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Bilateral Mastectomy Doesn’t Yield Better Breast Cancer Survival Rates, But Testing Surge Reflects “Angelina Jolie Effect.”

What is believed to be the first-ever major study comparing outcomes of breast cancer surgeries shows no survival benefit for women who had both breasts removed compared with women who underwent lumpectomy followed by radiation therapy. However, a Canadian study reports a 90 percent increase in numbers of women referred for breast cancer genetic counseling following actress Angelina Jolie‘s May 2013 announcement that she had undergone a preventive double mastectomy after testing positive for the BRCA1 gene mutation.

Researchers at the Stanford University School of Medicine and the Cancer Prevention Institute of California, found breast cancer patients treated with lumpectomy followed by radiation therapy survived as long as patients who had bilateral mastectomy.

The Stanford researchers’ comprehensive analysis of nearly 190,000 California women with the disease is the first to directly compare survival rates following the three most common surgical interventions: bilateral mastectomy (the removal of both breasts), unilateral mastectomy (the removal of the affected breast), and lumpectomy (the selective removal of cancerous tissue within the breast) plus radiation. Women in the study were diagnosed between 1998 and 2011 with cancer in one breast.

The study was published Sept. 2 in the Journal of the American Medical Association (JAMA).

The report coauthors note that among all women diagnosed with early-stage breast cancer in California, the percentage undergoing bilateral mastectomy increased substantially between 1998 and 2011, despite a lack of evidence supporting this approach. Bilateral mastectomy was not associated with lower mortality than breast-conserving surgery plus radiation, but unilateral mastectomy was associated with higher mortality than the other options. These results may inform decision-making about the surgical treatment of breast cancer.

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The researchers wanted to learn why increasing numbers of women are choosing bilateral mastectomies after a diagnosis of cancer in just one breast, finding that, in 2011, as many as 12 percent of newly diagnosed breast cancer patients opted for a bilateral mastectomy, despite uncertainty as to whether that approach is better than the alternatives. This study dispels much of that uncertainty.

“We can now say that the average breast cancer patient who has bilateral mastectomy will have no better survival than the average patient who has lumpectomy plus radiation,” says Allison Kurian, MD, an assistant professor of medicine and of health research and policy at Stanford in a release. “Furthermore, a mastectomy is a major procedure that can require significant recovery time and may entail breast reconstruction, whereas a lumpectomy is much less invasive with a shorter recovery period.”

Meanwhile, a study entitled “The impact of Angelina Jolie’s story on genetic referral and testing at an academic cancer centre,” by scientists at the Sunnybrook Odette Cancer Centre at Sunnybrook Hospital in Toronto, Canada reports a 90 percent increase in numbers of women referred for breast cancer genetic counseling after Ms. Jolie’s public revelation that she underwent a prophylactic bilateral mastectomy, even though she has no breast cancer raised popular awareness of gene testing by several magnitudes. Testing found that Ms. Jolie carries a defective gene, BRCA1, which doctors told her increased her estimated risk of developing breast cancer to 87%, and also increased her risk factor for ovarian cancer.

However, the researchers point out that similar proportions of women referred before or after the news were at very high genetic risk. The study was presented this week at the 2014 ASCO (American Society of Clinical Oncology) Breast Cancer Symposium in San Francisco.

The Canadian researchers at the Sunnybrook Odette Cancer Centre at Toronto’s Sunnybrook Hospital note that while BRCA1 or BRCA2 gene mutations are linked to hereditary breast and ovarian cancer. Everyone has BRCA1 and BRCA2 genes, known as tumor suppressor genes that make proteins to repair DNA, and suppress the growth of cancer. A mutation of the BRCA gene means that DNA damage cannot be repaired as well, which increases the risk for cancer.

“At our own cancer centre, we were encouraged by Ms. Jolie’s courageous story which seemed to have a significant and meaningful influence on health care providers and the public about awareness for breast cancer genetic screening and preventive options,” comments Dr. Jacques Raphael, breast oncology research fellow and lead author of the Sunnybrook, which he conducted under the supervision of Dr. Andrea Eisen, medical oncologist and head, Preventive Oncology of the Breast Cancer Care team at the Odette Cancer Centre which offers a highly specialized comprehensive cancer program, and is ranked sixth in North America among a select group of world-class institutions that are research intensive and provide the full spectrum of patient care.

Dr. Raphael reviewed the number of women referred for genetic counseling at the Odette Cancer Centre’s Familial Cancer Program, and compared rates six months before and after the release of Angelina Jolie’s story in May 2013.

“Among the larger number of women we saw for genetic counseling after the news, the proportion of women determined to be high risk, like Ms. Jolie, was about the same as the proportion seen before the news, suggesting that we continue to see many of the women who need screening most,” says Dr. Eisen.

The study found 916 women were referred for genetic counseling after her announcement, compared to 487 women prior, or an increase by 90 percent. 437 women in this group representing an increase of 105 percent (compared to 213 prior) were considered high risk (defined by the province of Ontario Ministry of Health and Long-Term Care) and qualified for genetic testing.

The presentation at the 2014 Breast Cancer Symposium, entitled “The impact of Angelina Jolie’s (AJ) story on genetic referral and testing at an academic cancer centre,” (J Clin Oncol 32, 2014 suppl 26; abstr 44), coauthored by Drs. Raphael (lead author) and Eisen, Sunil Verma, and Paul Hewitt, notes that Ms. Jolie had a family history of breast and ovarian cancer and tested positive for the BRCA1 gene mutation. Observing that media coverage has been extensive, it remains unclear what potentially misleading messages the public and professional medical staff have assumed from this personal story.

The investigators conducted a retrospective review in the Sunnybrook Odette Cancer Centre using data from the clinical database of the centre’s Familial Cancer Program in a tertiary care cancer centre. The impact of Angelina Jolie’s story on genetic counseling referrals was assessed by comparing the number of referrals made six months before and after the story. In addition, the quality of referrals was reported by comparing the number of patients who qualified for genetic testing as defined by the Ontario Ministry of Health and Long Term Care and the ones who carried a BRCA1/2 mutation before and after the media release.

Results of the research determined that the number of women referred for genetic counseling increased by 85 percent after the release of the actress’s story (479 before versus 887 after) translating to an increase of 99 percent in the number of women who qualified for a genetic testing (211 before versus 419 after). Among them, 120 and 254 women had a history of breast and ovarian cancer in their family, 16 and 37 women had a history of male breast cancer in their family, and 28 and 15 women were diagnosed with breast cancer at the age of 35 or less before and after AJs story respectively.

Furthermore, the number of BRCA1/2 carriers identified increased by 107 percent (29 (14 BRCA1, 15 BRCA2) before and 60 (32 BRCA1, 28 BRCA2) after).

The coauthors conclude that their study clearly shows that the number of genetic referrals doubled after the publicity surrounding Angelina Jolie’s story. Nevertheless, the quality of referral remained the same with nearly the same percentage of patients who qualified for genetic testing and who were identified as BRCA1/2 carriers. They contend that the challenge is to meet increased demand for cancer genetic services including screening, counseling, testing, and preventive surgery, and that after MS. Jolie’s story, the current model of genetic counseling may need to be revisited.

Genetic counseling at Sunnybrook involves screening, individual counseling and cancer risk discussions, testing and discussions about potential preventive surgical options. Specifically for BRCA gene mutation testing, individuals find out whether they have an inherited BRCA gene mutation, receive counseling and an assessment of their personal risk for breast cancer and or ovarian cancer, and discuss with genetic counsellors, management options including preventive (prophylactic) surgeries.

Dr. Allison Kurian is lead author and Scarlett Gomez, PhD, a research scientist at CPIC senior author of the Stanford study, entitled “Use of and Mortality After Bilateral Mastectomy Compared With Other Surgical Treatments for Breast Cancer in California, 1998-2011“ (JAMA. 2014;312(9):902-914. doi:10.1001/jama.2014.10707). Coauthors are: Christina A. Clarke, PhD, David O. Nelson, PhD, and Theresa H. M. Keegan, PhD, of the Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; and Daphne Y. Lichtensztajn, MD, MPH of the Cancer Prevention Institute of California at Fremont.

The researchers note that bilateral mastectomy is increasingly used to treat unilateral breast cancer, and because it may have medical and psychosocial complications, a better understanding of its use and outcomes is essential to optimizing cancer care.

“Given the recent attention around bilateral mastectomies, we wanted to know whether there are particular types of patients likely to receive a bilateral mastectomy,” says Dr. Gomez. “And, secondly, are there relative differences in mortality among the three procedures? We were able to address these questions using data from the California Cancer Registry, which covers nearly all women diagnosed with breast cancer in the state. The registry is enhanced with information on factors that may influence a treatment decision, including their socioeconomic status, health insurance and where they received their care.

Recent Increases In Double Mastectomies

Despite the fact that women who removed both breasts did not have better survival rates, the study found that rapidly increasing numbers of women are opting for the complex surgery, which requires a long recovery period and possibly reconstructive surgery.

The Stanford researchers say that the surge in bilateral mastectomy use despite absence of supporting evidence has puzzled clinicians and health policy makers, and that proposed explanations include increasing use of highly sensitive breast magnetic resonance imaging, with increases in anxiety-producing recall and biopsy rates that may drive patients to undergo preventive surgery, and the dissemination of genetic testing of BRCA1 (unigene cluster number Hs.194143) and BRCA2 (unigene cluster number Hs.34012), which facilitates identification of high-risk patients who benefit from bilateral mastectomy. BRCA1 and BRCA2 gene mutations are linked to up to half of hereditary breast cancers, about 5 to10 percent of all breast cancers, and about 15 percent of all ovarian cancers. However, the scientists observe that while genetic factors may legitimately be cited as justification for bilateral mastectomy, evidence for a survival benefit appears limited to rare patient subgroups, including women with BRCA1/2 mutations or strong family history of cancer, and although fear of cancer recurrence may prompt the decision for bilateral mastectomy, such fear usually exceeds the estimated risk.

Moreover, they maintain that because bilateral mastectomy is an elective procedure for unilateral breast cancer and may have detrimental effects in terms of complications and associated costs as well as on body image and sexual function, a better understanding of its use and outcomes is crucial to improving cancer care.

They observe that for the surgical treatment of early-stage breast cancer, available randomized trial data are limited to those showing no survival difference between unilateral mastectomy and breast-conserving surgery, but there is no randomized trial evidence to inform whether bilateral mastectomy improves survival, and they conclude that it is unlikely such a trial will ever be performed since patients are unlikely to accept randomization to a less extensive surgical procedure in a clinical trial. Consequently, observational studies offer a feasible alternative to address an important clinical question.

Physicians in California are legally required to report all cancer cases in the state to the Cancer Registry, and the researchers used this data to assess the outcomes of women diagnosed with stages 0 to 3 unilateral breast cancer that is, cancer affecting only one breast in the state from 1998 to 2011.

The Stanford release notes that the California registry is unique because it includes information about nearly every cancer case in the state. It captures important information, such as the stage of the disease, the surgical outcome chosen by the patient and her physician, and whether the patient eventually died from her disease. It also includes information about the patients racial or ethnic background and where she lived.

“The registry allows us to do a population-based study to gain a real-world picture of cancer cases in California,” comments Dr. Kurian. We can ask and answer questions that couldn’t be answered in a randomized clinical trial. For example, Drs. Kurian and Gomez point out that it would not be ethical to assign a woman randomly to one of the three common surgical options. But using the registry, they can simply track who received which intervention.

To minimize selection bias, the scientists designed a population-based study of the use and outcomes of bilateral mastectomy compared with other surgical treatments, using the California Cancer Registry (CCR, part of the National Cancer Institute [NCI] Surveillance, Epidemiology and End Results [SEER] program), which comprises about 99 percent of all breast cancer cases statewide.

The researchers found that of the 189,734 women in the study, 55 percent received a lumpectomy with follow-up radiation, 38.8 received a unilateral mastectomy and 6.2 percent received a bilateral mastectomy. Overall, the proportion of women receiving unilateral mastectomies declined during the study period, while the proportion of women receiving bilateral mastectomies increased. Racial and ethnic minorities, as well as women of lower socioeconomic status, were more likely than others to receive a unilateral mastectomy. In contrast, women who received a bilateral mastectomy were more likely to be middle- or upper-class, younger than 50 or non-Hispanic whites, or some combination of these.

The slightly lower survival rate among women who underwent a unilateral mastectomy could be due to the fact that these patients tended to be members of racial or ethnic minorities or have a lower socioeconomic status than other patient groups, or both, the researchers observe. Drs. Gomez and Kurian speculate that these patients may have been more likely to have other health problems, such as diabetes, that could have affected or limited the course or effectiveness of their cancer treatment. They may also have had difficulty securing transportation to radiation appointments or had other barriers in access to care.

The bilateral mastectomy procedure is particularly prevalent among non-Hispanic white women younger than 40 who have private insurance and receive care at a National Cancer Institute-designated cancer center. The release points out that in fact, 33 percent of women under age 40 received bilateral mastectomies in 2011, compared with 3.6 percent in 1998. (The prevalence of bilateral mastectomy among all patients in the study increased from 2 to 12.3 percent during the same time period.)

In contrast, racial or ethnic minorities and women with public insurance, such as Medicaid, were more likely to receive a unilateral mastectomy. One of Dr. Gomez’s particular research interests is Surveillance of cancer incidence, treatment, and survival among racial/ethnic, socioeconomic, immigrant, and underserved populations, and the roles of the social and built environment, institutional discrimination, immigration, and cultural factors on racial/ethnic disparities in cancer incidence and outcomes.

Drs. Kurian and Gomez emphasize that the study’s findings don’t mean that a woman with a BRCA1, BRCA2 or other gene mutation known to significantly increase the risk of developing breast cancer, or with a strong family history of breast cancer, should not get a bilateral mastectomy. A genetic predisposition may mean that removing both breasts is an effective option.

“We’re hopeful that this study will open a dialogue between a patient and her physician to discuss these kinds of questions.”

There are also other reasons why a woman might choose a bilateral mastectomy. Some newer breast-reconstruction methods achieve better symmetry when both breasts are reconstructed simultaneously. Removal of both breasts may also alleviate a woman’s fear and worry that a second cancer will occur in her remaining breast,” the researchers said.

“We’re hopeful that this study will open a dialogue between a patient and her physician to discuss these kinds of questions,” said Dr. Gomez. “It’s an important piece of evidence that can guide their decision-making process.”

The study was supported by the Suzanne Pride Bryan Fund for Breast Cancer Research, the Jan Weimer Junior Faculty Chair in Breast Oncology at the Stanford Cancer Institute, the National Cancer Institute, the California Department of Health Services and the U.S. Centers for Disease Control and Prevention.

More information about Stanford’s Department of Medicine and Department of Health Research and Policy, which also supported the work, can be found at http://hrp.stanford.edu and http://medicine.stanford.edu

Sources:
Stanford University School of Medicine
Journal of the American Medical Association
Sunnybrook Odette Cancer Centre
American Society of Clinical Oncology Breast Cancer Symposium
Cancer Prevention Institute of California

Image Credits:
Stanford University School of Medicine
Cancer Prevention Institute of California