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KirsimariAaltonen

Genetic Susceptibility to Breast Cancer

Essentials

  • About 5-10% of women developing breast cancer are estimated to have genetic susceptibility involving moderate or high risk of the disease.
  • Gene mutations causing susceptibility to breast cancer are autosomal dominantly inherited, the most significant mutations being located in the BRCA1 and BRCA2 tumour suppressor genes (susceptibility to breast cancer and ovarian cancer).
  • Genetic testing is done in specialized care. For patients with cancer, the tests are diagnostic, for healthy family members prognostic.
  • Gene mutation carriers are referred for intensified surveillance and/or assessment for interventions.
  • Local epidemiology and practices may differ from those presented in this article. Find out about local situation and policies.

Criteria for referral to a clinical geneticist

  • Below is a list of criteria for referral to a clinical geneticist as defined by the Finnish Breast Cancer Group care guideline. Find out about locally applied criteria.
    • At least 3 cases of breast and/or ovarian cancer in near relatives, with at least one before the age of 50 years
    • 2 cases of breast cancer in near relatives, both before the age of 50 years
    • Breast cancer before the age of 40 years
    • Medullary or triple-negative breast cancer before the age of 60 years
    • Bilateral breast cancer before the age of 50 years
    • Breast and ovarian cancer in the same woman
    • Male breast cancer
    • At least 2 cases of ovarian cancer in near relatives
    • Other cancers in addition to breast and ovarian cancer in near relatives at a young age, raising suspicion of a known cancer susceptibility syndrome
  • Near relatives here means first (parents, siblings, children) or second degree relatives (grandparents, aunts, uncles, grandchildren). When assessing first degree relatives, male relatives are not considered. Separate cancers occurring in an individual patient are counted separately. The patient's cancer(s) are included when counting cases of cancer in the family.

Genetic testing for susceptibility to breast cancer

  • A clinical genetics unit assesses whether the criteria for diagnostic genetic testing are met. Such testing is done for any woman with breast cancer who probably carries a gene mutation. A gene panel test covering all genes associated with genetic susceptibility for breast cancer that are considered significant is normally used as the diagnostic gene test.
  • Finding the gene mutation will facilitate predictive genetic testing of family members at risk Hereditary Susceptibility to Cancer.

Surveillance of gene mutation carriers

  • For any gene mutation carrier, the risk of developing breast cancer is assessed and surveillance planned accordingly.
    • If the risk is considered moderately increased:
      • Breast imaging (mammography and/or ultrasonography) about once a year is usually recommended.
      • Surveillance should be carried out according to locally agreed practice but it can often be done in outpatient care unless the patient's breast cancer is being followed up in specialized care.
      • The age of beginning surveillance is determined by the detected gene mutation and family history.
      • Attending a public screening mammography programme is usually sufficient from the age of 60 years if not earlier.
    • If the risk is considered high:
      • Annual breast imaging is normally started at the age of about 25 years. Imaging normally includes MRI as long as this is considered to provide additional benefit.
      • Surveillance is usually carried out in specialized care.
      • If the patient has several high-risk gene mutations, prophylactic mastectomy can be considered if he/she so wishes and if his/her health permits. After bilateral prophylactic mastectomy, there is no longer any need for surveillance by repeated imaging in specialized care.
  • If the detected gene mutation involves the risk of another type of cancer, surveillance is planned according to the recommendations approved at that time.

BRCA1 and BRCA2 gene mutations

  • About 2% of women developing breast cancer carry the BRCA1 or BRCA2 gene mutation.
  • The risk of such a gene mutation carrier of developing breast cancer within her lifetime is about 70%. The exact individual risk of disease may vary depending on family history, type of gene mutation and other risk factors. Breast surveillance should be planned according to the guideline for surveillance in high-risk cases.
  • The risk of breast cancer begins to increase earlier than in the general population.
  • Women with the gene mutation who have had breast cancer have a clearly increased risk of a second breast cancer.
  • Gene mutation carriers have an increased risk of epithelial ovarian, fallopian tube or peritoneal cancer.
    • In BRCA1 gene mutation carriers, the average risk is about 44%, in BRCA2 mutation carriers about 17%.
    • Ovariectomy and salpingectomy are recommended when having children is no longer relevant, usually no later than at the age of about 40 years for BRCA1 mutation carriers and 45 years for BRCA2 mutation carriers.
    • Ultrasound surveillance of the ovaries has not proved beneficial.
  • Men carrying the gene mutation have a higher lifetime risk of breast cancer than the general population but the absolute risk is still low (about 1-2% for BRCA1 carriers and 7-8% for BRCA2 carriers). Surveillance of asymptomatic men by imaging is not recommended but any palpable changes in the chest should be examined.
    • Male carriers have an increased risk of developing metastasizing prostate cancer, in particular, and PSA monitoring and examinations of the prostate have been recommended for them from the age of about 40 years. The increased risk has been shown more clearly in carriers of the BRCA2 gene mutation.
  • The risk of pancreatic cancer is slightly increased, particular if pancreatic cancer has been diagnosed in a near relative. Surveillance of the pancreas in asymptomatic people is not recommended but this can be considered based on family history.
  • BRCA1 or BRCA2 gene mutations do not necessarily affect the type of breast cancer developing in the carrier but medullary and triple-negative breast cancers are more common in BRCA1 mutation carriers than in the general population.
  • In BRCA1 or BRCA2 mutation carriers, mastectomy is used more often than conservative surgery to treat breast cancer. Gene mutation carriership does not affect pharmacotherapy of breast cancer, so far, but there is initial evidence of a higher sensitivity to carboplatin than to docetaxel.
  • Targeted genetic testing in the family is performed in adults; gene mutations are currently not considered to pose a significant cancer risk for children or adolescents.

High or moderate risk PALB2, CHEK2 and ATM gene mutations

  • Women carrying the PALB2 gene mutation have a lifetime risk of about 50% of developing breast cancer. The risk of disease varies depending on family history and may be even higher if there are several cases of breast cancer in near relatives. Surveillance including breast MRI is usually carried out in specialized care.
    • The risk of women carrying the PALB2 gene mutation of developing ovarian cancer is somewhat increased, at least if there has been ovarian cancer in near relatives. Not all factors affecting the risk are known as yet. The risk is not significantly increased before the age of 50. Prophylactic ovariectomy or salpingectomy can be considered in individual cases with ovarian cancer in near relatives.
    • The risk of other cancers or the risk in male carriers of the gene mutation does not appear to be increased significantly enough for surveillance to be automatically needed.
    • Among Finnish people, the most common PALB2 gene mutation is c.1592del, which can be found in about 1% of Finnish breast cancer patients.
  • CHEK2 gene mutations involve a high or moderate risk of breast cancer. The risk depends significantly on family history and other genetic factors.
    • In female carriers of the gene mutation, the risk and recommendations for surveillance are assessed individually, and breast surveillance can be done either in outpatient care or in specialized care.
    • In most cases, no other surveillance is automatically necessary.
    • Among Finnish people, the most common CHEK2 gene mutation is c.1100delC carried by about 1.5-2% of all Finns.
  • ATM, BARD1 and possibly FANCM gene mutations appear to involve a usually moderately increased risk of breast cancer and RAD51C, RAD51D and BRIP1 gene mutations appear to involve an increased risk of ovarian cancer. It is less clear whether the latter types of mutation involve any risk of breast cancer.

Cancer susceptibility syndromes involving (also) susceptibility to breast cancer

  • The cancer susceptibility syndrome caused by TP53 gene mutations (Li-Fraumeni syndrome)
    • Involves a high risk of developing breast cancer at an early age, even before the age of 30 years
    • Involves an increased risk of various types of cancer (such as osteosarcoma or soft-tissue sarcoma, adrenocortical carcinoma, CNS tumour, childhood cancers) at an earlier age than average, and an increased risk of developing multiple cancers
    • Breast surveillance should be implemented as for high-risk cases. Prophylactic mastectomy may be an option.
    • Regular imaging and clinical surveillance may be done if there are other risks for cancer. Surveillance is done in specialized care.
    • Radiotherapy should be avoided as far as possible. Smoking, sunburn and exposure to other carcinogens should also be avoided.
  • The Peutz-Jeghers syndrome due to STK11 gene mutations involves a high risk of breast cancer in women.
  • The PTEN hamartoma tumour syndrome due to PTEN gene mutations involves a high risk of breast cancer in women.
  • The susceptibility to diffuse gastric cancer due to CDH1 gene mutations involves also a high risk of lobular breast cancer in women.
  • Women with the NF1 syndrome have a high risk of developing breast cancer before the age of 50, and they are currently recommended annual breast MRI at the ages of 30-50 and mammography at the ages of 35-50.
  • Such cancer susceptibility syndromes can often be suspected based on a typical family cancer history. However, gene-panel tests can also reveal gene mutations in atypical families or, for example, in patients with a negative family history falling ill at a young age, in the case of new mutations.

Multifactorial susceptibility

  • In many families, no single gene mutation can be detected that would explain the cases of breast cancer. As breast cancer is a common disease, some cases may be incidental or there may be unknown or multifactorial susceptibility.
  • There may be a gene mutation type in a known susceptibility gene that is not recognized by current methods, or the gene mutation may be situated in a currently unknown susceptibility gene.
  • Clustering of breast cancers in certain families is thought to be largely due to multifactorial susceptibility.
  • Hundreds of common variants have been recognized that as such have little effect on the risk of breast cancer but combined will explain a lower or higher than average risk of breast cancer. The effect of such variants can be described by the polygenic risk score (PRS); calculation of the score is not yet common practice. Common risk variants also appear to partly explain why the CHEK2 gene mutation, for instance, involves a higher risk of disease in some families and a lower risk of disease in other families.
  • Due to multifactorial susceptibility or the possibility of an unknown gene mutation, the risk of breast cancer based on family history may be assessed as higher than average even if no mutation can be found in any known susceptibility genes. In such cases, beginning breast surveillance by imaging at an earlier age may be recommended for women who are near relatives.
  • The need for surveillance recommendations is assessed at a clinical genetics unit. A family member consulting a clinical geneticist is given a recommendation for surveillance of near relatives (which relatives should be involved, when imaging should be started and what form it should take).
    • Surveillance of family members can usually be done in outpatient care. Healthy women in the family need not be referred to the clinical genetics unit but breast surveillance should be carried out according to the recommendation given to the family member assessed by the clinical geneticist.

References

  • Kuchenbaecker KB, Hopper JL, Barnes DR et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017;317(23):2402-2416. [PubMed]
  • Breast Cancer Association Consortium., Dorling L, Carvalho S et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med 2021;384(5):428-439. [PubMed]
  • Hu C, Hart SN, Gnanaolivu R et al. A Population-Based Study of Genes Previously Implicated in Breast Cancer. N Engl J Med 2021;384(5):440-451. [PubMed]
  • Yang X, Leslie G, Doroszuk A et al. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol 2020;38(7):674-685. [PubMed]
  • Weischer M, Bojesen SE, Ellervik C et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 2008;26(4):542-8. [PubMed]
  • Lee AJ, Cunningham AP, Tischkowitz M et al. Incorporating truncating variants in PALB2, CHEK2, and ATM into the BOADICEA breast cancer risk model. Genet Med 2016;18(12):1190-1198. [PubMed]
  • Easton DF, Pharoah PD, Antoniou AC et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015;372(23):2243-57. [PubMed]
  • Frebourg T, Bajalica Lagercrantz S, Oliveira C et al. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet 2020;28(10):1379-1386. [PubMed]
  • Mavaddat N, Michailidou K, Dennis J et al. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes. Am J Hum Genet 2019;104(1):21-34. [PubMed]