Risk of second primary contralateral breast cancer by molecular phenotype of the first primary breast cancer

554 Background:
 Breast cancer survivors have a 60% higher risk of developing contralateral breast cancer compared to women who have never had breast cancer have of developing breast cancer. However, relatively little is known about what factors predispose breast cancer patients to develop contralateral breast cancer. In particular, it is largely unknown how the expression of various tumor markers and the molecular phenotypes of first primary breast cancers influence risk.
 Methods:
 We conducted a nested-case control study within the cohort of invasive breast cancer cases 21-64 years of age diagnosed in the Seattle-Puget Sound region from 1996-2007. Cases were women diagnosed with a first invasive breast carcinoma who subsequently developed contralateral breast cancer (n=268). Controls were frequency matched to cases by age at first breast cancer diagnosis and year of diagnosis (n=825). We abstracted available tumor marker information from pathology reports. Using conditional logistic regression we evaluated how the expression of markers in first tumors were associated with risk of developing contralateral breast cancer. In addition, we assessed risk by molecularly defined breast cancer phenotypes including luminal (ER+/PR+), basal-like (ER-/PR-/HER2-), and HER2-overexpressing (ER-/HER2+) tumors. We also conducted case-only analyses to assess the correlation between expression of markers in first and contralateral tumors.
 Results:
 Women with basal-like first tumors had a 3.3-fold (95% CI: 1.6-7.0) increased risk of contralateral breast cancer, and women with HER2-overexpressing first tumors had a 5.9-fold (95% CI: 0.3-101.6) increased risk, compared to women with luminal first tumors. Compared to women with HER2-negative first tumors, women with HER2-positive tumors had a 1.5-fold (95% CI: 0.9-2.5) increased risk of developing contralateral breast cancer. Women with HER2-positive first tumors were 9.2-fold (95% CI: 2.4-35.9) more likely to develop a second HER2-positive tumor compared to women whose first tumor was HER2-negative. Other tumor markers including Ki-67 and p53 did not influence contralateral breast cancer risk.
 Conclusion:
 These results suggest that women with particularly aggressive molecularly defined subtypes of breast cancer, including basal-like, HER2-overexpressing, and HER2+ tumors, have elevated risks of developing contralateral breast cancer. In addition to the established increased risks of mortality that these women experience, they may also have a disproportionately increased risk of contralateral breast cancer. If confirmed, these findings may also be relevant to advancing our understanding of the etiology of contralateral breast cancer.