Cora, Renata

Abstract Background Mammographic breast density (MBD) decline post-tamoxifen initiation is a favorable prognostic factor in estrogen receptor (ER)–positive breast cancer (BC) and has potential utility as a biomarker of tamoxifen response. However, the prognostic value of MBD decline may vary by molecular characteristics among ER–positive patients. Methods We investigated associations between MBD decline (≥10% vs <10%) and breast cancer–specific mortality (BCSM) among ER–positive breast cancer patients aged 36-87 years at diagnosis treated with tamoxifen at Kaiser Permanente Northwest (1990-2008). Patients who died of BC (case patients; n = 62) were compared with those who did not (control patients; n = 215) overall and by tumor molecular characteristics (immunohistochemistry [IHC]–based subtype [luminal A–like: ER–positive/progesterone receptor [PR]–positive/HER2–negative/low Ki67; luminal B–like: ER–positive and 1 or more of PR–negative, HER2–positive, high Ki67] and modified IHC [mIHC]–based recurrence score of ER/PR/Ki67). Percent MBD was measured in the unaffected breast at baseline mammogram (mean = 6 months before tamoxifen initiation) and follow-up (mean = 12 months post-tamoxifen initiation). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed from logistic regression models. All statistical tests were 2-sided. Results MBD decline was statistically significantly associated with reduced risk of BCSM overall (OR = 0.38, 95% CI = 0.15 to 0.92). This association was, however, stronger among women with aggressive tumor characteristics including luminal B–like (OR = 0.17, 95% CI = 0.04 to 0.73) vs A–like (OR = 0.74, 95% CI = 0.19 to 2.92); large (OR = 0.26, 95% CI = 0.08 to 0.78) vs small (OR = 0.41, 95% CI = 0.04 to 3.79) tumors; PR–negative (OR = 0.02, 95% CI = 0.001 to 0.37) vs PR–positive (OR = 0.50, 95% CI = 0.18 to 1.40) disease; and high (OR = 0.25, 95% CI = 0.07 to 0.93) vs low (OR = 0.44, 95% CI = 0.10 to 2.09) mIHC3 score. Conclusion The findings support MBD decline as a prognostic marker of tamoxifen response among patients with aggressive ER–positive BC phenotypes, for whom understanding treatment effectiveness is critical.

Abstract Reduced age-related terminal duct lobular unit (TDLU) involution has been linked to increased breast cancer risk and triple-negative breast cancer. Associations of TDLU involution levels with race and ethnicity remain incompletely explored. Herein, we examined the association between genetic ancestry and TDLU involution in normal breast tissue donated by 2014 healthy women in the United States. Women of African ancestry were more likely than European women to have increased TDLU counts (odds ratio [OR]trend = 1.36, 95% confidence interval [CI] = 1.07 to 1.74), acini counts per TDLU (OR = 1.47, 95% CI = 1.06 to 2.03), and median TDLU span (ORtrend = 1.44, 95% CI = 1.08 to 1.91), indicating lower involution, whereas East Asian descendants were associated with decreased TDLU counts (ORtrend = 0.52, 95% CI = 0.35 to 0.78) after controlling for potential confounders. These associations are consistent with the racial variations in incidence rates of triple-negative breast cancer in the United States and suggest opportunities for future work examining whether TDLU involution may mediate the racial differences in subtype-specific breast cancer risk.

Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990–2008) were defined as cases who died of breast cancer (n = 54) and matched controls (remained alive over similar follow-up; n = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm2, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls (p < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18–0.92) and after (OR: 0.41, 95% CI: 0.18–0.94) adjustment for TDLU count/mm2, TDLU span (OR: 0.34, 95% CI: 0.14–0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13–0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.

Extensive mammographic density (MD), a well‐established breast cancer risk factor, is a radiological representation of stromal and epithelial breast tissue content. In studies conducted predominantly among Caucasian women, histologic measures of reduced terminal duct lobular unit (TDLU) involution have been correlated with extensive MD, but independently associated with breast cancer risk. We therefore examined associations between TDLU measures and MD among Chinese women, a low‐risk population but with high prevalence of dense breasts. Diagnostic pre‐treatment digital mammograms were obtained from 144 breast cancer cases at a tertiary hospital in Beijing and scored using the Breast Imaging Reporting and Data System (BI‐RADS) density classification. TDLU features were assessed using three standardized measures (count/100 mm2, span [μm], and acini count/TDLU) in benign tissues.Associations between each of TDLU measures and MD were examined using generalized linear models for TDLU count and span and polytomous logistic regression for acini count with adjustment for potential confounders stratified by age. Among women ≥50 years, 63% had dense breasts; cases with dense breasts (BI‐RADS, c‐d) had greater TDLU count (21.1 [SE = 2.70] vs. 9.0 [SE = 1.83]; p = 0.0004), longer span (480.6 μm [SE = 24.6] vs. 393.8 μm [SE = 31.8]; p = 0.03), and greater acini count (ORtrend = 16.1; 95%CI = 4.08–63.1; ptrend < 0.0001) compared to those with non‐dense breasts (BI‐RADS, a‐b). Among women <50 years, 91% had dense breasts, precluding our ability to detect associations. Our findings are consistent with previously reported associations between extensive MD and reduced TDLU involution, supporting the hypothesis that breast cancer risk associated with extensive MD may be related to the amount of “at‐risk” epithelium.

Abstract Purpose: Expression of the tumor suppressor gene E-cadherin is diminished in lobular breast cancers and has been implicated in epithelial mesenchymal transition. We assessed risk factor associations for breast cancer stratified by low vs. high E-cadherin protein expression in a pooled analysis within the Breast Cancer Association Consortium (BCAC) studies. Methods: E-cadherin tumor tissue staining was performed centrally at the NCI on formalin-fixed paraffin-embedded tissue microarray (TMA) sections representing 6,010 breast cancer patients from 12 US and European BCAC studies. TMAs were digitally scanned and scored using the SlidePath Digital Image Hub (Leica Biosystems, Wetzlar, Germany). For 5,896 cancers with evaluable tumors, E-cadherin was visually scored as estimated percent of positive cells times stain intensity (0, 1+, 2+, 3+) (score range 0-300). E-cadherin low was defined as tumors with a score &lt; 100. Risk factor associations for low vs. high E-cadherin expressing tumors were evaluated by logistic regression, adjusted for age and study site, and stratified by ER status and histologic subtype. To assess the consistency in results by study, meta-analyses were performed using the random-effects model. All statistical tests were two-sided. Results: E-cadherin low cancers comprised 20% of tumors and were associated with lobular histology, well/moderately differentiated cancers, &gt; 2cm in size, and HER2-negative status (χ2, P &lt; 0.003 for all factors). E-cadherin low status was associated with family history of breast cancer (FH) (OR = 1.32, 95% CI = 1.09-1.60, P-het = 0.005) and ever use of menopausal hormones (OR = 1.26, 95% CI = 1.02-1.56, P-het = 0.03). Study specific meta-plots showed consistent effects across studies for menopausal hormone therapy (I2 = 0.0%, p = 0.64); however, E-cadherin loss by FH did show evidence of heterogeneity by study (I2 = 54%, P = 0.03). Differences in E-cadherin expression remained significant for FH, and menopausal hormone use when further adjusted for ER (P &lt; 0.05). We also found relationships with E-cadherin loss to vary by BMI, number of live births, age at first birth, and oral contraceptive use in stratified analysis by ER status and histologic subtype. Conclusion: This large pooled analysis shows that breast cancer risk factor associations may differ by E-cadherin expression independent of ER status, suggesting that it may represent a marker of etiologic heterogeneity. Citation Format: Hisani N. Horne, Hannah Oh, Mark E. Sherman, Maya Palakal, Stephen H. Hewitt, Marjanka Schmidt, Javier Benitez, Roger Milne, Hermann Brenner, Heli Nevanlinna, Arto Mannermaa, Georgia Chenevix-Trench, Fergus Couch, Peter Devilee, Diana Eccles, Maartje Hooning, Anthony J. Swerdlow, Nick Orr, Melissa A. Troester, Renata Cora, Paul D. Pharoah, Montserrat Garcia-Closas, Jonine D. Figueroa. Breast cancer risk factor associations by loss of E-cadherin tumor tissue expression: A pooled analysis of 5,896 cases in 12 studies from the Breast Cancer Association Consortium (BCAC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3451.

Abstract Introduction: Increased levels of circulating estrogens are associated with elevated risks of postmenopausal breast cancer. Previously, we showed that levels of sex steroid hormones in breast adipose tissue are positively correlated with circulating hormones. Further evaluation of hormone levels in breast tissues may help to explain the relationship between estrogens and breast cancer risk. Specifically, data suggest that focal breast lesions consisting of macrophages encircling dying adipocytes, referred to as “crown-like structures (CLS)”, are associated with increased aromatase activity, which could increase conversion of androgens to estrogens locally in the breast. Therefore, we assessed whether the presence of CLS affects the correlations between blood and breast adipose tissue hormone levels. Methods: Participants included 84 postmenopausal women with invasive breast cancer in the Polish Breast Cancer Study, a population based case-control study conducted from 2000 to 2003. We previously reported sex steroid hormone levels in cancer-free breast adipose tissue removed as part of breast excisions performed for cancer. Here, using immunohistochemical stains, we evaluated the number of CD68 positive macrophages and the presence of full CLS (i.e., complete adipocyte encirclement) in benign breast tissue sections prepared from surgical pathology specimens containing breast cancer. The relationship between the number of CD68 positive macrophages per unit area of fat and hormone levels was examined using Spearman rank correlations (rs). We assessed potential effect modification of the association between blood and tissue hormone levels by presence or absence of CLS by including an interaction term in linear regression models. Results: The number of CD68 positive macrophages per unit area of fat was not significantly correlated with levels of estrone, estradiol, androstenedione or testosterone measured in blood (rs = 0.001, -0.04, -0.07, and -0.09, respectively; p&gt;0.05) or breast adipose tissue (rs = -0.15, 0.06, -0.06, and -0.08, respectively; p&gt;0.05). Correlations between serum and adipose tissue hormones did not statistically significantly differ between women with CLS (n = 30) compared to those without CLS (n = 54). CLS were found more frequently in breast adipose tissue from overweight (i.e., women with a body mass index (BMI) between 25 and 29.9) (43%) and obese women (BMI &gt;30) (30%) versus normal weight women, with (BMI between 18.5 and 24.9), (27%); (p = 0.04, χ2 test). The number of CD68 positive macrophages per unit area of fat was not significantly related to BMI (p = 0.31). Conclusion: Among postmenopausal women with invasive breast cancer, the presence of CLS was more common among overweight and obese women, but CLS did not influence the correlation between circulating and breast adipose tissue sex steroid hormone levels. Citation Format: Maeve Mullooly, Hannah P. Yang, Roni T. Falk, Sarah Nyante, Renata Cora, Ruth M. Pfeiffer, Derek C. Radisky, Daniel W. Visscher, Lynn C. Hartmann, Amy C. Degnim, Frank Z. Stanczyk, Jonine F. Figueroa, Montserrat Garcia-Closas, Jolanta Lissowska, Melissa T. Troester, Louise A. Brinton, Mark E. Sherman, Gretchen L. Gierach. Investigation of the relationship between crown-like structures and adipose tissue hormone levels among postmenopausal women with breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2767. doi:10.1158/1538-7445.AM2015-2767