Identifying Risk Factors for Triple-Negative Breast Cancer

Barbara Boughton

March 04, 2011

March 4, 2011 — Two of the largest studies to date looking at triple-negative breast cancer have found that reproductive factors — specifically, pregnancy and multiple childbirth — and obesity and lack of physical activity increase the risk for the disease. This subtype of breast cancer, which is negative for estrogen receptor, progesterone receptor, and HER2, accounts for 10% to 20% of all breast cancers.

Both studies used data from more than 155,000 women enrolled in the Women Health's Initiative. In that cohort, 307 women were diagnosed with triple-negative breast cancer after a follow-up of 8 years, and 2610 were diagnosed estrogen-receptor (ER)-positive breast cancer.

One study, looking at body size and physical activity, was published online March 1 in Cancer Epidemiology, Biomarkers & Prevention; the other, looking at reproductive history, was published online February 23 in the Journal of the National Cancer Institute.

In the first study, the researchers found that obese women had a 35% higher risk for triple-negative breast cancer than women with the lowest body mass index (BMI); in the second study, women who had never given birth had a 40% lower risk for the disease than those who had experienced a full-term pregnancy. Surprisingly, the number of births affected the risk for triple-negative breast cancer; women who had given birth to 3 or more children were at higher risk than women who had given birth to 1 child (hazard ratio [HR], 1.46; 95% confidence interval [CI], 0.82 to 2.63).

"We found that there were very similar associations between obesity and physical inactivity and both triple-negative and ER-positive disease," said Amanda Phipps, PhD, the lead researcher for both studies and a postdoctoral fellow in the public health sciences division of the Fred Hutchinson Cancer Research Center, in Seattle, Washington, in an interview with Medscape Medical News.

"Our finding that there was a 40% decreased risk for triple-negative breast cancer among women who had never given birth is inconsistent with the existing literature, but not many people have looked at risk factors for this disease, because it's so rare," Dr. Phipps said. Previous research has found either a modest or no association between childbirth and risk for triple-negative breast cancer, she noted.

Different From Other Subtypes

"Our results suggest that triple-negative breast cancer can be a very different disease from other subtypes, and studies that look at risk factors really need to take that into account," Dr. Phipps said. The results suggest that although the hormonal changes of pregnancy make the breast less susceptible to ER-positive cancer, these mechanisms do not affect the risk for triple-negative disease, she noted. And the association between obesity and physical activity and triple-negative disease suggests that mechanisms other than hormonal levels influence the risk for this subtype of breast cancer, she added.

The study of obesity and physical activity found that women in the highest BMI quartile had a 1.35-fold increased risk for triple-negative breast cancer, compared with women in the lowest quartile (95% CI, 0.92 to 1.99); in contrast, women in the lowest quartile had a 1.39-fold increased risk for ER-positive breast cancer, compared with women in the highest quartile (95% CI, 1.22-1.58). Women in the highest physical activity tertile had a lower risk for both triple-negative (HR, 0.77; 95% CI, 0.51 to 1.1.3) and ER-positive (HR, 0.85; 95% CI 0.74 to 0.98) disease.

In the study on reproductive factors, nulliparity was linked to a decreased risk for triple-negative breast cancer (HR, 0.61; 95% CI, 0.37 to 0.97) but an increased risk for ER-positive breast cancer (HR, 1.35; 95% CI, 1.20 to 1.52). Although number of births was associated with an increased risk for triple-negative breast cancer in the study that looked at reproductive risk factors, it was inversely associated with the risk for ER-positive disease (HR for 3 or more births vs 1 birth, 0.88; 95% CI, 0.74 to 1.04).

The small number of women who developed triple-negative breast cancer was a limitation for both studies, and is most likely the reason that the findings on obesity and physical inactivity and risk for triple-negative breast cancer were not statistically significant, Dr. Phipps acknowledged.

Although both studies are among the largest studies ever done on triple-negative breast cancer, more research needs to be done to confirm the findings, Dr. Phipps said. "We'd also like to study the association between these risk factors and younger women," she added.

Dr. Phipps speculated that the findings on the association between pregnancy and an increased risk for triple-negative breast cancer might be due to an abnormal response of the breast to pregnancy. The researchers suggest that obesity and physical inactivity might increase the risk for triple-negative breast cancer by affecting insulin-like growth factors or inflammatory changes in the breast.

Other Mechanisms Involved?

"Obesity and physical inactivity are thought to affect estrogen levels, but this Women's Health Initiative study indicates that other mechanisms may be more important for triple-negative breast cancer," said Leena Hilakivi-Clarke, PhD, professor of oncology at the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC. She said that inflammatory changes to the breast are the most likely explanation for the findings on obesity and exercise, since they might promote or even initiate the cancer process.

Dr. Hilakivi-Clarke was not involved in these studies, but has conducted research into risk factors for breast cancer, and was approached for comment by Medscape Medical News.

Dr. Hilakivi-Clarke noted that the population of women with triple-negative breast cancer in both studies was too small to really advance our understanding of the disease. "But it does reinforce the fact that there are even more reasons for women to maintain a normal weight and to be physically active," she said.

Dr. Hilakivi-Clarke found the findings on reproduction and triple-negative breast cancer to be particularly interesting. "Future research might look at animal models to see what happens if a tumor that was ER-positive to begin with is exposed to pregnancy," she said. If women already have a malignancy, the hormonal load of pregnancy might cause them to turn the estrogen receptors off," she added.

Dr. Phipps and Dr. Hilakivi-Clarke have disclosed no relevant financial relationships.

Cancer Epidemiol Biomarkers Prev. Published online March 1, 2011. Abstract

J Natl Cancer Inst. Published online February 23, 2011. Abstract