A family history of breast cancer means having one or more blood relatives who have, or have had, breast cancer. These relatives could be on either the father’s or mother’s side of the family.
As breast cancer is common, many women will have a family history by chance. However, some women with a family history may have inherited a faulty gene which increases the risk of cancer. We all inherit a set of genes from each of our parents. Sometimes there is a fault, or mutation, in one copy of a gene which stops that gene working properly and this can lead to an increased risk of breast cancer.
Around 5% of breast cancers can be explained by an inherited gene fault. Genetic changes can also occur during our lifetime. On this page you will find information about family history of breast cancer and other cancers and genetic mutations which are associated with risk of breast cancer.
There are several genes in which mutations may be involved in the development of breast cancer, including rare to very rare high-risk gene mutations such as those in BRCA1 and BRCA2, TP53, PTEN, CDH1 and STK11 and some rare moderate-risk gene mutations such as PALB2, ATM and CHEK2.
It may be appropriate for some women who have a strong family history to be referred to a family cancer clinic. Family cancer clinics can provide a more precise risk assessment, advice about genetic testing and an individualised management plan.
- Information for women about family history of breast cancer and ovarian cancer (PDF 331.82 KB)
- Risk-reducing medication for women at increased risk of breast cancer due to family history (PDF 260.47 KB)
- Breast and ovarian cancer and inherited predisposition - educational genetics factsheet from NSW Health Centre for Genetics education.
Family history of breast cancer
Having a family history of breast cancer is associated with an increased risk of breast cancer.
However, most women who develop breast cancer do not have a family history of the disease. Because breast cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Only about 5% of breast cancer can be explained by an inherited gene fault. However, a family history on either the mother’s side or the father’s side increases a woman’s risk of breast cancer.
The significance of a family history of breast cancer increases with the number of family members affected and the younger their ages at diagnosis.
Women with one first-degree relative (parent, sibling or child) who has had breast cancer have about 2 times the risk of breast cancer compared to women with no family history. Women with two first-degree relatives who have had breast cancer have about 3 times the risk. Women with three or more relatives who have had breast cancer have nearly 4 times the risk.
Women with one or more second-degree relative who has had breast cancer have about 1.5 times the risk of breast cancer as women with no family history. A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.
It is important to note that a family history on the father’s side is just as important as on the mother’s side of the family.
The risk is higher if two or more relatives have other characteristics associated with increased risk, such as being diagnosed before age 50 or being of Ashkenazi Jewish descent.
Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.Family members have genetic factors in common and this might explain the association between family history of breast cancer and increased breast cancer risk. These genetic factors could include mutations in genes such as BRCA1 or BRCA2.
In addition, family members often have similar environments and lifestyles as each other. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that having a family history of breast cancer is associated with an increased risk of breast cancer
Women with one first-degree relative (parent, sibling or child) who has had breast cancer are estimated to have 1.80 (95% CI 1.69–1.91) times the risk of breast cancer as women with no family history.[1]
Women with two first-degree relatives who have had breast cancer are estimated to have 2.93 (95% CI 2.36–3.64) times the risk of breast cancer as women with no family history.[1]
Women with three or more first-degree relatives who have had breast cancer have about 3.9 (95% CI 2.03–7.49) times the risk of breast cancer as women with no family history.[1]
Women with one or more second-degree relatives who have had breast cancer are estimated to have 1.5 times (95% CI 1.4–1.6) the risk of breast cancer as women with no family history.[2] (A second-degree relative is an aunt, uncle, grandparent, grandchild, niece, nephew or half-sibling.)
Mechanisms
Family members share both genetic factors and environmental factors, both of which could contribute to an association between family history of breast cancer and increased risk of breast cancer. Genetic factors could include mutations in genes such as BRCA1 or BRCA2. Environmental factors include exposures, lifestyles and diets.[2,3]
Evidence
For women who have one affected first-degree relative (compared with women who have no affected relatives), meta-analyses have estimated a relative risk for breast cancer of 1.80 (95% confidence interval [CI] 1.69–1.91)[1] and 2.1 (95% CI 2.0–2.2).[2] Two more recent large cohort studies and a case–control study reported a similarly increased risk of breast cancer for women with 1 affected first-degree relative.[3-5]
For women with two affected first-degree relatives, a relative risk for breast cancer of 2.93 (95% CI 2.36–3.64) has been estimated in a meta-analysis.[1] For women with three or more affected first-degree relatives, a relative risk for breast cancer of 3.90 (95% CI 2.03–7.49) has been estimated in the same meta-analysis. Other studies have provided similar estimates of increased risk.[2,4,5]
For women with one or more affected second-degree relatives, the relative risk of breast cancer (compared with women who have no affected relatives) has been estimated in a meta-analysis as 1.5 (95% CI 1.4–1.6).[2]
The increased breast cancer risk associated with having a first-degree relative with breast cancer was found to be higher for younger compared with older women in a large meta-analysis[1] and in a cohort study.[3] One meta-analysis reported inconsistent findings on breast cancer risk according to the age of the person with a family history of breast cancer.[2]
The increased breast cancer risk associated with having a first-degree relative with breast cancer has also been found to be higher for women whose relative was diagnosed with breast cancer at a younger compared with an older age.[1-3,6]
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Family history of other cancers
Having a family history of some cancers other than breast cancer is associated with an increased risk of breast cancer.
The majority of evidence for increased risk of breast cancer for women with a family history of cancers other than breast cancer, exists for family history of ovarian cancer and/or prostate cancer and/or pancreas cancer.
Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.
Family members have genetic factors in common and this might explain the association between family history of cancers and increased breast cancer risk. For example, mutations or faults in the BRCA1 and BRCA2 genes increase the risk of ovarian cancer and prostate cancer as well as breast cancer. Faulty BRCA2 genes are also associated with pancreatic cancer. Since relatives share many genes, they also share the risk of cancers associated with the faulty genes.
In addition, family members often have similar environments and lifestyles, such as diet and levels of physical activity. These shared backgrounds could also contribute to the increased breast cancer risk in women with a family history of breast cancers.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that a family history of ovarian cancer and prostate cancer and probably some other cancers, including pancreatic cancer, is associated with an increased risk of breast cancer. The more relatives affected, the higher the risk. The risk is also higher if a woman also has a family history of breast cancer.
Mechanisms
Because cancer is a common condition, it is not unusual for more than one family member to develop cancer (including breast cancer) during their lifetime. Cancer can occur in more than one family member simply by chance or because of genetic, lifestyle or environmental factors.
Mutations in genes associated with increased risk of breast cancer are also associated with increased risk of some other cancers. For example, mutations in the BRCA1 and BRCA2 genes also increase the risk of ovarian cancer, and are associated with male breast cancer and prostate cancer. BRCA2 gene mutations are also associated with pancreatic cancer.[7]
Other gene mutations that increase the risk of both breast cancer and other cancers include PALB2 (pancreatic cancer), TP53 (associated with Li–Fraumeni syndrome and childhood sarcomas), CDH1 (associated with diffuse gastric cancer), PTEN (associated with Cowden syndrome, and thyroid and endometrial cancers) and STK11 (associated with Peutz–Jeghers syndrome, and gastrointestinal, pancreatic and gynaecological cancers). Similar biological mechanisms are likely to increase the risk of breast cancer and these other cancers.
In addition, family members tend to share environments and lifestyles, such as diet and levels of physical activity.
Some of these factors are associated with the risk of breast cancer.
Evidence
Family history of ovarian cancer
The risk of breast cancer in women from families with two or more first‐degree relatives with ovarian cancer has been estimated as 3.74 (95% confidence interval [CI] 2.04–6.28) for women under 50 years of age and 1.79 (95% CI 1.02–2.90) for women 50 years of age and older.[8]
From a large, population-based case-control study, the lifetime risks of developing breast cancer for a woman with one or two first-degree relatives with ovarian cancer were estimated to be 14% and 31%, respectively.[9]
Family history of prostate cancer
A large cohort study and a pooled analysis of case-control studies found that a family history of prostate cancer in a first-degree relative was associated with an increase in breast cancer risk (hazard ratio [HR] 1.14, 95% CI 1.02–1.26 and odds ratio [OR] 1.6, 95% CI 1.1–2.4, respectively).[10,11] A family history of both breast and prostate cancer in first-degree relatives was associated with a higher risk of breast cancer (HR 1.78, 95% CI 1.45–2.19).
An increased risk of breast cancer in women with a family history of prostate cancer was also found in a consecutive series study of prostate cancer families.[11] Breast cancer risk was higher for women who had more than one relative with prostate cancer, and relatives who were diagnosed with prostate cancer at younger ages.
Family history of pancreatic cancer
About 5% of patients with pancreatic cancer carry germline mutations in BRCA2. PALB2 gene mutations are also associated with increased risk of pancreatic cancer.
Family history of colorectal cancer
A large cohort study did not find a significant association between a family history of colorectal cancer and risk of breast cancer after adjustments for a family history of breast and prostate cancer (HR 1.08, 95% CI 0.99–1.19).[10] However, a family history of both breast and colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (HR 1.47, 95% CI 1.34–1.61).[10]
A pooled analysis of case–control studies found that a family history of colorectal cancer in first-degree relatives was associated with an increased risk of breast cancer (OR 1.5, 95% CI 1.1–1.9).[11] An increased risk of breast
cancer has also been found in women with either a first-degree (OR 1.26, 95% CI 1.08–1.45) or a second-degree relative (OR 1.21, 95% CI 1.07–1.36) with colon cancer in a population-based case–control study.[13]
Family history of other cancers
An association has been found between family history of haemolymphopoietic cancers and increased breast cancer risk in a network of case–control studies from Italy and Switzerland (OR 1.7, 95% CI 1.2–2.4).[14]
For Review
Single nucleotide polymorphisms
Having certain patterns of single nucleotide polymorphisms (SNPs) or variants in a woman’s DNA may be associated with an increased risk of breast cancer.
Information on a large number of individual SNPs associated with breast cancer risk can be combined into a ‘polygenic risk score’. Women who have the highest ‘score’ using this approach (in a study including 77 SNPs) have about 3 times the risk of breast cancer compared to women who have a score near the middle of the range of scores.
SNPs are normal variations in the genetic material (DNA) in our cells at many single locations (nucleotides) in the DNA. SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in human DNA. Most SNPs have no effect on health. They often act as ‘markers’ of genes that may be associated with a disease, such as breast cancer.
Summary of the evidence
Evidence classification: Convincing
There is convincing evidence that having a high polygenic risk score (PRS), based on certain patterns of a large number of individual single nucleotide polymorphisms (SNPs) or variants across the whole genome, is associated with an increased risk of breast cancer.
Women who have a PRS (based on 77 SNPs) in the highest 1% of the PRS distribution are estimated to have 3.36 times the risk of breast cancer as women in the middle quintile of the distribution (OR 3.36, 95% CI 2.95–3.83).[15] Women with a PRS in the lowest 1% of the PRS distribution are estimated to have 0.31 times the risk of breast cancer as women in the middle quintile of the distribution (OR 0.31, 95% CI 0.24–0.39).[15]
These data may be used in the future to provide more accurate risk prediction than family history alone. They may also be used to influence decisions on cancer risk management for women at high risk of breast cancer.[16,17]
Mechanisms
SNPs are normal variations in the DNA sequence at many single locations (nucleotides). SNPs are a common and normal type of genetic variation between people: about 10 million SNPs are thought to occur in the human genome. Most SNPs have no effect on health or development. They can act as biological markers of genes that may be associated with a disease such as breast cancer.[18]
SNPs associated with an increased risk of breast cancer are identified using genome-wide association studies (GWASs), which compare large numbers of SNPs between cases and controls. PRSs for breast cancer risk can then be developed based on combined scores for large numbers of SNPs.[15,19]
Evidence
A large GWAS and meta-analysis used an array of more than 500,000 SNPs for genotyping cases and controls.[18] It was estimated that 172 common susceptibility variants explain 18% of familial relative risk of breast cancer.[18] Another large GWAS estimated that 125 variants explain approximately 14% of the familial risk of oestrogen receptor-negative (ER-) breast cancer.[19]
A large collaborative case-control study found that the risk of breast cancer was increased for women in the highest 1% of a PRS based on 77 SNPs compared with women in the middle quintile, with an odds ratio (OR) of 3.36 (95% confidence interval [CI] 2.95–3.83).[15] Women in the lowest 1% of the PRS distribution had an estimated OR compared with women in the middle quintile of 0.31 (95% CI 0.24–0.39).[15] For women in the highest quintile of the PRS, the lifetime risk of breast cancer was 16.6% for women without a family history of breast cancer and 24.4% for women with a first-degree family history.1 For the lowest PRS quintile, women without a family history had a lifetime risk of breast cancer of 5.2%, and women with a family history had a lifetime risk of 8.6%.[15]
An association between PRS for breast cancer and breast cancer risk has also been found in other studies.[16,20,21] For example, a PRS based on 24 SNPs among women from two breast cancer familial cohorts in Australia, Canada, the US and NZ, was associated with increased breast cancer risk, with a hazard ratio [HR] for upper versus lower quintile PRS 3.18 (95% CI 1.84–5.23), and HR for continuous PRS (per standard deviation [SD]) 1.38 (95% CI 1.22–1.56).[21]
Incorporation of PRSs into models for predicting breast cancer risk has improved the performance of the models.[16,21]
For Review
References
[1] Collaborative Group on Hormonal Factors in Breast Cancer (2001). Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58 209 women with breast cancer and 101 986 women without the disease. Lancet 358(9291):1389–1399.
[2] Pharoah PDP, Day NE, Duffy S, et al. (1997). Family history and the risk of breast cancer: a systematic review and meta-analysis. International Journal of Cancer 71:800–809.
[3] Kharazmi E, Chen T, Narod S, et al. (2014). Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study. Breast Cancer Research and Treatment 144:185–192.
[4] Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
[5] Bevier M, Sundquist K, Hemminki K (2012). Risk of breast cancer in families of multiple affected women and men. Breast Cancer Research and Treatment 132:723–728.
[6] Colditz GA, Kaphingst KA, Hankinson SE et al. (2012). Family history and risk of breast cancer: nurses’ health study. Breast Cancer Research and Treatment 133(3):1097–1104.
[7] EviQ. 2018 Facts for people and families with a faulty BRCA2 gene https://www.eviq.org.au/cancer-genetics/consumer-information-sheets/3427-facts-for-people-and-families-with-a-faulty-b##what-is-the-risk-of-cancer-for-people-with-a-fault
[8] Sutcliffe S, Pharoah PD, Easton DF, et al. (2000) Ovarian and breast cancer risks to women in families with two or more cases of ovarian cancer. International Journal of Cancer 87(1): 110-117
[9] Claus EB, Risch N, Douglas Thompson W (1993). The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Research and Treatment 28(2):115–120.
[10] Beebe-Dimmer JL, Yee C, Cote ML, et al. (2015). Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121(8):1265–1272.
[11] Turati F, Edefonti V, Bosetti C, et al. (2013). Family history of cancer and the risk of cancer: a network of case-control studies. Annals of Oncology 24:2651–2656.
[12] Valeri A, Fournier G, Morin V, et al. (2000). Early onset and familial predisposition to prostate cancer significantly enhance the probability for breast cancer in first degree relatives. International Journal of Cancer 86:883–887.
[13] Slattery ML, Kerber RA (1993). A comprehensive evaluation of family history and breast cancer risk. JAMA: The Journal of the American Medical Association 270(13):1563–1568.
[14] Turati F, Negri E, La Vecchia C (2014). Family history and the risk of cancer: genetic factors influencing multiple cancer sites. Expert Review of Anticancer Therapy 14(1):1–4.
[15] Mavaddat N, Pharoah PD, Michailidou K, et al. (2015). Prediction of breast cancer risk based on profiling with common genetic variants. Journal of the National Cancer Institute 107(5):1–15.
[16] Li H, Feng B, Miron A, et al. (2016) Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab. Genetics & Medicine 19(1):30–35.
[17] Kuchenbaecker K, McGuffog L, Barrowdale D, et al. (2017) Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. JNCI: Journal of the National Cancer Institute 109(7).
[18] United States National Library of Medicine (2018). Genetics Home Reference: What are genome-wide association studies?, https://ghr.nlm.nih.gov/primer/genomicresearch/gwastudies.
[19] Milne RL, Kuchenbaecker KB, Michailidou K, et al. (2017). Identification of ten variants associated with risk of estrogen receptor-negative breast cancer. Nature Genetics 49(12):1767–1778.
[20] Dite GS, MacInnis RJ, Bickerstaffe A, et al. (2016). Breast cancer risk prediction using clinical models and 77 independent risk-associated SNPs for women aged under 50 years: Australian Breast Cancer Family Registry. Cancer Epidemiology, Biomarkers & Prevention 25(2):359–365.
[21] Shieh Y, Hu D, Ma L, et al. (2016). Breast cancer risk prediction using a clinical risk model and polygenic risk score. Breast Cancer Research and Treatment 159(3):513–525.
