New Research Findings

Noncarriers in BRCA1/BRCA2 families do not have increased risk of breast cancer
by Tracy M. Diaz

Women from high-risk families live with awareness
of their heightened risk. Even for women who test
negative in a family with a known BRCA mutation, it is sometimes difficult to let go of the fear of cancer. In 2007, a British research study written by Smith et. al. suggested that female family members of BRCA1/BRCA2 mutation carriers who tested negative for the gene mutation still carried a 5-fold increased risk of developing breast cancer. Many well-regarded genetics experts disputed this finding. FORCE published an article on this study in a previous FORCE newsletter. A recent study by Dr. Allison Kurian, of Stanford University, pulished in the Journal of Clinical Oncology, refutes the Smith study and shows that noncarriers in BRCA families do not have an increased risk of breast cancer.

Researchers looked at 3047 families enrolled in the Breast Cancer Family Registry (BCFR) sites in Australia, Canada, and Northern California that have tested for BRCA mutations. Of those tested, 160 were found to have BRCA1 mutations and 132 had BRCA2 mutations. In order to calculate breast cancer risk for noncarriers, the no mutation carrying first degree relatives (FDRs) of BRCA positive breast cancer patients were compared to the FDRs of breast cancer patients without BRCA mutations. In this comparison the relative risk for breast cancer was not significantly increased in non-mutation carriers from BRCA families compared with those from families who did not have BRCA. The comparison of 292 BRCA mutation carrying families to 2755 families without BRCA mutations in this study is the largest analysis of breast cancer risk for non-mutation-carriers from BRCA families. 

In an accompanying editorial to Dr. Kurian’s article, Dr. Mark E. Robson, Director of Clinical Genetics at Memorial Sloan-Kettering discusses the limitations of prior studies as well as how the Kurian study is different. Dr. Kurian’s approach is considered more representative of the cancer risk in this population than Smith’s study. The conclusion drawn from this and prior studies is that women who are mutation negative are not at a high enough increased risk to justify specialized surveillance or preventive strategies. While Dr. Robson cautions that this study, along with previous studies, does not exclude the possibility that mutation negative women are at a slightly higher cancer risk than women in the general population, it does show that the magnitude of the increased risk is not sufficient for noncarriers to be advised like their mutation carrying family members.

References:

Kurian AW, Gong GD, John EM, Wittemore AS, et al. Breast cancer risk for noncarriers of family-specific BRCA1 and BRCA2 mutations: Findings from the Breast Cancer Family Registry. Journal of Clinical Oncology, vol. 29(33), November, 2011.

Robson, M. Do Women Remain at Risk Even If They Do Not Inherit a Familial BRCA1/2 Mutation? Journal of Clinical Oncology; vol. 29(33), November, 2011.

Smith, A, Moran, A, Boyd, MC, et. al. Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet. 2007; vol. 44(1), January, 2007.

Research Result: Women with HBOC are diagnosed with cancer earlier than their mothers and grandmothers
by Lisa Rezende, PhD

One of the challenging questions facing women who carry mutations in BRCA1 or BRCA2 genes is the age when risk-management for hereditary cancer should begin. Cancer risk assessment is an evolving area of medicine and great strides have been made, but there is still no way to predict the exact risk for cancer and at what age it is most likely to develop. This has a profound impact on young, high-risk women.  Expert guidelines for high-risk women recommend breast screening with MRI and mammograms beginning at age 25 or 10 years earlier than the youngest onset of cancer in a family. But other factors beyond family cancer history and having a BRCA mutation impact the age of breast cancer diagnosis and the optimal time to begin breast screening is not well established. Prior research suggested that high-risk women from earlier generations had a later onset of breast cancer than women from more recent generations. New research seems to confirm this trend.

In a study of 106 families with hereditary breast and ovarian cancer (HBOC), the average age at cancer diagnosis was 7.9 years younger in the current generation when compared to the previous generation¹.  This finding of the younger generation being diagnosed with cancer at younger ages than the older generation held true when researchers classified the families by mutation type (BRCA1 vs BRCA2), type of cancer (family history of breast cancer only vs. family history of breast and ovarian cancers), or who the mutant gene was inherited from (mother’s side of the family vs. father’s side of the family).  

While the trend towards earlier age of diagnosis for later generations is statistically significant, more research is needed before the exact number of years earlier is confirmed.  The researchers acknowledge that in many cases the BRCA1 or BRCA2 mutational status of the older generation must be inferred from the mutational status of the daughter or granddaughter because genetic testing was not available when this older generation was diagnosed.   Furthermore, obtaining accurate medical histories, including age at diagnosis, is not always possible.  Finally, detection methods are much more powerful today, and women with known mutations in BRCA1 and BRCA2 are screened more frequently that previous generation, allowing for earlier (hence younger) diagnosis.  Given these factors, the actual difference in age of cancer developing might be less than 7.9 years.

Current guidelines recommend that women from families with HBOC begin regular screening for breast cancer at age 25 or 5-10 years earlier than the earliest age of diagnosis in their family. The researchers recommend that further research be done before changing guidelines as to when young women with BRCA1 or BRCA2 mutations should beginning regular screening for breast cancer.

¹Litton, J.K. et al, “Earlier age of onset of BRCA mutation-related cancers in subsequent generations,” Cancer, epublished ahead of print, September 12, 2011.

News from ASCO
by Lisa Schlager

Each year nearly 30,000 oncologists and oncology-related healthcare professionals come together at the annual meeting of the American Society of Clinical Oncology (ASCO). ASCO 2011 featured nearly 4,500 abstracts (research summaries) and sessions covering every aspect of cancer, including highly anticipated research news and drug studies that could change current standards of care for patients. Attendees include a few hundred patient advocates who represent their constituents in the cancer community. I was fortunate to take part in the Focus on Research program of the Research Advocacy Network’s Advocate Institute.

Hereditary Cancer

A study specifically related to BRCA (Abstract 1512) suggested that women with DCIS and a family history of breast and/or ovarian cancer have an increased chance of having BRCA mutations regardless of age, and should consider genetic counseling and testing even though they do not have invasive cancer. Another study (Abstract 1517) showed that BRCA-positive men are more likely to have aggressive prostate cancer with lymph node involvement and metastases. These study results underscore the importance of knowing BRCA status when determining treatment.

Hormone replacement therapy (HRT) by women who have undergone a prophylactic oophorectomy is of great interest to the HBOC community. Promising news from the Prevention and Observation of Surgical Endpoints (PROSE) study indicated no increased risk of breast cancer risk when HRT is used after risk-reducing salpingo-oophorectomy (Abstract 1501). Another study (Abstract 1510) suggested that women with paternally-inherited BRCA gene mutations (mutation passed from the father) are diagnosed with cancers at earlier ages compared to women who inherit gene mutations from their mothers.

Ovarian Cancer

Researchers presented promising findings from the OCEANS (Abstract LBA5007) and ICON7 (Abstract LBA5006) trials, two studies that examined use of the drug bevacizumab (Avastin) to treat ovarian cancer. While overall survival benefits were not indicated, patients in these studies did experience improved “progression-free survival.” The concept of progression-free survival (PFS) compared to overall survival (OS) were common themes throughout the conference. PFS refers to the chance of stabilizing a disease without further progression after a particular treatment. OS measures the specific length of survival after treatment. Scientists use these terms to measure the success or efficacy of new cancer therapies. There is great debate about whether or not a drug should be approved if it doesn’t demonstrate OS benefits. For patients facing advanced disease, PFS may seem like an acceptable endpoint.

Quality-of-Life

A number of ASCO meeting sessions focused on quality-of-life issues. One abstract described the development of a standard method for including patient-reported outcomes in oncology drug clinical trials that compare drug effectiveness. Additional studies focused on developing tools to foster enhanced physicianpatient interaction. Researchers reported that early palliative care (care or treatment that concentrates on reducing the severity of symptoms) results in increased overall survival and reduced depression. A session on “Assessing Patients’ Psychosocial Needs” highlighted an area needing improvement by many medical professionals; at least a quarter of cancer patients are thought to experience significant depression or anxiety.

A Weighty Issue

Numerous studies have looked at the issue of lifestyle, weight or Body Mass Index (BMI) in relation to cancer—especially breast, prostate and colorectal cancer. The “Overview of the Current Evidence Supporting Body Weight Status, Adiposity, and Weight Loss on Cancer Outcomes” session explained that obese and overweight people are more likely to develop and die from cancer and have an increase in risk of recurrence. Presenters made a provocative point: Overweight patients often receive the same level of chemotherapy as leaner individuals, and may in fact be underdosed, which leads to poorer treatment response rates. The good news is that most people can improve their treatment outcomes by modifying their lifestyle (Abstract 167); research indicates that individuals who lose weight experience a decreased risk of cancer recurrence.

Throughout the meeting, I was struck by the fact that genetics was a topic of numerous sessions and studies. Many researchers are focusing their efforts on identifying biomarkers and genetic changes in cancer tumors. This evolving area of science, in which genetics is linked to cancer biology, is very promising.

Improvements in gene sequencing and targeted therapies will ultimately help guide cancer treatment and move us toward more personalized medicine—the goal is for doctors to know exactly what treatments to give which patients—resulting in better outcomes. That is certainly something to strive for. Access the abstracts at the ASCO website (www.asco.org).

Updates on PARP Inhibitor Research

PARP inhibitors are a type of medication that holds promise for treating BRCA-related cancers. These drugs block an enzyme used by cells to repair damage to their DNA.  In women without BRCA mutations, PARP inhibitors may work by keeping cancer cells from repairing themselves once they’ve been damaged by chemotherapy, while sparing healthy cells.  Researchers believe that PARP inhibitors may be particularly effective against cancers in people with BRCA mutations, since their tumor cells have problems repairing DNA already, and the PARP inhibitors make that worse. The medications are still being tested in clinical trials, and are not yet FDA-approved for use outside the clinical research.

Early PARP inhibitor research in advanced hereditary cancers in people with BRCA mutations has been promising. In the first trials, the drugs effectively treated some people with BRCA mutations and advanced cancers; however, not all patients benefitted–the cancers of some research participants progressed while they were taking PARP inhibitors. More work is needed to determine who may best respond to this potential new treatment.

Early PARP inhibitor study results

In 2009 encouraging results of Phase II clinical trials involving PARP inhibitors were presented at the American Society of Clinical Oncology (ASCO) conference and published in peer-reviewed journals. One study involved women with metastatic breast cancer who were treated with chemotherapy, with or without iniparib (formerly called BSI 201). The women who received iniparib with chemotherapy showed impressive results—three times as many showed improvement compared to those who received chemotherapy alone. On average, women who received iniparib had no progression of their disease for about 3 ½ months longer than those on chemotherapy alone, lived about 3 ½ months longer, and suffered no greater side effects.

Another Phase II clinical trial investigated olaparib, the PARP inhibitor drug formerly known as AZD2281 in women with known BRCA1 or BRCA2 mutations and metastatic breast cancer. In this study the PARP inhibitor was given with no other treatment to women whose cancer had progressed after prior chemotherapy treatments. Participants received either a low dose (100 mg twice daily) or a high dose (400 mg twice daily). The higher dose resulted in a complete response (no measurable cancer during treatment) for one woman, and 10 partial responses (the cancer was at least 50% smaller or did not increase). Overall, the response rate for the group taking the higher dose was 41%, compared to 22% in the group who took the lower dose. Most side effects were not severe and were primarily fatigue and nausea. Researchers reported that the lung metastases of one woman in the study, who continues to take the medication, have not progressed in the 18 months since she began the olaparib.

A third study investigated olaparib for advanced ovarian cancer in BRCA mutation carriers. This Phase II clinical trial studied women with known BRCA 1 or BRCA 2 mutations and recurrent ovarian cancer. In this study the PARP inhibitor was given as a “single agent” (without other treatment) to women whose cancers had progressed after several previous courses of chemotherapy. As in the breast cancer study, women in this trial were given one of two doses: a low dose (100 mg twice daily) or a high dose (400 mg twice daily). Thirty-three of the women were evaluable at 400 mg bd and 24 at 100 mg bd. The overall response rate was 33% at the higher dose and 12.5% at the lower dose. Of the women on the high dose, 58% experienced clinical benefit compared to 17% of the women on the lower dose who experienced clinical benefit. Side effects were mild and included nausea (44%), fatigue (35%), and anemia (14%). More serious side effects were rare and were primarily nausea and a low white blood cell count. Researchers concluded that olaparib is well tolerated and active in women with advanced ovarian cancer.

The results of these Phase II studies led to larger Phase III studies to determine whether PARP inhibitors extend the life of women with advanced cancers.

Recent PARP inhibitor news

Iniparib

Iniparib was used in a Phase III clinical trial for patients with metastatic triple negative breast cancer as part of a randomized trial. Two distinct populations were enrolled: one group of women who were newly diagnosed with metastatic disease and had not yet received any therapy received iniparib as “first line therapy.” A second group had already been treated for metastatic cancer, which had progressed prior to beginning the clinical trial. All patients received the chemotherapy agents gemcitabine and carboplatin. Half of the patients also received iniparib; the others did not. The first-line therapy group of patients showed no overall improvement in survival or progression-free survival. However, patients who received iniparib as a second- or third-line therapy did show improvement in this preliminary data. 

It is too early to conclude that iniparib is ineffective against triple negative or hereditary breast cancer. Researchers are still assessing the study results to determine whether certain groups of participants did respond well to the medication. Unknown at this point is whether women who received iniparib as a second- or third-, or fourth-line treatment improved, whether some patients—those with BRCA mutations, for example—were among the people whose cancer responded best to treatment, and whether the medication might have a better effect on women with earlier stage cancers who receive the drug before their cancer has spread beyond the breast and lymph nodes. More information will likely be presented in June at ASCO’s annual meeting. Research updates were presented at our Joining FORCEs conference in several sessions, including  Focus on BRCA and triple-negative breast cancers, New treatments for hereditary ovarian cancer, and Metastatic breast cancer–what’s new?

Given the overwhelmingly positive Phase II study results, the less positive Phase III results may seem surprising . It is important to remember the difference in purpose and scope of the trials. Phase II trials involve fewer patients and aim to identify the appropriate dosage to maximize effectiveness and safety. Phase III trials are much larger and are intended to confirm or not confirm the effectiveness of a drug, as well as provide information for physician labeling.

International pharmaceutical company Sanofi-Aventis has indicated that patients who are currently enrolled in Phase II or Phase III trials for metastatic breast cancer should receive uninterrupted access to this drug, whether they are receiving it as a first-, second- or third-line treatment. Patients who are currently enrolled in the Expanded Access Protocol (EAP) can continue to get iniparib if they are second- or third-line patients. A new consent form will be required to continue. However, based on the analysis of the Phase III data, no new first-line patients will be accepted into the EAP, and the company recommends first-line study participants discontinue treatment with iniparib. If patients and their physicians think iniparib should be continued based upon the individual’s potential risk and benefit, a new consent form will be required. The enrollment process for patients who are waiting to be enrolled in the EAP program has not changed for second-, third- and fourth-line patients.

Sanofi- Aventis has not yet analysed data from the Phase III study showing which patients benefitted most from Iniparib.  They will be asking particularly whether women with BRCA1 or BRCA2 mutations are more sensitive, as would be expected from a PARP inhibitor.  This  analysis will be important in better understanding how iniparib works.

Sanofi-Aventis is communicating with physicians who have enrolled patients in the trial, and is seeking guidance from the FDA about sharing data with patient groups. The company has also submitted an abstract for this year’s ASCO meeting to report these findings. Sanofi-Aventis plans to continue its ongoing clinical trials with iniparib for breast, lung and ovarian cancers.

MK-4827

Preliminary results of a phase I study using the PARP Inhibitor MK-4827 for women with ovarian cancer were recently presented at the Society of Gynecologic Oncologists annual meeting. Before enrolling in the study, all participants had been previously treated with chemotherapy and had experienced progression of their cancer. Half of these patients benefited from the PARP inhibitor. Of 39 women enrolled, 10 had partial responses and eight others had stable disease for a minimum of 12 weeks. The two groups combined had a clinical benefit rate of 46%. The primary objectives of the study were safety and tolerability to determine the ideal dose for larger, phase II studies. The most common side effects were nausea, vomiting, anorexia, fatigue, low blood counts, and constipation.

The study included two phases: the initial dose-escalation phase included many BRCA1/2 mutation carriers as participants. The second dose-expansion phase included women with sporadic platinum-resistant ovarian cancer. Of the 39 patients included in the first study phase, 15 had unknown BRCA status, five were BRCA negative, and 19 were BRCA positive. Eleven of the 19 women with BRCA-positive mutations (58%) benefited from treatment with MK-4827—four achieved stable disease and seven had partial responses. Seven women with BRCA-unknown status (47%) had clinical benefit, but none of the small group of BRCA-negative patients had stable disease or partial responses. Several patients had progression-free survival (PFS) lasting a year or more, including one who had a partial response and associated PFS of more than 500 days, and another whose PFS fell just short of 500 days.

Olaparib

Despite encouraging early research on olaparib for breast cancer, AstraZeneca announced that new studies of the drug will focus primarily on women with ovarian cancer who do not carry BRCA1/2 mutations.

PARP Inhibitor Open Research Studies

There are several PARP inhibitor studies open for different populations of patients. There is some evidence that different PARP inhibitors work differently so not all may have similar results in clinical trials. If you are considering enrolling in a clinical trial, it is recommended that you discuss the study with your health care team and the research team for each study. You can view a list of PARP Inhibitor studies enrolling people with breast cancer. We will be adding links to the different studies based on cancer type, (and when applicable, cancer subtype), stage of cancer, and type of PARP inhibitor. Please check our PARP Inhibitor clinical trials page for updates.

 

Page updated 10/20/11

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