Posts Tagged ‘HER2’

Rapid regression of HER2 breast cancer

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

Rapid regression of HER2 breast cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Anti-HER2 Combo Shrunk Breast Tumors in Under 2 Weeks

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

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

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

EBCC-10 Searchable Programme – 

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

Are we personalising or just subtyping early breast cancer?

Speaker: G. Curigliano (Italy)

Key Objectives

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

Pros and cons on chemoprophylaxis of pre-invasive lesions

Speaker: T. Pienkowski (Poland)

Key Objectives

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

Translating genetic drivers into new targeted therapies for breast cancer

Speaker: D. Tripathy (USA)

Key Objectives

Translating Genetic Drivers into New Targeted Therapies for Breast Cancer

Key Objectives

Objective 1: To review critical genomic drivers of breast carcinogenesis

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

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

 

The role of tumour typing and grading

Speaker: M.P. Foschini (Italy)

Key Objectives

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

 

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

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

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

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

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

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

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

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

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

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

 

Breast Cancer Drug Combination Could Shrink Tumors in Days

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

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

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

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

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

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

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

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

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

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

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

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

 

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

 

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

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

The research may lead to fewer women needing chemotherapy.

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

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

Drug combination shrinks HER2-positive breast cancers within 11 days

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

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

The research may lead to fewer women needing chemotherapy.

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

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

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

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

‘Very promising’

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

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

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

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

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

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

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

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

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

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

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

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

 

Breast Cancer Vaccines and Checkpoint-Inhibitor Immunotherapy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

Prognostic DCIS Score: ‘Ready for Prime Time’

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

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

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

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

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

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

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

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

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

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

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

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

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

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Role of Progesterone in Breast Cancer Progression

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged breast cancer, ER/PR, HER2, Progesterone, RANKL, selective progesterone receptor modulators (SPRMs) on June 25, 2013| 3 Comments »

Role of Progesterone in Breast Cancer Progression

Author: Tilda Barliya PhD

Breast Cancer has been long discussed herein focusing on different aspects of the diseases: from diagnosis and all the way up to treatment modalities (I). The literature has put a lot of emphasis on the role of Estrogen receptor in the development of breast cancer, yet not much focus was placed on the counterpart partner–Progesterone Receptor.

Progesterone:

Progesterone is secreted by the empty egg follicle after ovulation has occurred. It is highest during the last phases of the menstrual cycle, after ovulation. Progesterone causes the endometrium to secrete special proteins to prepare it for the implantation of a fertilized egg (2). If conception has occurred, progesterone becomes the major hormone supporting pregnancy, with many important functions:

• Responsible for the growth and maintenance of the endometrium
• Suppresses further maturation of eggs by preventing release of LH and FSH (Follicle Stimulating Hormone).
• By relaxing the major muscle of the uterus, progesterone prevents early contractions and birth.
• It thicken the muscle, helping the body prepare for the hard work of labor.
• Suppresses prolactin (the primary hormone of milk production), preventing lactation until birth

A recent review by Prof. Cathrin Brisken from ISREC- Swiss Institute for Experimental Cancer Research, summarizes and highlights the important role of progesterone in breast cancer progression (1). So where do we stand?

“The ovarian steroid hormones, 17β‑oestradiol and progesterone, are pivotal in the control of breast development and physiology, and both experimental and  epidemiological studies indicate that the two hormones are intimately linked to mammary carcinogenesis”.

“Ever since the 1960s,  pharmacological antagonists of both estrogen and progesterone were developed. PR antagonists failed in the clinic because of severe side effects, such as liver toxicity. By contrast, drugs that interfere with estrogen signalling, such as tamoxifen and aromatase inhibitors have become mainstays of breast cancer therapy; they substantially prolong survival and have saved many lives”.

Agonists for both receptors have been developed and are used for both contraception and hormone replacement therapy (HRT), but there are growing concerns that they may increase breast cancer risk. Women receiving HRT have little or no increase in breast cancer risk when taking estrogens only, in fact there may even be a protective effect (1,3).

“By contrast, a substantial increase in breast cancer risk was noticed in women taking combinations of an estrogen and various synthetic progesterone agonists (progestins). This could be related to the increase in cell proliferation in the breast epithelium that has been reported with combination therapy”. These results however differ between women who took natural progesterone and those who received the synthetic form- progestin, which may be due to the fact that progestin may bound other nuclear receptors (i.e androgen and glucocorticoid receptors). Other factors aside from progesterone may advances this higher risk for HRT-related breast cancer and include for example breast density (fatty pad density).

Cellular Mechanism:

“Across species, ERα and PR are absent from the myoepithelial cells and basal cells and are expressed by 30–50% of the luminal cells. Most cells co-express ERα and PR, which is consistent with PR being an ERα target. A small subset of cells expresses either only ERα or only PR”.  It was found that cells that are either or both hormone receptor(s) positive may affect neighboring cells in a paracrine fashion by secreting signalling and proliferating factors . Some of the attractive target genes of this hormones include but excluded to WNT, fibroblast growth factors (FGF), epidermal growth factor (EGF) as well as direct intercellular signalling mediated by Notch, ephrins or gap junctions.

“Hormone Receptor (HR)+ cells seem to act as ‘sensor’ cells that translate the signals encoded by systemic hormones into local paracrine signals. To relay these signals they secrete paracrine factors that bind to receptors on HR–, luminal and basal cells, which act as the ‘secondary responder cells”.

This organizing principle ensures that the signal is amplified and prolonged in time and provides a means of coordinating different biological functions of distinct cell types.

Several experiments in MCF-7 cells showed that if a cell had recently been stimulated by estrogens it would be hormone receptor (HR)–. More so, later experiments showed that the HR expression, rather positive or negative, is a hallmark of a distinct cell type in the mammary epithelium.

There are many alternations in global gene expressions and protein factors during each menstrual cycle and more over in the life time of a woman. The entire sum of changes in the different cell population determine the proliferation and development of breast cancer.

There are two types of proliferation, cell-intrinsic and paracrine proliferation. For example, it was found in mice model, that the cell-intrinsic action of progesterone on HR+ cell proliferation requires cyclin D1. Whereas the proliferation of HR– cells does not (1).

Proliferation of HR– cells on progesterone stimulation requires RANKL, which is a tumour necrosis factor‑α (TNFα) family member. It was further noted that that RANKL is a crucial mediator of PR signalling function.

It is believed that recurrent activation of PR during repeated menstrual cycles and its downstream effectors, cyclin D1, WNT4 and RANKL promotes breast carcinogenesis (Fig.1). It was found for instance, that use of PR agonists or ectopic expression of RANKL induce mammary tumors in mice models.

Therefore, of clinical relevance  for example, soluble RANKL administered intravenously can elicit proliferation in the mammary epithelium, and systemic administration of its decoy receptor osteoprotegerin (OPG) can inhibit proliferation (1). There are obviously other genes associated with these phenotypes and the RANKL was given as an example.

Cathrin Brisken 2011

Novel preventive strategies are envisioned to PR itself and its downstream mediators. The new generation of selective progesterone receptor modulators (SPRMs)  used for gynaecological disorders, have fewer side effects than earlier ones, and are thought to be introduced as potential breast cancer therapy.

Reproductive hormones impinge on breast carcinogenesis at all stages and can determine whether the disease will progress (Fig 1). In particular, PR signalling has a pivotal role in controlling tumour promotion from the in situ stage onwards.

Clinical Aspect

Breast Cancers are generally divided into molecular subtypes which include:

• Basal-like: ER-, PR- and HER2-; also called triple negative breast cancer (TNBC). Most BRCA1 breast cancers are basal-like TNBC.
• Luminal A: ER+ and low grade
• Luminal B: ER+ but often high grade
• Luminal ER-/AR+: (overlapping with apocrine and so called molecular apocrine) – recently identified androgen responsive subtype which may respond to antihormonal treatment with bicalutamide.  
  
• ERBB2/HER2+: has amplified HER2/neu.
  
• Normal breast-like
  
• Claudin-low: a more recently described class; often triple-negative, but distinct in that there is low expression of cell-cell junction protein including E-cadherin and frequently there is infiltration with lymphocytes.

NCCN 2007

Onitilo et al suggested this subgroups in their 7-year retrospective study(6):

• ER/PR+, Her2+ = ER+/PR+, Her2+; ER−/PR+, Her2+; ER+/PR−, Her2+

• ER/PR+, Her2− = ER+/PR+, Her2−; ER−/PR+, Her2−; ER+/PR−, Her2−

• ER/PR−, Her2+ = ER−/PR−, Her2+

• ER/PR−, Her2− = ER−/PR−, Her2−

The independent prognostic and predictive role of PR expression irrespective of ER has been a subject of great controversy.

In their study, Onitilo & colleagues have evaluated numerous patients for different factors such as five-year overall and disease-free survival, recurrent site and age, depending on their subgroups (6).

Their study supports other studies which have shown both the triple negative and Her2+/ER− subtypes to have poorer clinical, pathologic and molecular prognoses. The triple negative group has the worst overall and disease-free survival. More so the prognosis according to ER/PR status was found to be:

ER-positive/PR-positive tumors >> ER-positive/PR-negative tumors >>> ER-negative/PR-negative tumors.

But what happens with the ER-negative/PR positive group? How many patients fall into this category and how important that is? Could it be an artifact?

Maleki et al believes that in their study tumor that were initially reported as ER-negative/PR-positive are actually grade I (low grade) ER positive tumors such as infiltrating lobular carcinoma and colloidal carcinoma (7).

Summary:

Reproductive hormones impinge on breast carcinogenesis at all stages and can determine whether the disease will progress. In particular, PR signalling has a pivotal role in controlling tumour promotion from the in situ stage onwards. It will therefore be a good opportunity to design new treatment strategies that include selective progesterone receptor inhibitors. Interfering with the breast-specific effects of increased serum progesterone levels may be an effective way to reduce their risk of dying of breast cancer without blocking all reproductive function.More so, the majority of the physicians and researchers would agree that more studies are necessary to refine IHC classification for better classification and clinical use.

Reference:

1. Cathrin Brisken. Progesterone signalling in breast  cancer: a neglected hormone coming  into the limelight. Nature Reviews Cancer June 2013, (13): 385-396. http://www.nature.com/nrc/journal/v13/n6/full/nrc3518.html

2. Nicole Galan RN. What is Progesterone? http://pcos.about.com/od/normalmenstrualcycle/f/Progesterone.htm

3. Anderson, G. L. et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomised placebo-controlled trial. Lancet Oncol 2012. 13, 476–486.

4. MJ, Möller MF, DG, Niggemann B, Zänker KS and Entschladen F. Luminal and basal-like breast cancer cells show increased migration induced by hypoxia, mediated by an autocrine mechanism. BMC Cancer 2011, 11:158. http://www.biomedcentral.com/1471-2407/11/158

5. MCU Cheang, J Parker, K DeSchryver, J Snider, T Walsh, S Davies, A Prat, T Vickery, J Reed, B Zehnbauer, S Leung, D Voduc, T Nielsen, E Mardis, P Bernard, C Perou, and M Ellis. Luminal A vs. Basal-like Breast Cancer: time dependent changes in the risk of relapse in the absence of treatment. Cancer Research: December 15, 2012; Volume 72, Issue 24, Supplement 3. http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/72/24_MeetingAbstracts/P6-07-10

6. Onitilo AA., Engel JM., Greenlee RT and Mukesh BN. Breast Cancer Subtypes Based on ER/PR and Her2 Expression: Comparison of Clinicopathologic Features and Survival. Clinical Medicine & Research  2009 June 1 7 (1-2); 4-13. http://www.clinmedres.org/content/7/1-2/4.long

7. Maleki Z., Shariat S., Mokri M and Atri M.  ER-negative /PR-positive Breast Carcinomas or Technical Artifacts in Immunohistochemistry? Arch Iran  Med. 2012; 15(6): 366 – 369. http://www.ams.ac.ir/AIM/NEWPUB/12/15/6/0010.pdf

Other articles from our Open Access Jounal:

I By: Larry Bernstein MD. “recurrence risk for breast cancer”. http://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/

II. By: Ritu Saxena PhD. “In focus: Triple Negative Breast Cancer”. http://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

III. By: Tilda Barliya PhD. The Molecular pathology of Breast Cancer Progression. http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/

IV. By: Sudipta Saha PhD. The FEMALE reproductive system and the hypothalamic-pituitary-thyroid axis. http://pharmaceuticalintelligence.com/2012/12/11/the-female-reproductive-system-and-the-hypothalamic-pituitary-thyroid-axis/

V. By: Tilda Barliya PhD. Nanotech Therapy for Breast Cancer. http://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/

 

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Treatment for Metastatic HER2 Breast Cancer

Posted in Advanced Drug Manufacturing Technology, Biomarkers & Medical Diagnostics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, FDA Regulatory Affairs, Genome Biology, Health Economics and Outcomes Research, Health Law & Patient Safety, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged antibody-drug conjugate, breast cancer, cytotoxicity, disease-free survival, DM1, Food and Drug Administration, Genentech, GlaxoSmithKline, HER2, ImmunoGen, Indianapolis, mertansine, metastatic, response rate, T-DM1, taxane, Trastuzumab, Trastuzumab emtansine on March 3, 2013| 10 Comments »

Treatment for Metastatic HER2 Breast Cancer

Word Cloud By Danielle Smolyar

Reporter: Larry H Bernstein, MD, FCAP
Leaders in Pharmaceutical Innovation
http://pharmaceuticalintelligence.com/2013/03/03/9680/Treatment for Metastatic HER2 Breast Cancer 

FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)

T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

Feb 22, 2013      http://www.medscape.com/viewarticle/779751

http://www.medscape.com/Oncology Medscape/FDA Approves New Treatment for Metastatic HER2 Breast Cancer (antibody-drug conjugate)

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.
T-DM1 is indicated for patients who were previously treated with

• the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the

• HER2-targeted antibody trastuzumab
• is chemically linked to the cytotoxin mertansine (DM1).

The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.  According to Richard Pazdur, MD, at the FDA Center for Drug Evaluation and Research, T-DM1 carries the drug-conjugate

• directly to the cancer site
• to shrink the tumor,
• slow disease progression, and
• prolong survival .

It is the fourth drug approved that targets the HER2 protein. Apart from lapatinib, which is marketed by GlaxoSmithKline, all the other HER2-targeted products have been developed and are marketed by Genentech/Roche. For T-DM1, the proprietary technology involved in the DM1 portion of the product was developed by ImmunoGen, working in collaboration with Genentech/Roche.

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of

• lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months).

There were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy

• 43.1% vs. 59.2%)

The approval represents a “momentous” day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

• HER2-positive patients with metastatic disease have a therapy that offers prolonged disease control with less toxicity

 T-DM1 was more effective in EMILIA than standard therapy on every outcome:

• overall response rate,
• disease-free survival,
• progression-free survival, and
• overall survival.

Herceptin Fab (antibody) – light and heavy chains (Photo credit: Wikipedia)

Ribbon diagram of the Fab fragment of , a , bound to the extracellular domain of HER2. Created using Accelrys DS Visualizer Pro 1.6 and . ; Legend Trastuzumab Fab fragment, Trastuzumab Fab fragment, HER2, extracellular domain (Photo credit: Wikipedia)

Breast cancer (Infiltrating ductal carcinoma of the breast) assayed with anti HER-2 (ErbB2) antibody. (Photo credit: Wikipedia)

English: Breast cancer incidence by age in women in the United Kingdom 2006-2008. Reference: Excel chart for Figure 1.1: Breast Cancer (C50), Average Number of New Cases per Year and Age-Specific Incidence Rates, UK, 2006-2008 at Breast cancer – UK incidence statistics at Cancer Research UK. Section updated 18/07/11. (Photo credit: Wikipedia)

Related articles

• Bel Marra Health Reports on a New Study: Software Originally Used for Star Gazing Now Being Used to Analyze Breast Cancer Tissue (prweb.com)
• Breast Cancer Stem Cells Express HER2, Even In ‘Negative’ Tumors, Study Finds (medicalnewstoday.com)
• http://pharmaceuticalintelligence.com/2013/03/02/recurrence-risk-for-breast-cancer/
• http://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

• http://pharmaceuticalintelligence.com/2013/01/17/mechanism-involved-in-breast-cancer-cell-growth-function-in-early-detection-treatment/

• http://pharmaceuticalintelligence.com/2013/01/10/the-molecular-pathology-of-breast-cancer-progression/
• http://pharmaceuticalintelligence.com/2012/12/24/breast-cancer-genomic-profiling-to-predict-survival-combination-of-histopathology-and-gene-expression-analysis/
• http://pharmaceuticalintelligence.com/2012/12/09/naotech-therapy-for-breast-cancer/
• http://pharmaceuticalintelligence.com/2012/09/18/breast-cancer-drug-resistance-and-biopharmaceutical-targets/
• http://venturebeat.com/2013/01/27/the-personalized-medicine-revolution-is-almost-here/

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