Breast cancer risk when there is a family history

 

In a newly updated comprehensive summary,[1] the PDQ Cancer Cancer Genetics editorial board estimates that in 2017, 250,000 women will be diagnosed with breast cancer and about 40,000 women will die of their cancer. The incidence of breast cancer, particularly estrogen-receptor positive tumors, continues to decline, with a marked decline beginning in 2003, about the time hormone therapy for menopausal symptoms was restricted to fewer years of use for symptom relief and many women discontinued use altogether due to the results from the randomized controlled trial conducted by the Women’s Health Initiative.[2] Still, some women face greater risk of developing breast cancer than do others. The question of risk is especially compelling for the 5% to 10% of women whose mother or sister who has had breast cancer.

Women whose first-degree relatives have breast cancer appear to bear a two-fold increased risk, with a tight confidence interval, of developing it themselves when compared with women without such family history. If multiple relatives have had breast cancer, the risk increases by nearly three-fold if, and to nearly four-fold if one of those relatives developed her cancer before the age of 40. The risk also is increased if one of those relatives developed cancer in both breasts or multiple cancers in one breast. Breast cancer occurring in multiple male relatives is also associated with an increase in a women’s risk. Although the risk drops somewhat if the relative developed breast cancer at age 60 or older, it nonetheless is higher than for women who have no history of breast cancer in a first-degree relative.

Breast cancer is considered an autosomal dominant inherited cancer syndrome. In this case, a potentially affected woman has acquired a normal gene from one parent and a defective gene from the other, which can be either the mother or the father. The risk of inheriting an autosomal dominant gene is 50:50. Not everyone with an inherited autosomal dominant gene will develop cancer, according to the PDQ summary. That risk varies, depending on a number of factors. A number of genetic variants are associated with breast cancer; some are more likely to lead to disease than others. Most common of the highly penetrant genes are BRCA1 and BRCA2.

What are some clues that a woman may be more likely to have an inherited predisposition to breast cancer?

• Multiple cancers within her family
• Family member(s) developed cancer at a young age
• A single family member has had two or more primary cancers, of same or different types
• A male relative has had breast cancer

In addition to genetic contributions, other risk factors may influence a woman’s risk, the PDQ summary notes. Protective factors include parity and breastfeeding. Studies have suggested an increased risk associated with older age; early menarche and late menopause; benign breast disease or dense breast tissue; and early pregnancy among BRCA carriers. Oral contraceptive use may slightly increase a woman’s risk, independent of family history. Women who use hormone therapy for 5 or more years after menopause appear to have a 35% increased risk, based on the well-known randomized controlled trial by the Women’s Health Initiative.

Beyond reproductive factors, exposures and lifestyle behaviors may influence risk. Women who have one drink of alcohol every day could have an increased risk, with risk rising with increased intake.  Cigarette smoking has been found to have a weak association. Preliminary data suggests that BRCA carriers may have an increased sensitivity to radiation associated with breast cancer risk. A sedentary lifestyle might possibly contribute to risk. And being or becoming overweight also influences risk: increasing the risk for postmenopausal breast cancer but decreasing the risk for premenopausal cancer. For more information, see previous LateBreaker Body weight link to breast and endometrial cancer (and 11 others).

In very general terms, the relative risk posed by modifiable lifestyle risk factors is in the range of 30%, explains the summary. In other words, a woman who has a risk factor listed above, such as oral contraceptive use, late age at first birth, alcohol consumption, or overweight has a 1.3 increased relative risk compared to a woman who doesn’t have that specific risk factor. That 30% increased risk from a modifiable risk factor is imposed upon an underlying risk based on family or genetic history. For example, women who have no family history or genetic pathogenic variants may have a lifetime risk of 8.5%, but with an added modifiable risk factor, their risk will rise to about 11%. Women with two or three first degree relatives with breast cancer may have 21% or 25% lifetime risk, rising to 27% to 32%, respectively, with an added modifiable risk factor.

The PDQ summary cites studies showing that screening high risk women at younger ages and at more frequent intervals does detect breast cancer earlier. However, a family history of breast cancer is not associated with a woman’s likelihood of adhering to screening regimens. One survey cited did suggest that a significant motivator for screening was a physician’s recommendation. Women who undergo genetic testing undergo little distress, no matter whether they turn out to be carriers or non-carriers. Among carriers, risk-reducing surgery has shown to improve survival and to reduce the risk of developing breast cancer and chemoprophylaxis has shown to reduce the risk of contralateral breast cancer.

[1] PDQ Cancer Genetics Editorial Board. Genetics of breast and gynecologic cancers. January 20, 2017. Accessed at https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0032757/?report=printable#CDR0000062855__2725

[2] Writing Group for the Women’s Health Initiative Investigators . Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321