As genetic testing grows, individualized management of BRCA mutations urged

Genetic tests capable of detecting inherited BRCA1 and BRCA2 mutations, which significantly increase one’s risk for breast and ovarian cancers, have been available since 1996.

However, two high-profile developments in the past 5 months have dramatically increased patients’ knowledge of the tests and their potential benefits.

In May, actress Angelina Jolie announced in an editorial in The New York Times that she underwent a double mastectomy after testing positive for the BRCA1 mutation. In the following days, Dana-Farber Cancer Institute received a steady stream of inquiries from women, many of whom had a family history of cancer, who wanted to learn more about their risks.

“Angelina Jolie’s experience and editorial definitely put these genes in the spotlight and increased awareness of the power of genetic testing,” Huma Q. Rana, MD, a physician in the cancer genetics and prevention department at Dana-Farber Cancer Institute and an instructor in medicine at Harvard Medical School, told HemOnc Today. “They resulted in families openly communicating their family histories with one another and, subsequently, this translated to patients calling our group in order to undergo genetic testing.”

A month after Jolie’s announcement, the US Supreme Court unanimously ruled that genes and the information they encode are not eligible for patents. The decision — based on a case that involved patents held by Myriad Genetics for the BRCA1 and BRCA2 genes — already has led to a reduction in cost for genetic testing that can help evaluate patients’ cancer risks. The price reduction may increase the number of insurers willing to cover such tests, which could dramatically expand access.

Although genetic testing can provide valuable information about a person’s cancer risk, it should not dictate a one-size-fits-all treatment approach, Clifford A. Hudis, MD, ASCO president and chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, told HemOnc Today.

Detection of a BRCA mutation does not require a person to undergo a mastectomy, Hudis said.

“Conversely, there is no situation where you can definitively say that — despite a mutation — you can avoid a mastectomy,” Hudis said. “It all comes down to a person’s tolerance for living with the risk. The mutation indicates you have an elevated risk for breast cancer. It does not mean you are going to get breast cancer this month, year or decade. For some people, this means, ‘Where do I sign up for surgery?’ For other people, it does not.”

HemOnc Today spoke with several experts about the benefits associated with increased awareness of genetic testing, the need for those who meet criteria for BRCA testing to receive screening recommendations from their physicians, and the most appropriate risk management strategies for patients with known BRCA mutations.

Lack of recommendations

Women who have an inherited mutation in BRCA1 or BRCA2 are at five times greater risk for breast cancer than women who do not have the mutation, according to the NCI.

The average woman in the United States has a 1.4% chance of being diagnosed with ovarian cancer, but the risk is 15% to 40% among BRCA1 or BRCA2 mutation carriers.

BRCA1 and BRCA2 testing is recommended to those at highest risk for these mutations. They include women younger than 45 years, those of Ashkenazi Jewish ancestry, and those with a strong family history of breast and/or ovarian cancer.

However, results of a study by Anne Marie McCarthy, PhD, an epidemiologist at the University of Pennsylvania, and colleagues suggest a considerable number of patients with breast cancer who met the criteria for BRCA testing did not receive recommendations for testing from their health care providers.

McCarthy and colleagues used the Pennsylvania Cancer Registry to identify women aged 18 to 64 years diagnosed with invasive breast cancer in 2007. Researchers sent the women surveys designed to determine their family cancer history, physician treatment recommendations, and their testing history for BRCA1 and BRCA2 mutations. Study participants were categorized as being at high risk, moderate risk or low risk for BRCA1 or BRCA2 mutations based on age at diagnosis and family history.

Results of the analysis, which included 2,258 women, appeared online in July in Cancer.

“As we would expect, high-risk women were most likely to undergo genetic testing and to say that their physician recommended genetic testing,” McCarthy told HemOnc Today. “However, one thing we were surprised about was — even among the high-risk group — only about 50% of those women were recommended to undergo genetic testing. We thought this number seemed low, and this might represent a need to work on ensuring that breast cancer patients have their genetic risk evaluated at the time of diagnosis.”

McCarthy and colleagues determined older, employed and low-income women were least likely to receive a physician recommendation for genetic testing.

“When a patient is diagnosed with breast cancer at a young age, it prompts the physician to think about a genetic component,” McCarthy said. “In older women, this might not be the first thing the physician thinks of. Also, it takes time and effort on the physician’s part to take a detailed family history to evaluate the genetic risk for breast cancer, so physicians may be more likely to take a family history if a woman presents young than if a woman presents at an older age.”

The researchers since expanded the study to include a much larger cohort, which will include women who live in Pennsylvania and Florida diagnosed with breast cancer during an additional 5-year period. Surgeons and medical oncologists who saw study participants are also being surveyed. Data collection is underway, and results are expected next year.

“We are going to look at how both patient and physician factors affect utilization of genetic testing,” McCarthy said. “We also want to look at racial disparities in testing because prior studies suggest black women are less likely to be tested for BRCA1 and BRCA2 mutations than whites.”

Racial disparities

Results from several studies demonstrate racial disparities among patients who receive physician recommendations for BRCA testing.

In a case-control study published in JAMA, Armstrong and colleagues assessed the association between race and BRCA1 and BRCA2 testing recommendations in women with a family history of breast or ovarian cancers.

The study included 408 women who received primary care at a large health care system in Philadelphia. Of them, 217 women underwent BRCA1 and BRCA2 genetic counseling and 191 did not.

Black women who had a family history of breast or ovarian cancers were significantly less likely than white women to undergo genetic counseling for BRCA testing (OR=0.22; 95% CI, 0.12-0.40), results showed. The disparity persisted after researchers adjusted for probability of BRCA mutation, socioeconomic characteristics, breast and ovarian cancer risk perception and worry, patient attitudes about the risks and benefits of testing, and physician discussion of BRCA testing (adjusted OR=0.28; 95% CI, 0.09-0.89).

“The complex and highly charged relationship between race and genetics presents a substantial challenge to the translation of advances in human genetics into improvements in health,” Armstrong and colleagues wrote. “Although empirical evidence of racial disparities in the utilization of BRCA1 and BRCA2 counseling provides important information about this challenge, it only further highlights the need to move forward in developing a health and social policy that ensures the potential benefits of the Human Genome Project are realized for all segments of the US population.”

Risk management

Patients with a known BRCA1 or BRCA2 mutation can choose one of several risk management strategies, including earlier or more frequent cancer screening.

Some opt to undergo risk-reducing surgery — either prophylactic mastectomy to remove at-risk breast tissue or salpingo-oophorectomy to remove the ovaries and fallopian tubes.

The value of chemoprevention in women with BRCA mutations is not yet clear, although multiple studies have suggested the chemopreventive drug tamoxifen may reduce breast cancer risk and contralateral breast cancer recurrence in this population.

Stephanie L. Hines, MD, assistant professor of medicine in the breast clinic and the department of consultative and diagnostic medicine at Mayo Clinic in Jacksonville, Fla., said considerably more patients with BRCA mutations have contacted her institution recently to request information about their risk management and treatment options.

“This is always an individualized decision,” Hines told HemOnc Today. “It used to be that when we saw patients with BRCA mutations, we would say that the risks are high — the risk is up to 87% for getting cancer — and we would almost push patients to consider mastectomies as the best option. But we have now learned that there are ways to screen patients very effectively, and many facilities have high-risk screening programs that include annual mammograms, MRIs, and clinical breast exams two or three times per year. These patients are watched very closely.”

The decision to pursue risk-reducing surgery should be made only after extensive communication.

“This decision should be patient-driven,” Hines said. “We listen and talk with the patient about their fears and concerns and try to help them come to the conclusion of what is going to be right for them. We provide the information and coach them along. If they are unsure, I always tell them there is time to think about it. I give them the information and tell them to talk to family and friends and to make the decision another time.”

Surgical options for women who have known BRCA mutations are considerably better today than in years past because of advanced techniques, said Joshua D.I. Ellenhorn, MD, clinical professor of surgery at Cedars-Sinai Medical Center and adjunct professor at John Wayne Cancer Center.

“For many women, bilateral mastectomy is a more reasonable approach because it will avoid lifelong hassles, mammograms, MRIs, biopsies and all the negative implications and stress,” he said in an interview. “Although we don’t recommend mastectomies for women who are easy to follow, I don’t try to convince them not to have them. The only woman for whom I would not perform bilateral mastectomies is someone who does not have a strong family history, is BRCA-negative, and who does not have a breast cancer. I don’t see many of those patients, but if I did, I would definitely discourage or refuse mastectomy.”

Multiple studies have examined the effectiveness of enhanced screening in patients with BRCA mutations.

In a study published in 2010 in the Journal of Clinical Oncology, Warner and colleagues compared the use of MRI vs. mammography as surveillance in women with a BRCA1 or BRCA2 mutation. The analysis included 1,275 women; of them, 445 underwent MRI and 830 underwent mammography.

Mean follow-up was 3.2 years. Researchers estimated cumulative incidence for ductal carcinoma in situ, early-stage and late-stage breast cancers at 6 years.

Researchers hypothesized that MRI screening would be associated with reduced mortality and reduced incidence for advanced-stage breast cancers.

Warner and colleagues reported 41 breast cancer cases in the MRI cohort and 76 cases in the mammography cohort. Cumulative incidence of stage II to stage IV breast cancer was 1.9% (95% CI, 0.2-3.7) in the MRI cohort compared with 6.6% (95% CI, 3.8-9.3) in the mammography cohort. The adjusted HR for the development of stage II to stage IV breast cancer in women who underwent MRI was 0.3 (95% CI, 0.12-0.72).

“The researchers found that women in both groups were just as likely to get breast cancer,” Hines said. “However, women who had MRIs were 70% more likely to be diagnosed with stage zero or stage I disease — obviously the most likely women to be cured and have the best prognosis.”

Ovarian cancer

Considerably less data exist on appropriate ovarian cancer screening and risk-reduction measures for BRCA mutation carriers.

In a study published earlier this year in JAMA Internal Medicine, Gabriel N. Mannis, MD, a fellow in the department of hematology/oncology at the University of California, San Francisco, and colleagues set out to assess the impact of BRCA testing on patients’ decisions to undergo ovarian screening interventions and/or prophylactic risk-reducing surgeries.

Results showed 71.8% of women referred for BRCA testing received uninformative results. Despite a lack of guidelines for this scenario, a substantial percentage went on to undergo ovarian cancer screenings or prophylactic surgeries.

Overall, 19.1% of women in the study cohort underwent risk-reducing salpingo-oophorectomy and 39.6% utilized screening procedures. Researchers found that a positive BRCA test result predicted the occurrence for risk-reducing salpingo-oophorectomy (OR=28.1; 95% CI, 16.2-48.6), whereas a true-negative test result decreased the OR for risk-reducing salpingo-oophorectomy (OR=0.1; 95% CI, 0.0-0.6).

However, 12.3% of women who received uninformative results from their BRCA tests underwent risk-reducing salpingo-oophorectomy and 33.8% underwent screening to check for elevated levels of CA-125 in their blood serum, a predictor of advanced ovarian cancer. Also, 37.3% underwent screening with transvaginal ultrasound, even though data on the effectiveness of these interventions in this patient population is insufficient, according to the researchers.

“These findings highlight the need for better ovarian cancer risk stratification in a significantly understudied population whose risk is likely quite heterogeneous,” Mannis told HemOnc Today. “On a broader level, these findings highlight that — with any cancer screening program — a negative test does not always allay patient fears. Physicians must play a key role in discussing the potential risks and benefits of any screening test with their patients.”

Expanded access

The Supreme Court ruling that declared human genes and the information they encode are not eligible for patents has allowed for increased competition in the genetic testing arena. Additional entities now are allowed to perform BRCA testing, although they are not allowed to use the same methodology used by Myriad Genetics. Myriad Genetics acquired patents on the BRCA1 and BRCA2 genes in the mid-1990s and, since then, had been the only commercial provider of BRCA testing services in the United States.

“[The] decision will be an important symbol for those who seek to foster scientific discovery by protecting and expanding the public domain,” Aaron S. Kesselheim, MD, JD, MPH, of the department of medicine at Brigham & Women’s Hospital, and colleagues wrote in a commentary published in The New England Journal of Medicine. “It also has symbolic resonance with the ideal that our common humanity cannot be owned. The Universal Declaration on the Human Genome and Human Rights declares the human genome to be ‘the heritage of humanity’ and that ‘the human genome in its natural state shall not give rise to financial gains.’ The Supreme Court quietly came to a similar conclusion, though with attention to preserving the incentives important for biomedical innovation.”

The effects of the ruling already are visible, although some questions remain.

“There are more clinical labs that are providing BRCA testing, and they are providing it at a reduced cost of about 50% from what testing traditionally costs,” Rana said. “However, it is too early to tell how insurance companies will approach this in terms of preferred laboratories and bundling of genetic testing.”

“The clinical implications of this ruling haven’t yet fully hit, but I imagine this will change very quickly as newer tests come to market,” Ellenhorn said. “This was a very positive ruling. It will result in improved testing at lower expense to patients, and this is always good.”

Ultimately, the ruling may allow institutions to perform the test and bill for it under certain circumstances, Hudis said.

“The availability of BRCA testing, for appropriate patients, represents a major advance in our ability to assess and manage risk,” Hudis said. “It holds great promise for a future where we can select therapies with greater precision and lower the disease burden of an increasing number of malignancies.” – by 
Jennifer Southall

References:

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For more information:

Joshua D.I. Ellenhorn, MD, can be reached at Cedars-Sinai Medical Towers, 8635 W. Third St., Suite 1090W, Los Angeles, CA 90048; email: dr@ellenhornmd.com.

Stephanie L. Hines, MD, can be reached at Mayo Clinic, 4055 San Pablo Road, Jacksonville, FL 32224; email: hines.stephanie@mayo.edu.

Clifford A. Hudis, MD, can be reached at Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: hudisc@mskcc.org.

Gabriel N. Mannis, MD, can be reached at University of California, San Francisco, 505 Parnassus Ave., M1286, Box 1270, San Francisco, CA 94143; email: gabriel.mannis@ucsf.edu.

Anne Marie McCarthy, PhD, can be reached at University of Pennsylvania, 423 Guardian Drive, Room 1009, Philadelphia, PA 19104; email: annemcc@mail.med.upenn.edu.

Huma Q. Rana, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215; email: humaq_rana@dfci.harvard.edu.

Disclosure: Ellenhorn, Hines, Hudis, Mannis, McCarthy and Rana report no relevant financial disclosures.

Is surveillance for ovarian cancer safe for women with a BRCA mutation?

Surveillance should serve as a bridge to risk-reducing surgery.

Women diagnosed with a BRCA mutation face important cancer risk-reduction decisions. Although breast cancer screening methods — such as mammogram and breast MRI — have been proven to detect cancer at earlier stages in women with BRCA mutations, early detection methods for ovarian cancer are far less effective. At present, the only intervention shown to reduce ovarian cancer-specific mortality in BRCA carriers is risk-reducing bilateral salpingo-oophorectomy (RRSO). However, undergoing RRSO limits fertility options and yields immediate surgical menopause. As such, recommendations for ovarian cancer surveillance exist for those delaying or declining RRSO.

Current recommendations for women at high risk for hereditary ovarian cancer include semiannual pelvic examinations, transvaginal ultrasounds, and serum CA-125 levels beginning at age 30 years, or 5 to 10 years earlier than the youngest diagnosed relative with ovarian cancer, whichever comes first. However, data supporting these recommendations is relatively limited. It is unknown if recommended surveillance methods detect ovarian cancer at earlier stages in BRCA mutation carriers, and contemporary surveillance methods have not been shown to reduce ovarian cancer-specific mortality.

The first phase of the United Kingdom Familial Ovarian Cancer Screening Study (UKFOCSS) provides the most recent data supporting the use of surveillance in high-risk women. Women enrolled in a surveillance program consisting of annual CA-125 and transvaginal ultrasound were more likely to be diagnosed with early-stage disease. However, 60% of stage I cases were in women with Lynch syndrome, in which ovarian cancer is hypothesized to have a longer latency period, and nearly all of the screen-negative, occult ovarian cancers were among women with BRCA mutations and were of advanced stage. As such, alternative approaches to serum CA-125 utilization are being investigated.

Given that CA-125 levels can be elevated secondary to factors unrelated to ovarian cancer, rather than utilizing a static cutoff value for CA-125, the Risk of Ovarian Cancer Algorithm (ROCA) was developed using longitudinal changes in CA-125 coupled with age-specific risk. ROCA is being investigated in high-risk cohorts — phase 2 of UKFOCSS, Gynecologic Oncology Group (GOG) protocol 199, and the ROCA trial headed by the NCI’s Cancer Genetics Network —as well as in average-risk cohorts. Results of phase 2 of the UKFOCSS, presented at the ASCO Annual Meeting earlier this year, suggest every 4-month CA-125 levels combined with annual transvaginal ultrasound in high-risk women may detect ovarian cancer at a lower volume of disease, which may lead to a higher likelihood of complete surgical cytoreduction. However, the impact of ROCA on ovarian cancer-specific mortality remains unknown, and mature trial results are eagerly awaited.

At present, RRSO is superior to intensive surveillance in reducing ovarian cancer risk (HR=0.28), both breast and ovarian cancer-specific mortality (HR=0.44 and HR=0.21, respectively), and overall mortality (HR=0.4) in BRCA mutation carriers. Contemporary surveillance methods should continue to be considered a bridge to risk-reducing surgery.

References:

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For more information:

Jamie N. Bakkum-Gamez, MD, is a gynecologic oncologist and assistant professor of obstetrics and gynecology at Mayo Clinic in Rochester, Minn. She can be reached at bakkum.jamie@mayo.edu. Disclosure: Bakkum-Gamez reports no relevant financial disclosures.

Risk-reducing salpingo-oophorectomy is the most effective ovarian cancer prevention available.

The “holy grail” in the world of ovarian cancer is to identify an effective screening tool that will detect pre-malignant disease or disease that is curable with surgery. We don’t have the equivalent of the Pap smear or mammogram for ovarian cancer. Thus, for women with a deleterious BRCA mutation, prophylactic removal of the ovaries and fallopian tubes through risk-reducing salpingo-oophorectomy (RRSO) is recommended once a woman has completed child-bearing.

Unfortunately, this comes with significant medical complications, particularly for younger women. The premature menopause induced by RRSO can have negative effects on bone health, lipid profile and libido, and it can induce significant vasomotor effects (hot flashes) that can impair sleep and reduce quality of life. Nonetheless, RRSO is the most effective ovarian cancer prevention currently available.

Screening with physical examination, trans-vaginal ultrasound (TVUS) and CA-125 measurement have not been shown to be reliable means to detect early disease. Although there are promising preliminary findings using sequential CA-125 measures to calculate a Risk of Ovarian Cancer Algorithm (ROCA), this approach has not yet been shown to improve ovarian cancer survival.

Recent observations suggest that cells in the fallopian tube may be the true source for many cancers ultimately diagnosed as ovarian cancer. This has led to the concept that removing the fallopian tubes, leaving the ovaries intact, might be an effective prevention strategy. However, this is a completely unproven approach and cannot currently be recommended as effective prevention for women with a BRCA mutation. Thus, for now, RRSO remains the prevention strategy of choice for BRCA mutation carriers. For women who defer RRSO, the American College of Obstetricians and Gynecologists and the National Comprehensive Cancer Network recommend screening starting at age 30 to 35 years, or 5 to 10 years before the earliest diagnosis in a family member, using a combination of CA-125 and TVUS every 6 to 12 months. As noted above, the effectiveness of this screening approach has not been documented, and patients should not be falsely reassured by negative screening.

References:

Berek JS. Obstet Gynecol. 2010;116:733-743.

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Lu KH. Cancer. 2013;119:3454-3461.

For more information:

Deborah K. Armstrong, MD, is associate professor of oncology and gynecology and obstetrics at Johns Hopkins Kimmel Cancer Center. She also is a HemOnc Today Editorial Board member. She can be reached at armstde@jhmi.edu. Disclosure: Armstrong reports no relevant financial disclosures.