulation promotes microtubule polymerisation.

• Increased cell spreading downstream of miR‐515‐5p overexpression or MARK4 silencing hinders cell motility and invasiveness.

• miR‐515‐5p overexpression or MARK4 silencing prevent organ colonisation by circulating tumour cells.

• MARK4 inhibitors may represent novel therapeutic agents to control cancer dissemination.breasat cancer

 

Liquid Biopsy for NSCLC

http://www.technologynetworks.com/Diagnostics/news.aspx?ID=190276

‘Liquid biopsy’ blood test accurately detects key genetic mutations in most common form of lung cancer, study finds.

A simple blood test can rapidly and accurately detect mutations in two key genes in non-small cell lung tumors, researchers at Dana-Farber Cancer Institute and other institutions report in a new study – demonstrating the test’s potential as a clinical tool for identifying patients who can benefit from drugs targeting those mutations. The test, known as a liquid biopsy, proved so reliable in the study that Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC) expects to offer it soon to all patients with non-small cell lung cancer (NSCLC), either at the time of first diagnosis or of relapse following previous treatment. NSCLC is the most common form of lung cancer, diagnosed in more than 200,000 people in the United States each year, according to the American Cancer Society. An estimated 30 percent of NSCLC patients have mutations in either of the genes included in the study, and can often be treated with targeted therapies. The study is being published online today by the journal JAMA Oncology. The liquid biopsy tested in the study – technically known as rapid plasma genotyping – involves taking a test tube-full of blood, which contains free-floating DNA from cancer cells, and analyzing that DNA for mutations or other abnormalities. (When tumor cells die, their DNA spills into the bloodstream, where it’s known as cell-free DNA.) The technique, which provides a “snapshot” of key genetic irregularities in a tumor, is a common tool in research for probing the molecular make-up of different kinds of cancers. “We see plasma genotyping as having enormous potential as a clinical test, or assay – a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies,” said the senior author of the study, Geoffrey Oxnard, MD, thoracic oncologist and lung cancer researcher at Dana-Farber and Brigham and Women’s Hospital. “Our study was the first to demonstrate prospectively that a liquid biopsy technique can be a practical tool for making treatment decisions in cancer patients. The trial was such a success that we are transitioning the assay into a clinical test for lung cancer patients at DF/BWCC.” The study involved 180 patients with NSCLC, 120 of whom were newly diagnosed, and 60 of whom had become resistant to a previous treatment, allowing the disease to recur. Participants’ cell-free DNA was tested for mutations in the EGFR and KRAS genes, and for a separate mutation in EGFR that allows tumor cells to become resistant to front-line targeted drugs. The test was performed with a technique known as droplet digital polymerase chain reaction (ddPCR), which counts the individual letters of the genetic code in cell-free DNA to determine if specific mutations are present. Each participant also underwent a conventional tissue biopsy to test for the same mutations. The results of the liquid biopsies were then compared to those of the tissue biopsies. The data showed that liquid biopsies returned results much more quickly. The median turnaround time for liquid biopsies was three days, compared to 12 days for tissue biopsies in newly diagnosed patients and 27 days in drug-resistant patients. Liquid biopsy was also found to be highly accurate. In newly diagnosed patients, the “predictive value” of plasma ddPCR was 100 percent for the primary EGFR mutation and the KRAS mutation – meaning that a patient who tested positive for either mutation was certain to have that mutation in his or her tumor. For patients with the EGFR resistance mutation, the predictive value of the ddPCR test was 79 percent, suggesting the blood test was able to find additional cases with the mutation that were missed using standard biopsies. “In some patients with the EGFR resistance mutation, ddPCR detected mutations missed by standard tissue biopsy,” Oxnard remarked. “A resistant tumor is inherently made up of multiple subsets of cells, some of which carry different patterns of genetic mutations. A single biopsy is only analyzing a single part of the tumor, and may miss a mutation present elsewhere in the body. A liquid biopsy, in contrast, may better reflect the distribution of mutations in the tumor as a whole.” When ddPCR failed to detect these mutations, the cause was less clear-cut, Oxnard says. It could indicate that the tumor cells don’t carry the mutations or, alternatively, that the tumor isn’t shedding its DNA into the bloodstream. This discrepancy between the test results and the presence of mutations was less common in patients whose cancer had metastasized to multiple sites in the body, researchers found. The ddPCR-based test, or assay, was piloted and optimized for patients at the Translational Resarch lab of the Belfer Center for Applied Cancer Science at Dana-Farber. It was then validated for clinical use at Dana-Farber’s Lowe Center for Thoracic Oncology. An advantage of this form of liquid biopsy is that it can help doctors quickly determine whether a patient is responding to therapy. Fifty participants in the study had repeat testing done after starting treatment for their cancer. “Those whose blood tests showed a disappearance of the mutations within two weeks were more likely to stay on the treatment than patients who didn’t see such a reduction,” said the study’s lead author, Adrian Sacher, MD, of Dana-Farber and Brigham and Women’s Hospital. And because tumors are constantly evolving and acquiring additional mutations, repeated liquid biopsies can provide early detection of a new mutation – such as the EGFR resistance mutation – that can potentially be treated with targeted agents. “The study data are compelling,” said DF/BWCC pathologist Lynette Sholl, MD, explaining the center’s decision to begin offering ddPCR-based liquid biopsy to all lung cancer patients. “We validated the authors’ findings by cross-comparing results from liquid and tissue biopsies in 34 NSCLC patients. To work as a real-world clinical test, liquid biopsy needs to provide reliable, accurate data and be logistically practical. That’s what we’ve seen with the ddPCR-based blood test. “The test has great utility both for patients newly diagnosed with NSCLC and for those with a recurrence of the disease,” she continued. “It’s fast, it’s quantitative (it indicates the amount of mutant DNA in a sample), and it can be readily employed at a cancer treatment center.” The co-authors of the study are Cloud Paweletz, PhD, Allison O’Connell, BSc, and Nora Feeney, BSc, of the Belfer Center for Applied Cancer Science at Dana-Farber; Ryan S. Alden BSc, and Stacy L. Mach BA, of Dana-Farber; Suzanne E. Dahlberg, PhD, of Dana-Farber and Harvard T.H. Chan School of Public Health; and Pasi A. Jänne, MD, PhD, of Dana-Farber, the Belfer Center, and Brigham and Women’s Hospital.

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Rapid regression of HER2 breast cancer

Posted in Cancer and Current Therapeutics, Clinical Genomics, Pharmaceutical Analytics, Pharmacologic toxicities, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged breast cancer, dual drug therapy, EPHOS-B, HER2 on March 14, 2016| Leave a Comment »

Rapid regression of HER2 breast cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Anti-HER2 Combo Shrunk Breast Tumors in Under 2 Weeks

News | March 11, 2016 | Breast Cancer, HER2-Positive Breast Cancer

By Anna Azvolinsky, PhDhttp://www.cancernetwork.com/news/anti-her2-combo-shrunk-breast-tumors-under-2-weeks

A quarter of women with HER2-positive breast cancer treated with a combination of lapatinib plus trastuzumab prior to surgery had significant tumor shrinkage within 11 days. These results, from the EPHOS-B clinical trial in the United Kingdom were presented at the 10th Annual European Breast Cancer Conference (EBCC-10), held March 9–11, in Amsterdam (abstract LBA6).

EBCC-10 Searchable Programme – 

European Society of Medical Oncology Workshop: Is Personalised Medicine a Reality in Today’s Clinical Breast Care Practice?

Are we personalising or just subtyping early breast cancer?

Speaker: G. Curigliano (Italy)

Key Objectives

1) Providing an overview on design of clinical trials in early breast cancer in the genomic era (neoadjuvant, residual disease and window of opportunity trials). 2) Addressing challenges in delivering trials in the era of precision medicine. 3) Why drug development is changing?

Pros and cons on chemoprophylaxis of pre-invasive lesions

Speaker: T. Pienkowski (Poland)

Key Objectives

1. To understand clinical relevance of estrogens in pathogenisis of breast cancer 2.To understand the potential benefit and risk connected with chemoprotection of breast cancer 3. To be familiar with clinical trials connected with chemoprevention

Translating genetic drivers into new targeted therapies for breast cancer

Speaker: D. Tripathy (USA)

Key Objectives

Translating Genetic Drivers into New Targeted Therapies for Breast Cancer

Key Objectives

Objective 1: To review critical genomic drivers of breast carcinogenesis

Objective 2: To describe resistance drivers and evolutionary changes that develop under treatment pressure

Objective 3: To understand the rationale, early results, and future clinical applications of targeted biological therapies for breast cancer

 

The role of tumour typing and grading

Speaker: M.P. Foschini (Italy)

Key Objectives

1) Explain the importance of histotyping, with special focus on low grade tumours and on triple negative low grade tumours.
2) Explain the prognostic importance of correct grading on surgical specimens.
3) Explain the value and limits of grading and histotyping on pre-operative biopsies.

 

“This has groundbreaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumors disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy,” said researcher Nigel Bundred, MD, professor of surgical oncology at the University of Manchester in the United Kingdom, in a statement. “This offers the opportunity to tailor treatment for each individual woman.”

Following initial news reports of the EPHOS-B trial, the authors earlier today issued a statement urging caution in interpreting the results: “While we do not wish to downplay the significance of the findings,” they wrote, “we wish to emphasize that our research has shown this treatment to be suitable for a group of women with a particular type of breast cancer. We have no evidence that it would be effective for anything other than patients with newly diagnosed, HER2-positive breast tumors.”

The trial was split into two parts and included 257 newly diagnosed, operable, HER2-positive breast cancer patients.

In the first part of the trial, 130 patients were randomized to a control group that received no pre-operative treatment, or to one of three treatment arms that received therapy for 11 days prior to surgery: trastuzumab alone, lapatinib alone, or the combination of trastuzumab and lapatinib. All patients were treated with standard of care after surgery.

In the second part of the trial, 127 patients were randomized to receive trastuzumab alone (n = 32), the combination of trastuzumab and lapatinib (n = 66), or a control group that received no pre-operative treatment (n = 29). Results from this part of the trial showed that in patients who received the combination treatment, 11% had a pathologic complete response (pCR) and 17% had minimal residual disease (MRD). In patients who received trastuzumab alone, none had a pCR and only 3% had MRD. No patient in the control group had either a pCR or MRD. Patients in the combination treatment arm also had a reduction in Ki67, a marker of apoptosis.

Median age of patients in the trial was 52 years, 48% of women had tumors greater than 2 cm, and 51% were grade 3 as assessed by biopsy.

“These results show that we can get an early indication of pathologic response within 11 days, in the absence of chemotherapy, in these patients on combination treatment. Most previous trials have only looked at the pathologic response after several months of treatment,” said Judith Bliss, MD, of the Institute of Cancer Research in London and Vice-Chair of the UK Breast Intergroup, who took part in the clinical trial, at a press conference.

The study researchers emphasized that these results need to be confirmed in larger trials.

“This study proposes a simple way to identify those patients very early on, which could help spare them unnecessary chemotherapy. What is now indispensable is to confirm if these early responses translate into better or equal long-term survival,” said Fatima Cardoso, MD, chair of EBCC-10 and director of the breast unit at the Champalimaud Clinical Centre in Lisbon, in a statement.

The EPHOS-B trial was funded by Cancer Research UK and GlaxoSmithKline.

 

Breast Cancer Drug Combination Could Shrink Tumors in Days

Seth Augenstein, Digital Reporter    http://www.biosciencetechnology.com/news/2016/03/breast-cancer-drug-combination-could-shrink-tumors-days

A combination of breast cancer drugs administered before surgery could drastically shrink particular tumors within days – and potentially eliminate the need for chemotherapy in some patients, according to British researchers.

Herceptin (trastuzumab) in concert with lapatinib on tumors that are HER-2 positive can shrink or even destroy tumors within just 11 days before surgery, according to The Institute of Cancer Research in London.

Some 20 percent of all breast cancers are HER-2 positive, according to analysis by the Mayo Clinic.

The theory was the two drugs would work as a one-two punch: the Herceptin would block the HER-2 proteins on which the tumors rely, and then the lapatinib would inhibit other enzymes that may potentially remain unaffected by the other drug.

The study observed the tumor size in 257 women in the days-long window between diagnosis and removal of the tumors.

The participants were initially split up into three groups – one each getting one of the drugs, and a third getting no treatment for the 11 days before the surgery, according to the scientists.

However, other trials had indicated the drug combination could have a dramatic effect, so additional women were put in the lapatinib group and also given the Herceptin.

Roughly a quarter of the 66 women who got both drugs had tumors that were too small for the second measurement before surgery, they found.

“Our trial set out to try to use the window between diagnosis and surgery to find clues that combined treatment with (Herceptin) and lapatinib was having a biological effect on HER-2 positive tumors,” said Judith Bliss, director of the Cancer Research Clinical Trials and Statistics Unit at the Institute of Cancer Research. “So it was unexpected to see quite such dramatic responses to the (Herceptin) and lapatinib within 11 days.”

The results were presented at the European Breast Cancer Conference on Thursday.

“These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER-2 positive breast cancers,” said Arnie Purushotham, senior clinical adviser at Cancer Research UK.

 

Breast cancer cells stained for DNA (red), NFkB (green), and a reactive oxygen species probe (blue) (photo: Julia Sero/the ICR)

 

A drug combination – of lapatinib and trastuzumab (Herceptin) – before surgery shrinks and may even destroy tumours in women with HER2 positive disease within 11 days, according to new research.

The EPHOS B trial, led by researchers at The Institute of Cancer Research, London, the University of Manchester and University Hospital of South Manchester NHS Foundation Trust, studied 257 women with HER2 positive breast cancer in the short gap between initial diagnosis and surgery to remove their tumours.

The research may lead to fewer women needing chemotherapy.

The results, from a Cancer Research UK-funded trial, are being presented at the 10th European Breast Cancer Conference (EBCC10) today (Thursday).

In the trial, women were split into three groups and treated for 11 days before their surgery. Initially, women were randomised to receive either trastuzamab, or lapatinib or no treatment – but halfway through the trial, after evidence emerged from other trials of the effectiveness of the combination, the design was altered so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

Drug combination shrinks HER2-positive breast cancers within 11 days

A drug combination – of lapatinib and trastuzumab (Herceptin) – before surgery shrinks and may even destroy tumours in women with HER2 positive disease within 11 days, according to new research.

The EPHOS B trial, led by researchers at The Institute of Cancer Research, London, the University of Manchester and University Hospital of South Manchester NHS Foundation Trust, studied 257 women with HER2 positive breast cancer in the short gap between initial diagnosis and surgery to remove their tumours.

The research may lead to fewer women needing chemotherapy.

The results, from a Cancer Research UK-funded trial, are being presented at the 10th European Breast Cancer Conference (EBCC10) today (Thursday).

In the trial, women were split into three groups and treated for 11 days before their surgery. Initially, women were randomised to receive either trastuzamab, or lapatinib or no treatment – but halfway through the trial, after evidence emerged from other trials of the effectiveness of the combination, the design was altered so that additional women allocated to the lapatinib group were also prescribed trastuzumab.

The trial set out to study the biological effects of the drug combination by measuring biological markers of cellular proliferation after 11 days of therapy. But when trying to measure this, the researchers discovered that in roughly a quarter of the 66 women who received both drugs, the remaining tumour was too small for the second measurement of cell proliferation.

Seventeen per cent of the women receiving both drugs had only minimal residual disease – defined as an invasive tumour smaller than 5mm in size – and 11% had a pathological complete response, meaning no biological sign of invasive tumour could be found in the breast.

‘Very promising’

Three per cent of the women treated with trastuzumab only had residual disease or complete response.

HER2-positive breast cancer is more likely to come back after treatment than some other types of breast cancer. It is generally treated with surgery, chemotherapy, endocrine therapy and targeted anti-HER2 drugs.

Around 53,400 women are diagnosed with invasive breast cancer – with about 10-15% of these characterised as HER2 positive breast cancer – and around 11,600 women die from the disease in the UK every year.

Current treatments are effective and complete response is common after three to four months, but the researchers say observing a disease response after 11 days was very surprising.

Trial Co-leader Professor Judith Bliss, Director of the Cancer Research UK-funded Clinical Trials and Statistics Unit at the ICR, said: “Our trial set out to try to use the window between diagnosis and surgery to find clues that combined treatment with trastuzumab and lapatinib was having a biological effect on HER2 positive tumours. So it was unexpected to see quite such dramatic responses to the trastuzumab and lapatinib within 11 days.

“Our results are a strong foundation on which to build further trials of combination anti-HER2 therapies prior to surgery – which could reduce the number of women who require subsequent chemotherapy, which is also very effective but can lead to long-term side-effects.”

Clinical Chief Investigator and Trial Co-leader Professor Nigel Bundred, Professor of Surgical Oncology at The University of Manchester and Clinical Consultant at University Hospital of South Manchester NHS Foundation Trust, said: “These early and significant tumour regressions seen on dual anti-HER2 therapy suggest that we will be able to personalise treatment for these cancers on the basis of early response, allowing us to identify patients who in the future may avoid treatment morbidity or avoid chemotherapy”.

Professor Arnie Purushotham, Senior Clinical Adviser at Cancer Research UK, said: “These results are very promising if they stand up in the long run and could be the starting step of finding a new way to treat HER2-positive breast cancers. This could mean some women can avoid chemotherapy after their surgery – sparing them the side-effects and giving them a better quality of life.”

Official 10th European Breast Cancer Conference (EBCC-10)

http://www.ecco-org.eu/EBCC

Statement on EPHOS-B (lapatinib/trastuzumab combination) trialLead researchers: Prof. Judith Bliss, Prof. Nigel  Bundred, Prof. David Cameron

We wish to emphasise that our research has shown this treatment to be suitable for a group of women with a particular type of breast cancer. We have no evidence that it would be effective for anything other than patients with newly-diagnosed, HER2 positive breast tumours. In addition, we do not yet know what effect the treatment will have on long-term survival.  While we do not wish to downplay the significance of the findings, we also urge caution in their interpretation.  Further trials will be needed before we can confirm these results, even in HER2 positive patients.

 

Breast Cancer Vaccines and Checkpoint-Inhibitor Immunotherapy

Q&A | March 15, 2016 | MBCC 2016, Breast Cancer
By Elizabeth A. Mittendorf, MD, PhD

Elizabeth A. Mittendorf, MD, PhD
As part of our coverage of the 33rd Annual Miami Breast Cancer Conference, held March 10-13 in Miami Beach, Florida, we spoke with Elizabeth A. Mittendorf, MD, PhD, associate professor at the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center in Houston, Texas, who presented at the meeting on cancer vaccines and checkpoint inhibitors.
Cancer Network: How has being both a surgeon and immunologist, shaped your views of the potential clinical roles of cancer vaccines?

Dr. Mittendorf: As a surgeon, I see and treat patients with early-stage breast cancer that is potentially curable. Unfortunately, despite our best treatment—surgery, chemotherapy when indicated, radiation if required—we still see recurrences in up to 20% of these patients. I think it is not unreasonable to hypothesize that this recurrence is in part attributable to a failure of the immune response against the cancer—hence my enthusiasm for vaccines that could potentially augment that antitumor immunity, thereby decreasing the risk of recurrence.

Cancer Network: In what settings do breast cancer vaccines show the most promise?

Dr. Mittendorf: Secondary prevention. There is currently one vaccine that is being investigated in a phase III trial—NeuVax—which is made up of an immunogenic peptide combined with an immunoadjuvant. The trial is vaccinating patients in the adjuvant setting with the goal being to determine if vaccination can decrease the risk of recurrence.

Cancer Network: Is there reason for optimism that cancer vaccines might prove useful against advanced breast cancers?

Dr. Mittendorf: In my opinion, vaccines as monotherapy are not likely to be successful in advanced breast cancer. With that said, it is possible that vaccines could be administered as part of a combination strategy with other drugs that could augment the immune response such as certain chemotherapy regimens, trastuzumab, or other immunomodulatory drugs such as the checkpoint blockade agents.

Cancer Network: What insights do epidemiologic studies, such as those regarding childhood infections and cancer risk, offer for cancer immunotherapy?

Dr. Mittendorf: There is epidemiologic data to suggest that individuals who have had childhood infections (ie, chicken pox, pertussis, and other febrile illnesses) have a decreased risk of developing cancer. It is likely that these individuals develop adaptive immune responses against epithelial antigens. These responses could be augmented in the setting of a premalignant condition (ie, a colonic adenoma, or ductal carcinoma in situ), thereby tipping the scales back in favor of the immune response, leading to elimination of the threat of malignancy.

Cancer Network: Are the KEYNOTE trial reports to date reason for optimism about immune checkpoint blockade’s potential against breast cancer?

Dr. Mittendorf: Absolutely. These trials have confirmed that pembrolizumab (anti-PD-1 antibody) is fairly well tolerated by breast cancer patients and suggest some clinical activity. Through the portfolio of KEYNOTE trials, which have enrolled the different subtypes of breast cancer, we’re likely to learn more about which subtypes of breast cancer are most likely to respond to pembrolizumab as monotherapy, which in turn would suggest which subtypes might need additional immune stimulation (ie, a combination strategy) in order for the checkpoint blockade agent to be effective.

Cancer Network: What is the significance of PD-L1 expression in tumor cells vs the tumor microenvironment?

Dr. Mittendorf: Whether PD-L1 expression on the tumor cells is required for response to anti-PD-1 or anti-PD-L1 therapy remains a subject of much discussion. Data from the JAVELIN trial presented at the San Antonio Breast Cancer Symposium in December suggested that PD-L1 expression on the tumor was less important than PD-L1 expression on immune cells in the microenvironment—what they referred to as “immune hotspots.”

Cancer Network: Do you anticipate clinical roles for checkpoint blockade in secondary prevention? Breast cancer treatment in combination with other agents, like trastuzumab? (Are there other promising combinations? Do you anticipate immunotherapy combinations that exploit different immune system pathways?)

Dr. Mittendorf: I see a potential role for checkpoint blockade in the adjuvant setting (effectively secondary prevention) in high-risk patients in whom the risk/benefit ratio favors using these agents, which do have some toxicity associated with them. As an example, the SWOG cooperative group is developing a trial that will evaluate pembrolizumab in patients with triple-negative breast cancer who have at least 1 cm of tumor or positive lymph nodes after neoadjuvant chemotherapy. With respect to using in combination with other agents—yes; in fact the PANACEA trial currently accruing in Europe is combining pembrolizumab with trastuzumab in patients with HER2-positive metastatic breast cancer.

http://www.cancernetwork.com/mbcc-2016/breast-cancer-vaccines-and-checkpoint-inhibitor-immunotherapy#sthash.UenTvjsF.dpuf

 

 

Prognostic DCIS Score: ‘Ready for Prime Time’

News | March 14, 2016 | MBCC 2016, Breast Cancer
By Bryant Furlow
Not all ductal carcinoma in situ (DCIS) is dangerous, and the prognostic genomic Oncotype DX DCIS Score allows for routine risk stratification of patients to avoid unnecessary treatment, reported Patrick I. Borgen, MD, chair of the department of surgery at Maimonides Medical Center in Brooklyn, New York. Dr. Borgen spoke at the 33rd Annual Miami Breast Cancer Conference, held March 10–13 in Miami Beach, Florida.
Recent jumps in DCIS diagnoses have been driven by overdetection. “There’s a reservoir of DCIS in the female breast that was never going to become invasive—or would do so, so slowly that it was never going to threaten our patient,” Dr. Borgen noted.

Graphing the utilization of mammography over time, one sees that it “completely parallels the increase in DCIS diagnoses,” Dr. Borgen said. “There’s a similar slope of percent-change over time for DCIS and mammography screening. That either means the mammograms are causing DCIS, or, much more likely, that some of this [DCIS] was not going to become clinically relevant.”

When more sensitive digital mammography became more widely used, DCIS rates jumped again, he added. “Better imaging, more DCIS.”

The prevalence of occult DCIS in autopsy studies is “about an order of magnitude higher” than what we see in screening studies, Dr. Borgen noted, as further evidence for subclinical DCIS.

Thanks to landmark prospective randomized studies like the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 study, the standard of care for DCIS is lumpectomy and radiation. Those studies did not identify subsets of patients who failed to benefit from radiation, but they did find that 80% of patients would do well with surgery alone. “We focus on the 10% who do better with radiotherapy, but 10% recur despite radiotherapy. The challenge is, how do we find the 80% of patients who, much later—15, 20, 25 years later—are going to be well?”

Nomograms “leave significant room for improvement,” he noted. “It is possible that clinical parameters alone are insufficient to predict outcome. We have moved away from morphology—from looking down a microscope to determine whether it’s a bad lesion.”

Instead, the field has turned to prognostic analyses of DCIS genomics.

“The Oncotype DX DCIS Score isn’t a mathematical model and doesn’t require bootstrapping,” he said. “It looks at DCIS genomics in the patient in front of you—a subset of the 21-gene assay that we use routinely.”

It has been validated in the Eastern Cooperative Oncology Group (ECOG) E5194 and Ontario DCIS Cohort studies for recurrence prognostication and risk stratification of women with DCIS who underwent breast-conserving surgery and had negative margins.

“I would argue that it’s ready for prime time” in routine clinical use, Dr. Borgen told attendees.

The DCIS Score divides patients into low, intermediate, and high-risk DCIS categories, with 65% of patients falling into the low-risk group, meaning that at 10 years, they face a 4% chance of developing invasive breast cancer.

Dr. Borgen noted that the addition of radiation doesn’t diminish the DCIS Score’s predictability. “The DCIS Score is associated with the risk of local recurrence in a population of patients with pure DCIS treated with breast-conserving surgery, with or without radiation. It’s almost certain there’s a very high-risk cohort of the disease, as well, and those patients may benefit from an entirely different treatment.”

http://www.cancernetwork.com/mbcc-2016/prognostic-dcis-score-ready-prime-time

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Breast Cancer Extratumor Microenvironment has Effect on Progression

Posted in Biochemical pathways, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Informatics, Cell Biology, Signaling & Cell Circuits, Clinical & Translational, Clinical Diagnostics, Computational Biology/Systems and Bioinformatics, Curation, Cytoskeleton, Diagnostics and Lab Tests, Disease Biology, Gene Regulation, Genome Biology, Genomic Endocrinology, Human Immune System in Health and in Disease, Lipid metabolism, Metabolism, Metabolomics, Micronutrients, Mutagenesis, tagged breast cancer, extratunot microenvironment, metastasis on February 20, 2016| Leave a Comment »

Breast Cancer Extratumor Microenvironment has Effect on Progression

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Tumor Microenvironment Diversity Predicts Breast Cancer Outcomes

GEN News Highlights   Feb 17, 2016   http://www.genengnews.com/gen-news-highlights/tumor-microenvironment-diversity-predicts-breast-cancer-outcomes/81252378/

 

Intratumor heterogeneity, it is known, can complicate cancer treatments. Now it appears the same may be true of tumor microenvironment heterogeneity. According to a new study from the Institute of Cancer Research (ICR), London, breast cancers that develop within an “ecologically diverse” breast cancer microenvironment are particularly likely to progress and lead to death.

The study took an unusual approach: It combined ecological scoring methods with genome-wide profiling data. This approach, besides showing clinical utility in the evaluation of breast cancer outcomes, demonstrated that even so contextual a discipline as genomics can benefit from being placed within a larger context. In this case, the context is essentially Darwinian, albeit at a small scale.

Natural selection is typically studied at the level of ecosystems consisting of animals and plants. In the current study, however, it was assessed at the level of the tumor microenvironment, which consists of cancer cells, immune system lymphocytes, and stromal cells.

The ICR scientists, led by Yinyin Yuan, Ph.D., presented their work February 16 in the journal PLoS Medicine, in an article entitled “Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.” The article describes how the scientists developed a tumor ecosystem diversity index (EDI), a scoring system that indicates the degree of microenvironmental heterogeneity along three spatial dimensions in solid tumors. EDI scores take account of “fully automated histology image analysis coupled with statistical measures commonly used in ecology.”

“[EDI] was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set,” wrote the authors. “In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types.”

By using the EDI, the ICR team was able to identify several particularly aggressive subgroups of breast cancer. In fact, the EDI was a stronger predictor of survival than many established markers for the disease.

The ICR researchers also looked at the EDI in addition to genetic factors. For example, the researchers found that the prognostic value of EDI was enhanced with the addition of TP53 mutation status. By integrating EDI data and genome-wide profiling data, the researchers identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors. These tumors, which showed high microenvironmental diversity, substratified patients into poor prognostic groups.

“Our findings show that mathematical models of ecological diversity can spot more aggressive cancers,” said Dr. Yuan. “By analyzing images of the environment around a tumor based on Darwinian natural selection principles, we can predict survival in some breast cancer types even more effectively than many of the measures used now in the clinic.

“In the future, we hope that by combining cell diversity scores with other factors that influence cancer survival, such as genetics and tumor size, we will be able to tell apart patients with more or less aggressive disease so we can identify those who might need different types of treatment.”

“This ingenious study…teaches us a valuable lesson,” added Paul Workman, Ph.D., chief executive of the ICR. “[We] should always remember that cancer cells are not developing and growing in isolation, but are part of a complex ecosystem that involves normal human cells, too. By better understanding these ecosystems, we aim to create new ways to diagnose, monitor and treat cancer.”

 

Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis

Rachael Natrajan, Heba Sailem, Faraz K. Mardakheh, Mar Arias Garcia, Christopher J. Tape, Mitch Dowsett, Chris Bakal, Yinyin Yuan    

 

    Feb 16, 2016   http://dx.doi.org:/10.1371/journal.pmed.1001961

 

Background

The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.

Methods and Findings

We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10⁻⁴, hazard ratio = 1.47, 95% CI 1.17–1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26–2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.

Conclusions

To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.

Background

The human body contains millions of cells, all of which grow, divide, and die in an orderly fashion to build tissues during early life and to replace worn-out or dying cells and repair injuries during adult life. Sometimes, however, normal cells acquire genetic changes (mutations) that allow them to divide uncontrollably and to move around the body (metastasize), resulting in cancer. Because any cell in the body can acquire the mutations needed for cancer development, there are many types of cancer. For example, breast cancer, the most common cancer in women, begins when the cells in the breast that normally make milk become altered. Moreover, different types of cancer progress and evolve differently—some cancers grow quickly and kill their “host” soon after diagnosis, whereas others can be successfully treated with drugs, surgery, or radiotherapy. The behavior of individual cancers depends both on the characteristics of the cancer cells within the tumor and on the interactions between the cancer cells and the normal stromal cells (the connective tissue cells of organs) and other cells (for example, immune cells) that surround and feed cancer cells (the tumor microenvironment).

Why Was This Study Done?

Although recent studies have highlighted the importance of the tumor microenvironment for disease-related outcomes, little is known about how the heterogeneity of the tumor microenvironment—the diversity of non-cancer cells within the tumor—affects outcomes. Mathematical modeling suggests that tumors with heterogeneous and homogeneous microenvironments have different growth patterns and that heterogeneous microenvironments are more likely to be associated with aggressive cancers than homogenous microenvironments. However, the lack of methods to quantify the spatial variability and cellular composition across solid tumors has prevented confirmation of these predictions. Here, the researchers develop a computational system for quantifying microenvironmental heterogeneity in breast cancer based on tumor morphology (shape and form) in histological sections (tissue samples taken from tumors that are examined microscopically). They then use this system to analyze the associations between clinical outcomes, molecular changes, and microenvironmental heterogeneity in breast cancer.

What Did the Researchers Do and Find?

The researchers used automated image analysis and statistical analysis to develop the ecosystem diversity index (EDI), a numerical measure of microenvironmental heterogeneity in solid tumors. They compared the EDI with prognosis (likely outcome), key mutations, genome-wide copy number (tumor cells often contain abnormal numbers of copies of specific genes), and expression profiling data (the expression of several key proteins is altered in tumors) in a test set of 510 samples from patients with breast cancer and in a validation set of 516 additional samples. Among high-grade breast cancers (grade 3 cancers; the grade of a cancer indicates what the cells look like; high-grade breast cancers have a poor prognosis), but not among low-grade breast cancers (grades 1 and 2), a high EDI (high microenvironmental heterogeneity) was associated with a poor prognosis. Specifically, patients with grade 3 tumors and a high EDI had a ten-year disease-specific survival rate of 51%, whereas the remaining patients with grade 3 tumors had a ten-year survival rate of 70%. Notably, the combination of a high EDI with specific DNA alterations—mutations in a gene called TP53 and loss of genes on Chromosomes 4p14 and 5q13—improved the accuracy of prognosis among patients with grade 3 breast cancer and stratified them into subgroups with disease-specific five-year survival rates of 35%, 9%, and 32%, respectively.

What Do These Findings Mean?

These findings establish a method for measuring the spatial heterogeneity of the microenvironment of solid tumors and suggest that the measurement of tumor microenvironmental heterogeneity can be coupled with information about genomic alterations to provide an accurate way to predict outcomes among patients with high-grade breast cancer. The association between EDI, specific genomic alterations, and outcomes needs to be confirmed in additional patients. However, these findings suggest that microenvironmental heterogeneity might provide an additional biomarker to help clinicians identify those patients with advanced breast cancer who have a particularly bad prognosis. The ability to identify these patients is important because it will help clinicians target aggressive treatments to individuals with a poor prognosis and avoid the overtreatment of patients whose prognosis is more favorable. Finally, and more generally, these findings describe a new way to investigate the interactions between the tumor microenvironment and genomic alterations in cancer cells.

Additional Information

This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001961.

• The US National Cancer Institute provides comprehensive information about cancer and its development (in English and Spanish), including detailed information about breast cancer and an online booklet for patients
• Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information about breast cancer and a science blog on the tumor microenvironment
• Breast Cancer Now is a not-for-profit organization that provides up-to-date information about breast cancer (in English and Spanish)
• The UK National Health Service Choices website has information and personal stories about breast cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer
• Wikipedia has a page about the tumor microenvironment (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

Citation: Natrajan R, Sailem H, Mardakheh FK, Arias Garcia M, Tape CJ, Dowsett M, et al. (2016) Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.
PLoS Med 13(2): e1001961.     http://dx.doi.org:/10.1371/journal.pmed.1001961

http://journals.plos.org/plosmedicine/article/figure/image?size=large&id=info:doi/10.1371/journal.pmed.1001961.g001

Fig 1. In silico tumor dissection pipeline for quantifying spatial diversity in the tumor ecosystem. (A) Flow diagram depicting the overall study design. (B) Schematic of our pipeline for quantifying spatial diversity in pathological samples. H&E sections are morphologically classified and divided into regions to be spatially scored. The number of clusters k in the regional scores is indicative of the number of sub-populations of cell types in the tumor regions. (C) Examples of tumor regions with low and high diversity scores using the Shannon diversity index, accounting for cancer cells (outlined in green), lymphocytes (blue), and stromal cells (red). Cell classification is automated by image analysis. (D) The 3-D landscape of cell diversity scores on an example H&E section; the x- and y-axes are the geometric axes of the image, and the z-axis is cell diversity computed on a region-by-region basis. (E) The distribution of regional scores in a tumor from the METABRIC study with two regional clusters identified using Gaussian mixture clustering (grey shading: histogram; dashed black line: density; solid black lines: mixture components/clusters).

http://journals.plos.org/plosmedicine/article/figure/image?size=medium&id=info:doi/10.1371/journal.pmed.1001961.g002

Fig 2. Application of EDI to 1,026 breast tumors from the METABRIC study. (A) The frequencies of EDI scores in breast tumors. (B) H&E staining, distribution of classified cells (green: cancer; blue: lymphocyte; red: stromal cells), and the heatmap of regional diversity scores for a tumor with the highest EDI score (EDI = 5). (C) Representative regions from each of the clusters k1–k5 are shown in a tumor with EDI = 5, with cluster k1 having the lowest diversity score and k5 the highest. By mapping regional clusters to the H&E image, we can begin to interpret these clusters with different cell diversity. We observed predominantly cancer cells in k1, increasingly more stromal cells and ductal in situ carcinoma cells (DCIS) in k2, and a vessel in k3. Cluster k4 features extensive stromal lymphocytes between ductal in situ carcinoma components, while k5 shows tumor-infiltrating lymphocytes (TIL) associated with invasive carcinoma cells.

Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors.

http://journals.plos.org/plosmedicine/article/figure/image?size=large&id=info:doi/10.1371/journal.pmed.1001961.g003

Fig 3. Reproducibility, stability, and independence of the EDI-high group in 507 grade 3 breast tumors. (A) Kaplan–Meier curves of disease-specific survival to illustrate the prognosis of EDI-high samples compared to other grade 3 samples in two independent patient cohorts. Shown below the graph are the number of patients (the number of disease-specific events) per group for EDI-low (grey) and EDI-high (red). (B) Agreement of the EDI subtyping between 100% data and resampling with progressively fewer tumor regions in 200 repeats. (C) Distribution of known subtypes in grade 3 tumors stratified by EDI; asterisks mark subtypes enriched in the EDI-high group. (D) Kaplan–Meier curves illustrating the duration of disease-specific survival according to tumor size (left) and improvement of stratification with the addition of EDI information (right).

Accumulating evidence suggests that the interactions of cancer cells and stromal cells within their microenvironment govern disease progression, metastasis, and, ultimately, the evolution of therapeutic resistance [1–3]. Recent reports have highlighted the significance of the contribution of stromal gene expression and morphological structure as powerful prognostic determinants for a number of tumor types, emphasizing the importance of the tumor microenvironment in disease-related outcomes [4–7]. In breast cancer, a number of studies have demonstrated the prognostic correlation of individual cell types, including the immune cell infiltrate that predicts response to therapy [8–10], and the high percentage of tumor stroma that predicts poor prognosis in triple-negative disease but good prognosis in estrogen receptor (ER)–positive disease [11,12]. Nevertheless, different types of cells coexist with varying degrees of heterogeneity within a tumor. This fundamental feature of human tumors and the combinatorial effects of cell types have been largely ignored, and the collective implications for clinical outcome remain elusive. Consistent observations from mathematical models have highlighted that tumors with diverse microenvironments show growth patterns dramatically different from those of tumors with homogeneous environments [13] and are more likely to be associated with aggressive cancer phenotypes [2] that select for cell migration and eventual metastasis by allowing cancer cells to evolve more rapidly [14]. These observations highlight the need to understand the collective physiological characteristics and heterogeneity of tumor microenvironments. However, there is a lack of methods to quantify the high spatial variability and diverse cellular composition across different solid tumors. Moreover, the interplay of genomic alterations in cancer cells and microenvironmental heterogeneity and its subsequent role in treatment response have not been explored. Our aims were (i) to develop a computational system for quantifying microenvironmental heterogeneity based on tumor morphology in routine histological sections, (ii) to define the clinical implications of microenvironmental heterogeneity, and (iii) to integrate this histologybased index with RNA gene expression and DNA copy number profiling data to identify molecular changes associated with microenvironmental heterogeneity.

The Ecosystem Diversity Index To characterize the tumor ecosystem based on cell compositions, we developed a new index to be used in conjunction with our image analysis tool [16]. First, we used our automated morphological classification method [16] to identify and classify cells into cancer, lymphocyte, or stromal cell classes in H&E sections (Fig 1B). We next divided sections into smaller spatial regions and quantified the diversity of the tumor ecosystem in a tumor region j using the Shannon diversity index: dj ¼ Sm i pi logpi ; ð1Þ where m is the number of cell types and pi is the proportion of the ith cell type (Fig 1B and 1C). A high value of the Shannon diversity index dj reports a heterogeneous environment populated by many cell types, whilst a low value indicates a homogeneous environment (Fig 1C). Compared to other methods such as the Simpson index, the Shannon diversity index accounts for rare species and, hence, is less dominated by main species [17]. Subsequently, we derived the ecosystem diversity index (EDI) by applying unsupervised clustering that identifies the optimum number of clusters in the dataset in an unbiased manner, in order to group tumor regions and quantify the degree of spatial heterogeneity. Let D = d1,d2,…,dn be the Shannon index for n regions in a tumor. We used Gaussian mixture models to fit data D: D SK k¼1okNðmk; s2 kÞ: ð2Þ where μk, ,s2 k, and ωk are the mean, variance, and weight of a Gaussian distribution k, and K is the number of clusters. The Bayesian information criterion was then used to select the best number of clusters K [18]. We used K = 1–5 as the range of K to avoid small EDI groups (S1 Text). The final value of K thus is a measurement of heterogeneity and the score of EDI for a tumor.

Fig 5. The relationship between ecological heterogeneity and cancer genomic aberrations in 507 grade 3 tumors. (A) Genome-wide copy number aberrations in grade 3 breast tumors and genomic coordinates of genes with copy number aberrations enriched in the EDI-high group. Lengths of black lines denote level of enrichment significance with copy number gains (above the horizontal line) or losses (below the horizontal line). (B) Kaplan–Meier curves illustrating the duration of disease-specific survival in grade 3 breast cancer patients according to copy number loss of the 4p14 region (left) and the EDI-high group with additional information of 4p14 copy number loss (right). (C) Kaplan–Meier curves illustrating the duration of disease-specific survival according to copy number loss of the 5q13 region (left) and the EDI-high group with additional information of 5q13 copy number loss (right).

http://dx.doi.org:/10.1371/journal.pmed.1001961.g005

This study has a number of limitations. The motivation for our computational development was to use a data-driven model and measure the degree of spatial heterogeneity in tumor pathological specimens. In this model, only three major cell types in breast tumors were considered. Further sub-classification of the different types of stromal and immune cells by immunohistochemistry may add additional discriminatory value to our model. For dissecting spatial heterogeneity, we chose to use square regions with equal sizes. We found that EDI was correlated with the size of the region chosen for calculation of the Shannon diversity index, and as such the spatial heterogeneity is scale dependent. This phenomenon has been well described in a number of studies in ecology that show that a scale needs to be chosen that is appropriate for the ecological process under study [38,39], further highlighting the analogy between tumor studies and ecology. Similar to the recent observation that breast cancer subclonal heterogeneity is correlated with tumor size [35], we also found an association between microenvironmental heterogeneity and tumor size; hence, EDI may have more limited value in smaller tumors. However, small tumors were present in the EDI-high group, and addition of EDI within tumors grouped by size further stratified their prognosis. We found that EDI was prognostic only in grade 3 tumors in our study, which could be a limitation, given the possible discordance in grading between pathologists.

The identification of additional biomarkers in subgroups of patients that identify them as high risk is important for patient management and to avoid overtreatment for low-risk patients. We envision that the use of our measure of microenvironment heterogeneity, together with key genomic alterations, will enable the diagnosis of patients at very high risk of relapse and facilitate the enrollment of these patients into additional clinical trials for novel therapies or treatment intensification. Our novel computational approach provides a fully automated tool that is relatively easy to implement. Integration of this measure with genomic profiling provides additional prognostic information independent of known clinical parameters. The results of this study highlight the possibility of a grade-3-specific prognostic tool that may aid in further classification of high-grade breast cancer patients beyond standard assays such as ER and HER2 status.

 

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Recent Breakthroughs in Cancer Research at the Technion-Israel Institute of Technology- 2015

Posted in BioTechnology - Venture Creation, BioTechnology - Venture Creation, Venture Capital, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cancer Screening, Clinical Diagnostics, Uncategorized, Venture Capital, tagged American Association for Cancer Research, breast cancer, Cancer - General, cancer detection, cancer diagnostics, enose, Global Partnering & Biotech Investment, Innovation, NYU, Technion – Israel Institute of Technology, Ubiquitin on February 3, 2016| Leave a Comment »

Recent Breakthroughs in Cancer Research at the Technion-Israel Institute of Technology- 2015

Curator: Stephen J. Williams, PhD

Below are recent advances which occurred in 2015 on Cancer at the Technion-Israel Institute of Technology

including:

• role of proteosome, metabolomics, cell signaling and ubiquitin system in cancer progression
• partnerships with pharma and academic centers around the globe
• development of early detection kits and novel therapeutic strategies including nanoparticle drug delivery systems

 

At: http://www.technion.ac.il/en/2015/04/breakthrough-in-cancer-research/

 

The ubiquitin system produces a protein that greatly restricts the development of cancerous tumors.

A new study by researchers at the Technion-Israel Institute of Technology could hold one key to control cancer cell growth and development. In a paper published in the April 9, 2015 edition of CELL, the team reports on the discovery of two cancer-suppressing proteins.

Distinguished Professor Aaron Ciechanover. Photographer: Dan Porges

The research was conducted in the laboratory of Distinguished Professor Aaron Ciechanover, of the Technion Rappaport Faculty of Medicine. The team was led by research associate Dr. Yelena Kravtsova-Ivantsiv and , included additional research students and colleagues, as well as physicians from the Rambam, Carmel and Hadassah Medical Centers, who are studying tumors and their treatment.

The heretofore-undiscovered proteins were found during ongoing research on the ubiquitin system, an important and vital pathway in the life of the cell, which is responsible for the degradation of defective proteins that could damage the cell if not removed. The ubiquitin system tags these proteins and sends them for destruction in the cellular complex known as the proteasome.  The system also removes functional and healthy proteins that are not needed anymore, thereby regulating the processes that these proteins control.

Usually, the proteins that reach the proteasome are completely broken down, but there are some exceptions, and the current line of research examined p105, a long precursor of a key regulator in the cell called NF-κB. It turns out that p105 can be broken down completely in certain cases following its tagging by ubiquitin,  but in other cases it is only cut and shortened and becomes a protein called p50.

NF-κB has been identified as a link between inflammation and cancer. The hypothesis of the connection between inflammatory processes and cancer was first suggested in 1863 by German pathologist Rudolph Virchow, and has been confirmed over the years in a long series of studies. Ever since the discovery (nearly 30 years ago) of NF-κB, numerous articles have been published linking it to malignant transformation. It is involved in tumors of various organs (prostate, breast, lung, head and neck, large intestine, brain, etc.) in several parallel ways, including: inhibition of apoptosis (programmed cell death) normally eliminates transformed cells; acceleration of uncontrolled division of cancer cells; formation of new blood vessels (angiogenesis), which are vital to tumor growth; and increased resistance of cancerous cells to irradiation and chemotherapy.

The dramatic effect of these proteins on cancer growth: above the two tumors in the foreground (the control group) are tumors that express high levels of the proteins

As noted, the precursor p105 is “handled” by the ubiquitin system in one of two parallel and equally prevalent ways. It is either destroyed completely, or shortened and transformed to p50. The current research deciphers the decision-making mechanism that determines which process will be applied to the protein: when a ubiquitin system component called KPC1 is involved in the process and attaches ubiquitin to p105, the protein is shortened to become p50. When ubiquitination is mediated by another component of the system (and without KPC1), p105 is degraded.

The ubiquitin molecule within all living cells

The decision between these two options has significant implications on the cell, as the presence of high levels of KPC1 (which generates p50) and p50 (the product of the process) – with the accompanying disruption of the normal ratios between the processes – suppresses the malignant growth and apparently protects the healthy tissue. The current research was conducted on models of human tumors grown in mice, as well as on samples of human tumors, and a strong connection was discovered between the suppression of malignancy and the level of the two proteins, clearly indicating that the increased presence of KPC1 and/or p50 in the tissue can protect it from cancerous tumors.

Professor Ciechanover, who is also the president of the Israel Cancer Society, notes that many more years are required “to establish the research and gain a solid understanding of the mechanisms behind the suppression of the tumors. The development of a drug based on this discovery is a possibility, although not a certainty, and the road to such a drug is long and far from simple.”

Professor Ciechanover won the Nobel Prize in Chemistry in 2004 (jointly with Professors Avram Hershko – also from the Technion – and Irwin Rose, of the Fox Chase Cancer Center) for the discovery of the ubiquitin system. The current line of research is a continuation of that discovery.

Indian generic drugmaker giant Sun Pharma to work with Technion to explore new ways to fight tumors

By David Shamah April 17, 2015, 3:09 pm 10

President Reuven Rivlin and Indian Prime Minister Narendra Modi, March 29, 2015 (photo credit: Courtesty Tomer Reichmann)
President Reuven Rivlin and Indian Prime Minister Narendra Modi, March 29, 2015 (photo credit: Courtesty Tomer Reichmann)

 

Days after the Technion announced that a team led by Nobel Prize laureate Professor Aaron Ciechanover had discovered how proteins could be used to suppress cancer and control tumor growth and development, the institute revealed that it had entered into an exclusive agreement with India’s Sun Pharmaceuticals — the world’s fifth-largest specialty generic pharmaceutical company and India’s top pharmaceutical company.

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Under the agreement, researchers from the Technion and Sun will conduct studies on how high concentrations of two proteins can protect tissue from tumors. A study published in the medical journal Cell this week discussed how the proteins can suppress malignancies.

Along with Ciechanover, the research team included Dr. Gila Maor and Professor Ofer Binah. In a statement, Ciechanover said that the research held a great deal of promise of an effective drug for treating cancer, “although this is not a certainty, and the road to such a drug is long and far from simple.”

The deal with Sun is just one of several R&D ventures between Israel and India, on both the business and government levels. So far, the two countries have signed seven bilateral economic and R&D agreements, including one that fosters joint projects on space travel and satellite development.

 

NYU and Technion to forge ‘groundbreaking’ partnership in cancer research

The joint program aims at attracting additional, world-class support from institutions and individuals who are dedicated to eradicating cancer through focused and efficient research.

Two of the world’s preeminent academic and research institutions — New York University’s Langone Medical Center and Haifa’sTechnion-Israel Institute of Technology — have made a “groundbreaking step forward to advance global collaboration in the fight against cancer formally.

On Wednesday night, they announced a $9 million gift from philanthropists Laura and Isaac Perlmutter that will fund two major, joint research endeavors with potentially far-reaching impact in advancing cancer research. The joint program aims at attracting additional, world-class support from institutions and individuals who are dedicated to eradicating cancer through focused and efficient research, they said in a joint statement.

The first $3 million of the grant will finance six cancer-focused research projects to be conducted by teams spearheaded by co-investigators from both NYU and the Technion. The remaining $6 million will be used to establish a state-of-the-art research facility on Technion’s campus that will support these and other research projects and focus mainly on the emerging field of cancer metabolomics.

“NYU Langone and the Technion have a shared, longstanding commitment to advancing cancer research,” said Dr. Dafna Bar-Sagi, senior vice president and vice dean for science at the New York hospital, chief science officer at NYU School of Medicine and a principal architect of the NYU Langone-Technion partnership.  “We are now at a great moment in our institutions’ illustrious histories, a point from which we can jointly leverage the talent and creativity of our researchers toward accelerating breakthroughs. The foresight and the generosity of the Perlmutters, particularly at this time of financial challenge in funding for basic research, will have tremendous impact.”

“Bringing together the unique expertise of researchers from both NYU and the Technion will hopefully enable us to overcome some of the most difficult challenges in treating cancer patients,” said Technion Prof.  Aaron Ciechanover, the 2004 Nobel Prize Laureate in Chemistry and Distinguished Research Professor and head of the David and Janet Polak Cancer and Vascular Biology Research Center at the Technion Faculty of Medicine.

Renowned cancer biologist Dr. Benjamin Neel, an expert in the field of cell signal transduction, recently joined the Langone faculty as director of the Perlmutter Cancer Center, and Dr. Eyal Gottlieb, a world leader in cancer metabolism, has been recruited to lead the new research facility at the Technion funded by the Perlmutter gift. Neel will work closely with Ciechanover to lead the collaborative cancer research effort between the two institutions, they said.

In addition, Neel will oversee at NYU the building of world-class translational programs in immunotherapy, cancer genetics/targeted therapies and epigenetics, imaging, as well as expanded programs in clinical care, community outreach and supportive oncology.

New technology for early detection of stomach cancer

The innovative method, developed at the Technion, identifies persons at risk for developing stomach cancer and for detecting tumors at an earlier stage. The prestigious journal Gut, which published the research, notes that the detection method is quick, simple, inexpensive and non-invasive.

Innovative gastric cancer-detection technology

Innovative gastric cancer-detection technology developed by the Technion can be used for the early detection of stomach cancer and for identifying persons at risk for developing the disease. The new detection method, based on breath analysis, has significant advantages over the existing detection technology: Gut reports that the new method is quick, simple, inexpensive and non-invasive.

Gastric cancer is one of the most lethal forms of cancer and in most cases, its diagnosis involves an endoscopy (the insertion of a tube into the esophagus, requiring that the patient fast and receive an intravenous sedative). Treatment is aggressive chemotherapy, radiation and the full or partial removal of the stomach. The disease develops in a series of well-defined steps, but there’s currently no effective, reliable, and non-invasive screening test for picking up these changes early on. Thus, many people succumb to stomach cancer only because it was not diagnosed in time.

The new technology, developed by Prof. Hossam Haick of the Wolfson Faculty of Chemical Engineering, can be used to detect premalignant lesions at the earliest stage, when healthy cells start becoming cancerous.

The research, published in Gut as part of the doctoral thesis of Mr. Haitham Amal, was conducted in conjunction with a Latvian research group headed by Prof. Marcis Leja, based on the largest population sample ever in a trial of this type. 484 people participated in the trial, 99 of whom had already been diagnosed with stomach cancer. All the participants were tested for Helicobacter pylori, a bacterium known to increase the risk for stomach cancer, and two breath samples were taken from each person.

The first sample from each participant was analyzed using the GCMS technique, which measures volatile organic substances in exhaled breath. The researchers noted that GCMS technology cannot be used to detect stomach cancer because the testing is very expensive and requires lengthy processing times and considerable expertise to operate the equipment.

The second breath sample was tested using nanoarray analysis, the unique technology developed by Prof. Haick, combined with a pattern recognition algorithm.

The findings:

1. Based on the concentrations of 8 specific substances (out of 130) in the oral cavity, the new technology can distinguish between three groups: gastric cancer patients, persons who have precancerous stomach lesions, and healthy individuals.
2. The new technology accurately distinguishes between the various pre-malignant stages.
3. The new technology can be used to identify persons at risk for developing gastric cancer.
4. The diagnosis is accurate, regardless of other factors such as age, sex, smoking habits, alcohol consumption and the use of anti-oxidant drugs.

In short, the nano-array analysis method developed by Prof. Haick is accurate, sensitive technology that provides a simple and inexpensive alternative to existing tests (such as GCMS). This new technology offers early, effective detection of persons at risk for developing stomach cancer, without unnecessary invasive tests (endoscopy). In order to assess the accuracy and effectiveness of the new, a wide-scale clinical trial is currently under way in Europe, with thousands of participants who have cancerous or pre-cancerous tumors.

About Prof. Hossam Haick

Prof. Hossam Haick, who joined the senior staff at the Technion Wolfson Faculty of Chemical Engineering in 2006, has been working since that year on the development of innovative, non-invasive technology for detecting cancer and other diseases. This technology is based on an “electronic nose” – an apparatus capable of detecting illnesses by analyzing a patient’s exhaled breath.

Prof. Haick, a native of Nazareth, completed his Ph.D. studies at the Technion by the time he was 27 and went to the Weizmann Institute of Science in Rehovot and Caltech Institute of Technology in California. He returned to the Technion in 2006 and his research group was awarded one million euros in grants by the European Union, which was very impressed by his research into artificial olfactory systems. Today he heads a consortium that includes Siemens and several universities, research institutes and companies in Germany, Austria, Finland, Ireland, Latvia and Israel. Since joining the senior faculty in the Chemical Engineering Department in 2006, Prof. Haick has won dozens of awards, grants and international honors. These include the Marie Curie Excellence Grant, European Research Council (ERC) grant and the Bill & Melinda Gates Award. Prof. Haick was nominated to MIT’s list of the 35 leading young scientists worldwide, received the Knight of the Order of Academic Palms, from the French Government and won the Hershel Rich Technion Innovation Award (twice), as well as the Tenne Prize for Excellence in the Science of Nanotechnology. He has also been recognized for his outstanding teaching skills and is the recipient of the Yanai Prize for Academic Excellence. In 2014, at the initiative of the president of the Technion, Prof. Haick headed an MOOC (Massive Open Online Course) in nanotechnology and nano-sensors that had an enrollment of 42,000.

Early Warning of Cancer Metastasis

October 28, 2015 Technion Admin

This month is Breast Cancer Awareness Month in Israel and around the world. Innovative technology developed at the Technion Faculty of Biomedical Engineering will enable the prediction of cancer metastasis after the appearance of breast cancer. The technology, whose efficacy has been proven in preliminary laboratory-trials, is entering into advanced testing using cells from patients undergoing surgery.

Assistant Professor Daphne Weihs recently achieved a research breakthrough: the unique technology that she developed – a biomechanical method for early detection of metastatic cancer – was approved by the Ethics Committee. This means that the technology that was found to be effective in tests on cell lines will advance to trials with tumor cells collected directly after surgery, in cooperation with Rambam Healthcare Campus.

According to Assistant Professor Weihs, the practical concept is that “during or immediately after a biopsy or surgery on a malignant tumor, the system will enable the medical team to quantitatively evaluate the likelihood of the presence or development of tumor metastases in other organs, and to propose which organ or organs are involved. Such knowledge will make it possible to act at a very early stage to identify and curb these metastases and, moreover, to prevent the primary tumor from metastasizing further.

Cancer is a general name for a wide family of diseases – more than 200 – whose common denominator is that the cell division rate becomes uncontrolled and the cells become immortal. In other words, the cancer mechanism disrupts the normal cell division process and converts it into “wild” and rapid division. Since the cells do not age and do not die, the original, primary tumor expands, invades and takes over more and more nearby tissue. In addition, apart from spreading to its immediate vicinity, a tumor that has become very aggressive “knows” how to send metastases to more distant tissues through the lymph and circulatory systems. Metastases (secondary tumors) are usually more dangerous than the primary tumor because it is difficult to identify them at their inception. When they are detected at an advanced stage, treating them medically is more complicated and the medical prognosis is typically not good.

“In fact, most cancer-related deaths are caused by metastases rather than by the primary tumor, and therefore vast resources are invested in developing methods for early detection of metastases,” explains Assistant Professor Daphne Weihs. “Early detection means timely and more effective treatment. The new approach that we are developing will enable early prediction of the likelihood of the formation of metastases and where in the body their development is probable. This prediction is based on identifying the biomechanics of the primary tumor cells, and does not require us to know the specific genetic makeup of the tumor.”

Mobile SniffPhone will detect cancer on a user’s breath

Diagnostic system developed by Technion professor is to pair with tiny smell-sensitive sensor that can go anywhere
By David Shamah February 3, 2015, 2:05 pm

A patient uses the NaNose breathalyzer (Photo credit: Courtesy Technion)

Writers
David Shamah

An innovative early disease detection system that uses the sense of smell is going mobile.

 

The NaNose breathalyzer technology developed by Professor Hossam Haick of the Technion will soon be installed in a mobile phone – to be called, appropriately, the SniffPhone. A tiny smell-sensitive sensor will be installed onto a phone add-on, and using specially designed software, the phone will be able to “smell” users’ breath to determine if they have cancer, among other serious diseases.

By identifying the special “odor” emitted by cancer cells, the NaNose system can detect the presence of tumors, both benign and malignant, more quickly, efficiently and cheaply than previously possible, said Haick.

“Current cancer diagnosis techniques are ineffective and impractical,” he said. NaNose technology, he said, “could facilitate faster therapeutic intervention, replacing expensive and time-consuming clinical follow-up that would eventually lead to the same intervention.”

According to research done by Haick’s team, the NaNose system has a 90 percent accuracy rate.

The smartphone device is just a vehicle to implement the NaNose technology that can be taken anywhere and used in any circumstances, including in rural areas of the developing world where bringing in sophisticated testing equipment is impossible.

The plan calls for a chip with NaNose technology to be installed in a device that is attached to a smartphone, and for an app to read the sensor data, analyzing it on the device or uploading it to the cloud for processing.

NaNose technology will be especially useful in battling lung cancer, said Haick. According to US government statistics, lung cancer kills more Americans annually than the next three most common cancers — colon, breast, and pancreatic — combined. The reason, doctors say, is because lung cancer is so difficult to detect. Currently, the only way to detect early-stage lung cancer is through an extensive process involving blood tests, biopsies, CT scans, ultrasound tests, and other procedures — and even then, detection is difficult.

“Mostly the patient arrives for diagnosis when the symptoms of the sickness have already begun to appear,” said Haick, describing the drawbacks in current detection protocols. “Months pass before a real analysis in completed. And the process requires complicated and expensive equipment such as CT and mammography imaging devices. Each machine costs millions of dollars, and ends up delivering rough, inaccurate results.”

Dr. Hossam Haick (Photo credit: Courtesy)

 

The NaNose-based system, on the other hand, doesn’t require anything more than a patient’s breathing into the device in order to come up with an initial diagnosis. Lung cancer tumors produce chemicals called volatile organic compounds (VOCs), which easily evaporate into the air and produce a discernible scent profile. Haick’s NaNose chip detects the unique “signature” of VOCs in exhaled breath. In four out of five cases, the device differentiated between benign and malignant lung lesions and even different cancer subtypes.

The project is being funded by the European Commission, which has given the consortium developing it a six million euro grant. The developers include universities and research institutes from Germany, Austria, Finland, Ireland and Latvia, as well as Irish cell biology research firm Cellix, with the NaNose system the centerpiece of the technology. That Israeli-developed component will be delivered by an Israeli start-up called NanoVation-GS, a spinoff of the Technion. Professor Haick serves as the start-up’s Chief Science Officer.

“The SniffPhone is a winning solution. It will be made tinier and cheaper than disease detection solutions currently, consume little power, and most importantly, it will enable immediate and early diagnosis that is both accurate and non-invasive,” said Haick. “Early diagnosis can save lives, particularly in life-threatening diseases such as cancer.”

 

Nanotech Drug Delivery Method For Cancer Could Replace Conventional Chemotherapy

By NoCamels Team March 03, 2015 5 Comments

at http://nocamels.com/2015/03/nanotech-drug-delivery-method-cancer-replace-chemotherapy-eliminate-side-effects/

Anyone who knows a person in the midst of chemotherapy is aware that anti-cancer drugs often take a very harsh toll on the body. This is one reason scientists have been trying to develop improved means of drug delivery for years. Now, a Technion research team discovered a way to improve drug delivery to tumors using Nanostructured Porous Silicon (PSi) particles (instead of an IV drip), a method that’s emerging as a promising new platform for drug delivery. In the future, PSi could be used in cancer treatments, potentially offering an alternative to traditional chemotherapy, which is notorious for its agonizing side effects.

The silicon “carriers” used in this study to deliver chemotherapy drugs behave differently in cancerous tumors than they do in healthy tissues. Therefore, the findings could help scientists to design nano-carriers that deliver drugs to tumors, instead of treating patients with traditional, intravenous chemotherapy. However, it would take years to develop and apply this new type of drug delivery method, which would potentially be taken orally.

     SEE ALSO: Study: How To Make Chemotherapy Side-Effects Less Deadly

So far, these nano-silicon “containers” have been studied in vitro – outside of a living organism – rather than in an environment that behaves more closely to that of a tumor in a cancer patient’s body. The Technion research team looked at what happens to PSi particles when they’re injected into the area around the tumor in mice. The significant differences in the area around a cancerous growth and regular healthy tissue have been widely described and studied; however, the effect on these porous silicon “containers,” or carriers, was unknown until now.

Prof. Ester Segal of the Technion – Israel Institute of Technology, who led this joint study with the Massachusetts Institute of Technology (MIT) and the Harvard Medical School, said the team has “shown for the first time that bio-materials in general, and Nanostructured Porous Silicon in particular, behave differently when they are injected (or implanted) at the tumor micro-environment.”

Revolutionizing cancer treatments

Silicon materials could revolutionize treatments in a way that no existing drug delivery does. Prof. Segal tells NoCamels that the silicon containers “could deliver drugs over a long period of time – weeks or even months”, something no existing chemotherapeutic delivery mechanism can do currently.

Cancer cells

The special properties of these porous nano-silicon carriers lie in their large surface area, which can ferry many or large drug molecules. Additionally, due to their biodegradability they’re able to break down into harmless silicic acid, which is expelled through urination. They are also biocompatible, so they do not stimulate any inflammation or clotting. Another benefit to these nano-silicon containers is their versatility. They can be ingested, injected or implanted, and they can be designed to carry a wide range of dosage sizes. In the process of their study, lab members also developed an approach to determining how biomaterials will react in settings more similar to their eventual clinical purpose – treating cancer, for example.

     SEE ALSO: Israeli Researchers Create ‘Trojan Horse’ Of Chemotherapy

In a separate study, Tel Aviv University scientists recently found a strategy that would stop brain tumor cell proliferation with similar nano-particles. “It is a basic, elegant mechanism and much less toxic than chemotherapy,” TAU’s Prof. Dan Peer said in a statement.

These works underline the importance of such studies in successfully developing bio-delivery materials that will have therapeutic benefits in the near future.

The ‘Magic Bullet’ of Chemotherapy

http://www.technion.ac.il/en/2015/03/the-magic-bullet-of-chemotherapy/

“Nano-skeletons’ (in red) delivered to human tissue infected by prostate cancer. The infected cells are colored in blue (PIP) and green (cytoplasmic); it is possible to see how the ‘nano-skeletons’ reach them

Florida native Dr. Beth Schoen, is part of a team developing a novel platform for delivering anti-cancerous drugs directly to its mark as part of her postdoctoral research at the Technion

Beth Schoen, born in Hollywood Florida, came to the Technion to conduct her postdoctoral research at age 26. In her very limited spare time she plays soccer for the leading all women’s soccer team – Maccabi Hadera – and studies Hebrew. “The Hebrew thing is no simple matter,” she confesses, “but I’m willing to make the effort, because it’s clear to me that Israel is where I want to live.”

Dr. Beth Schoen completed her undergraduate degree at the University of Florida, and her doctorate at Michigan State University in chemical engineering. “My doctoral studies focused on synthetic organic chemistry, particularly on the development of polymers with unique thermodynamic attributes especially resistant to high temperatures. These types of materials are used in part for the production of jet engine parts, body armor and Nomex (used for making fire-resistant gloves and overalls). One of our tasks was to create soft sheets that were not brittle, to be worn to be both bulletproof and fire resistant. It was a theoretical study, but as part of the process I also produced some of these polymers and tested them.”

Dr. Schoen planned to come to the Technion as part of her doctoral studies, but, she adds, “It didn’t work out, so I started to check where I could best fit in here in my future studies.” She decided to join Prof. Marcelle Machluf’s laboratory, at the Faculty of Biotechnology and Food Engineering, “I was eager to move from chemistry to biology and pursue cancer research in particular. I was very glad for the tremendous opportunity that Marcelle gave me in taking me on – perhaps it was because of my experience in nanomaterials and polymers.”

Prof. Marcelle Machluf’s research team consists of 17 female and 3 males students, researchers and technicians working on two main projects: (1) the development of scaffolds to rehabilitate damaged heart-tissue, and (2) the development of new technology to deliver drug treatment to damaged (sick) tissue (specifically related to cancer therapy). In an interview with her she focused on the second project.

“The current treatment for cancer involves radiotherapy and chemotherapy usually administered through intravenous infusion. The cancer drugs available are extremely effective, yet the way they are put to use in present day treatment, they also cause damage to healthy tissues. These are very potent drugs – they are intended to kill cancer cells – and on their way they also end up killing healthy ones.”

“The greatest damage is caused to rapidly dividing cells, which are similar to cancer cells. Hair follicle cells, for example, are a type of rapidly dividing cells and they damage easily from these types of treatment, which explains the hair loss in patients undergoing chemotherapy. Other side-effects include nausea and hearing loss, sometimes even leading to deafness. The drug Cisplatin for example, is a type of chemo drug used to treat various types of lung and breast cancers; some of its side-effects include damage to renal and immune system functioning, putting patients at risk to infections and diseases.”

These impediments are what fuel Prof. Machluf’s drive to develop a new drug delivery platforms capable of delivering anti-cancer drugs directly to the tumor without damaging healthy tissues on its way. “This is the top priority of cancer treatment: to develop a ‘magic bullet’ that target cancer cells,” explains Prof. Machluf. “And our new platform may be the solution to this great challenge.”

The new platform is based on ‘depleting’ specific cells – mesenchymal stem cells – so that there is nothing left of them save for the membrane. This membrane, called a ghost cells can be down sized to nano-vesicles, termed nano-ghosts, which can be loaded with any drug and delivered by injection directly into the blood stream. The immune system falls for the trap and does not recognize the ‘intruder,’ instead it treats these cells as if they were naturally part of the system and sends them to the afflicted area. On the way to their target they do not release the drug they are carrying and therefore do not do any damage to healthy tissues. Only upon reaching the malignant tissue, which they know how to identify, do they break down and secrete their contents at the site of the tumor cells.

This original idea was tested in a long series of experiments, and the results are very impressive: these nano-ghosts are in fact tumor selective, no matter the type of tumor. They ‘dash’ straight to the malignant tissue without emitting their drug on the way and without damaging healthy cells. Moreover, this unique ‘parcel’ increases the effectiveness of the treatment by ten-fold. Animal studies have shown that the employment of nano-ghosts for anti-cancer drug delivery have led to an 80% delay of prostate cancer – an unprecedented rate.

Still, there is a lot of work ahead, as Prof. Machluf’s research team works on improving the mechanism of this novel new platform: some of them are focusing on compatibility with specific drugs while others, like Dr. Beth Schoen, are concentrating on improving the nano-ghosts “This platform must be very precise,” explains Schoen. “It must be able to endure travelling through the entire human body, and release its contents only inside the tumor.”

The research is being carried out in collaboration with the Russell Berrie Nanotechnology Institute.

For a Full Report From the President of Technion on all Innovations Occurring at Technion during 2015 please click below

http://pard.technion.ac.il/view-the-report/

Other Resources

http://www.technioncancer.co.il/ResearchGroups.php
http://www.ats.org/site/PageServer?pagename=about_research_cancer
http://www.technioncancer.co.il/lab.php?id=3

http://www.rappaport.org.il/Rappaport/Templates/ShowPage.asp?DBID=1&TMID=610&FID=77&PID=0&IID=1268 

Governor Cuomo Delivers Remarks at Zuckerman Scholars Program in STEM Leadership

Other related articles on Cancer Research @Technion were published in this Open Access Online Scientific Journal, including the following:

Medical Breakthrough: Israeli Researcher Predicts Where Cancer Will Spread

Pancreatic Cancer at the Crossroads of Metabolism

Next-generation Universal Cell Immunotherapy startup Adicet Bio, Menlo Park, CA is launched with $51M Funding by OrbiMed

Solutions for Multiple Myeloma – a cancer formed by Malignant Plasma Cells: Collaboration of NYU and Technion Integrative Cancer Center

List of Breakthroughs in Cancer Research and Oncology Drug Development by Awardees of The Israel Cancer Research Fund

Biomarkers of Cancer detected by BreathAnalyzer – An Collaborative effort of three Universities

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Bioinformatic Tools for Cancer Mutational Analysis: COSMIC and Beyond

Posted in BioIT: BioInformatics, Cancer - General, Clinical Diagnostics, Clinical Genomics, tagged Bioinformatics, breast cancer, Cancer Genome Atlas, Cancer Genomics, CGAP, clinical genomics, colon cancer, COSMIC, gene mutations, mutational analysis, mutational signatures, mutational spectrum, TCGA, Wellcome trust sanger institute on December 2, 2015| Leave a Comment »

Bioinformatic Tools for Cancer Mutational Analysis: COSMIC and Beyond

Curator: Stephen J. Williams, Ph.D.

Updated 7/26/2019

Updated 04/27/2019

Signatures of Mutational Processes in Human Cancer (from COSMIC)

From The COSMIC Database

The genomic landscape of cancer. The COSMIC database has a fully curated and annotated database of recurrent genetic mutations founds in various cancers (data taken form cancer sequencing projects). For interactive map please go to the COSMIC database here: http://cancer.sanger.ac.uk/cosmic

 

 

Somatic mutations are present in all cells of the human body and occur throughout life. They are the consequence of multiple mutational processes, including the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA and defective DNA repair. Different mutational processes generate unique combinations of mutation types, termed “Mutational Signatures”.

In the past few years, large-scale analyses have revealed many mutational signatures across the spectrum of human cancer types [Nik-Zainal S. et al., Cell (2012);Alexandrov L.B. et al., Cell Reports (2013);Alexandrov L.B. et al., Nature (2013);Helleday T. et al., Nat Rev Genet (2014);Alexandrov L.B. and Stratton M.R., Curr Opin Genet Dev (2014)]. However, as the number of mutational signatures grows the need for a curated census of signatures has become apparent. Here, we deliver such a resource by providing the profiles of, and additional information about, known mutational signatures.

The current set of mutational signatures is based on an analysis of 10,952 exomes and 1,048 whole-genomes across 40 distinct types of human cancer. These analyses are based on curated data that were generated by The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and a large set of freely available somatic mutations published in peer-reviewed journals. Complete details about the data sources will be provided in future releases of COSMIC.

The profile of each signature is displayed using the six substitution subtypes: C>A, C>G, C>T, T>A, T>C, and T>G (all substitutions are referred to by the pyrimidine of the mutated Watson–Crick base pair). Further, each of the substitutions is examined by incorporating information on the bases immediately 5’ and 3’ to each mutated base generating 96 possible mutation types (6 types of substitution ∗ 4 types of 5’ base ∗ 4 types of 3’ base). Mutational signatures are displayed and reported based on the observed trinucleotide frequency of the human genome, i.e., representing the relative proportions of mutations generated by each signature based on the actual trinucleotide frequencies of the reference human genome version GRCh37. Note that only validated mutational signatures have been included in the curated census of mutational signatures.

Additional information is provided for each signature, including the cancer types in which the signature has been found, proposed aetiology for the mutational processes underlying the signature, other mutational features that are associated with each signature and information that may be relevant for better understanding of a particular mutational signature.

The set of signatures will be updated in the future. This will include incorporating additional mutation types (e.g., indels, structural rearrangements, and localized hypermutation such as kataegis) and cancer samples. With more cancer genome sequences and the additional statistical power this will bring, new signatures may be found, the profiles of current signatures may be further refined, signatures may split into component signatures and signatures

See their COSMIC tutorial page here for instructional videos

Updated News: COSMIC v75 – 24^th November 2015

COSMIC v75 includes curations across GRIN2A, fusion pair TCF3-PBX1, and genomic data from 17 systematic screen publications. We are also beginning a reannotation of TCGA exome datasets using Sanger’s Cancer Genome Project analyis pipeline to ensure consistency; four studies are included in this release, to be expanded across the next few releases. The Cancer Gene Census now has a dedicated curator, Dr. Zbyslaw Sondka, who will be focused on expanding the Census, enhancing the evidence underpinning it, and developing improved expert-curated detail describing each gene’s impact in cancer. Finally, as we begin to streamline our ever-growing website, we have combined all information for each gene onto one page and simplified the layout and design to improve navigation

may be found in cancer types in which they are currently not detected.

Mutational signatures across human cancer

Patterns of mutational signatures [Download signatures]

 COSMIC database identifies 30 mutational signatures in human cancer

Please goto to COSMIC site to see bigger .png of mutation signatures

Signature 1

Cancer types:

Signature 1 has been found in all cancer types and in most cancer samples.

Proposed aetiology:

Signature 1 is the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine.

Additional mutational features:

Signature 1 is associated with small numbers of small insertions and deletions in most tissue types.

Comments:

The number of Signature 1 mutations correlates with age of cancer diagnosis.

Signature 2

Cancer types:

Signature 2 has been found in 22 cancer types, but most commonly in cervical and bladder cancers. In most of these 22 cancer types, Signature 2 is present in at least 10% of samples.

Proposed aetiology:

Signature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 3

Cancer types:

Signature 3 has been found in breast, ovarian, and pancreatic cancers.

Proposed aetiology:

Signature 3 is associated with failure of DNA double-strand break-repair by homologous recombination.

Additional mutational features:

Signature 3 associates strongly with elevated numbers of large (longer than 3bp) insertions and deletions with overlapping microhomology at breakpoint junctions.

Comments:

Signature 3 is strongly associated with germline and somatic BRCA1 and BRCA2 mutations in breast, pancreatic, and ovarian cancers. In pancreatic cancer, responders to platinum therapy usually exhibit Signature 3 mutations.

Signature 4

Cancer types:

Signature 4 has been found in head and neck cancer, liver cancer, lung adenocarcinoma, lung squamous carcinoma, small cell lung carcinoma, and oesophageal cancer.

Proposed aetiology:

Signature 4 is associated with smoking and its profile is similar to the mutational pattern observed in experimental systems exposed to tobacco carcinogens (e.g., benzo[a]pyrene). Signature 4 is likely due to tobacco mutagens.

Additional mutational features:

Signature 4 exhibits transcriptional strand bias for C>A mutations, compatible with the notion that damage to guanine is repaired by transcription-coupled nucleotide excision repair. Signature 4 is also associated with CC>AA dinucleotide substitutions.

Comments:

Signature 29 is found in cancers associated with tobacco chewing and appears different from Signature 4.

Signature 5

Cancer types:

Signature 5 has been found in all cancer types and most cancer samples.

Proposed aetiology:

The aetiology of Signature 5 is unknown.

Additional mutational features:

Signature 5 exhibits transcriptional strand bias for T>C substitutions at ApTpN context.

Comments:

Signature 6

Cancer types:

Signature 6 has been found in 17 cancer types and is most common in colorectal and uterine cancers. In most other cancer types, Signature 6 is found in less than 3% of examined samples.

Proposed aetiology:

Signature 6 is associated with defective DNA mismatch repair and is found in microsatellite unstable tumours.

Additional mutational features:

Signature 6 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 6 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 15, 20, and 26.

Signature 7

Cancer types:

Signature 7 has been found predominantly in skin cancers and in cancers of the lip categorized as head and neck or oral squamous cancers.

Proposed aetiology:

Based on its prevalence in ultraviolet exposed areas and the similarity of the mutational pattern to that observed in experimental systems exposed to ultraviolet light Signature 7 is likely due to ultraviolet light exposure.

Additional mutational features:

Signature 7 is associated with large numbers of CC>TT dinucleotide mutations at dipyrimidines. Additionally, Signature 7 exhibits a strong transcriptional strand-bias indicating that mutations occur at pyrimidines (viz., by formation of pyrimidine-pyrimidine photodimers) and these mutations are being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 8

Cancer types:

Signature 8 has been found in breast cancer and medulloblastoma.

Proposed aetiology:

The aetiology of Signature 8 remains unknown.

Additional mutational features:

Signature 8 exhibits weak strand bias for C>A substitutions and is associated with double nucleotide substitutions, notably CC>AA.

Comments:

Signature 9

Cancer types:

Signature 9 has been found in chronic lymphocytic leukaemias and malignant B-cell lymphomas.

Proposed aetiology:

Signature 9 is characterized by a pattern of mutations that has been attributed to polymerase η, which is implicated with the activity of AID during somatic hypermutation.

Additional mutational features:

Comments:

Chronic lymphocytic leukaemias that possess immunoglobulin gene hypermutation (IGHV-mutated) have elevated numbers of mutations attributed to Signature 9 compared to those that do not have immunoglobulin gene hypermutation.

Signature 10

Cancer types:

Signature 10 has been found in six cancer types, notably colorectal and uterine cancer, usually generating huge numbers of mutations in small subsets of samples.

Proposed aetiology:

It has been proposed that the mutational process underlying this signature is altered activity of the error-prone polymerase POLE. The presence of large numbers of Signature 10 mutations is associated with recurrent POLE somatic mutations, viz., Pro286Arg and Val411Leu.

Additional mutational features:

Signature 10 exhibits strand bias for C>A mutations at TpCpT context and T>G mutations at TpTpT context.

Comments:

Signature 10 is associated with some of most mutated cancer samples. Samples exhibiting this mutational signature have been termed ultra-hypermutators.

Signature 11

Cancer types:

Signature 11 has been found in melanoma and glioblastoma.

Proposed aetiology:

Signature 11 exhibits a mutational pattern resembling that of alkylating agents. Patient histories have revealed an association between treatments with the alkylating agent temozolomide and Signature 11 mutations.

Additional mutational features:

Signature 11 exhibits a strong transcriptional strand-bias for C>T substitutions indicating that mutations occur on guanine and that these mutations are effectively repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 12

Cancer types:

Signature 12 has been found in liver cancer.

Proposed aetiology:

The aetiology of Signature 12 remains unknown.

Additional mutational features:

Signature 12 exhibits a strong transcriptional strand-bias for T>C substitutions.

Comments:

Signature 12 usually contributes a small percentage (<20%) of the mutations observed in a liver cancer sample.

Signature 13

Cancer types:

Signature 13 has been found in 22 cancer types and seems to be commonest in cervical and bladder cancers. In most of these 22 cancer types, Signature 13 is present in at least 10% of samples.

Proposed aetiology:

Signature 13 has been attributed to activity of the AID/APOBEC family of cytidine deaminases converting cytosine to uracil. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family. Signature 13 causes predominantly C>G mutations. This may be due to generation of abasic sites after removal of uracil by base excision repair and replication over these abasic sites by REV1.

Additional mutational features:

Transcriptional strand bias of mutations has been observed in exons, but is not present or is weaker in introns.

Comments:

Signature 2 is usually found in the same samples as Signature 13. It has been proposed that activation of AID/APOBEC cytidine deaminases is due to viral infection, retrotransposon jumping or to tissue inflammation. Currently, there is limited evidence to support these hypotheses. A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with the presence of large numbers of Signature 2 and 13 mutations and with predisposition to breast cancer. Mutations of similar patterns to Signatures 2 and 13 are commonly found in the phenomenon of local hypermutation present in some cancers, known as kataegis, potentially implicating AID/APOBEC enzymes in this process as well.

Signature 14

Cancer types:

Signature 14 has been observed in four uterine cancers and a single adult low-grade glioma sample.

Proposed aetiology:

The aetiology of Signature 14 remains unknown.

Additional mutational features:

Comments:

Signature 14 generates very high numbers of somatic mutations (>200 mutations per MB) in all samples in which it has been observed.

Signature 15

Cancer types:

Signature 15 has been found in several stomach cancers and a single small cell lung carcinoma.

Proposed aetiology:

Signature 15 is associated with defective DNA mismatch repair.

Additional mutational features:

Signature 15 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 15 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 20, and 26.

Signature 16

Cancer types:

Signature 16 has been found in liver cancer.

Proposed aetiology:

The aetiology of Signature 16 remains unknown.

Additional mutational features:

Signature 16 exhibits an extremely strong transcriptional strand bias for T>C mutations at ApTpN context, with T>C mutations occurring almost exclusively on the transcribed strand.

Comments:

Signature 17

Cancer types:

Signature 17 has been found in oesophagus cancer, breast cancer, liver cancer, lung adenocarcinoma, B-cell lymphoma, stomach cancer and melanoma.

Proposed aetiology:

The aetiology of Signature 17 remains unknown.

Additional mutational features:

Comments:

Signature 1Signature 18

Cancer types:

Signature 18 has been found commonly in neuroblastoma. Additionally, Signature 18 has been also observed in breast and stomach carcinomas.

Proposed aetiology:

The aetiology of Signature 18 remains unknown.

Additional mutational features:

Comments:

Signature 19

Cancer types:

Signature 19 has been found only in pilocytic astrocytoma.

Proposed aetiology:

The aetiology of Signature 19 remains unknown.

Additional mutational features:

Comments:

Signature 20

Cancer types:

Signature 20 has been found in stomach and breast cancers.

Proposed aetiology:

Signature 20 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 20 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 20 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15, and 26.

Signature 21

Cancer types:

Signature 21 has been found only in stomach cancer.

Proposed aetiology:

The aetiology of Signature 21 remains unknown.

Additional mutational features:

Comments:

Signature 21 is found only in four samples all generated by the same sequencing centre. The mutational pattern of Signature 21 is somewhat similar to the one of Signature 26. Additionally, Signature 21 is found only in samples that also have Signatures 15 and 20. As such, Signature 21 is probably also related to microsatellite unstable tumours.

Signature 22

Cancer types:

Signature 22 has been found in urothelial (renal pelvis) carcinoma and liver cancers.

Proposed aetiology:

Signature 22 has been found in cancer samples with known exposures to aristolochic acid. Additionally, the pattern of mutations exhibited by the signature is consistent with the one previous observed in experimental systems exposed to aristolochic acid.

Additional mutational features:

Signature 22 exhibits a very strong transcriptional strand bias for T>A mutations indicating adenine damage that is being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 22 has a very high mutational burden in urothelial carcinoma; however, its mutational burden is much lower in liver cancers.

Signature 23

Cancer types:

Signature 23 has been found only in a single liver cancer sample.

Proposed aetiology:

The aetiology of Signature 23 remains unknown.

Additional mutational features:

Signature 23 exhibits very strong transcriptional strand bias for C>T mutations.

Comments:

Signature 24

Cancer types:

Signature 24 has been observed in a subset of liver cancers.

Proposed aetiology:

Signature 24 has been found in cancer samples with known exposures to aflatoxin. Additionally, the pattern of mutations exhibited by the signature is consistent with that previous observed in experimental systems exposed to aflatoxin.

Additional mutational features:

Signature 24 exhibits a very strong transcriptional strand bias for C>A mutations indicating guanine damage that is being repaired by transcription-coupled nucleotide excision repair.

Comments:

Signature 25

Cancer types:

Signature 25 has been observed in Hodgkin lymphomas.

Proposed aetiology:

The aetiology of Signature 25 remains unknown.

Additional mutational features:

Signature 25 exhibits transcriptional strand bias for T>A mutations.

Comments:

This signature has only been identified in Hodgkin’s cell lines. Data is not available from primary Hodgkin lymphomas.

Signature 26

Cancer types:

Signature 26 has been found in breast cancer, cervical cancer, stomach cancer and uterine carcinoma.

Proposed aetiology:

Signature 26 is believed to be associated with defective DNA mismatch repair.

Additional mutational features:

Signature 26 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 26 is one of four mutational signatures associated with defective DNA mismatch repair and is often found in the same samples as Signatures 6, 15 and 20.

Signature 27

Cancer types:

Signature 27 has been observed in a subset of kidney clear cell carcinomas.

Proposed aetiology:

The aetiology of Signature 27 remains unknown.

Additional mutational features:

Signature 27 exhibits very strong transcriptional strand bias for T>A mutations. Signature 27 is associated with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.

Comments:

Signature 28

Cancer types:

Signature 28 has been observed in a subset of stomach cancers.

Proposed aetiology:

The aetiology of Signature 28 remains unknown.

Additional mutational features:

Comments:

Signature 29

Cancer types:

Signature 29 has been observed only in gingivo-buccal oral squamous cell carcinoma.

Proposed aetiology:

Signature 29 has been found in cancer samples from individuals with a tobacco chewing habit.

Additional mutational features:

Signature 29 exhibits transcriptional strand bias for C>A mutations indicating guanine damage that is most likely repaired by transcription-coupled nucleotide excision repair. Signature 29 is also associated with CC>AA dinucleotide substitutions.

Comments:

The Signature 29 pattern of C>A mutations due to tobacco chewing appears different from the pattern of mutations due to tobacco smoking reflected by Signature 4.

Signature 30

Cancer types:

Signature 30 has been observed in a small subset of breast cancers.

Proposed aetiology:

The aetiology of Signature 30 remains unknown.

 

---

 

Examples in the literature of deposits into or analysis from the COSMIC database

The Genomic Landscapes of Human Breast and Colorectal Cancers from Wood et al., 318 (5853): 1108–1113 Science 2007

“analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. “

• found cellular pathways with multiple pathways
• analyzed a highly curated database (Metacore, GeneGo, Inc.) that includes human protein-protein interactions, signal transduction and metabolic pathways
• There were 108 pathways that were found to be preferentially mutated in breast tumors. Many of the pathways involved phosphatidylinositol 3-kinase (PI3K) signaling
• the cancer genome landscape consists of relief features (mutated genes) with heterogeneous heights (determined by CaMP scores). There are a few “mountains” representing individual CAN-genes mutated at high frequency. However, the landscapes contain a much larger number of “hills” representing the CAN-genes that are mutated at relatively low frequency. It is notable that this general genomic landscape (few gene mountains and many gene hills) is a common feature of both breast and colorectal tumors.
• developed software to analyze multiple mutations and mutation frequencies available from Harvard Bioinformatics at

 

http://bcb.dfci.harvard.edu/~gp/software/CancerMutationAnalysis/cma.htm

 

 

R Software for Cancer Mutation Analysis (download here)

 

CancerMutationAnalysis Version 1.0:

R package to reproduce the statistical analyses of the Sjoblom et al article and the associated Technical Comment. This package is build for reproducibility of the original results and not for flexibility. Future version will be more general and define classes for the data types used. Further details are available in Working Paper 126.

CancerMutationAnalysis Version 2.0:

R package to reproduce the statistical analyses of the Wood et al article. Like its predecessor, this package is still build for reproducibility of the original results and not for flexibility. Further details are available in Working Paper 126

 

 

 

 

 

 

 

 

 

Update 04/27/2019

Review 2018. The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Z. Sondka et al. Nature Reviews. 2018.

The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) reevaluates the cancer genome landscape periodically and curates the findings into a database of genetic changes occurring in various tumor types.  The 2018 CGC describes in detail the effect of 719 cancer driving genes.  The recent expansion includes functional and mechanistic descriptions of how each gene contributes to disease etiology and in terms of the cancer hallmarks as described by Hanahan and Weinberg.  These functional characteristics show the complexity of the cancer mutational landscape and genome and suggest ” multiple cancer-related functions for many genes, which are often highly tissue-dependent or tumour stage-dependent.”  The 2018 CGC expands a second tier of genes, expanding the list of cancer related genes.

Criteria for curation of genes into CGC (curation process)

• choosing candidate genes are selected from published literature, conference abstracts, large cancer genome screens deposited in databases, and analysis of current COSMIC database
• COSMIC data are analyzed to determine presence of patterns of somatic mutations and frequency of such mutations in cancer
• literature review to determine the role of the gene in cancer
• Minimum evidence

– at least two publications from different groups shows increased mutation frequency in at least one type of cancer (PubMed)

–  at least two publications from different groups showing experimental evidence of functional involvement in at least one hallmark of cancer in order to classify the mutant gene as oncogene, tumor suppressor, or fusion partner (like BCR-Abl)

• independent assessment by at least two postdoctoral fellows
• gene must be classified as either Tier 1 of Tier 2 CGC gene
• inclusion in database
• continued curation efforts

definitions:

Tier 1 gene: genes which have strong evidence from both mutational and functional analysis as being involved in cancer

Tier 2 gene: genes with mutational patterns typical of cancer drivers but not functionally characterized as well as genes with published mechanistic description of involvement in cancer but without proof of somatic mutations in cancer

Current Status of Tier 1 and Tier 2 genes in CGC

Tier 1 genes (574 genes): include 79 oncogenes, 140 tumor suppressor genes, 93 fusion partners

Tier 2 genes (719 genes): include 103 oncogenes, 181 tumor suppressors, 134 fusion partners and 31 with unknown function

Updated 7/26/2019

The COSMIC database is undergoing an extensive update and reannotation, in order to ensure standardisation and modernisation across COSMIC data. This will substantially improve the identification of unique variants that may have been described at the genome, transcript and/or protein level. The introduction of a Genomic Identifier, along with complete annotation across multiple, high quality Ensembl transcripts and improved compliance with current HGVS syntax, will enable variant matching both within COSMIC and across other bioinformatic datasets. As a result of these updates there will be significant changes in the upcoming releases as we work through this process. The first stage of this work was the introduction of improvedHGVS syntax compliance in our May release. The majority of the changes will be reflected in COSMIC v90, which will be released in late August or early September, and the remaining changes will be introduced over the next few releases. The significant changes in v90 include: Updated genes, transcripts and proteins from Ensembl release 93 on both the GRCh37 and GRCh38 assemblies. Full reannotation of COSMIC variants with known genomic coordinates using Ensembl’s Variant Effect Predictor (VEP). This provides accurate and standardised annotation uniformly across all relevant transcripts and genes that include the genomic location of the variant. New stable genomic identifiers (COSV) that indicate the definitive position of the variant on the genome. These unique identifiers allow variants to be mapped between GRCh37 and GRCh38 assemblies and displayed on a selection of transcripts. Updated cross-reference links between COSMIC genes and other widely-used databases such as HGNC, RefSeq, Uniprot and CCDS. Complete standardised representation of COSMIC variants, following the most recent HGVS recommendations, where possible. Remapping of gene fusions on the updated transcripts on both the GRCh37 and GRCh38 assemblies, along with the genomic coordinates for the breakpoint positions. Reduced redundancy of mutations. Duplicate variants have been merged into one representative variant. Key points for you COSMIC variants have been annotated on all relevant Ensembl transcripts across both the GRCh37 and GRCh38 assemblies from Ensembl release 93. New genomic identifiers (e.g. COSV56056643) are used, which refers to the variant change at the genomic level rather than gene, transcript or protein level and can thus be used universally. Existing COSM IDs will continue to be supported and will now be referred to as legacy identifiers e.g. COSM476. The legacy identifiers (COSM) are still searchable. In the case of mutations without genomic coordinates, hence without a COSV identifier, COSM identifiers will continue to be used. All relevant Ensembl transcripts in COSMIC (which have been selected based on Ensembl canonical classification and on the quality of the dataset to include only GENCODE basic transcripts) will now have both accession and version numbers, so that the exact transcript is known, ensuring reproducibility. This also provides transparency and clarity as the data are updated. How these changes will be reflected in the download files As we are now mapping all variants on all relevant Ensembl transcripts, the number of rows in the majority of variant download files has increased significantly. In the download files, additional columns are provided including the legacy identifier (COSM) and the new genomic identifier (COSV). An internal mutation identifier is also provided to uniquely represent each mutation, on a specific transcript, on a given assembly build. The accession and version number for each transcript are included. File descriptions for each of the download files will be available from the downloads page for clarity. We have included an example of the new columns below. For example: COSMIC Complete Mutation Data (Targeted screens) [17:Q] Mutation Id – An internal mutation identifier to uniquely represent each mutation on a specific transcript on a given assembly build. [18:R] Genomic Mutation Id – Genomic mutation identifier (COSV) to indicate the definitive position of the variant on the genome. This identifier is trackable and stable between different versions of the release. [19:S] Legacy Mutation Id – Legacy mutation identifier (COSM) that will represent existing COSM mutation identifiers. We will shortly have some sample data that can be downloaded in the new table structure, to give you real data to manipulate and integrate, this will be available on the variant updates page. How this affects you We are aware that many of the changes we are making will affect integration into your pipelines and analytical platforms. By giving you advance notice of the changes, we hope much of this can be mitigated, and the end result of having clean, standardised data will be well worth any disruption. The variant updates page on the COSMIC website will provide a central point for this information and further technical details of the changes that we are making to COSMIC.

Kind Regards, The COSMIC Team cosmic@sanger.ac.uk Wellcome Sanger Institute Wellcome Genome Campus, Hinxton CB10 1SA

 

 

 

 

 

 

 

 

 

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