Study: New cancer risk estimates for BRCA1/2 mutation carriers

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Women with an inherited mutation in BRCA1 or BRCA2

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Cancer risk estimates for BRCA1 and BRCA2 mutation carriers are important because they impact patient decision-making. Until now, almost all risk estimates for mutation carriers were based on results of retrospective studies that looked back on mutation carriers who had cancer. This new study is prospective—it followed almost 10,000 BRCA mutation carriers without cancer to see if or when they developed breast or ovarian cancer. The cancer risk estimates of this study may be more accurate because it followed mutation carriers who did not have cancer over time. (7/28/17)


At a glance In-depth                            
Findings     Limitations               
Guidelines Resources and reference
Questions for your doctor  


This study is about:

Estimating age-specific risk of breast, ovarian and contralateral breast cancer (breast cancer in the other breast of patients who are already diagnosed with breast cancer) for BRCA mutation carriers.

Why is this study important?

Accurate cancer risk estimates are especially important for BRCA mutation carriers, because they impact patient medical decision-making. With more accurate cancer risk estimates, health care providers can better advise mutation carriers on when to begin cancer screening or consider risk reduction options.

Previously, most studies that estimated cancer risk for BRCA mutation carriers were retrospective—they developed estimates by looking back at patients who already had cancer. This new study is important because it included a large number of women and is prospective, meaning that it followed BRCA mutation carriers who did not have cancer forward over time. While prospective studies take a very long time, they can provide better risk estimates for use in patient decision-making.

Study findings:

  • Among the 9,856 women who had a BRCA mutation:
    • The lifetime breast cancer risk to age 80 was 72% for BRCA1 and 69% for BRCA2.
    • The lifetime ovarian cancer risk to age 80 was 44% for BRCA1 and 17% for BRCA2.
    • The lifetime risk of contralateral breast cancer 20 years after a breast cancer diagnosis was 40% for BRCA1 and 26% for BRCA2.
    • Cancer risks were different depending on family history and where a mutation was located in the BRCA1 or BRCA2 gene.

What does this mean for me?

This study may provide more accurate risk estimates for breast, ovarian and contralateral breast cancer for BRCA1/2 mutation carriers than previous retrospective studies. Because cancer risk estimates are used to help guide the timing of important decisions, these new estimates may change when BRCA mutation carriers consider screening and risk reduction options.  This study suggests that cancer risk estimates should be more personalized, and that they can be more precise with consideration of an individual’s unique family cancer history and where the mutation is located in the gene. Together, these results emphasize the importance of genetic counseling for BRCA mutation carriers.

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Expert Guidelines

The National Comprehensive Cancer Network (NCCN) is a consortium of experts in cancer and genetics. They create guidelines for cancer screening and prevention for people with inherited mutations associated with cancer risk. NCCN guidelines for women with BRCA1 and BRCA2 mutations include the following. 

Breast cancer screening

  • Learning to be aware of changes in breasts beginning at age 18
  • Clinical breast exam every 6-12 months beginning at age 25
  • Annual breast MRI with contrast (or mammogram if MRI is unavailable) beginning at age 25 
  • Annual breast MRI with contrast and mammogram at ages 30-75 
  • Consider 3D mammography if available
  • Screening after age 75 should be considered on an individual basis
  • Consider participation in an imaging or screening clinical trial

Breast cancer risk reduction

  • Discussion of risk-reducing mastectomy
  • Consider medication to reduce breast cancer risk
  • Ovarian cancer risk management
  • Risk-reducing removal of ovaries and fallopian tubes between age 35 and 40 and upon completion of child bearing.
  • Delaying risk-reducing removal of ovaries and fallopian tubes until age 40-45 is “reasonable” for BRCA2 mutation carriers, because the average age of ovarian cancer onset is 8-10 years later than in BRCA1 mutation carriers.
  • Routine ovarian cancer screening using transvaginal ultrasound and a CA-125 blood test is “of uncertain benefit” but may be performed at the doctor’s discretion starting at age 30-35.
  • Removal of Fallopian tubes only (salpingectomy) is not standard of care for ovarian cancer risk reduction.  There are ongoing clinical trials studying salpingectomy in women at high risk of ovarian cancer.

Pancreatic cancer and melanoma screening

  • No specific guidelines exist for pancreatic cancer and melanoma.  Screening for these cancer should be individualized based on cancers seen in the family.

Questions To Ask Your Health Care Provider

  • What is my risk for developing breast, ovarian, contralateral breast or other cancers?
  • What are my options for managing my risk for these cancers?
  • Was my particular family history of cancer included in estimating my cancer risk?
  • Does the type of mutation or the location of the mutation on the gene affect my cancer risk?


Study background:

For BRCA mutation carriers, accurate, age-specific cancer risk estimates are important because they affect medical decisions and their timing. Virtually all previous cancer risk estimates for BRCA mutation carriers have been based on retrospective studies. These studies reported breast cancer risk estimates ranging from 40% to 87% for BRCA1 mutation carriers and from 27% to 84% for BRCA2 mutation carriers.

Previous ovarian cancer risk estimates ranged from 16% to 68% for BRCA1 mutation carriers and from 11% to 30% for BRCA2 mutation carriers. The wide range of estimates was likely due to the way the different studies were designed: how families were selected, different characteristics of individual families, how the data were analyzed, and other genetic and lifestyle factors. 

Retrospective studies are less likely to produce accurate cancer risk estimates, particularly if an analysis is not adjusted for these factors. On the other hand, prospective studies in which participants are recruited based on their BRCA mutation status and are followed over a long period of time can avoid the limitations associated with retrospective studies. Thus, prospective studies are thought to provide more accurate cancer risk estimates.

For prospective studies, the accuracy of cancer risk estimates depends on both the number of people followed and length of follow-up. The more people followed for substantial periods of time, the more accurate the cancer risk estimates. This prospective study was conducted by Karoline Kuchenbaecker, PhD, of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, England and colleagues.

Researchers of this study wanted to:

  • Use data from a large prospective study to estimate age-specific risks of breast, ovarian, and contralateral breast cancer.
  • Determine how a family’s cancer history and location of the BRCA1 or 2 mutation in the gene modified an individual’s cancer risk.

Population(s) looked at in the study:

This study only included women with a known BRCA mutations. Women were recruited to participate in this study through several registries: the International BRCA1/2 Carrier Cohort Study (IBCCS), the Breast Cancer Family Registry (BCRF), and the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). The 9,856 study participants were from Europe, Australia, New Zealand, Canada, and the United States. Follow up for all participants was approximately 15 years.

  • The breast cancer risk analysis included 3,886 participants (39% of participants). Women were excluded if they were previously diagnosed with breast, ovarian, or other cancer before joining the study; had a risk-reducing bilateral mastectomy; or did not participate in scheduled follow-ups. 
  • The ovarian cancer risk analysis included 5,066 participants (51%). Women were excluded if they were previously diagnosed with ovarian or other cancer, had a risk-reducing salpingo-oophorectomy, or did not participate in scheduled follow-ups. 
  • The contralateral cancer risk analysis included 2,213 participants (22%) Women were excluded if they were previously diagnosed with contralateral breast cancer, ovarian cancer, or other cancer; or did not have a first breast cancer diagnosis at the end of the follow-up period. They were also excluded if they had risk-reducing bilateral mastectomy or did not participate in scheduled follow-ups.

Study findings: 

  • Of the 3,886 women eligible for the breast cancer risk analysis, 426 were diagnosed with breast cancer during follow-up.
    • Lifetime breast cancer risk estimates to age 80 were:
      • 72% for BRCA1  mutation carriers
      • 69% for BRCA2 mutation carriers
    • Breast cancer diagnoses increased rapidly in early adulthood until ages 30-40 for BRCA1 mutation carriers and until ages 40-50 for BRCA2 mutation carriers. The number of breast cancer diagnoses then remained constant.
  • Of the 5,066 women eligible for the ovarian cancer risk analysis, 109 were diagnosed with ovarian cancer during follow-up.
    • Lifetime ovarian cancer risk estimates to age 80 were:
      • 44% for BRCA1 mutation carriers
      • 17% for BRCA2 mutation carriers
  • Of the 2,213 women eligible for contralateral breast cancer risk analysis, 245 were diagnosed with contralateral breast cancer during follow-up.
    • Lifetime risk estimates of contralateral breast cancer 20 years after a breast cancer diagnosis were:
      • 40% for BRCA1 mutation carriers
      • 26% for BRCA2 mutation carriers
  • Breast cancer risks estimates differed depending on family history.
    • Risk was higher with increasing number of first- and second-degree relatives diagnosed with breast cancer for both BRCA1 and BRCA2 mutation carriers.
    • For women with a BRCA1 mutation and 2 or more first- or second-degree relatives diagnosed with breast cancer, the risk was 73% to age 70 compared to 53% for women with no family history.
    • For women with a BRCA2 mutation and 2 or more first- or second-degree relatives diagnosed with breast cancer, the risk was 65% to age 70 compared to 39% for women with no family history.
  • Cancer risks were different depending on the location of a mutation in the BRCA gene. (BRCA1 and BRCA2 mutations were grouped by location: in the beginning, middle, or end of the gene.)
    • BRCA1: Breast cancer risks were higher for mutations located in the beginning (68%) and end (71%) of the gene compared to those in the middle (56%).
    • BRCA2: Breast cancer risks were higher for mutations located in the beginning (69%) and end (67%) compared to those in the middle (51%).
    • The large middle region of the BRCA2 gene was previously described as the “ovarian cancer cluster region"; however, this study found no significant difference in ovarian cancer risk for mutations located in this region.


This study had several limitations.  Although this study found that cancer risk varied by family history, participants were identified through clinical genetic centers and were more likely to have a family history of cancer. Therefore, the overall cancer risk estimates may not be directly relevant for women who have a BRCA1 or BRCA2 mutation with no family history of cancer. The results of this study suggest that cancer risks are likely lower for mutation carriers with no family history; however, carriers who have small families, limited knowledge of their families cancer history, few female relatives or female relatives who died young of other causes, or had prophylactic removal of breasts or ovaries should not use these data to assume lower risks. Additionally, because no data (stage, hormone receptor status, etc.) were available on breast and ovarian cancers that developed in study participants, the results represent averages across all tumor types. Furthermore, life time risk estimates were based on a follow-up of 15 years. Actual life time risk may vary for younger participants (i.e. a participant who entered the study at age 30 and was followed to age 45 versus a participant who entered the study at age 60 and was followed to age 75). Finally, this study did not take into consideration the use of chemoprevention strategies (tamoxifen, aromatase inhibitors, etc.) to reduce breast cancer risk or the use of oral contraceptives to reduce ovarian cancer risk. 


For women with a BRCA mutation, the results of this study may provide less biased age-related cancer risk estimates than previous retrospective studies. These results should be used in conjunction with careful genetic counseling and family cancer assessment to guide mutation carriers and their health care providers in clinical decision making. This study demonstrates the importance of knowing your family history and the location of your BRCA mutation because this information may impact individual cancer risk.    

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Posted 7/28/17


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