ICARE Newsletter Summer 2016

What Are the Endometrial Cancer Risks Among BRCA Carriers?

Although BRCA mutations confer increased risk for ovarian, fallopian tube, and primary peritoneal cancer, there have been limited and conflicting risks reported for endometrial cancer. Consequently, current practice guidelines only recommend the removal of the fallopian tubes and ovaries as a risk-reducing option for BRCA carriers.1 Specifically, through a prospective study of 4500 women with a BRCA mutation, there were 17 women identified with endometrial cancers (13 in BRCA1 and 4 in BRCA2) with an average follow-up time of 5.7 years.2 This suggested an overall endometrial cancer risk of 2-fold; although risks were higher (~4-fold) in those who received tamoxifen. The incidence of endometrial cancer was 2% at 10-years among those treated with tamoxifen. A subsequent study by the same group suggested the increased endometrial cancer risks among those with a history of tamoxifen use was associated with progesterone-only hormone replacement therapy, which warrants further study.3 These findings suggest that tamoxifen contributed substantially to the endometrial cancers seen among BRCA1 mutation carriers, although the actual risk is still fairly small. Consequently, in those considering tamoxifen, it may be important to discuss hysterectomy at the time of risk-reducing salpingo-oophorectomy (RRSO).

More recently, a prospective study of almost 1,100 BRCA carriers who had previously undergone removal of their tubes and ovaries, demonstrated an increased risk in BRCA1 carriers for a type of endometrial cancer called serous/serous-like. In this study, 8 women with endometrial cancer (of which 5 were serous/serous-like) were identified over an average follow-up time of 5.1 years.4 This suggested an overall elevation in endometrial cancer risk of almost 2-fold. The association of serous/serous-like endometrial cancer is particularly relevant as it only accounts for approximately 10% of endometrial cancer cases in the general population and is typically associated with aggressive disease and poor prognosis. As eloquently reviewed in the Leath et al editorial for this article,5 the risk of serous endometrial cancer among BRCA1 carriers may warrant a discussion of the potential risks and benefits of hysterectomy at the time of RRSO as well as a discussion about the limitations of our current knowledge in order for patients to make an individualized decision. In fact, a recent report of cancer risks among relatives of over 1000 BRCA mutation carriers detected no increased risk of endometrial cancer,6 highlighting the limited (if any) elevation of endometrial cancer risk. Taken together, these findings emphasize the need for further studies to refine risks and determine the need for hysterectomy both at time of RRSO as well as the role (if any) of risk-reducing hysterectomy among those who have already had an RRSO (as the risk of a second surgery may be greater than the risk of endometrial cancer).

1National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Genetic Familial High-Risk Assessment: Breast and Ovarian. Version 1.2016. Retrieved from: www.nccn.org.
2Segev Y, et al. Gynecol Oncol. 2013 Jul;130(1):127-31. PMID: 23562522.
3Segev Y, et al. Fam Cancer. 2015 Sep;14(3):383-91. PMID: 25838159.
4Shu CA, et al. JAMA Oncol. 2016 Jun 30. PMID: 27367496.
5Leath CA, et al. JAMA Oncol. 2016 Jun 30. PMID: 27367041.
6Streff H, et al. Oncologist. 2016 Jul;21(7):869-74. PMID: 27306910.




ICARE Newsletter Winter 2015

Ask the Expert

The following question was addressed to Dr. Steven Narod who is a Tier I Canada Research Chair in Breast Cancer and a senior scientist at Women’s College Research Institute in Toronto, Canada. Dr. Narod is a world-leader in the field of breast and ovarian cancer genetics. Over the course of his career, he has profoundly shaped current knowledge about cancer risks, prevention and screening amongst carriers of BRCA1 and BRCA2 mutations.

Q. As a BRCA mutation carrier, how much does Tamoxifen reduce my chance of developing contralateral breast cancer?

A. Following an initial breast cancer diagnosis in BRCA mutation carriers, the annual risk for developing contralateral breast cancer (i.e., breast cancer in the other breast) is 3%.1 We have mainly relied on studies evaluating contralateral breast cancer risk reduction with Tamoxifen. These studies have suggested that in women with breast cancer and a BRCA mutation, Tamoxifen reduces the lifetime risk of contralateral breast cancer by ~50%, particularly among those who still have their ovaries.3, 4, 5 Only one study to date with fewer than 20 carriers evaluated Tamoxifen for primary breast cancer prevention and showed risk reduction in BRCA2; however, risk reduction was not confirmed in BRCA1 (but it is important to note that this was a small sample size because there might not have been enough women to find an effect).2 Consequently, Tamoxifen may be considered in BRCA carriers with at risk breast tissue, especially among those who are premenopausal and have their ovaries.

More recently, we evaluated how the duration of Tamoxifen use affected contralateral breast cancer risk.6 We found that the risk of contralateral breast cancer was reduced by about half in those who used Tamoxifen for a short time (less than one year). These results do not imply any changes to the recommended course of Tamoxifen in the context of a breast cancer diagnosis because the primary goal in this situation would be to reduce risk of recurrence. However these results may be relevant for women without a breast cancer diagnosis who are considering Tamoxifen for primary prevention. In these women, consideration of a short course of Tamoxifen may be preferred over the recommended 5-year course, particularly given that many women are reluctant to take the drug because of the fear of side effects.7

Ultimately, we urge women to have a balanced discussion of the potential benefits and harms of Tamoxifen with their healthcare providers to enable them to make an informed decision about using this medication.

1. Metcalfe K, et al. British Journal of Cancer. Apr 26 2011;104(9):1384-1392. 2. King MC, et al. Jama. Nov 14 2001;286(18):2251-2256. 3. Gronwald J, et al. International Journal of Cancer.May 1 2006;118(9):2281-2284. 4. Narod SA, et al. Lancet. Dec 2 2000;356(9245):1876-1881. 5. Phillips KA, et al. J Clin Oncol. Sep 1 2013;31(25):3091-3099. 6. Gronwald J, et al. Breast Cancer Res Treat. Jul 2014;146(2):421-427. 7. Cuzick J, et al. Lancet. Mar 22 2014;383(9922):1041-1048.




ICARE Newsletter Winter 2014

Tamoxifen May Reduce Contralateral Breast Cancer Risk in BRCA Carriers

There have been suggestions that Tamoxifen may reduce risks for contralateral breast cancer (i.e., breast cancer in the other breast) in BRCA carriers if taken after the initial breast cancer diagnosis, based mainly on retrospective studies. Only one prospective study has looked at this question, and showed that Tamoxifen may be useful in BRCA2, but did not find an association in BRCA1 (however there were less than 20 BRCA carriers in this study, which is limiting).1 More recently, a study led by Australian researchers investigated almost 2500 women based on combined prospective and retrospective data.2 Although this was a nonrandomized design, the study was able to demonstrate that Tamoxifen use was significantly associated with a reduction in contralateral breast cancer risk in both BRCA1 and BRCA2 mutation carriers. These findings suggest that Tamoxifen may be considered for breast cancer prevention in BRCA carriers with breast tissue, particularly those who are pre-menopausal and have their ovaries. A balanced discussion of the potential benefits and harms of Tamoxifen enables these women to make an informed decision as to whether they may wish to consider this medication.

1. King MC et al. JAMA. 2001 Nov 14;286(18):2251-6. PMID: 11710890.2. Phillips KA et al.  J Clin Oncol. 2013 Sep 1;31(25):3091-9. PMID: 23918944.