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What`s new in pancreatic cancer research and treatment?

Reporter: Aviva Lev-Ari, PhD, RN

What`s new in pancreatic cancer research and treatment?

Research into the causes, diagnosis, and treatment of pancreatic cancer is under way in many medical centers throughout the world.

Genetics and early detection

Scientists are learning more about some of the changes in DNA that cause cells in the pancreas to become cancerous. Inherited changes in genes such as BRCA2p16, and the genes responsible for hereditary non-polyposis colorectal cancer (HNPCC) can increase a person’s risk of developing pancreatic cancer. Researchers are now looking at how these and other genes may be altered in cases of pancreatic cancer that do not seem to be inherited. They have discovered that pancreatic cancer does not form suddenly. It develops over many years in a series of steps known as pancreatic intraepithelial neoplasia or PanIN. In the early steps, such as PanIN 1, there are changes in a small number of genes, and the duct cells of the pancreas do not look very abnormal. In later steps such as PanIN 2 and PanIN 3, there are abnormalities in several genes and the duct cells look more abnormal.

Researchers are using this information to develop tests for detecting acquired (not inherited) genetic changes in pancreatic cancer pre-cancerous conditions. One of the most common DNA changes in these conditions affects theKRAS oncogene and alters regulation of cell growth. New diagnostic tests are often able to recognize this change in samples of pancreatic juice collected during an ERCP (endoscopic retrograde cholangiopancreatography).

For now, imaging tests like endoscopic ultrasound (EUS), ERCP, and genetic tests for changes in certain genes (such as KRAS) are options for people with a strong family history of pancreatic cancer. But these tests are not recommended for widespread testing of people at average risk who do not have any symptoms.

Treatment

The major focus of much research is on finding better treatments for pancreatic cancer. Improving surgery and radiation therapy are major goals, as is determining the best combination of treatments for people with certain stages of cancer.

Chemotherapy

Many clinical trials are testing new combinations of chemotherapy drugs for exocrine pancreatic cancer. Studies have looked to see if combining gemcitabine with other drugs would help patients live longer. Adding cisplatin, docetaxel, or irinotecan doesn’t seem to be helpful, but adding capecitabine (Xeloda) does seem to help some patients. Also, the combination of gemcitabine, irinotecan, and celecoxib (an arthritis drug) shows promise. Other studies are testing the best ways to combine chemotherapy with radiation therapy or newer targeted therapies.

Targeted therapies

As researchers have learned more about what makes pancreatic cancer cells different from normal cells, they have started to develop newer drugs that should be able exploit these differences by attacking only specific targets. These “targeted therapies” may provide another option for treating pancreatic cancer. They may prove to be useful along with, or instead of, current treatment regimens. In general, they seem to have fewer side effects than traditional chemotherapy drugs. Looking for new targets to attack on cancers is an active area of research.

Growth factor inhibitors: Many types of cancer cells, including pancreatic cancer cells, have certain molecules on their surface that help them to grow. These molecules are called growth factor receptors. One example is epidermal growth factor receptor (EGFR). Several drugs that target EGFR are now being studied. One, known as erlotinib (Tarceva), is already approved for use along with gemcitabine.

Anti-angiogenesis factors: All cancers depend on new blood vessels to nourish their growth. To block the growth of these vessels and thereby starve the tumor, scientists have developed anti-angiogenesis drugs. These are being studied in clinical trials and may be used in patients with pancreatic cancer.

Other targeted therapies: Many drugs targeting other aspects of cancer cells are now being studied for use in pancreatic cancer. For example, drugs that target the action of farnesyl transferase, an enzyme that is thought to stimulate the growth of many cancers, are now being tested. Other drugs, such as sunitinib, have several different targets.

Immune therapy

Immune therapies attempt to boost a person’s immune system or give them ready-made components of an immune system to attack cancer cells. Some studies of these treatments have shown promising results.

One form of immune therapy injects man-made monoclonal antibodies into patients. These immune system proteins are made to home in on a specific molecule, such as carcinoembryonic antigen (CEA), which is sometimes found on the surface of pancreatic cancer cells. Toxins or radioactive atoms can be attached to these antibodies, which bring them directly to the tumor cells. The hope is that they will affect cancer cells while leaving normal cells alone. For use in pancreatic cancer, these types of treatments are available only in clinical trials at this time.

Radiation therapy

Some current studies are looking at different ways to give radiation to treat exocrine pancreas cancer. One study is looking at the effect of intraoperative radiation therapy, in which a single large dose of radiation is given to the pancreas at the time of surgery (in the operating room). Another study is looking at using a special type of radiation called proton beam radiation with chemo.

Individualization of therapy

Some drugs seem to work better if certain types of mutations can be found in the patient’s tumor. For example, erlotinib may work better in patients if their tumors have a particular change in the gene for EGFR. This concept is an area of intense study. There might also be some genetic alterations that affect how well gemcitabine will work in a particular patient. Identifying markers that may predict how well a drug will work before it is given is an important area of research in many types of cancer.

New treatments for pancreatic neuroendocrine cancers

Many pancreatic neuroendocrine tumors have receptors for somatastatin on their cells. These tumors can be treated with octreotide and other drugs like it. A new drug has been developed in which the octreotide has been labeled with radiation. This drug shrunk some tumors and kept others from growing in an early trial. It also helped patients live longer.

Last Medical Review: 01/28/2013
Last Revised: 09/06/2013

SOURCE

http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-new-research

 

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Personalized Medicine and Colon Cancer

Author: Tilda Barliya, PhD

According to Dr. Neil Risch a leading expert in statistical genetics and the director of the UCSF Institute for Human Genetics,  “Personalized medicine, in which a suite of molecules measured in a patient’s lab tests can inform decisions about preventing or treating diseases, is becoming a reality” (7).

Colorectal cancer (CRC) is the third most common cancer and the fourth-leading cause of cancer death worldwide despite advances in screening, diagnosis, and treatment. Staging is the only prognostic classification used in clinical practice to select patients for adjuvant chemotherapy. However, pathological staging fails to predict recurrence accurately in many patients undergoing curative surgery for localized CRC (1,2). Most of the patients who are not eligible for surgery need adjuvant chemotherapy in order to avoid relapse or to increase survival. Unfortunately, only a small portion of them shows an objective response to chemotherapy, becoming problematic to correctly predict patients’ clinical outcome (3).

CRC patients are normally being tested for several known biomarkers which falls into 4 main categories (5):

  1. Chromosomal Instability (CIN)
  2. Microsatellite Instability (MSI)
  3. CpG Island methylator phynotype (CIMP)
  4. Global DNA hypomethylation

In the past few years many studies have exploited microarray technology to investigate gene expression profiles (GEPs) in CRC, but no established signature has been found that is useful for clinical practice, especially for predicting prognosis.  Only a subset of CRC patients with MSI tumors have been shown to have better prognosis and probably respond differently to adjuvant chemotherapy compared to microsatellite stable (MSS) cancer patients (6).

Pritchard & Grady have summarized the selected biomarkers that have been evaluated in colon cancer patients (10).

Table 1

Selected Biomarkers That Have Been Evaluated in Colorectal Cancer

Biomarker Molecular Lesion Frequency
in CRC
Prediction Prognosis Diagnosis
KRAS Codon 12/13 activating
mutations; rarely codon
61, 117,146
40% Yes Possible
BRAF V600E activating
mutation
10% Probable Probable Lynch
Syndrome
PIK3CA Helical and kinase
domain mutations
20% Possible Possible
PTEN Loss of protein by IHC 30% Possible
Microsatellite Instability (MSI) Defined as >30%
unstable loci in the NCI
consensus panel or
>40% unstable loci in a
panel of mononucleotide
microsatellite repeats9
15% Probable Yes Lynch
Syndrome
Chromosome Instability (CIN) Aneuploidy 70% Probable Yes
18qLOH Deletion of the long arm
of chromosome 18
50% Probable Probable
CpG Island Methylator
Phenotype (CIMP)
Methylation of at least
three loci from a selected
panel of five markers
15% +/− +/−
Vimentin (VIM) Methylation 75% Early
Detection
TGFBR2 Inactivating Mutations 30%
TP53 Mutations Inactivating Mutations 50%
APC Mutations Inactivating Mutations 70% FAP
CTNNB1 (β-Catenin) Activating Mutations 2%
Mismatch Repair Genes Loss of protein by IHC;
methylation; inactivating
mutations
1–15% Lynch
Syndrome

CRC- colorectal cancer; IHC- immunohistochemistry; FAP- Familial Adenomatous Polyposis

Examples for the great need of personalized medicine tailored according to the patients’ genetics is clearly seen with two specific drugs for CRC:  Cetuximab and panitumumab are two antibodies that were developed to treat colon cancer. However, at first it seemed as if they were a failure because they did not work in many patients. Then, it was discovered that if a cancer cell has a specific genetic mutation, known as K-ras, these drugs do not work.  This is an excellent example of using individual tumor genetics to predict whether or not treatment will work (8).

According to Marisa L et al, however, the molecular classification of CC currently used, which is based on a few common DNA markers as mentioned above (MSI, CpG island methylator phenotype [CIMP], chromosomal instability [CIN], and BRAF and KRAS mutations), needs to be refined.

Genetic Expression Profiles (GEP)

CRC is composed of distinct molecular entities that may develop through multiple pathways on the basis of different molecular features, as a consequence, there may be several prognostic signatures for CRC, each corresponding to a different entity. GEP studies have recently identified at least three distinct molecular subtypes of CC (4). Dr. Marisa Laetitia and her colleagues from the Boige’s lab however, have conducted a very thorough study and identifies 6 distinct clusters for CC patients. Herein, we’ll describe the majority of this study and their results.

Study  Design:

Marisa L et al (1) performed a consensus unsupervised analysis (using an Affymertix chip) of the GEP on tumor tissue sample from 750 patients with stage I to IV CC. Patients were staged according to the American Joint Committee on Cancer tumor node metastasis (TNM) staging system. Of the 750 tumor samples of the CIT cohort, 566 fulfilled RNA quality requirements for GEP analysis. The 566 samples were split into a discovery set (n = 443) and a validation set (n = 123).

Several known mutations were used as internal controls, including:

  • The seven most frequent mutations in codons 12 and 13 of KRAS .
  • The BRAF c.1799T>A (p.V600E)
  • TP53mutations (exons 4–9)
  • MSI was analyzed using a panel of five different microsatellite loci from the Bethesda reference panel
  • CIMP status was determined using a panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1)

Results:

The results revealed six clusters of samples based on the most variant probe sets. The consensus matrix showed that C2, C3, C4, and C6 appeared as well-individualized clusters, whereas there was more classification overlap between C1 and C5. In other words:

  • Tumors classified as C1, C5, and C6 were more frequently CIN+, CIMP−TP53 mutant, and distal (p<0.001), without any other molecular or clinicopathological features able to discriminate these three clusters clearly.
  • Tumors classified as C2, C4, and C3 were more frequently CIMP+ (59%, 34%, and 18%, respectively, versus <5% in other clusters) and proximal.
  • C2 was enriched for dMMR (68%) and BRAF- mutant tumors (40%).
  • C3 was enriched for KRAS- mutant tumors (87%).

Note: No association between clusters and TNM stage (histopathology) was found, except enrichment for metastatic (31%) tumors in C4.

Figure: These signaling pathways associated with the molecular subtype (by cluster)

Figure 2 Signaling pathways associated with each molecular subtype.

Marisa L et al. Signaling pathways associated with each molecular subtype

These clusters fall into several signaling pathways:

  • up-regulated immune system and cell growth pathways were found in C2, the subtype enriched for dMMR tumors
  • C4 and C6 both showed down-regulation of cell growth and death pathways and up-regulation of the epithelial–mesenchymal transition/motility pathways. displaying “stem cell phenotype–like” GEPs (91%)
  • Most signaling pathways were down-regulated in C1 and C3.
  • In C1, cell communication and immune pathways were down-regulated.
  • In C5, cell communication, Wnt, and metabolism pathways were up-regulated.

These results are further summarized in table 2:

Figure 3 Summary of the main characteristics of the six subtypes.

Marisa L et al. Gene Expression Classification of Colon Cancer into Molecular Subtypes

The authors have identified six robust molecular subtypes of CC individualized by distinct clinicobiological characteristics (as summarized in table 2).

This classification successfully identified the dMMR tumor subtype, and also individualized five other distinct subtypes among pMMR tumors, including three CIN+ CIMP− subtypes representing slightly more than half of the tumors. As expected, mutation of BRAF was associated with the dMMR subtype, but was also frequent in the C4 CIMP+ poor prognosis subtype. TP53– andKRAS-mutant tumors were found in all the subtypes; nevertheless, the C3 subtype, highly enriched in KRAS-mutant CC, was individualized and validated, suggesting a specific role of this mutation in this particular subgroup of CC.

Current Treatments for colon cancer- Table 3 (11) .

Constant S et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Exploratory analysis of each subtype GEP with previously published supervised signatures and relevant deregulated signaling pathways improved the biological relevance of the classification.

The biological relevance of our subtypes was highlighted by significant differences in prognosis. In our unsupervised hierarchical clustering, patients whose tumors were classified as C4 or C6 had poorer RFS than the other patients.

Prognostic analyses based solely on common DNA alterations can distinguish between risk groups, but are still inadequate, as most CCs are pMMR CIMP− BRAFwt.

The markers BRAF-mutant, CIMP+, and dMMR may be useful for classifying a small proportion of cases, but are uninformative for a large number of patients.

Unfortunately, 5 of the 9 anti-CRC drugs approved by the FDA today are basic cytotoxic chemotherapeutics that attack cancer cells at a very fundamental level (i.e. the cell division machinery) without specific targets, resulting in poor effectiveness and strong side-effects (Table 3) (11).

An example for side effects induction mechanisms have also been reported in CRC for the BRAF(V600E) inhibitor Vemurafenib that triggers paradoxical EGFR activation (12).

Summary:

The authors of this study “report a new classification of CC into six robust molecular subtypes that arise through distinct biological pathways and represent novel prognostic subgroups. Our study clearly demonstrates that these gene signatures reflect the molecular heterogeneity of CC. This classification therefore provides a basis for the rational design of robust prognostic signatures for stage II–III CC and for identifying specific, potentially targetable markers for the different subtypes”.

These results further underline the urgent need to expand the standard therapy options by turning to more focused therapeutic strategies: a targeted therapy-for specific subtype profile.. Accordingly, the expansion and the development of new path of therapy, like drugs specifically targeting the self-renewal of intestinal cancer stem cells – a tumor cell population from which CRC is supposed to relapse, remains relevant.

Therefore, the complexity of these results supports the arrival of a personalized medicine, where a careful profiling of tumors will be useful to stratify patient population in order to test drugs sensitivity and combination with the ultimate goal to make treatments safer and more effective.

References:

1. Marisa L,  de Reyniès A, Alex Duval A,  Selves J, Pierre Gaub M, Vescovo L, Etienne-Grimaldi MC, Schiappa R, Guenot D, Ayadi M, Kirzin S, Chazal M, Fléjou JF…Boige V. Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value. PLoS Med May 2013 10(5): e1001453. doi:10.1371. http://www.plosmedicine.org/article/info%3Adoi/10.1371/journal.pmed.1001453

2. Villamil BP, Lopez AR, Prieto SH, Campos GL, Calles A, Lopez- Asenjo JA, Sanz Ortega J, Perez CF, Sastre J, Alfonso R, Caldes T, Sanchez FM and Rubio ED. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 2012, 12:260.  http://www.biomedcentral.com/1471-2407/12/260/

3. Diaz-Rubio E, Tabernero J, Gomez-Espana A, Massuti B, Sastre J, Chaves M, Abad A, Carrato A, Queralt B, Reina JJ, et al.: Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial. J Clin Oncol 2007, 25(27):4224-4230. http://jco.ascopubs.org/content/25/27/4224.long

4. Salazar R, Roepman P, Capella G, Moreno V, Simon I, et al. (2011) Gene expression signature to improve prognosis prediction of stage II and III colorectal cancer. J Clin Oncol 29: 17–24. http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Salazar%5Bauthor%5D%20AND%20Gene%20expression%20signature%20to%20improve%20prognosis%20prediction%20of%20stage%20II%20and%20III%20colorectal%20cancer

5.  By: Global Genome Knowledge. Colorectal Cancer- Personalized Medicine, Now a Clinical Reality.  http://www.srlworld.com/innersense/Voice-135-Colorectal-Cancer-Sept-2012-IS.pdf

6. Popat S, Hubner R and Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005 Jan 20;23(3):609-618. http://www.ncbi.nlm.nih.gov/pubmed/15659508

7. By: Jeffrey Norris. Value of Genomics and Personalized Medicine Is Wrongly Downplayed.http://www.ucsf.edu/news/2012/04/11864/value-genomics-and-personalized-medicine-wrongly-downplayed

8. By: James C Salwitz. The Future is now: Personalized Medicine. http://www.cancer.org/cancer/news/expertvoices/post/2012/04/18/the-future-is-now-personalized-medicine.aspx

9. Jeffrey A. Meyerhardt., and Robert J. Mayer. Systemic Therapy for Colorectal Cancer. N Engl J Med 2005;352:476-487. http://www.med.upenn.edu/gastro/documents/NEJMchemotherapycolorectalcancer.pdf

10. Pritchard CC and Grady WM. Colorectal Cancer Molecular Biology Moves Into Clinical Practice. Gut. Jan 2011 60(1): 116-129.  Gut. 2011 January; 60(1): 116–129http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006043/

11. Constant S, Huang S, Wiszniewski L andMas C. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies.  Pharmacology, Toxicology and Pharmaceutical Science » “Drug Discovery”, book edited by Hany A. El-Shemy, ISBN 978-953-51-0906-8.  http://www.intechopen.com/books/drug-discovery/colon-cancer-current-treatments-and-preclinical-models-for-the-discovery-and-development-of-new-ther

12. Prahallad, C. Sun, S. Huang, F. Di Nicolantonio, R. Salazar, D. Zecchin, R. L. Beijersbergen, A. Bardelli, R. Bernards, 2012 Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature Jan 2012 483 (7387): 100-103. http://www.nature.com/nature/journal/v483/n7387/full/nature10868.html

Other related articles on this Open Access Online Scientific Journal include the following:

*. By Tilda Barliya PhD. Colon Cancer. https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

**. By: Tilda Barliya PhD. CD47: Target Therapy for Cancer. https://pharmaceuticalintelligence.com/2013/05/07/cd47-target-therapy-for-cancer/

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

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Colon Cancer

Author/Editor: Tilda Barliya PhD

 

Colorectal cancer is the third most common type of cancer diagnosed in the United States and is the third most common cause of cancer-related death. The majority of cases are sporadic, with hereditary colon cancer contributing up to 15% of all colon cancer diagnoses. Treatment consists of surgery for early-stage disease and the combination of surgery and adjuvant chemotherapy for advanced-stage disease. Management of metastatic disease has evolved from primary chemotherapeutic treatment to include resection of single liver and lung metastases in addition to resection of the primary disease and chemotherapy (1-4).

Courtesy WebMD site

In the United States, colorectal cancer (CRC) is the third most common type of cancer diagnosed and the third most common cause of cancer-related death in men and women. In 2010, an estimated 102,900 new cases of colon cancer were diagnosed (49,470 male, 53,430 female) and 51,370 patients (26,580 male, 24,790 female) died from CRC. The death rate from colon cancer decreased over the preceding decade, from 30.77 per 100,000 people to 20.5 per 100,000 people. The lifetime risk of developing colon cancer in industrialized nations is 5% and is stable or decreasing. In contrast, the incidence in developing countries continues to rise, hypothesized to be due to increased exposure to risk factors. It has been estimated that 1.5 million people in the United States will be living with CRC by 2020.The financial burden of caring for this population is significant: $4.5 to $9.6 billion per year.

Colon Cancer is divided into 5 types:

  1. Sporadic: 60-85%
  2. Familial: 10-30%
  3. Hereditary non-Polyposis Colon Cancer (HNPCC): 5%
  4. Familial Adenomatous Polyposis (FAP): 1%
  5. Autosomal Dominant Inheritance

The molecular defects are of two types:

  • alterations that lead to novel or increased function of oncogenes
  • alterations that lead to loss of function of tumor-suppressor genes (TSGs)

Multiple genes are associated with the initiation and progression of the different syndromes of colon cancer and are summarized by Fearon ER in Table 1 (6):

Table 1  Genetics of inherited colorectal tumor syndromesa
Syndrome Common features Gene defect(s)
FAP Multiple adenomatous polyps (>100) and carcinomas of the colon and rectum; duodenal polyps and carcinomas; fundic gland polyps in the stomach; congenital hypertrophy of retinal pigment epithelium APC (>90%)
Gardner syndrome Same as FAP; also, desmoid tumors and mandibular osteomas APC
Turcot’s syndrome Polyposis and colorectal cancer with brain tumors (medulloblastomas); colorectal cancer and brain tumors (glioblastoma) APC
MLH1PMS2
Attenuated adenomatous polyposis coli Fewer than 100 polyps, although marked variation in polyp number (from 5 to >1,000 polyps) observed in mutation carriers within a single family APC(predominantly 5′ mutations)
Hereditary nonpolyposis colorectal cancer Colorectal cancer without extensive polyposis; other cancers include endometrial, ovarian and stomach cancer, and occasionally urothelial, hepatobiliary, and brain tumors MSH2
MLH1
PMS2
GTBPMSH6
Peutz-Jeghers syndrome Hamartomatous polyps throughout the GI tract; mucocutaneous pigmentation; increased risk of GI and non-GI cancers LKB1STK11(30–70%)
Cowden disease Multiple hamartomas involving breast, thyroid, skin, central nervous system, and GI tract; increased risk of breast, uterus, and thyroid cancers; risk of GI cancer unclear PTEN (85%)
Juvenile polyposis syndrome Multiple hamartomatous/juvenile polyps with predominance in colon and stomach; variable increase in colorectal and stomach cancer risk; facial changes DPC4 (15%)
BMPR1a(25%)
PTEN (5%)
MYH-associated polyposis Multiple adenomatous GI polyps, autosomal recessive basis; colon polyps often have somatic KRAS mutations MYH

aAbbreviations: FAP, familial adenomatous polyposis; GI, gastrointestinal.

Essentially all of the genes discussed above are conclusively implicated in subsets of CRC due to specific somatic defects that either activate or inactivate gene and protein function. It is hypothesized that essentially any gene with dysregulated expression in CRC—either increased or decreased expression—may have a functionally significant role as an oncogene or a TSG, respectively. The aggregate data on the mutations and function of any given gene must be carefully evaluated to establish whether the gene truly contributes to CRC pathogenesis and whether it should be designated as an oncogene or a TSG (5,6).

The first proposed genetic model of CRC assumed that most CRCs arise from preexisting adenomatous lesions and that the accumulation of multiple gene defects is required for CRCs.

Benign GI tumors are a varied group, but localized lesions that project above the surrounding mucosa are commonly termed polyps. In humans, most colorectal polyps, particularly small polyps less than 5 mm in size, are hyperplastic (6). Most data indicate that hyperplastic polyps are not a major precursor to CRC; rather, the adenomatous polyp, or adenoma, is probably the important precursor lesion (7).

” Adenomas arise from glandular epithelium and are characterized by dysplastic morphology and altered differentiation of the epithelial cells in the lesion. The prevalence of adenomas in the United States is approximately 25% by age 50 and approximately 50% by age 70 (8)”. Only a fraction of adenomas progress to cancer, and progression probably occurs over years to decades. Individuals affected by syndromes that strongly predispose to adenomas, such as FAP, invariably develop CRCs by the third to fifth decade of life if their colons are not removed”.

A more recent and modified version of the genetic model postulate that each gene defect described in the model occurs at high frequency only at particular stages of tumor development. This observation is the basis for assigning a relative order to the defects in a multistep pathway.

Colon Cancer and clinical Trails:

Mutations in the KRAS proto-oncogene are found in 40-45% of patients with CRC and occur mainly in exon 2 (codon 12 and 13) and to a lesser extent in exon 3 (codon 61) and exon 4 (codon 146). A number of studies have evaluated a potential prognostic role of KRAS  in clinical practice for the treatment of colorectal cancer. However, clinical study design, reproducibility, interpretation and reporting of the clinical data remain important challenges.

Laurent-Puig’s group was the first to show the negative predictive value of KRAS mutations for response to the EGFR monoclonal antibody (mAb) cetuximab (11, 12, 13). Ever since then, a number of large phase II-III randomized studies have confirmed the negative predictive value of KRAS mutations for response to cetuximab and panitumumab treatment.

The role of KRAS mutations in predicting response to other therapies remains unclear. A subset analysis of patients treated in the phase III study of bevacizumab plus IFL (irinotecan, bolus 5-FU, and folinic acid) versus IFL showed that the clinical benefit of bevacizumab is independent of KRAS mutational status (11, 14).

The KRAS biomarker story is unique in several ways. It represents the first biomarker integrated into clinical practice in CRC“.

The high prevalence of KRAS mutations in CRC and its strong negative predictive value for EGFR mAb therapies, has led to its rapid acceptance as a valuable biomarker. The EMEA, FDA and ASCO47 now recommend that all patients with metastatic CRC who are candidates for anti-EGFR mAb therapy should be tested for KRAS mutations and, if a KRAS mutation in codon 12 or 13 is detected, then patients should not receive anti-EGFR antibody therapy.

More so, Data from the PETACC-3 trial, presented at ASCO 2010, have shown that KRAS and BRAF mutant CRC tumors induce different gene-expression profiles, further reiterating that these tumors have a distinct underlying biology. Despite intensive progress in the field of genomic research, none of these genomic markers are used routinely in clinical trials.  Only, nowadays, trials are starting to use specific gene-pathway” target in CRC clinical trials.

Samuel Constant et al. Colon Cancer: Current Treatments and Preclinical Models for the Discovery and Development of New Therapies

Summary:

Early studies are underway to understand the role of DNA methylation, chromatin modification, changes in the patterns of mRNA and noncoding RNA expression, and changes in protein expression and posttranslational modification. However,  we do not yet have an indepth and comprehensive understanding of the pathogenesis of the biologically and clinically distinct subsets of CRC. Careful design of clinical trials end points and validation of the genes as potential prognostic markers will allow a better outcome for these patients.

Ref:

1. Sarah Popek, MD, and Vassiliki Liana Tsikitis, MD. Colorectal Cancer: A Review. OncLive  November 10, 2011. http://www.onclive.com/publications/contemporary-oncology/2011/fall-2011/Colorectal-Cancer-A-Review

x. Martin Hefti.,  H.Maximilian Mehdorn., Ina Albert and Lutz Dörner. Fluorescence-Guided Surgery for Malignant Glioma: A Review on Aminolevulinic Acid Induced Protoporphyrin IX Photodynamic Diagnostic in Brain Tumors.  Current Medical Imaging Reviews, 2010, 6, 1-5. http://www.hirslanden.ch/content/global/en/startseite/gesundheit_medizin/mediathek_bibliothek/fachartikel/verschiedenes/fluorescence_guidedsurgeryformalignantglioma/_jcr_content/download/file.res/FluorescenceGuidedSurgeryforMalignantGlioma.pdf

2. Oguz Akin, Sandra B. Brennan., D. David Dershaw., Michelle S. Ginsberg., Marc J. Gollub., Heiko Sch€oder., David M. Panicek, and Hedvig Hricak. Advances in Oncologic Imaging: Update on 5 Common Cancers. CA CANCER J CLIN 2012;62:364–393. http://onlinelibrary.wiley.com/doi/10.3322/caac.21156/pdf

3. O’Donnell, Kevin et al. Nanoparticulate systems for oral drug delivery to the colon. International Journal of Nanotechnology, 2010, 8, 1/2, 4-20. “Colonic Navigation: Nanotechnology Helps Deliver Drugs to Intestinal Target”. http://www.sciencedaily.com/releases/2010/11/101104154553.htm

4. Perumal V. Molecular Therapy and Nanocarrier Based Drug Delivery to Colon Cancer: Targeted Molecular Therapy (AEE788 and Celecoxib) and Drug Delivery (Celecoxib) To Colon Cancer. http://www.amazon.com/Molecular-Therapy-Nanocarrier-Delivery-Cancer/dp/3659162558

5. Xiaoyun Liao, Paul Lochhead, Reiko Nishihara, Teppei Morikawa, Aya Kuchiba, Mai Yamauchi, Yu Imamura, Zhi Rong Qian, Yoshifumi Baba, Kaori Shima, Ruifang Sun, Katsuhiko Nosho, Jeffrey A. Meyerhardt, Edward Giovannucci, Charles S. Fuchs, Andrew T. Chan, Shuji Ogino. Aspirin Use, TumorPIK3CAMutation, and Colorectal-Cancer Survival. New England Journal of Medicine, 2012; 367 (17): 1596 DOI:10.1056/NEJMoa1207756http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532946/

Gene Mutation Identifies Colorectal Cancer Patients Who Live Longer With Aspirin Therapy. http://www.sciencedaily.com/releases/2012/10/121024175357.htm

6. Fearon ER. Molecular Genetics of Colorectal Cancer. Annual Review of Pathology: Mechanisms of Disease 2011; 6: 479-507.http://www.annualreviews.org/doi/pdf/10.1146/annurev-pathol-011110-130235

7.  Jass JR. 2007. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Hisopathology 50:113–130. http://www.amedeoprize.com/ap/pdf/histopathology.pdf

8.  Rex DK, Lehman GA, Ulbright TM, Smith JJ, Pound DC, et al.  Colonic neoplasia in asymptomatic persons with negative fecal occult blood tests: influence of age, gender, and family history. Am. J. Gastroenterol 1993. 88:825–831.http://www.ncbi.nlm.nih.gov/pubmed/8503374

9. Kerber RA, Neklason DW, Samowitz WS, Burt RW. Frequency of familial colon cancer and hereditary nonpolyposis colorectal cancer (Lynch syndrome) in a large population database. Fam. Cancer 2005; 4:239–44. http://www.ncbi.nlm.nih.gov/pubmed/16136384

10. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell 1996: 87:159–170. http://users.ugent.be/~fspelema/les%204-5%20HMG/kinzler%20clon.pdf

11. Sandra Van Schaeybroeck, Wendy L. Allen, Richard C. Turkington & Patrick G. Johnston. Implementing prognostic and predictive biomarkers in CRC clinical trials.(colorectal cancer)(Clinical report). Nature Reviews Clinical Oncology 2011: 8; 222-232. http://www.nature.com/nrclinonc/journal/v8/n4/abs/nrclinonc.2011.15.html

12. Lievre, A. et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66 2006: 3992-3995. http://hwmaint.cancerres.aacrjournals.org/cgi/content/full/66/8/3992

13. Lievre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 2008: 26, 374-379. http://jco.ascopubs.org/content/26/3/374.full.pdf

14. Hurwitz, H. I., Yi, J., Ince, W., Novotny, W. F. & Rosen, O. The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist  2009: 14, 22-28. http://theoncologist.alphamedpress.org/content/14/1/22.full

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Aviva Lev-Ari, PhD, RNCancer Genomic Precision Therapy: Digitized Tumor’s Genome (WGSA) Compared with Genome-native Germ Line: Flash-frozen specimen and Formalin-fixed paraffin-embedded Specimen Needed. https://pharmaceuticalintelligence.com/2013/04/21/cancer-genomic-precision-therapy-digitized-tumors-genome-wgsa-compared-with-genome-native-germ-line-flash-frozen-specimen-and-formalin-fixed-paraffin-embedded-specimen-needed/

II. By: Aviva Lev-Ari, PhD, RN. Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection. https://pharmaceuticalintelligence.com/2013/04/12/critical-gene-in-calcium-reabsorption-variants-in-the-kcnj-and-slc12a1-genes-calcium-intake-and-cancer-protection/

III.  By: Stephen J. Williams, Ph.DIssues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

IV. By: Ritu Saxena, Ph.DIn Focus: Targeting of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

V.  By: Ziv Raviv PhD. Cancer Screening at Sourasky Medical Center Cancer Prevention Center in Tel-Aviv. https://pharmaceuticalintelligence.com/2013/03/25/tel-aviv-sourasky-medical-center-cancer-prevention-center-excellent-example-for-adopting-prevention-of-cancer-as-a-mean-of-fighting-it/

VI. By: Ritu Saxena, PhD. In Focus: Identity of Cancer Stem Cells. https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

VII. By: Dror Nir, PhD. State of the art in oncologic imaging of Colorectal cancers. https://pharmaceuticalintelligence.com/2013/02/02/state-of-the-art-in-oncologic-imaging-of-colorectal-cancers/

Other posts by the group: Please see https://pharmaceuticalintelligence.com/?s=colon+cancer

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Personalized Medicine in NSCLC

Reviewer: Larry H Bernstein, MD, FCAP

Introduction

Early in the 21st century, gefitinib, an epi­dermal growth factor receptor (EGFRtyrosine kinase inhibitor became available  for the treatment of non-small cell lung can­cer (NSCLC). Over 80% of selected patients

  • EGFR mutation-positive patients, respond to gefitinib treatment;
  • most patients develop acquired resistance to gefitinib within a few years.
Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects.
Lung cancers are classified according to their his­tological type. Because each variant has different bio­logical and clinical properties, including response to treatment, a precise classification is essential to pro­vide appropriate therapy for individual patients. Lung cancer consists of two broad categories—non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC  – 20%–40% RR to chemotherapy

  • ade­nocarcinoma (AC),  40%–50% ( most common form)
    • higher sensitivity to chemotherapy than SCC or LC
  • squamous cell carcinoma (SCC),  ∼30%
  •  large cell carcinoma (LCC). 10%
The majority of patients with SCLC are diagnosed with
  • advanced cancer with distant metastasis
  • high sensitivity to chemotherapy.
  • response rate (RR) for SCLC is reportedly 60%–80%
  • complete remission is observed in only 15%–20% of patients
The Potential of Personalized Medicine in Advanced NSCLC
Personalized medicine—
  • matching a patient’s unique molecular profile with an appropriate targeted therapy—
  • is transforming the diagnosis and treatment of non–small-cell lung cancer (NSCLC).

Through molecular diagnostics, tumor cells may be differentiated based on the presence or absence of

  • receptor proteins,
  • driver mutations, or
  • oncogenic fusion/rearrangements.

The convergence of advancing research in drug development and genetic sequencing has permitted the development of therapies specifically targeted to certain biomarkers, which may offer a differential clinical benefit.

Putting personalized medicine in NSCLC into practice
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC.1,2
Biomarker Testing in Advanced NSCLC: Evolution in Pathology Clinical Practice
http://www.medscape.com/infosite/letstest/article-3
Multidisciplinary Approaches in the Changing Landscape of Advanced NSCLC
http://www.medscape.com/infosite/letstest/article-4
Oncology Perspectives on Biomarker Testing
http://www.medscape.com/infosite/letstest/article-1

References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                   August 6, 2012.
2. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Over the last decade, a growing number of biomarkers have been identified in NSCLC.3,4 To date, 2 of these molecular markers have been shown to have both prognostic and predictive value in patients with advanced NSCLC: epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.5-8 Testing for these biomarkers may provide physicians with more information on which to base treatment decisions, and reflex testing may permit consideration of appropriate therapy from the outset of treatment.2,9,10

References:
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK).                       Sept 17, 2012
http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm.

Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Presented at: 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, J Clin Oncol. 2011;29(suppl). Abstract 7503.                        Aug 6, 2012.                    http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf.                        Aug 6, 2012
College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf.      Aug 6, 2012.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

 Background Studies
In 2002, gefitinib (ZD1839; AstraZeneca) , the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, became available as an innovative molecular-targeted drug for the treatment of unresectable NSCLC. Initially, many NSCLC patients were expected to respond to gefitinib because many solid tumors, including NSCLC, are known to overexpress EGFR, which has a role in tumor pro­liferation and is used as a biomarker to predict poor prognosis. Gefitinib was shown to have a dra­matic effect on a limited number of patients; but  it was ineffective in 70%–80% of patients with NSCLC. There have been reports of death caused by interstitial pneumonia (IP), one of the critical adverse drug reactions (ADRs) associated with gefitinib use. Therefore, there is a need for  predicting the effects of gefitinib, and criteria for select­ing patients who could be treated with gefitinib.
 In 2004, Lynch et al. and Paez et al. each pub­lished, on the same day, sensational reports in the New England Journal of Medicine and Science, identifying somatic mutations in the tyrosine kinase domain of the EGFR gene in patients with gefitinib-sensitive lung cancer, as compared with none of the patients who had no response. Therefore, screening for EGFR mutations in lung cancer showed potential for identifying patients who would respond to gefi­tinib therapy. It then was found that patients with EGFR mutations in the area of the gene cod­ing for the ATP-binding pocket of the tyrosine kinase domain responded to gefitinib. Consequently, the EGFR genotyping has been used to select patients who will respond to gefitinib. Other genetic mutations have also been reported as indicators of the response or resistance to gefitinib; for example, mutations of the KRAS gene are associated with primary resistance to gefitinib. Thus, screening of EGFR and KRAS is used to
  • predict the effects of gefi­tinib and
  • to select patients who will respond to gefitinib in the clinical setting.
Until now, the effects of gefitinib have been predicted only by genotyping factors, such as EGFR and KRAS mutations. However, Nakamura et al showed a relationship between the blood concentration of gefitinib and its clinical effects. In their study of 23 NSCLC patients with EGFR mutations, the ratio of the gefitinib concentration on day 8 to that on day 3 after the first administration of gefitinib (C8/C3) correlated with the progression-free survival (PFS) period. Patients with a higher C8/C3 ratio had a significantly lon­ger PFS (P = 0.0158, 95% confidence interval [CI]: 0.237–0.862), which  suggests the importance of the PK of gefitinib on its clinical outcome.   Chmielecki et al. concurrently reported that maintain­ing a high concentration of erlotinib, another EGFR tyrosine kinase inhibitor (EGFR-TKIs) with the same mechanism of action as gefitinib, could
  1. delay the establishment of drug-resistant tumor cells and
  2. decrease the proliferation rate of drug-resistant cells compared to
    • treatment using a lower concentration of erlotinib.
Pharmacogenetic profile
Initially, gefitinib was expected to induce a response in patients with tumors that overexpressed EGFR because it exerts its antineoplastic effects by com­petitively inhibiting the binding of ATP to the ATP-binding site of EGFR.  A number of studies contradict this hypothesis:
(1) while approxi­mately 40%–80% of NSCLC overexpress EGFR, only 10%–20% of NSCLC patients respond to gefi­tinib;5,6 and
(2) while EGFR overexpression is known to be more common in SCC than AC, gefitinib shows a higher antineoplastic effect on AC than on SCC, while other reports indicated no correlation between the expression levels of EGFR and clinical outcomes.
In 2004, somatic mutations were identified in the EGFR tyrosine kinase domain of patients with gefitinib-responsive lung cancer, as compared with no mutations in patients exhibiting no response, and the presence of an EGFR mutation was highly correlated with a good response to gefitinib.The conformational change of the EGFR ATP-binding site caused by genetic mutations constitutively acti­vates the EGFR downstream signaling pathway and increases the malignancy of cancer. Conversely, the conformational change of the ATP-binding site can also increase its affinity for gefitinib; therefore, gefi­tinib can inhibit the downstream signaling pathway more easily, strongly induces apoptosis, and reduces the proliferation of cancer cells.
Mutations in exons 18–21 of EGFR are predictive factors for the clinical efficacy of gefitinib;
  • deletions in exon 19 and missense mutations in exon 21 account for ∼90% of these mutations.

The detection of EGFR muta­tions in exons 19 and 21 is considered to be essential to predict the clinical efficacy of gefitinib.
Acquired resistance
All responders eventually develop resistance to gefitinib but in 2005, an EGFR mutation in exon 20, which substitutes methionine for threonine at amino acid position 790 (T790M), was reported to be one of the main causes of acquired resistance to gefitinib. The EGFR T790M vari­ant

  1. changes the structural conformation of the ATP-binding site, thereby
  2. increasing the affinity of ATP to EGFR, while
  3. the affinity of gefitinib to ATP is unchanged.

Screening methods for EGFR and KRAS mutations
The detection of EGFR and KRAS mutations has been usually achieved by sequencing DNA amplified from tumor tissues; however, sequencing techniques are too complex, time-consuming, and expensive.  The selection of an appropri­ate method to detect EGFR and KRAS mutations is essential to make an exact prediction of the efficacy of gefitinib in individual patients. Advances in diagnostics and treatments for NSCLC have led to better outcomes and higher standards of what outcomes are expected. These new understandings and treatments have raised multiple new questions and issues with regard to the decisions on the appropriate treatment of NSCLC patients.

  • Biomarkers are increasingly recognized and applied for guidance in diagnosis, prognosis and treatment decisions and evaluation.
  • Biologics and newer cancer treatments are enabling the possibility for new combined treatment modalities in earlier stage disease
  • Maintenance therapy has been shown to be useful, but optimal therapy choices before and after maintenance therapy need clarification
  • The importance of performance status on treatment decisions
  • Comparative effectiveness is becoming an expectation across all treatments and diseases, and will prove difficult to accomplish within the complexity of cancer diseases
NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement
PF Engstrom, MG Bloom,GD Demetri, PG Febbo, et al.
Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decisionmaking is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility. The NCCN Molecular Testing Work Group identified
challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. (JNCCN 2011;9[Suppl 6]:S1–S16)
Executive Summary
The FDA recently announced plans for oversight of laboratory-developed tests (LDTs) and released draft guidance regarding the development of companion diagnostics concurrently with therapeutics, both areas over which the FDA has regulatory authority. As recognized by the FDA, these types of diagnostic tests are used increasingly to directly inform treatment decisions, and this especially impacts patients with cancer and their oncologists. However, because of the increasing complexity of some LDTs and increasing commercial interest in oncology-related LDTs in general, the FDA is considering whether its policy of exercising “enforcement discretion”

for LDTs is still appropriate. To provide guidance regarding challenges of molecular testing to health care providers and other stakeholders, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations external to NCCN.  The NCCN Molecular Testing Work Group agreed to define molecular testing in oncology as

  • procedures designed to detect somatic or germline mutations in DNA and
  • changes in gene or protein expression that could impact the
    • diagnosis,
    • prognosis,
    • prediction, and
    • evaluation of therapy of patients with cancer.
Therefore, the discussion focused on molecular tests that predict outcomes for therapy.
Realizing the importance of personalized medicine in advanced NSCLC
E Topol, B Buehler, GS Ginsburg.       Medscape Molec Medicine
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/
Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna

Lung cancer in the never smoker population is a distinct disease entity with specific molecular changes, offering the potential for targeted therapy.
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007

An Update on New and Emerging Therapies for NSCLC
Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD
On completion of these readings participants will be thoroughly familiar with these issues:
  1. The influence of histologic types and genetic and molecular markers on choosing and personalizing therapy in patients with advanced NSCLC
  2. The role of the pathologist in properly classifying subtypes of NSCLC and reporting the presence of molecular markers in tumor samples
  3. Familiarize themselves with effective methods of obtaining adequate tissue samples from patients and recognize the importance of accurate pathologic assessment of NSCLC
The rapid developments in molecular biology have opened up new possibilities for individualized treatment of non-small cell lung cancer (NSCLC), and, in recent years, has mainly focused on the epidermal growth factor receptor (EGFR). A greater understanding of the molecular mechanisms behind
  • tumorigenesis and
  • the identification of new therapeutic targets
    • have sparked the development of novel agents
    • intended to improve the standard chemotherapy regimens for NSCLC.
Along with the advent of targeted therapy, identifying biomarkers to predict the subset of patients more likely to benefit from a specific targeted intervention has become increasingly important.
EGFR TYROSINE KINASE INHIBITORS 
tumor-associated mutations in the tyrosine kinase domain of EGFR have been associated with response to EGFR TKIs
The most common EGFR-sensitizing mutations encompass deletions in exon 19 and a point mutation at L858R in exon 21; together,
  • they account for approximately 85% of EGFR mutations in NSCLC.
  • Other EGFR mutations have been detected, particularly in exon 20.
    •  mutations identified in exon 20 have been linked to resistance to EGFR TKIsNon-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
      Taofeek K. Owonikoko, MD, PhD
What is the role and application of molecular profiling in the management of NSCLC?
It is essential to:
  1. Identify advances in the understanding of molecular biology and histologic profiling in the treatment of NSCLC
  2. Summarize clinical data supporting the use of tumor biomarkers as predictors of therapeutic efficacy of targeted agents in NSCLC
  3. Devise an individualized treatment plan for patients with advanced NSCLC based on a tumor’s molecular profile
  4. Identify methods for overcoming barriers to effective incorporation of molecular profiling for the management of NSCLC into clinical practice
Non-small cell lung cancer (NSCLC),the most common type of lung cancer, usually grows and spreads more slowly than small cell lung cancer.
The three common forms of NSCLC are:
  1. Adenocarcinomas are often found in an outer area of the lung.
  2. Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  3. Large cell carcinomas occur in any part of the lung and tend to grow and spread faster than the other two types
Smoking causes most cases of lung cancer. The risk depends on the number of cigarettes you smoke every day and for how long you have smoked. Some people who do not smoke and have never smoked develop lung cancer.
Working with or near the following cancer-causing chemicals or materials can also increase your risk:
  • Asbestos
  • Chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust
  • Certain alloys, paints, pigments, and preservatives
  • Products using chloride and formaldehyde
Non-small cell lung c

ancer
(NSCLC) accounts for
  • approximately 85% of all lung cancers.
Lung cancer  may produce no symptoms until the disease is well advanced, so early recognition of symptoms may be beneficial to outcome.
At initial diagnosis,
  • 20% of patients have localized disease,
  • 25% of patients have regional metastasis, and
  • 55% of patients have distant spread of disease.
Revisiting Doublet Maintenance Chemo in Advanced NSCLC 
H. Jack West, MD
  • Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
Ardizzoni A, Tiseo M, Boni L, et al
J Clin Oncol. 2102;30:4501-4507
Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib — each well-tested as single agents — and evidence indicating a survival benefit in previously treated patients.
A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and
  • it provides more evidence that our current approach of sequential singlet therapy remains appropriate.
This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll
  • only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.
Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m2 IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days.
The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands. The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.
The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically,
  • median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed.
  • Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen
      • RR 12.6% vs 12.5%, median OS 9.2 vs 8.8 months, for pemetrexed and carboplatin/pemetrexed.

Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that

  • the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone.

Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint
Putting it in the context of previous data, these results only provide further confirmation that more is not better.
  • combinations are associated with more toxicity than single-agent therapy, and
  • this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced.

It is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.

Epidermal growth factor receptor (EGFR) signal...

Epidermal growth factor receptor (EGFR) signaling pathway. (Photo credit: Wikipedia)

EGFR structure

EGFR structure (Photo credit: Wikipedia)

ATP synthase

ATP synthase (Photo credit: Ethan Hein)

Non-small cell carcinoma - FNA

Non-small cell carcinoma – FNA (Photo credit: Pulmonary Pathology)

Articles on NSCLC in Pharmaceutical Intelligence:
Key Sources:
  1. Realizing the importance of personalized medicine in advanced NSCLC
    E Topol, B Buehler, GS Ginsburg. 

    Medscape Molec Medicine The Potential of Personalized Medicine in Advanced NSCLC

    With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
  2. Revisiting Doublet Maintenance Chemo in Advanced NSCLC
    H. Jack West, MD     http://www.medscape.com/viewarticle/777367
    Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
    Ardizzoni A, Tiseo M, Boni L, et al
    J Clin Oncol. 2102;30:4501-4507
  3. Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna
    Experts And Viewpoint, Medscape Hematology-Oncology, December 2007
  4. Non-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
    Taofeek K. Owonikoko, MD, PhD   August 24, 2011.   Medscape
  5. An Update on New and Emerging Therapies for NSCLC
    Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD     Medscape
  6. Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
  7. Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.

  8. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
  9. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy.

    Cancer Metastasis Rev. 2010;29:37-48.

  10. NCCN Oncology Insights Report on Non-Small Cell Lung Cancer 1.2010
  11.   Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib
    T Araki, H Yashima, K Shimizu, T Aomori
    Clinical Medicine Insights: Oncology 2012:6 407–421  http://dx.doi.org/10.4137/CMO.S7340

 

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Non-small Cell Lung Cancer drugs – where does the Future lie?

In focus: Tarceva, Avastin and Dacomitinib

 

UPDATED on July 5, 2013

(from reports published in New England Journal of Medicine on drug, crizotinib)

 

Curator: Ritu Saxena, Ph.D.

 

Introduction

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and usually grows and spreads more slowly than small cell lung cancer.

There are three common forms of NSCLC:

  • Adenocarcinomas are often found in an outer area of the lung.
  • Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
  • Large cell carcinomas can occur in any part of the lung. They tend to grow and spread faster than the other two types.

Lung cancer is by far the leading cause of cancer death among both men and women. Each year, more people die of lung cancer than of colon, breast, and prostate cancers combined. The American Cancer Society’s most recent estimates for lung cancer in the United States for 2012 reveal that about 226,160 new cases of lung cancer will be diagnosed (116,470 in men and 109,690 in women), and there will be an estimated 160,340 deaths from lung cancer (87,750 in men and 72,590 among women), accounting for about 28% of all cancer deaths.

Treatment

Different types of treatments are available for non-small cell lung cancer. Treatment depends on the stage of the cancer. For patients in whom the cancer has not spread to nearby lymph nodes are recommended surgery. Surgeon may remove- one of the lobes (lobectomy), only a small portion of the lung (wedge removal), or the entire lung (pneumonectomy). Some patients require chemotherapy that uses drugs to kill cancer cells and stop new cells from growing.

FDA approved drugs for NSCLC

Abitrexate (Methotrexate)
Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation) 
Alimta (Pemetrexed Disodium)
Avastin (Bevacizumab)
Bevacizumab
Carboplatin
Cisplatin
Crizotinib
Erlotinib Hydrochloride
Folex (Methotrexate)
Folex PFS (Methotrexate)
Gefitinib
Gemcitabine Hydrochloride
Gemzar (Gemcitabine Hydrochloride)
Iressa (Gefitinib)
Methotrexate
Methotrexate LPF (Methotrexate)
Mexate (Methotrexate)
Mexate-AQ (Methotrexate)
Paclitaxel
Paclitaxel Albumin-stabilized Nanoparticle Formulation
Paraplat (Carboplatin)
Paraplatin (Carboplatin)
Pemetrexed Disodium
Platinol (Cisplatin)
Platinol-AQ (Cisplatin)
Tarceva (Erlotinib Hydrochloride)
Taxol (Paclitaxel)
Xalkori (Crizotinib)

On the basis of target, the drugs have been classified as follows:

Image

NSCLC Drug Market Analysis

NSCLC drug market expected to grow from $4.2 billion in 2010 to $5.4 billion in 2020

Although, a whole list of agents is available for the treatment of NSCLC, the market for NSCLC drugs is expected to expand from $4.2 billion in 2010 to $5.4 billion in 2020 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan.   

However, drug sales for metastatic/advanced squamous cell non-small-cell lung cancer, which comprises only a small fraction of the market, will decrease from nearly 17 percent in 2010 to approximately 13 percent in 2020. According to surveyed U.S. oncologists and MCO pharmacy directors, increasing overall survival is one of the greatest unmet needs in first-line advanced squamous non-small-cell lung cancer.

In 2009, antimetabolites dominated the NSCLC market, with Eli Lilly’s Alimta (Pemetrexed) accounting for nearly three-quarters of sales within this drug class. Since then, Alimta has faced tough competition from a number of similar drugs and from emerging therapies. It was speculated that the antimetabolites market share would reduce significantly making it the second-largest drug class in NSCLC, while the epidermal growth factor receptor (EGFR) inhibitor class will garner the top market share by 2019.

Genentech/OSI Pharmaceuticals/Roche/Chugai Pharmaceutical’s Tarceva belongs to the EGFR inhibitor class, and has been prescribed principally along with Eli Lilly’s Alimta, to NSCLC patients.Both these drugs have dominated the NSCLC market till 2010, however, their market hold is expected to weaken from 2015-2020, as claimed by Decision Resources Analyst Karen Pomeranz, Ph.D. Decision Resources is a research and advisory firms for pharmaceutical and healthcare issues.

Tarceva (Erlotinib)

Generic Name: Erlotinib, Brand Name: Tarceva

Other Designation: CP 358774, OSI-774, R1415, RG1415, NSC 718781

Mechanism of Action: Tarceva, a small molecule quinazoline, directly and reversibly inhibits the epidermal growth factor receptor (EGFr) tyrosine kinase. Detailed information on how it works could be found at the Macmillian Cancer support website.

Tarceva has been approved for different cancers and several indications have been filed-

  • non-small cell lung cancer (nsclc), locally advanced or metastatic, second line, after failure of at least one prior chemotherapy regimen (2004)
  • pancreatic cancer, locally advanced or metastatic, in combination with gemcitabine, first line (2005)
  • non-small cell lung cancer (nsclc), advanced, maintenance therapy in responders following first line treatment with platinum-based chemotherapy (2010)
  • non-small cell lung cancer (nsclc) harboring epidermal growth factor (EGFr)-activating mutations, first line treatment in advanced disease

Sales of Tarceva 

May, 2012 sales of Tarceva in the US have been reported to be around $564.2 million.

In a recent article published by Vergnenègre et al in the Clinicoeconomic Outcomes Research journal (2012), cross-market cost-effectiveness of Erlotinib was analyzed. The study aimed at estimating the incremental cost-effectiveness of Erlotinib (150 mg/day) versus best supportive care when used as first-line maintenance therapy for patients with locally advanced or metastatic NSCLC and stable disease.

It was determined that treatment with erlotinib in first-line maintenance resulted in a mean life expectancy of 1.39 years in all countries, compared with a mean 1.11 years with best supportive care, which represents 0.28 life-years (3.4 life-months) gained with erlotinib versus best supportive care.

According to the authors analysis, there was a gain in the costs per-life year as $50,882, $60,025, and $35,669 in France, Germany, and Italy, respectively. Hence, on the basis of the study it was concluded that Erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for locally advanced or metastatic NSCLC.

Avastin (Bevacizumab)

Generic Name: Avastin, Brand Name: Bevacizumab

Other Designation: rhuMAb-VEGF, NSC-704865, R435, RG435

Mechanism of Action

Bevacizumab is a recombinant humanized Mab antagonist of vascular endothelial growth factor A (VEGFA) acting as an angiogenesis inhibitor.

Targets

Vascular endothelial growth factor (VEGF, VEGF-A, VEGFA)

Avastin is the only currently approved VEGF inhibitor that selectively targets VEGF-A.

Three other approved oral drugs, pazopanib (Votrient; GlaxoSmithKline), sunitinib (Sutent; Pfizer) and sorafenib (Nexavar; Onyx Pharmaceuticals) are orally available multi-targeted receptor tyrosine kinase inhibitors that include VEGF receptors among their tar­gets.

Avastin has been approved for different cancers and several indications have been filed:

  • colorectal cancer, advanced, metastatic, first line, in combination with a 5-FU based chemotherapy regimen
  • colorectal cancer, relapsed, metastatic, second line, in combintion with 5-FU-based chemotherapy (2004)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with carboplatin and paclitaxel chemotherapy, first line (2006)
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, in combination with taxane chemotherapy (2008, revoked in 2011)
  • non-small cell lung cancer (nsclc), non-squamous, inoperable, locally advanced, recurrent or metastatic, in combination with platinum-based chemotherapy, first line
  • renal cell carcinoma (RCC), metastatic, in combination with interferon (IFN) alpha, first line (2009)
  • glioblastoma multiforme (GBM), relapsed after first line chemoradiotherapy
  • breast cancer, chemotherapy naive, first line, locally recurrent or metastatic, HEr2 negative, in combination with capecitabine (2009)
  • ovarian cancer, in combination with standard chemotherapy (carboplatin and paclitaxel) as a first line treatment following surgery for women with advanced (Stage IIIb/c or Stage IV) epithelial ovarian, primary peritoneal or fallopian tube cancer
  • ovarian cancer, in combination with carboplatin and gemcitabine as a treatment for women with recurrent, platinum-sensitive ovarian cancer

SOURCE:

New medicine Oncology Knowledge Base

Sales of Avastin 

As of May, 2012, sales of Avastin in the US have been reported to be around $2.66 billion.

It attracted a lot of attention over the past few years after its use as a breast cancer treatment. Avastin was approved by the FDA under its fast-track program. However, the data released by the FDA from follow-up studies led to questioning the use of Avastin as a breast cancer drug. Infact, Genentech pulled the indication from Avastin’s label. Henceforth, the FDA did cancel that approval in late 2011. Doctors, however, can still prescribe it off-label. Potential adverse effects of Avastin that came under scrutiny along with unfavorable cost benefit analyses might pose challenges to its growth potential and continued widespread use. However, the sales of Avastin have continued to increase and it has been reported by Fierce Pharma as one of the 15 best-selling cancer drugs list. (Fierce Pharma)

Dacomitinib: New promising drug for NSCLC

Generic Name: Dacomitinib

Other Designation: PF-299804, PF-00299804, PF-299,804, PF00299804

PF-299804 is an orally available irreversible pan-HEr tyrosine kinase inhibitor.

Dacomitinib is a promising new drug on the market. Phase III trials are ongoing for advanced and refractory NSCLC, locally advanced or metastatic NSCLC and the EGFr mutation containing locally advanced or metastatic NSCLC in several countries including those in Europe, Asia, and America.

SOURCE:

New medicine Oncology Knowledge base

Dacomitinib bests Erlotinib in advanced NSCLC:  Comparison of its Progression-Free Survival (PFS) with the NSCLC marketed drug, Erlotinib.

In September of 2012, a study was published by Ramalingam et al in the Journal of Clinical Oncology, which was a randomized open-label trial comparing dacomitinib with erlotinib in patients with advanced NSCLC. On the basis of the study it was concluded that dacomitinib demonstrated significantly improved progression-free survival (PFS*) as compared to erlotinib, with a certain degree of toxicity.

SOURCE:

Randomized Phase II Study of Dacomitinib Versus Erlotinib in Patients With Advanced Non-Small-Cell Lung Cancer

The results indicated indicated the following:

  • Median PFS was significantly greater with Dacomitinib than Erlotinib, at 2.86 versus 1.91.
  • Mean duration of response was 16.56 months for dacomitinib and 9.23 months for erlotinib.

Patients were divided into groups by tumor type and following results were obtained:

  • Median PFS was 3.71 months with dacomitinib and 1.91 with erlotinib in patients with KRAS wild-type tumors
  • Median PFS was 2.21 months and 1.68 months, in patients with KRAS wild-type/EGFR wild-type tumors.
  • PFS was significantly better in the molecular subgroups harboring a mutant EGFR genotype.

The study also highlighted the side effects which might be more of concern and probably limiting for Dacomitinib.

Although adverse side effects were uncommon in both the groups, certain side effects such as:

  • mouth sores,
  • nailbed infections, and
  • diarrhea

were more common and tended to be more severe with Dacomitinib as compared to Tarceva.

Therefore, for patients for whom side effects of Tarceva seem challenging might face more difficulty with Dacomitinib treatment. Nonetheless, the results of PFS were promising enough and provide a greater efficacy in several clinical and molecular subgroups targeting a larger population than Tarceva. Authors, thus, suggested a larger, randomized phase III trial with the same design.

Current status of Dacomitinib

Based on positive performance of Dacomitinib published in research studies, Pfizer has entered into a collaborative development agreement with the SFJ Pharmaceuticals Group to conduct a phase III clinical trial across multiple sites in Asia and Europe, to evaluate dacomitinib (PF-00299804) as a first line treatment in patients with locally advanced or metastatic non-small cell lung cancer (nsclc) with activating mutations in the epidermal growth factor receptor (EGFr). Under the terms of the agreement, SFJ will provide the funding and clinical development supervision to generate the clinical data necessary to support a registration dossier on Dacomitinib for marketing authorization by regulatory authorities for this indication. If approved for this indication, SFJ will be eligible to receive milestone and earn-out payments.

SOURCE:

New medicine Oncology Knowledge base

*PFS or Progression-free survival is defined as the length of time during and after the treatment of as disease, such as cancer, that a patient lives with the disease but it does not get worse. In a clinical trial, measuring the progression-free survival is one way to see how well a new treatment works.

REFERENCES

Recently, another drug PF-02341066 (crizotinib), was tested on patients with non-small cell lung cancer and the results were published in New England Journal of Medicine (2013). Crizotinib is an orally available aminopyridine-based inhibitor of the) and the c-Met/hepatocyte growth factor receptor (HGFR). Crizotinib, in an ATP-competitive manner, binds to and inhibits ALK kinase and ALK fusion proteins. In addition, crizotinib inhibits c-Met kinase, and disrupts the c-Met signaling pathway. Altogether, this agent inhibits tumor cell growth.

  • Shaw and colleagues (2013) investigated whether crizotinib is superior to standard chemotherapy with respect to efficacy. To answer the question, Pfizer launched a phase III clinical trial (NCT00932893; http://clinicaltrials.gov/show/NCT00932893) comparing the safety and anti-tumor activity of PF-02341066 (crizotinib) versus pemetrexed or docetaxel in patients with advanced non-small cell lung cancer harboring a translocation or inversion event involving the ALK gene. Shaw and colleagues (2013) published the results of the clinical trial in a recent issue of New England Journal of Medicine.  A total of 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen were recruited for the trial and patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. According to the results, the median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group. Hazard ratio (HR) for progression or death with crizotinib was 0.49 (95% CI, P<0.001). The response rates were 65% with crizotinib, as compared with 20% with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.In conclusion, the results from the trial indicate that crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Shaw AT, et al, Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. N Engl J Med 2013; 20 June, 368:2385-2394; http://www.ncbi.nlm.nih.gov/pubmed/23724913).

However, in the same issue of New England Journal of Medicine, Awad and colleagues (2013) reported from a phase I clinical trial (NCT00585195; http://clinicaltrials.gov/show/NCT00585195), that a patient with metastatic lung adenocarcioma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment, showed resistance to crizotinib. Biopsy of the resistant tumor identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. The study was funded by Pfizer (Awad MM, et al, Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med. 2013 Jun 20;368(25):2395-401; http://www.ncbi.nlm.nih.gov/pubmed/23724914)

Reference: 

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Pancreatic stellate cell activation in chronic...

Pancreatic stellate cell activation in chronic pancreatitis and pancreatic cancer. Pancreatic stellate cells are activated by profibrogenic mediators, such as ethanol metabolites and cytokines/growth factors. Perpetuation of stellate cell activation under persisting pathological conditions results in pancreatic fibrosis. Jaster Molecular Cancer 2004 3:26 doi:10.1186/1476-4598-3-2 (Photo credit: Wikipedia)

Larry H. Bernstein, MD,  Reporter

Cancer-Causing Gene Alone Doesn’t Trigger Pancreatic Cancer, Mayo-led Study Finds
More than a cancer-causing gene is needed to trigger pancreatic cancer, a study led by Mayo Clinic, Jacksonville, Fla, has found.

A second factor creates a “perfect storm” that allows tumors to form, the researchers say. The study, published in a recent issue of Cancer Cell, overturns the current belief that a mutation in the KRAS oncogene is enough to initiate pancreatic cancer and unrestrained cell growth.

The findings uncover critical clues on how pancreatic cancer develops and why few patients benefit from current therapies. The findings also provide ideas about how to improve treatment and prevention of pancreatic cancer.

The research team, led by Howard C. Crawford, PhD, a cancer biologist at Mayo Clinic’s campus in Florida, and Jens Siveke, MD, at Technical University in Munich, Germany, found that for pancreatic cancer to form, mutated KRAS must recruit a second player: the epidermal growth factor receptor, or EGFR.A third genetic participant known as Trp53 makes pancreatic tumors very difficult to treat, the study showed.

The scientists also found that EGFR was required in pancreatic cancer initiated by pancreatic inflammation known as pancreatitis.

Imatinib May Help Treat Aggressive Lymphoma

Based on the results of a new study, researchers are developing a clinical trial to test imatinib (Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

The authors decided to investigate the effect of imatinib after finding a link between PDGFRB and a genetic abnormality that is found in many patients with ALCL. Previous work had shown that this genetic change—a translocation that leads to the production of an abnormal fusion protein called NPM-ALK—stimulates the production of two proteins, transcription factors called JUN and JUNB.

In the new study, experiments in mice revealed that these proteins promote lymphoma development by increasing the levels of PDGFRB.

Because imatinib inhibits PDGFRB, the authors tested the effect of the drug in mice with the NPM-ALK change and found that it improved their survival. They also found that imatinib given together with the ALK inhibitor crizotinib (Xalkori) greatly reduced the growth of NPM-ALK-positive lymphoma cells in mice.

To test the treatment strategy in people, they identified a terminally ill patient with NPM-ALK-positive ALCL who had no other treatment options and agreed to try imatinib. The patient began to improve within 10 days of starting the therapy and has been free of the disease for 22 months, the authors reported.

The observation that inhibiting both ALK and PDGFRB “reduces lymphoma growth and alleviates relapse rates” led the authors to suggest that the findings might be relevant to lymphomas with PDGFRB but without the NPM-ALK protein. “Our findings suggest that imatinib is a potential therapeutic option for patients with crizotinib-resistant lymphomas.”

A planned clinical trial will be based on the expression of PDGFRB in tumors.

Researchers Identify Possible Biomarker for Early-Stage Lung Cancer

A protein that can be detected in blood samples may one day serve as a biomarker for early-stage lung cancer, according to new study results. The findings, published October 16 in the Proceedings of the National Academy of Sciences, suggest that measuring the levels of a variant form of the protein Ciz1 may help detect lung cancer early and noninvasively in high-risk individuals.

“We have struggled to find cancer biomarkers that are disease-specific, and this may be a step in the right direction,” said Dr. Sudhir Srivastava, chief of NCI’s Cancer Biomarkers Research Group. He called the study “promising” but noted that the results will need further validation.

Researchers led by Dr. Dawn Coverley of the University of York in the United Kingdom found that the “b-variant” form of Ciz1 was present in 34 of 35 lung tumors but not in adjacent tissue. Additional experiments showed that an antibody specific for this Ciz1 variant could detect the protein in small samples of blood from individuals with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

In two independent sets of blood samples—from 170 and 160 patients, respectively—the researchers showed that variant Ciz1 levels above a certain threshold correctly identified 95 to 98 percent of lung cancer patients, with an overall specificity of 71 to 75 percent. Using the second set of samples, they showed that the level of variant Ciz1 could discriminate between patients with stage I NSCLC and age-matched heavy smokers without diagnosed cancer, individuals with benign lung nodules, and patients with inflammatory lung disease.

Although the high rate of false-positive test results seen with variant Ciz1 is a concern, the authors noted that a blood test for the Ciz1 variant might ultimately be shown to be useful when combined with low-dose helical computed tomography, also called spiral CT, for lung cancer screening. In that context, the test could confirm the presence of lung cancer in patients who have suspicious spiral CT results, reducing the need for invasive procedures to confirm a lung cancer diagnosis. And, if used before spiral CT, “the test could reduce the number of people who undergo imaging…[because] the false-negative rate is very low,” Dr. Coverley wrote in an e-mail message.

To assess variant Ciz1 levels, the researchers used a laboratory method known as Western blot analysis. However, this approach could not be routinely applied in a clinical context, the researchers acknowledged, so “a more streamlined method” for testing would need to be developed.

Supported in part by NCI Early Detection Research Network Grant U01CA086137.

NCI Reports

Study Looks at Terminal Cancer Patients’ Expectations of Chemotherapy

A majority of patients who opt to receive chemotherapy to treat newly diagnosed metastatic lung or colorectal cancer believe chemotherapy might cure their cancer, according to a recent survey. The survey results suggest that optimistic assumptions about the benefits of chemotherapy may hamper patients’ abilities to make informed treatment decisions that align with their preferences, said the researchers who led the study. The findings were published October 25 in the New England Journal of Medicine.

Dr. Jane Weeks of the Dana-Farber Cancer Institute and her colleagues interviewed 1,193 patients tracked by the prospective, observational Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study, 4 to 7 months after diagnosis. All of the patients had been diagnosed with stage IV lung or colorectal cancer and had chosen to receive chemotherapy. A surrogate was interviewed when a patient was too ill to participate. The survey asked patients how likely it was that chemotherapy would cure their disease, extend life, or relieve symptoms. The researchers also collected data on patients’ physical functioning, communication with their physicians, and social and demographic factors.

The majority of patients did not appear to understand that chemotherapy was very unlikely to cure their cancer (81 percent of those with colorectal cancer and 69 percent of those with lung cancer). Black, Hispanic, and Asian/Pacific Islander patients were more likely than white patients to believe that chemotherapy would cure them. Nevertheless, most patients believed that chemotherapy was more likely to extend their life than cure them.

Educational level, functional status, and the patient’s role in treatment decision making were not associated with inaccurate expectations about chemotherapy.

In an accompanying editorial, Drs. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Cancer Center and Dan L. Longo of the National Institute on Aging wrote, “if patients actually have unrealistic expectations of a cure from a therapy that is administered with palliative intent, we have a serious problem of miscommunication that we need to address.”

This research was supported by grants from the National Institutes of Health (U01 CA093344, U01 CA093332, U01CA093324, U01 CA093348, U01 CA093329, U01 CA093339, and U01 CA093326).

 

Researchers Identify Possible Biomarker for Early-Stage Lung Cancer

A protein that can be detected in blood samples may one day serve as a biomarker for early-stage lung cancer, according to new study results. The findings, published October 16 in the Proceedings of the National Academy of Sciences, suggest that measuring the levels of a variant form of the protein Ciz1 may help detect lung cancer early and noninvasively in high-risk individuals.

“We have struggled to find cancer biomarkers that are disease-specific, and this may be a step in the right direction,” said Dr. Sudhir Srivastava, chief of NCI’s Cancer Biomarkers Research Group. He called the study “promising” but noted that the results will need further validation.

Researchers led by Dr. Dawn Coverley of the University of York in the United Kingdom found that the “b-variant” form of Ciz1 was present in 34 of 35 lung tumors but not in adjacent tissue. Additional experiments showed that an antibody specific for this Ciz1 variant could detect the protein in small samples of blood from individuals with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

In two independent sets of blood samples—from 170 and 160 patients, respectively—the researchers showed that variant Ciz1 levels above a certain threshold correctly identified 95 to 98 percent of lung cancer patients, with an overall specificity of 71 to 75 percent. Using the second set of samples, they showed that the level of variant Ciz1 could discriminate between patients with stage I NSCLC and age-matched heavy smokers without diagnosed cancer, individuals with benign lung nodules, and patients with inflammatory lung disease.

Although the high rate of false-positive test results seen with variant Ciz1 is a concern, the authors noted that a blood test for the Ciz1 variant might ultimately be shown to be useful when combined with low-dose helical computed tomography, also called spiral CT, for lung cancer screening. In that context, the test could confirm the presence of lung cancer in patients who have suspicious spiral CT results, reducing the need for invasive procedures to confirm a lung cancer diagnosis. And, if used before spiral CT, “the test could reduce the number of people who undergo imaging…[because] the false-negative rate is very low,” Dr. Coverley wrote in an e-mail message.

To assess variant Ciz1 levels, the researchers used a laboratory method known as Western blot analysis. However, this approach could not be routinely applied in a clinical context, the researchers acknowledged, so “a more streamlined method” for testing would need to be developed.

Supported in part by NCI Early Detection Research Network Grant U01CA086137.

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mRNA Interference with Cancer Expression

 

Reporter: Larry H Bernstein, MD, FCAP

 

Genetic switch shuts down lung cancer tumors

Genetic switch shuts down lung cancer tumors in mice October 25, 2012 in Cancer Yale researchers manipulated a tiny genetic switch and halted growth of aggressive lung cancer tumors in mice and even prevented tumors from forming. Ads by Google Stage 4 Cancer Treatments – Chat w/a Cancer Info Expert About Stage 4 Cancer Treatment Options. – http://www.CancerCenter.com The activation of a single microRNA managed to neutralize the effects of two of the most notorious genes in cancer’s arsenal, suggesting it may have a role treating several forms of cancer, the researchers report in the Nov. 1 issue of the journal Cancer Research. “This is pretty much the best pre-clinical data that show microRNAs can be effective in lung cancer treatment,” said Frank Slack, professor of molecular, cellular & developmental biology, researcher for the Yale Cancer Center, and senior author of the paper. “These cancer genes are identical to ones found in many forms of human cancers and we are hopeful the microRNA will be of therapeutic benefit in human cancer.” Unlike drugs that act upon existing proteins, microRNAs are small pieces of genetic material that can shut down and turn off genes that produce the proteins. Slack and co-author Andrea Kasinski wanted to see if one of these microRNAs, miR-34, could block the actions of K-Ras and p53 genes, which promote proliferation and survival of cancer cells, respectively. Mice with these two mutant genes invariably develop tumors but were cancer-free when researchers activated miR-34. Also, tumor growth was halted in mice that were treated with miR-34 after they had developed cancer. Journal reference: Cancer Research Provided by Yale University

Read more at: http://medicalxpress.com/news/2012-10-genetic-lung-cancer-tumors-mice.html#jCp

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