Role of common risk factors in ER-positive, ER-negative breast cancer

What was the aim of the study?

The goal of the study was to examine how common breast cancer risk factors play a role in the development of estrogen receptor (ER)-positive versus ER-negative invasive breast cancer. Some breast cancer cells contain receptors that attach to the hormone estrogen that can fuel the growth of breast cancer cells. ER-positive tumors have receptors that attach to the hormone estrogen, whereas ER-negative breast cancers do not.

What led you to pursue this question?

Primary prevention with hormone therapy (selective estrogen receptor modulators or aromatase inhibitors) blocks the effects of estrogen in the breast tissue so cells don't receive the hormone estrogen's signals to grow and multiply. Hormone therapy leads to a decrease in the risk of estrogen receptor positive- but not estrogen receptor negative breast cancer. It is important to know which women are at increased risk for each cancer subtype so women at increased risk of ER-positive cancer can discuss with their provider hormone therapy as an option for prevention.

Does the study address gaps in existing research?

Most studies examining the role of risk factors in the development of breast cancer have examined risk of breast cancer overall, rather than by ER cancer subtype. Studies that have examined risk factors for ER cancer subtype have been small and inconsistent in their results. Our large prospective Breast Cancer Surveillance Consortium (BCSC) cohort study was able to examine risk for ER-positive and ER-negative invasive cancer with strong, prevalent risk factors according to a woman's age and menopausal status.

What are your chief findings?

We found family history of breast cancer in a first degree relative, benign breast disease, and breast density increased the risk for both ER-positive and ER-negative invasive breast cancer, but the level of risk varied by age. We also found postmenopausal women who were overweight or obese were similarly at increased risk of ER-positive and ER-negative cancer while peri/premenopausal women who were overweight or obese were at increased risk of ER-negative cancer to a greater extent than ER-positive cancer. Women at highest risk in our study had benign breast lesions with proliferative changes (overgrowth of the cells that line the ducts or the milk glands). These women were at high risk of ER-positive cancer.

Why is this new information? And why is it significant?

Prior studies show premenopausal women who are overweight or obese are not at increased risk of 'premenopausal' breast cancer because assessment of weight is measured close to the time of diagnosis. We found premenopausal women who are overweight or obese are at increased risk of breast cancer in the next ten years, and at greatest risk of ER-negative breast cancer which is more difficult to treat than ER-positive breast cancer.

Premenopausal covers a huge age variance -- is there heightened risk for overweight women in their 20s, 30s?

Premenopausal was defined as women who reported a menstrual period within the last 180 days, were under age 40, or birth control hormone users. Perimenopausal women were not sure if their periods had stopped; or their last menstrual period was 180-364 days ago.

What is the link between extra weight and increased risk?

Postmenopausal women who are overweight or obese have elevated circulating estrogens to promote breast tumor growth. Premenopausal women who are overweight or obese have high blood levels of insulin and insulin-like growth factor and chronic low-grade inflammation. It has been hypothesized that they are possible mechanisms by which obesity increases breast cancer risk in these women.

What are the implications of the findings?

These findings provide new information for women and providers about which women are at increased risk of ER-positive versus ER-negative breast cancer. This will aid discussions about preventive measures such as losing weight or the option of preventive hormone therapy.

Can the findings be incorporated into clinical practice?

Peri/premenopausal and postmenopausal women who are overweight or obese should be encouraged to lose weight to decrease breast cancer risk. Women with benign lesions that show proliferative changes on breast biopsies are at increased risk of ER-positive breast cancer and should calculate their 5-year risk of breast cancer using the BCSC risk calculator (https://tools.bcsc-scc.org/BC5yearRisk/). If risk is >3%, women should be counseled on preventive measures such as taking hormone therapy.

How much do premenopausal women have to be overweight to have higher risk? Can it be just 5 or 10 lbs. or does it have to be significant, say, 30 or more lbs.?

Overweight is six to seven pounds or more above what is considered ideal body weight for a woman's height.

What should women do to lower their risk?

Maintain ideal body weight for their height and exercise regularly.