JNCI: Breast density tied to more aggressive tumors

Mammogram reveals increased density (arrow) of the right breast. Image source: Indian J Radiol Imaging 2010 May;20(2):98–104.

Women with mammographically dense breasts not only face a higher risk of breast cancer, but their tumors also are more likely to have more aggressive characteristics than women with less dense breasts, according to a study published online July 27 in the Journal of the National Cancer Institute.

Although the connection between higher breast density and higher cancer risk is well-established, the association between breast density and breast cancer tumor characteristics has been unclear.

A research team, led by Lusine Yaghjyan, MD, PhD, from the department of medicine at Brigham and Women’s Hospital and Harvard Medical School in Boston, aimed to clarify differences in the association between breast density and subsequent risk of breast cancer according to invasiveness, histological type, grade, size, involvement of lymph nodes and the status of estrogen receptor (ER), progesterone receptor (PR) and HER2.

The prospective study comprised a subset of postmenopausal women from the Nurses’ Health Study: 1,042 women diagnosed with breast cancer between June 1, 1989 and June 30, 2004 and 1,794 matched controls.

Researchers estimated breast density with the assistance of software and divided women into four groups (< 10 percent density, 10 to 24 percent, 25 to 49 percent and > 50 percent). They investigated differences in the association of breast density with various pathological subtypes of breast cancer.

Yaghjyan and colleagues confirmed that the risk of breast cancer increased progressively with increasing breast density. “In the multivariable analysis, the risk of breast cancer statistically significantly increased by 3.39-fold in women with 50 percent or greater breast density compared with women with 10 percent or less breast density,” they wrote.

In addition, breast density was linked with both in situ and invasive breast cancer; however, the association was stronger for in situ disease.

Yaghjyan and colleagues offered several explanations for these findings, which diverged from previous data. The stronger link between density and in situ cancers could be due to chance. Alternately, women with dense breasts are more likely to have an abnormal mammogram followed by biopsy, which could detect in situ tumors. Finally, mammography is more sensitive for in situ tumors than invasive disease.

The associations between density and subtypes were stronger for larger (> 2 cm) tumors than for smaller tumors; for high-grade than for low-grade tumors; and for ER^- than for ER⁺ tumors.

The researchers noted that ER^- and ER⁺ tumors are believed to be etiologically different and added, “Identifying the risk factors specific to ER^- tumors would help researchers understand the etiology of ER^- breast cancer and develop subtype-specific risk prediction models.”

There was no association between density and other markers of tumor aggressiveness, such as nodal involvement and HER2 status.

Yaghjyan and colleagues acknowledged limitations to the study. Specifically, it was restricted to postmenopausal women, so findings may not apply to premenopausal breast cancer.

The authors concluded that higher mammographic density is associated with more aggressive tumor characteristics and also with DCIS. “Our results suggest that breast density influences the risk of breast cancer subtypes by potentially different mechanisms,” they wrote. “Further studies are warranted to explain underlying biological processes and elucidate the possible pathways from high breast density to the specific subtypes of breast carcinoma.”

The accompanying JNCI editorial agreed that understanding the biological links between breast density and specific tumor subtypes could help physicians understand more about breast cancer risk and the molecular causes of breast cancer.

Karla Kerlikowske, MD, of the University of California, San Francisco, and Amanda I. Phipps, PhD, of Fred Hutchinson Cancer Research Center, Seattle, emphasized that the study was the first to find a stronger association between breast density and ER^- tumors than ER⁺ tumors.

They cautioned, however, that this stronger association might be partly due to the masking effect. “Masking of a tumor can occur because cancerous tissue and mammographically dense tissue have similar x-ray attenuation, allowing tumors to go undetected on screening mammography examination and progress to a more advanced and aggressive stage before detection,” they wrote. This may have contributed to the link between breast density and ER^- tumors because ER^- tumors are more frequently missed by screening mammography. The authors did not determine whether the tumors were detected by screening mammography.

The editorialists also offered other possible reasons for the strong link between density and aggressive tumors, including the interaction of increased numbers of stromal and epithelial cells in dense breasts and exposure to postmenopausal hormones.

“Given that the magnitude of the association with breast density is strong across all breast cancer subtypes and particularly for ER-negative disease, breast density should be included in risk prediction models across tumor subtypes,” Kerlikowske and Phipps concluded.