#1 | October 2023

Hereditary breast and ovarian cancer: BRCA1/2

For most women who get breast and ovarian cancer, the condition will be of the sporadic variety rather than one of the inherited types. Most women with inherited breast and/or ovarian cancer carry a deleterious mutation in one of two susceptibility genes: breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2).

These mutations are inherited in an autosomal dominant way. In families with BRCA mutations, several generations of women may be found to have had breast and/or ovarian cancer. Males with these mutations are also at risk of developing breast cancer. [1] [2]

Women with a BRCA1 mutation are more likely to have triple-negative breast cancer compared to those with a BRCA2 mutation or BRCA mutation negative. In the US the chance of having a BRCA mutation is approximately 1 in 400. [1]

Table 1: Lifetime risk in percent

Isaacs C et al. Cancer risks and management of BRCA1/2 carriers without cancer. Available at uptodate.com. Accessed 31/07/2023

BRCA1 mutations are associated with early onset breast cancer before the age of 50 years. One study showed the mean age of BRCA1 breast cancer to be 43 years compared to 47 years for BRCA2 breast cancers. The risk of developing ovarian cancer is higher for BRCA1 carriers compared to BRCA2 carriers but the overall risk of onset of ovarian cancer before the age of 40 is low. [3]

Women with a BRCA mutation who have developed breast cancer are at much higher risk of developing a second primary breast cancer compared to women with breast cancer without a BRCA mutation (60% vs. 10% lifetime risk). [1]

Other cancers for which women with BRCA mutations appear to be at higher risk of developing are listed below.[1] [2]

Cancers for which female BRCA carriers are at increased risk of include:

  • Fallopian tube carcinoma
  • Primary peritoneal carcinoma
  • High-risk uterine carcinoma

Cancers for which both male and female BRCA carriers are at increased risk of include:

  • Pancreas
  • Colorectal

Cancers for which male BRCA carriers are at increased risk of include:

  • Male breast cancer
  • Prostate cancer

BRCA1/2 Cancer Risk Management

Major recommendations for BRCA mutation carriers are as follows:

Female BRCA Carriers

  • Breast awareness starting at age 18
  • Clinical breast exams every 6-12 months starting age 25
  • Annual breast MRI from ages 25 to 29
  • Annual mammogram and breast MRI from ages 30 to 75
  • Consideration of chemoprevention and risk-reducing mastectomy
  • Risk-reducing salpingo-oophorectomy between age 35 and 40 and when childbearing is complete

Male BRCA Carriers

  • Breast self-examination training and education
  • Clinical breast exam every 12 months starting at age 35
  • Prostate cancer screening with annual PSA at age 40 and annual physical examination for BRCA2 mutation carriers

Isaacs C et al. Cancer risks and management of BRCA1/2 carriers without cancer. Available at uptodate.com. Accessed 31/07/2023

BRCA1/2 mutation carriers mortality considerations

Cause-specific mortality drivers for female BRCA1 carriers by decreasing magnitude are ovarian cancer in 41% of cases, followed by breast cancer 36% of cases, followed by other causes in 23% of cases. For female BRCA2 carriers the cause-specific mortality drivers by decreasing magnitude arise from causes other than breast and ovarian cancer in 44% of cases, followed by breast cancer in 36% of cases, followed by ovarian cancer 20% of cases. [4]

Markov models of breast and ovarian cancer mortality in BRCA1/2 mutation positive women have shown that BRCA1 mutation carriers who do not undertake any form of ovarian or breast cancer risk-reducing management appear to have estimated mortality ratios of approximately 2 to 3 times that of standard mortality. For those who opt for annual screening only, the mortality remains double that of standard mortality. For those who opt for a single surgical intervention (either prophylactic bilateral mastectomy or prophylactic bilateral oophorectomy) their relative risk of mortality is approximately 1.5. Women with BRCA1 that opt for both prophylactic surgeries (bilateral mastectomies and bilateral oophorectomy) start to approximate the mortality of their non-carrier peers. [5]

For female BRCA2 mutation carriers who do not engage with recommended forms of ovarian and breast cancer risk-reducing interventions the estimated mortality ratios appear to be between 1.2 to 1.4 times that of standard mortality. For BRCA2 women who undergo enhanced screening the relative risk of mortality is reduced to 1.1 - 1.2 and those who opt for prophylactic mastectomies only appear to have mortality ratios of approximately 1.0 to 1.1. For those that undertake combinations of recommended interventions the mortality risk from breast and ovarian cancer appears to be the same as their unaffected peers with mortality ratios approximating standard mortality. [5]

Based on limited available data BRCA mutations in males appear to exert a modest mortality effect with one study estimating an average 3.7-year reduction in life expectancy when compared to non-carriers. [6]

Underwriting BRCA1/2 Mutation Carriers

For assistance underwriting BRCA1/2 mutation carriers Hannover Re’s hr | Ascent underwriting manual offers an easy-to-use BRCA Mutation Calculator – see image below. For more information, speak to your local Hannover Re underwriting contact.

Author

Nico van Zyl MBBCh MSc

VP & Chief Medical Director

Hannover Life Reassurance Company of America

References

  1. Isaacs C et al. Cancer risks and management of BRCA1/2 carriers without cancer. Available at uptodate.com. Viewed on 31 July 2023.
  2. Mersch J et al. Cancers Associated With BRCA1 and BRCA2 Mutations Other Than Breast and Ovarian. Cancer 2015;121:269-75
  3. van der Kolk, D.M., de Bock, G.H., Leegte, B.K. et al. Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age. Breast Cancer Res Treat 124, 643–651 (2010). https://doi.org/10.1007/s10549-010-0805-3
  4. Kurian AW et al. Survival Analysis of Cancer Risk Reduction Strategies for BRCA1/2 Mutation Carriers. Journal of Clinical Oncology, January 10, 2010.
  5. Sigal BM et al. A Simulation Model to Predict the Impact of Prophylactic Surgery and Screening on the Life Expectancy of BRCA1 and BRCA2 Mutation Carriers. Cancer Epidemiology, Biomarkers and Prevention, 21(7) July 2012.
  6. Mai PL et al. Potential Excess Mortality in BRCA1/2 Carriers Beyond Breast, Ovarian, Prostate, and Pancreatic Cancers and Melanoma. PLoS ONE, March 2009 Vol 4 Issue 3.

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