Esnakula, Ashwini

Quadruple-negative breast cancer (QNBC) is a triple-negative breast cancer (TNBC) subtype that lacks expression of the androgen (AR) receptor. Few studies have focused on this highly aggressive breast cancer, portending worse survival rates. We aimed to determine the following: (1) QNBC’s molecular and clinical characteristics and compare them with other subtypes and (2) QNBC’s association with clinicopathological factors and prognostic markers. We performed immunohistochemical evaluations of ARs on tissue tumor microarrays from FFPE tumor blocks of invasive ductal breast carcinomas in 202 African American women. Univariate analysis was performed using the chi-square test, with survival rates calculated using Kaplan–Meier curves. Overall, 75.8% of TNBCs were AR-negative. Compared to the luminal subtypes, TNBC and QNBC tumors were likely to be a higher grade (p < 0.001); HER2+/AR- and QNBCs were also larger than the other subtypes (p < 0.001). They also expressed increasing mean levels of proteins involved in invasion, such as CD44, fascin, and vimentin, as well as decreasing the expression of proteins involved in mammary differentiation, such as GATA3 and mammaglobin. We found no association between QNBC and stage, recurrence-free survival, or overall survival rates. The high prevalence of TNBC AR-negativity in these women could explain observed worse outcomes, supporting the existence of the unique QNBC subtype.

Abstract Background: High mammographic breast density is a strong, well-established breast cancer risk factor. A recent study found increased expression of stem cell markers in the areas of high breast density, but, whether stem cells may explain high breast cancer risk due to high breast density is unknown. We investigated the association between breast density and the risk of breast cancer by the status of stem cell markers CD44, CD24, and ALDH1A1 in the tumor. Methods: We included 223 postmenopausal women with primary invasive or in-situ breast cancer and 399 age-matched controls from Mayo Clinic Mammography Study. Percent breast density, absolute dense area and non-dense area were assessed using computer-assisted thresholding technique. Immunohistochemical analysis of the markers was performed on tumor tissue microarrays according to a standard protocol with commercial antibodies. Cases with positive staining (≥1% positively stained cells) on one or more cores were considered marker-positive. We used polychotomous logistic regression to quantify the associations of breast density measures with breast cancer risk by the status of each of the markers. Heterogeneity tests were conducted to compare the differences in associations by marker-defined tumor subtypes. Results: Of the 223 cancers in the study, 182 (82%) were positive for CD44, 83 (37%) for CD24 and 52 (23%) for ALDH1A1. Associations of percent density were not significantly different across any of the marker-defined subtypes (density 51%+ vs. 11-25%: OR=2.83, 95% CI 1.49-5.37 for CD44+ vs. OR=1.87, 95% CI 0.47-7.51 for CD44-, p-heterogeneity=0.66; OR=2.80, 95% CI 1.27-6.18 for CD24+ vs. OR=2.44, 95% CI 1.14-5.22 for CD24-, p-heterogeneity=0.61; OR=3.04, 95% CI 1.14-8.10 for ALDH1A1+ vs. OR=2.57. 95% CI 1.30-5.08 for ALDH1A1-, p-heterogeneity=0.94). Positive associations of absolute dense area and inverse associations of non-dense area with breast cancer risk were similar across marker-defined subtypes. Similar associations of breast density measures with breast cancer were seen when cancer subtypes were defined using combined marker expression status (none, one positive marker, or two and more positive markers). Conclusions: We found no evidence of differential associations of breast density measures with breast cancer risk by the status of stem cell markers. However, our power was limited and further studies in larger study populations are warranted to confirm these associations in a larger sample. Citation Format: Lusine Yaghjyan, Ashwini Esnakula, Christopher Scott, Akemi Wijayabahu, Matthew Jensen, Celine Vachon. Associations of mammographic breast density with breast stem cell marker-defined breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 592.