Surgical Management of BRCA Carriers: Risk Reducing Mastectomy and BSO Mary L. Gemignani, MD, MPH Attending Surgeon, Breast Service, Department of Surgery Program Director, Breast Surgical Fellowship Memorial Sloan Kettering Cancer Center New York, NY

[Audio] I would like to thank Dr. El Tamer and Dr. Albashir for the invitation to participate in the 5th International Multidisciplinary Breast Conference. I will be discussing surgical management of BRCA carriers..

[Audio] Topics for today will include surgery for risk reduction in unaffected carriers including the use of bilateral mastectomy and risk reducing salpingo oophorectomy for breast and ovarian cancer risk reduction. I will also discuss surgery in affected carriers, breast conserving surgery and mastectomy with use of contralateral prophylactic mastectomy. I will cover recent data on the role of risk reducing mastectomy in women who have breast cancer. As we go along I will highlight controversies, and newer data regarding each topic..

[Audio] As we know the majority of breast cancers are not associated with hereditary genes. The two most common genes linked to the hereditary breast and ovarian cancer syndrome are BRCA1 and BRCA2..

[Audio] Tumor biology is different for the cancers associated with these mutations. For BRCA1 the cancers are more likely to be high grade, with very low amount of DCIS. 70- 90% are ER negative, more aggressive subtypes were the use of chemotherapy is likely. Breast cancer associated with BRCA2 are moderate to high grade, with low amount of Dcis. 75% are likely to be ER+ ( same profile we see in sporadic, and thus more likely to have better clinical outcomes..

Cancer Risks and Estimates. Considerable variability in published estimates for carriers of BRCA1 and BRCA2 mutations Variations in study design and analysis Differences in populations studied Likelihood of developing breast and/ or ovarian cancer multifactorial Age at time of counseling/ intervention 10-year risks and lifetime risks Family history Higher among carriers with positive family history Type of cancer and age of onset.

[Audio] Interquartile range Estimated Cumulative Risks of Breast and Ovarian Cancer in Mutation Carriers Kaplan-Meier estimates of cumulative risks of breast and ovarian cancers. In the breast cancer analysis, women were censored at risk-reducing bilateral mastectomy. In the ovarian cancer analysis, women were censored for risk-reducing salpingo-oophorectomy. Number at risk indicates the number of women who remained at risk at the end of the 10-year age category (eg, in panel A, there were 138 women with BRCA1 mutations still at risk of breast cancer at the end of the age 50- 60 years period). The earliest follow-up started at age 18 years. Prospective Cohort 6036 BRCA1 and 3820 BRCA2 carriers 5036 unaffected; 4810 with breast and/or ovarian cancer 1997- 2011 Recruited from large national studies in the UK, Netherlands and France Follow up ended Dec 2015 ( median 5 year).

[Audio] Genotyping information available Mostly population based No overlap of patients included in other studies Tables such as these are very helpful for discussion of 10 year risks for women as they are making decisions for risk reducing surgery. For example a 30 year old womn has a 10% 10 year risk of developing breast cancer with a BRCA1 mutation, and that will increase in the next decade or so. A 50 year old wom has about a 2%/ year risk of develoing breast cancer in the next decade of her life.

[Audio] Screen-detected cancers smaller and more likely to be lymph node negative Interval cancers more frequent than non-carriers No impact on survival.

Selection of Preventive Options. Prophylactic surgery remains the most effective modality for reducing both cancer risk and mortality No comparison of surgical vs non-surgical intervention in randomized studies For those choosing surgical intervention type of surgery recommended and timing is an issue.

Risk Reducing Mastectomy.

[Audio] It is now well established form multiple studies showing significant risk reduction with use of bilateral risk reducing mastectomy., magnitude in risk reduction of 90- 95% in pathogenic gene carriers. It is important to discuss with women that this is a strategy for risk reduction and that it is impossible to remove 100% of the breast tissue during a mastectomy, and practicing breast awareness in the future is important..

[Audio] NCCN and other groups have emphasized discussion of options of RRM for affected carries. It is important to discuss the high degree of protection, but also a multidisciplinary approach as well as a review of the potential side effects and complications of the procedure..

[Audio] Although we discuss risk reducing surgery very much in the clinic, the uptake for use of the type of risk reducing surgery does vary by intervention. Greater percentage of women are more likely to proceed with RRSO after testing, than RRM. Makes sense given poor screening tools for early detection of ovarian cancer. And although with increase media and more social acceptance of the use of RRM the numbers the percentage of women choosing these interventions is increasing. Chai X 2014 1499 NR 46[break]% 45% BRCA1 34% BRCA2 RSO by age 40.

[Audio] RRM is associated with significant body iimage changes, and the issue of regret is an important component in decision making. In this.

[Audio] In this older study utilizing a volunteer national registry from 43 states 370 women completed detailed questionnaires. It identified patient acceptance of BPM quite high, but more important the physician initiated discussion and recommendation for BPM had a significant impact on regret, and those women who were engaged in the decision process were less likely to have regrets compared to women who felt that they were told they should do it. These consultations are often long and quite complex, with multiple visits.

[Audio] Retrospective review from Mayo clinic1 Prophylactic surgery 1960- 1993 ( 639 women) Two groups: high risk and moderate risk Controls: sisters of high risk proband, and Gail model for moderate risk Risk reduction 90[break]% 1Hartmann LC, et al. N Engl J Med. 1999; 340( 2): 77- 84..

[Audio] It has been noted that preservation of the nipple areolar complex is associated with improved body image and patient satisfaction. Use of NSM in BRCA carriers is more prevalent. These 3 studies do highlight the potential for complications, and only 1 subsequent cancer after NSM was noted with a median follow up of less than 3 years in the studies. Long term data will be forth coming as these data mature..

[Audio] Changing gears to use of risk reducing bilateral salpingo oophorectomy.

[Audio] We know that RRSO offers excellent risk reduction for ovarian cancer. Most ovarian cancer presents in a late stage, and there are limited alternative and screening options for detection. NCCN a recommend between age 35- 40 Risk reduction of ovarian cancer 85- 100[break]% Limited alternatives and screening options for ovarian cancer Although ovarian cancer rarely occurs in pre-menopausal women, RRSO prior to menopause is recommended Breast cancer risk reduction 46- 68[break]% Reduces cancer incidence and overall mortality Laparoscopic surgery low associated morbidity 4[ break]%.

RRSO. Common choice for surgical intervention for BRCA carriers Survey of BRCA carriers 1 60% underwent RRSO 25% underwent BRRM 12% tamoxifen use Quality of life survey – RRSO associated with fewer breast and ovarian cancer worries and more favorable cancer risk perception 2.

[Audio] In this recent Cochrane Review we note that the use of risk reducing salpingo-oophorectomy in women with BRCA mutations has a significant reduction in overall mortatlity of 68[break]%.

[Audio] Further examination of the impact of risk reducing salpingo oophorectomy on high grade serous ovarian cancer shows a specific 94% reduction in mortality..

[Audio] The impact of the use of Risk reducing salpingo oophorectomy on breast cancer risk reduction is debatable..

[Audio] Multiple older studies have shown a significant risk reduction for breast cancer with use of bilateral salpingo oophorectomy. In a meta analysis by Rebbeck et all, there was a reduction for both BRCA1 and 2 with a hazard ratio of 0.49. However, more recent studies have been less encouraging. Kotsopolos et al recently reported on 3,722 women of which 1522 had BSO. They did not a breast cancer risk reduction for either, and only risk reduction they noted was for those women with BRCA2 who had risk reducing salpingo oophorectomy before the age of 50.

[Audio] In this prospective study of 2,482 with BRCA mutations from the Prevention and Observation of Surgical Endpoints Consortium risk reducing salpingo oophorectomy was associated with a redcution of all cause mortaility HR 0.4, breast cancer specific mortality HR 0.44 and more evident if bilateral salpingo oophorectomy was done prior to age 50 and ovarian cancer specific mortality..

[Audio] Another study also did not find a risk reduction and controlled for potential bias by requiring no history of cancer at the date of testing, and inclusion of person-time analysis..

[Audio] A Cochrane review incorportating the previous study and others concluded that the impact of risk reducing salpingo oophorectomy on breast cancer incident to have a modest reduction. However these results should be interprerted with caution because of study designs, risk of bias proiiles as well as very low numbers of women with BRCA2 mutations. Very low certainty data. Further research on these outcomes is warranted to explore differential effects for BRCA1 and BRCA2..

[Audio] All of this studies highlight the question whether RRSO alone is sufficient intervention for reduction of breast cancer risk in carriers, outside of its protection for risk of ovarian cancer? This should be discussed for women who are contemplating the choices for risk reducing surgery..

[Audio] It is now though that most or all ovarian cancer originates in the fallopian tubes, thus such an interest in the use of salpingectomy for ovarian cancer risk reduction in BRCA carriers..

[Audio] Interesting in using the strategy of salpingectomy with delayed oophorectomy can certainly be debated. In the pro argument, the salpingectomy avoids a portion of pelvic serous cancer, ( and serous tubal intraepithelial carcinoma) while avoiding premature menopause. It can certainly be an option for those women who will not agree to risk reducing bilateral salpingo-oophorectomy, and maintains potential for an IVF pregnancy. However, the con argument it is important to note it subjects women to 2 surgery, may results in further delay in removing the ovary, may not be as effective, and certainly does not offer ANY reduction in breast cancer risk. Salpingectomy is currently not the standard of care and should be discouraged outside of clinical trial. ( NIH trial started recruiting 2013, and in active follow up- non randomized – proof of concept study. SEROUS TUBAL INTRAEPITHELIAL CARCINOMA IS A RARE PATHOLOGIC finding arising in the distal fimbriated end of fallopian tube and likely represents a precursor lesion to high grade pelvic serous carcinoma Hysterectomy and opportunistic salpingectomy registry study.

[Audio] What about the uterus?. Hysterectomy at time of RRSO.

[Audio] 6- 7% complication rate. PROS. Ensures removal of all tube Simplifies hormonal management Potential advantage of Estrogen only hormonal replacement on Breast cancer risk Decreases risk of endometrial cancer ? Association of BRCA 1 mutation and uterine serous carcinoma For Tamoxifen users.

What is the Role of HRT?. Sexual symptomatology is the single biggest predictor of satisfaction with RRSO. 1 Data from WHI likely does not apply to women having premenopausal RRSO Early studies HRT does not increase breast cancer risk in BRCA mutation carriers after oophorectomy – regardless of HRT type Subsequent studies suggest that cHRT (E+P) does increase risk 1 Robson M, et al. Gynecol Oncol 2003.

[Audio] One such study that further explores the issue of type of hormone replacement therapy after oophorectomy on breast cancer risk among BRCA1 carriers was recently published in 2018. This prospective analysis of 872 BRCA1 carriers undergoing risk reducing salpingo-oophorectomy found that the use of estrogen only hormone replacement therapy does not increase risk while those women taking both estrogen and progestin had increased risk. Perhaps this argues for the consideration of hysterectomy at time of risk reducing salpingo-oophorectomy..

Timing and Surgical Decisions.

Choice of Risk Reducing Options. RRSO as top choice Highest overall cancer protection Reduces risk of both ovarian and some breast cancer RRSO reduces overall mortality and cancer specific mortality Lower morbidity of intervention Side effect profile favorable Acceptable quality of life.

Timing of Procedure RRSO. BRCA1 : 11-21% risk of ovarian cancer by age 50. 1,2 BRCA2 : 2-3% risk of ovarian cancer by age 50. 1,2 Oophorectomy after menopause is not associated with a decrease in breast cancer risk. 3 1 King MC, et al. Science 2003 2 Satagopan J, et al. Clin Can Res 2002 3 Rebbeck TR et al. JNCI 1999.

[Audio] Switching discussion to surgical treatment in affected carriers.

[Audio] We know outcomes are similar for breast conservation as for mastectomy, but multiple studies have shown that breast conservation is associated with second primary breast cancer risk of 1.7%- 4% depending on age of diagnosis. An older woman with a BRCA2 mutation for example would not have the same risk as a 30 year old woman with breast cancer who carries a BRCA1 mutation. We do know there is increased risk of Contralateral breast cancer in mutation carriers. A meta analysis of 11 studies showed pooled contralateral breast cancer risk of about 24% in carriers compared to 6.8% in non carriers. Younger age at diagnosis and multiple first affected relatives is associated with increased risk of contralateral breast cancer.

[Audio] Kuckenbaecker et al, reported on 2,213 women and found that the contralateral breast cancer risk at 20 years form diagnosis varied by mutation type, and higher for the BRCA1 carriers..

[Audio] As we think about contralateral breast cancer risk, lets explore the effect of Contralateral mastectomy on survival.

[Audio] Data from studies examining contralateral prophylactic mastectomy in BRCA carriers after diagnosis of breast cancer show reduction in mortaility of 66- 81%. All these Studies include long study time periods Difference in treatment options, less modern approach No routine MRI screening It is also important to note that CPM was carried out many years after initial diagnosis and survival calculated from initial diagnosis thus leading to a potential increased survival bias..

[Audio] A more recent study by the Danish Breast Cancer Group noted differences in outcomes between BRCA1 and 2 and were likely due to differences in tumor biology. They did note a a benefit of CPM on overall survival but no effect on disease free survival. It was also noted that RRSO had no effect on either disease free or overall survival.

[Audio] Turning further attention into the issue of RRSO on survival in BRCA carriers.

[Audio] Data from studies with use of risk reducing salpingo oophorectomy in BRCA carriers after diagnosis of breast cancer show reduction in mortality. Finch et al, found reduction in all cancers before age 70 by 77[break]% Domechek et al found reduction in mortality but did not reduce the incidence of contralateral breast cancer. Metclafe et al reported on 676 BRCA carriers of which 345 had bilateral salpingoophorectomy however the mean time from diagnosis was 6 years. They found the strongest protective effect for ER- breast cancers in BRCA1 patients. However, this is counterintuitive, as women with BRCA1 mutations have higher proportion of ER- breast cancers where hormonal manipulation and endocrine therapies have never been effective. Further research is necessary, for the youngest of women where the risk of ovarian cancer is low, and the long term side effects from surgical menopause are high..

Conclusions. Surgical risk reduction strategies are effective Important to consider Magnitude of risks based on age at counseling The effectiveness of surgical interventions and side effects associated with each Understand individual patient’s risk tolerance and preferences regarding surgery or alternative options such as surveillance, and chemoprevention.

Conclusions. Surgical Discussion in women with BRCA mutations Contralateral Risk Discussion of all surgical options risks and benefits NSM, BCT, Bilateral Role of RRSO for ovarian cancer protection in both affected and unaffected carrier is well defined.

Thank you for your Attention!.