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Highlights from ASCO 2014

by Lisa Rezende, PhD

Majority of women who undergo risk-reducing salpingo-oophorectomy report quality of life issues

Dr. Susan Domchek from the Basser Research Center for BRCA presented research on the quality of life of BRCA mutation carriers after risk-reducing salpingo-oophorectomy.  The study included 789 BRCA mutation carriers who elected to remove their ovaries and fallopian tubes to manage breast and/or ovarian cancer risk. Dr. Domchek noted that FORCE recruited close to 90% of the study’s participants. 

Early reports from the study show that majority of patients showed significant quality of life issues, including:

  • 59% reporting symptoms of stress
  • 51% reporting menopausal hot flashes
  • 76% reporting sexual issues
  • 59% reporting sleep issues

Women on hormone replacement therapy (HRT) reported fewer hot flashes and sexual issues than those who were not. Only 23% of women in the study were currently taking HRT, with 35% saying that they had ever taken HRT. We look forward to more data from this study, including the results from memory tests.

Why is this study important? For many women in surgical menopause these symptoms are familiar.  This work demonstrates the extent of the problem to the medical and research communities.   For researchers, it is a critical first step to support research into finding the best way to manage surgical menopause.  The importance of this study to health care providers was apparent during the presentation at ASCO.  A physician noted that these symptoms are not trivial and must be taken into account in follow-up care of BRCA mutation carriers who undergo risk-reducing salpingo-oophorectomy.

Multiplex testing to assess cancer risk
New genetic tests that look at multiple genes were front and center at ASCO this year, with a session devoted to the topic. Genetics experts presented research papers and conducted educational sessions of this rapidly changing field. A few highlights included:

  • Dr. Kara Maxwell and colleagues at the Basser Center for BRCA sequenced DNA from 277 women with early-onset breast cancer who tested negative for BRCA1 or BRCA2 mutations. Looking for mutations in 19 different genes that are associated with increased cancer risk, the researchers found that 30% of the women had mutations in one or more of these genes, while only 2.5% had mutations in genes with defined clinical guidelines for managing cancer risk.
  • Dr. Lucy Langer and colleagues of Northwest Cancer Specialists reported the results of using a 25-gene panel to test 263 women diagnosed with ovarian cancer. These researchers found mutations in at least one gene associated with cancer risk in 16.3% of the women tested; 60% of the mutations were in BRCA1 or BRCA2, and 5.8% of mutations were in a gene that causes Lynch Syndrome, a hereditary cancer syndrome associated with increased risk of colon and other cancers.
  • Dr. Matthew Yurgelun of the Dana Farber Cancer Institute presented the results of a study using multiple gene panels to screen 1,260 patients who had been previously tested for Lynch Syndrome. He found that 155 patients had mutations in genes known to increase cancer risk—73% of the mutations were in genes associated with Lynch Syndrome. The remaining patients had mutations in other genes, including 10 patients with mutations in BRCA1 or BRCA2.

PARP inhibitor combined with a second drug increases survival in women with recurrent ovarian cancer
Dr. Joyce Liu of Dana-Farber Cancer Institute presented results from a phase II trial that compared treatment with olaparib (a PARP inhibitor) alone, to olaparib in combination with the drug cediranib. The trial enrolled 90 patients with ovarian cancer that had recurred after initial treatment. Some patients had a mutation in BRCA1 or BRCA2, while others did not. Half of the patients were given olaparib alone while the other half received both olaparib and cediranib. Progression-free survival for patients given olaparib and cediranib was almost twice as long (17.7 months) as those who were given only olaparib (9 months). Current therapy for recurrent ovarian cancer has an average progression-free survival time of 8-13 months.

Other PARP inhibitor news

  • A phase I/II trial of the PARP inhibitor rucaparib found that 89% of ovarian cancer patients with a BRCA mutation responded to the drug. Phase II and III studies will compare the response of rucaparib given alone to the response of rucaparib combined with standard chemotherapy.
  • A phase I trial involving 60 BRCA mutation carriers with breast, ovarian, pancreatic, or prostate cancer who received the PARP inhibitor veliparib showed that the drug is well tolerated. Phase II trials of veliparib are ongoing.

BRCA mutations in African American breast cancer survivors
Dr. Tuya Pal of Moffitt Cancer Center presented her study showing that BRCA1 and BRCA2 mutations are more common in black breast cancer survivors under age 50 than previously thought, with 28 of 283 women (9.9%) testing positive for BRCA mutations. Dr. Pal noted that although all 283 women qualified for referral to genetic counseling under current national guidelines, only about one-third were tested prior to the study.

Removal of ovaries was associated with increased survival for breast cancer survivors with BRCA1 mutations
Surgical removal of the ovaries and fallopian tubes is associated with increased survival among BRCA mutation carriers. In a new report, Dr. Kelly Metcalfe of the University of Toronto presented work that followed BRCA mutation carriers for up to 20 years after being diagnosed with early-stage breast cancer. The survival rate for BRCA1 mutation carriers with breast cancer was higher among women who removed their ovaries, even after adjusting for clinical features and other treatments. The greatest increase in survival was observed among BRCA1 mutation carriers with estrogen receptor-negative breast cancer.

Preserving fertility of premenopausal breast cancer patients
Women with early breast cancer who are treated with chemotherapy that includes the drug cyclophosphamide sometimes experience ovarian failure after treatment has ended. Dr. Halle Moore of the Cleveland Clinic presented data from a phase III trial that showed combining the drug goserelin with chemotherapy helps to preserve fertility. Patients were followed for 2 years after treatment: 45% of the women who received standard chemotherapy had ovarian failure, while only 20% of those whose treatment included goserelin had ovarian failure. Women from both groups had successful pregnancies after fertility was restored.

Growing up in a family with breast cancer risk
Dr. Angela Bradbury and colleagues at the Perelman School of Medicine, University of Pennsylvania, compared cancer-related worry, anxiety, and depression in teenage girls from families at increased risk of breast cancer to teenage girls at normal risk. High-risk was defined as having a known familial mutation in BRCA1 or BRCA2 or having at least one relative with breast cancer. Teenage girls from high-risk families had higher general anxiety and more breast-cancer related worry than those from families at average risk; they were also more likely to perform breast self-exams. No differences between the two groups were apparent in risky behavior or preventative healthy behaviors.

 

Is Risk of Uterine Cancer increased in BRCA Mutation Carriers?

by Lisa Rezende, PhD

To reduce their risk of developing ovarian cancer, experts recommend that women with BRCA mutations remove their ovaries and fallopian tubes (also known as risk-reducing salpingo-oophorectomy or RRSO) once they are done having children, and ideally between age 35-40. Some gynecologic experts also recommend removal of the uterus (hysterectomy) at the same time, but not all experts agree this is necessary. One concern is whether BRCA may increase the risk for uterine cancer. Previous studies produced mixed results: some research has shown small increases in uterine cancer risk while other studies have not.1-3 and national guidelines for women with BRCA mutations do not include recommendations for hysterectomy. Using tamoxifen has been shown to increase uterine cancer risk, and has been suggested to be responsible for at least some of the uterine cancer risk that has been reported in BRCA mutation carriers.4

Many women come to FORCE asking if they should have their uterus removed during RRSO.  Understanding the benefits and risks to hysterectomy, is critical to help women make this difficult decision.

A study by Dr. Noah Kauff and colleagues at Memorial Sloan Kettering Cancer Center provides new data of a link between BRCA1 mutations and rare forms of uterine cancer.5 Presented at the Society of Gynecologic Oncology National Meeting this past March, the study followed 525 BRCA mutation carriers who had their ovaries and fallopian tubes surgically removed, but kept the uterus intact.  During the follow-up period of 0.1-16.9 years (with a median of 5.8 years), 4 women—all of whom had BRCA1 mutations—were diagnosed with aggressive uterine cancer; two of the women had used tamoxifen, while two others had not. Despite the small numbers, this increase in uterine cancer risk was statistically significant. Still, it is important to note that these aggressive forms of uterine cancer are relatively rare and the researchers estimate the 10-year risk of these forms of uterine cancer in BRCA1 mutation carriers is about 2%. Larger research studies will need to confirm these findings before experts change national guidelines to recommend hysterectomy for BRCA1 carriers. BRCA2 carriers are not considered to be at increased risk for uterine cancer, but like all women, they may be at higher risk if they have taken tamoxifen or are on hormone replacement that doesn’t include progesterone.

Many women with BRCA1 mutations who have not removed their uterus may wonder if they should take additional steps to manage their risk for uterine cancer.  Currently, there are no national guidelines for follow-up care of women who have undergone RRSO without hysterectomy.  Members of our advisory board recommend continuing annual pelvic exam, having Pap smears as recommended by their healthcare providers, and knowing the signs and symptoms of uterine cancer.  Any signs of unexpected bleeding or spotting should be reported to your gynecologist or gynecological oncologist.

If you are deciding whether or not to remove your uterus as well as your ovaries and fallopian tubes, you should discuss the choice with your health care providers. Other factors to consider include your age, whether or not you use or have used tamoxifen,  personal history of any uterine or cervical abnormal symptoms or findings, and whether or not you plan on using hormone replacement therapy to manage symptoms of surgical menopause.

Please take this quick survey (it takes about 10 minutes). and share your thoughts on this research for the greater good! You will instantly be able to see how your responses compare with others. This survey is a tool of the ABOUT Network led by FORCE. The goals of the ABOUT Network are to collect and measure real-life experiences, questions, decisions, and health outcomes of people like you who are concerned about or living with a cancer-causing mutation or hereditary cancer risk.

References             

1Levine, D.A., Boyd, J., et al. “Risk of Endometrial Carcinoma Associated with BRCA Mutation.” Gynecologic Oncology, Vol. 80, No. 3, p. 393-98, March 2001.

2Lavie, O., Gemer, O, et al. ”BRCA Germline Mutations in Women with Uterine Serous Cancer—Still a Debate.” International Journal of Gynecological Cancer Vol. 20, No. 9, p. 1531-34, December 2010.

3Pennington, K.P., Swisher, E.M., et al. “BRCA1, TP53, and CHEK2 Germline Mutations in Uterine Serous Carcinoma.” Cancer, Vol. 119, No. 2, p. 332-38, January 2013.

4Beiner, M.E., Narod, S.A., et al. “The Risk of Endometrial Cancer in Women with BRCA1 and BRCA2 mutations. A Prospective Study,” Gynecologic Oncology, Vol. 104, No. 1, p. 7-10, January 2007.

5Shu, CA, Kauff, N.D., et al.Risk of Developing Uterine Corpus Cancer (Ut Ca) Following Risk-Reducing Salpingo-Oophorectomy (RRSO) in Women with BRCA Mutations.” Abstract #LBA-5 Presented at Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.  March 22-24, 2014.           

BRCA1 and Brain Development

By Lisa Rezende, PhD

This article is in response to the press release found on this link. The press release quotes the study author who later clarified the quote used in the release.

A new research study found the BRCA1 gene to be important in the brain development of mice. Reports of the research raised concerns for some members of the BRCA1 community. Although this study is important for understanding more about the basic biology of BRCA1, it is not a clinical study and cannot be used to draw conclusions about BRCA1 mutations in humans. Dr. Inder Verma, one of the study’s authors, notes that the mice in this experiment did not have a functional copy of the BRCA1 gene. Women with BRCA1 mutations all have one functional copy of this gene. Dr. Verma told FORCE that there is no link between the results of this study and the brain development of BRCA1 mutation carriers.

Clinical research studies are designed to find out how BRCA1 mutations affect humans. At this time, there are no published research studies showing any link between BRCA1 mutations and seizures or other brain abnormalities in people.

Breast MRI Contrast Agent

By Lisa Rezende, PhD

Breast MRI is an important surveillance tool for finding cancer in high-risk women. This article, prepared in conjunction with our advisory board members, addresses concerns submitted by FORCE members about the use of gadolinium, an MRI contrast agent. These concerns are based on studies that question the safety of gandolinium under certain circumstances.

Gadolinium-containing contrast agent is commonly administered during breast MRI to improve imaging. Because gadolinium is a metal, it is given in a form that is rapidly removed from the body, limiting side effects and making it safe for most patients.1 A 2014 study of 10,595 patients who received a gadolinium-based contrast agent found it to be very safe. None of the patients had severe reactions –43 had mild reactions, and 5 had moderate reactions, including swelling and mild blood pressure changes.2 Precautions are often taken when using gadolinium-containing contrast agents in patients with a history of allergic reactions to imaging agents, women who are pregnant or nursing, and patients with kidney disease, who are risk for a rare kidney disorder known as nephrogenic systemic fibrosis if exposed to gadolinium.

The long-term effects of gadolinium-based contrast agents remain an area of research. A recent small study of 35 patients with existing brain disease showed changes in brain MRI after six or more brain MRI scans with gadolinium3. Dr. Tomonori Kanda, the paper’s lead author, states in the accompanying press release that the study does not prove that gadolinium caused the changes, nor is it clear that these findings affect patient health. Another small study looking at 31 patients undergoing hip replacement surgery found that those who previously had MRI with gadolinium-based contrast agents had a higher concentration of gadolinium in their bones than those who did not4.

Experts on our advisory board feel that these and prior research studies do not raise concern that mutation carriers are more sensitive to the effects of gadolinium, and that the benefits from enhanced contrast on breast MRIs outweigh the theoretical risks. They continue to recommend annual breast MRI with contrast for women at high-risk for breast cancer who have not undergone mastectomy.

1Hao D, Tweedle M, Hu X, et al. “MRI Contrast Agents: Basic Chemistry and Safety,” Journal of Magnetic Resonance Imaging, Volume 36, Number 5, p. 1060-71, November 2012.

2Okigawa T, Utsunomiya D, Yamashita Y, et al., “Incidence and Severity of Acute Adverse Reactions to Four Different Gadolinium-based MR Contrast Agents,” Magnetic Resonance in Medical Science, Volume 13, Number 1, p. 1-6, January 21, 2014.

3Kanda T, Takenaka D, et al., “High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-weighted MR Images: Relationship with Increasing Cumulative Dose of a Gadolinium-based Contrast Material,” Radiology, Volume 270, Number 3, p. 834-41, March 2014.

4Darrah TH, Hannigan RE, et al., “Incorporation of Excess Gadolinium into Human Bone from Medical Contrast Agents,” Metallomics, Issue 6, p. 445-528, November 1, 2009.

 

Update: Preventative Removal of Ovaries Reduces Risk of Cancer and Increases Survival for Woman with BRCA Mutations

by Lisa Rezende, PhD

Current guidelines recommend that women who carry a mutation in the BRCA1 or BRCA2 genes undergo salpingo-oophorectomy (BSO), the surgical removal of the ovaries and fallopian tubes, to reduce their risk of ovarian and fallopian tube cancers. In the largest study to date, a new report in the Journal of Clinical Oncology from Dr. Steven Narod and colleagues confirms this recommendation by showing that BRCA mutation-carriers who undergo risk-reducing oophorectomy have an 80% reduced risk of ovarian, fallopian tube, and peritoneal cancer and an estimated 77% decreased risk of death from all causes. This confirms the 2010 study from Dr. Susan Domchek, Dr. Timothy Rebbeck, and colleagues that linked BSO in mutation carriers to increased survival (reviewed in the Spring 2011 issue of Joining FORCEs Newsletter).

The new study followed 5,783 women for an average of 5 years. These women were participants in a registry of confirmed BRCA mutation-carriers, enrolled by 43 different clinical centers. Each woman was given a survey of health history— including risk-reducing surgeries and cancer diagnosis—upon entering the registry and at least once during the follow-up period. From this group, 3,513 women had preventative oophorectomy either before entering the registry or during the follow-up period, while 2,270 women did not have the surgery at any point during the study. One advantage of a large study population is that the researchers could separate risk by mutation type and age.

At the end of the follow-up period the researchers found:

  • 108 cases of ovarian, fallopian tube, or peritoneal cancer were diagnosed in women who had not had oophorectomy; 39 of these women died from their cancer during the study period.
  • An additional 46 cancers were detected at the time of oophorectomy; 3 of these women died of their cancer during the study period.
  • 32 women were diagnosed with primary peritoneal cancer after oophorectomy; 13 of these women died of their cancer during the study period. The estimated 20-year risk of primary peritoneal cancer in women who underwent oophorectomy was 3.9% for BRCA1 mutation carriers and 1.9% for BRCA2 mutation carriers.
  • The highest incidence of ovarian cancer for BRCA1 mutation carriers occurred between the ages of 50 and 59
  • The highest incidence of ovarian cancer for BRCA2 mutation carriers was between the ages of 60 and 69.

The researchers used the data to make estimates about the decade-by-decade risks for mutation carriers. They estimated that if a woman with a BRCA1 mutation delays oophorectomy until age 40, she will have about a 4% absolute risk of being diagnosed with ovarian cancer by age 40. The authors estimated that a woman with a BRCA1 mutation who waits until age 50 to undergo oophorectomy will have about a 14.2% absolute risk of being diagnosed with ovarian cancer by age 50. Based on their estimates, the study authors conclude that results of this research support the recommendation that BRCA mutation carriers undergo prophylactic oophorectomy after they have completed childbearing. The authors also conclude that for BRCA1 mutation carriers, the age of oophorectomy should be around 35 years.

Although this is the largest study of this question to date, more research is needed to address some of the study’s limitations, including:

  • The questionnaire did not ask whether or not the fallopian tubes were also removed at the time of oophorectomy, raising the possibility that some of the women in the oophorectomy group still had fallopian tubes in which cancer could occur.
  • The surgeries were performed at medical facilities around the world. There was no way to standardize the type of surgery performed, or the type of pathology done at oophorectomy. Some of the primary peritoneal cancers diagnosed after oophorectomy could have been present but not detected at the time of oophorectomy.
  • A longer follow-up period will allow researchers to better determine the all-cause mortality rate as it may take more time for effects of surgical menopause to become apparent. Longer follow up will allow experts to refine recommendations on the ideal timing of oophorectomy.

If you wish hear more about the study, Dr. Elizabeth Swisher, Professor of Gynecological Oncology at University of Washington School of Medicine and FORCE advisory board member discusses it on a podcast at the Journal of Clinical Oncology website.

Dr. Narod will be speaking at our annual Joining FORCEs Conference, June 12-14, 2014 in Philadelphia.

Finch, A.P.M, Narod, S.A., et al., “Impact of Oophorectomy on Cancer Incidence and Mortality in Women With a BRCA1 or BRCA2 Mutation,” Journal of Clinical Oncology, published online February 24, 2014.

Domchek, S.M., Rebbeck, T.R., et.al “Association of Risk Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers with Cancer Risk and Mortality,” JAMA. 2010;304(9):967-975.

 

Page updated 04/07/14

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