PARITY, OBESITY AND BREAST CANCER SURVIVAL: DOES INTRINSIC SUBTYPE MODIFY OUTCOMES?

Purpose: Parity and obesity have shown distinct associations with the breast cancer risk by intrinsic subtype. Little is known whether their influence on prognosis also varies by intrinsic subtype, although their general prognostic associations have been reported previously. Methods: Study subjects were 1,140 invasive breast cancer patients from the phases I and II of the population-based Carolina Breast Cancer Study (CBCS), with tissue blocks available for subtyping using immunohistochemical markers. Parity was measured by number of full-term birth and time since last birth. Obesity was measured by body mass index (BMI) and waist hip ratio (WHR). Vital status was determined using the National Death Index. The association of exposures with breast cancer (BC)-specific and overall survival was assessed using the Cox proportional hazards model. Results: During the follow-up (median =13.5 years), 450 patients died, with 61% due to breast cancer (n=276). For obesity, WHR, but not BMI, was associated with an increased risk of all-cause mortality (0.84+ vs. <0.77, adjusted hazard ratio (HR) = 1.50, 95% confidence interval (CI) =1.11-2.05), independent of age, race, adjusted lifestyle and socioeconomic factors. According to intrinsic subtypes, high BMI (30+ kg/m2) was an independent factor for all-cause mortality (adjusted HR=2.25, 95% CI=1.14-4.46, <0.25 kg/m2 as reference) among patients with basal-like tumors, while high WHR (0.84+) was associated with poor overall survival (adjusted HR=1.75, 95% CI=1.20-2.56, <0.77 as reference) among patients with luminal tumors. For parity, both high parity (3+ births) and recent birth (< 5 years before diagnosis) were associated with BC-specific mortality (parity: adjusted HR=1.76, 95% CI=1.13-2.73; birth recency: adjusted HR=1.90, 95% CI=1.10-3.34), with stronger effect observed in luminal tumors than basal-like tumors. The subtype-specific prognostic associations of parity and obesity were suggested to vary by follow-up period (greater HRs detected in patients surviving 5+ years), but not by race or menopause. Conclusions: Our study suggests the influence of obesity and parity on breast cancer prognosis may vary by intrinsic subtype. These results may contribute to a better understanding of how pregnancy and obesity influence the natural history of different breast cancer subtype, and help tailor treatment and optimize intervention strategies.Doctor of Philosoph

BMI, reproductive factors, and breast cancer molecular subtypes: A case-control study and meta-analysis

BACKGROUND: The effects of body mass index (BMI) and reproductive factors may vary among breast cancer molecular subtypes, evidence of which is lacking in East Asia. METHODS: From 2002 to 2010, 1256 breast cancer patients and 1416 healthy women were recruited. Anthropometric and reproductive factors were collected from medical charts. Breast cancer subtype was defined by ER, PR, and HER2 status. Polytomous logistic regression was used to evaluate associations between risk factors and breast cancer subtypes, with subgroup analysis by menopausal status. A meta-analysis of relevant published studies in East Asia was also performed. RESULTS: In our case-control study, late menarche was negatively associated with luminal tumor risk (Ptrend = 0.03). Higher BMI was associated with risk of both luminal and triple-negative tumors (Ptrend<0.001). Late age at first live birth was associated with a 1.41- to 2.08-fold increased risk of all subtypes, while late menopause increased risk by 2.62-5.56 times. Heterogeneity of these associations was not detected for different menopausal statuses. The meta-analysis revealed a positive dose-response relationship between BMI and risk of both luminal and ER-PR- subtypes (Ptrend<0.05). Early menarche and nulliparity increased luminal tumor risk by 1.39 and 1.26 times, respectively. Non-breastfeeding also increased the risk of all subtypes. CONCLUSIONS: For East Asian women, overweight, late menopause, and lack of breastfeeding appear to increase risk of both luminal and ER-PR- tumors. Early menarche and nulliparity mainly impacted luminal tumor risk. These associations were not impacted by menopausal status

Association of Parity and Time since Last Birth with Breast Cancer Prognosis by Intrinsic Subtype

Parity and time since last birth influence breast cancer risk and vary by intrinsic tumor subtype, but the independent effects of these factors on prognosis has received limited attention

Post-diagnosis adiposity and survival among breast cancer patients: influence of breast cancer subtype

Adiposity has been linked with increased breast cancer risk and mortality. It is established that etiologic associations for adiposity vary by tumor subtype, but the influence of adiposity on subtype-specific survival is unknown

Benign Breast Tissue Composition in Breast Cancer Patients: Association with Risk Factors, Clinical Variables, and Gene Expression

Breast tissue composition (epithelium, non-fatty stroma, and adipose) changes qualitatively and quantitatively throughout the lifespan, and may mediate relationships between risk factors and breast cancer initiation. We sought to identify relationships between tissue composition, risk factors, tumor characteristics, and gene expression

Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression

Activation of inflammatory pathways is one plausible mechanism underlying the association between obesity and increased breast cancer risk. However, macrophage infiltration and local biomarkers of inflammation in breast adipose tissue have seldom been studied in association with obesity

Intratumoral heterogeneity as a source of discordance in breast cancer biomarker classification

Abstract Background Spatial heterogeneity in biomarker expression may impact breast cancer classification. The aims of this study were to estimate the frequency of spatial heterogeneity in biomarker expression within tumors, to identify technical and biological factors contributing to spatial heterogeneity, and to examine the impact of discordant biomarker status within tumors on clinical record agreement. Methods Tissue microarrays (TMAs) were constructed using two to four cores (1.0 mm) for each of 1085 invasive breast cancers from the Carolina Breast Cancer Study, which is part of the AMBER Consortium. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) was quantified using automated digital imaging analysis. The biomarker status for each core and for each case was assigned using clinical thresholds. Cases with core-to-core biomarker discordance were manually reviewed to distinguish intratumoral biomarker heterogeneity from misclassification of biomarker status by the automated algorithm. The impact of core-to-core biomarker discordance on case-level agreement between TMAs and the clinical record was evaluated. Results On the basis of automated analysis, discordant biomarker status between TMA cores occurred in 9 %, 16 %, and 18 % of cases for ER, PR, and HER2, respectively. Misclassification of benign epithelium and/or ductal carcinoma in situ as invasive carcinoma by the automated algorithm was implicated in discordance among cores. However, manual review of discordant cases confirmed spatial heterogeneity as a source of discordant biomarker status between cores in 2 %, 7 %, and 8 % of cases for ER, PR, and HER2, respectively. Overall, agreement between TMA and clinical record was high for ER (94 %), PR (89 %), and HER2 (88 %), but it was reduced in cases with core-to-core discordance (agreement 70 % for ER, 61 % for PR, and 57 % for HER2). Conclusions Intratumoral biomarker heterogeneity may impact breast cancer classification accuracy, with implications for clinical management. Both manually confirmed biomarker heterogeneity and misclassification of biomarker status by automated image analysis contribute to discordant biomarker status between TMA cores. Given that manually confirmed heterogeneity is uncommon (<10 % of cases), large studies are needed to study the impact of heterogeneous biomarker expression on breast cancer classification and outcomes

Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study

Abstract Background We examined racial differences in the expression of eight genes and their associations with risk of recurrence among 478 white and 495 black women who participated in the Carolina Breast Cancer Study Phase 3. Methods Breast tumor samples were analyzed for PAM50 subtype and for eight genes previously found to be differentially expressed by race and associated with breast cancer survival: ACOX2, MUC1, FAM177A1, GSTT2, PSPH, PSPHL, SQLE, and TYMS. The expression of these genes according to race was assessed using linear regression and each gene was evaluated in association with recurrence using Cox regression. Results Compared to white women, black women had lower expression of MUC1, a suspected good prognosis gene, and higher expression of GSTT2, PSPHL, SQLE, and TYMS, suspected poor prognosis genes, after adjustment for age and PAM50 subtype. High expression (greater than median versus less than or equal to median) of FAM177A1 and PSPH was associated with a 63% increase (hazard ratio (HR) = 1.63, 95% confidence interval (CI) = 1.09–2.46) and 76% increase (HR = 1.76, 95% CI = 1.15–2.68), respectively, in risk of recurrence after adjustment for age, race, PAM50 subtype, and ROR-PT score. Log2-transformed SQLE expression was associated with a 20% increase (HR = 1.20, 95% CI = 1.03–1.41) in recurrence risk after adjustment. A continuous multi-gene score comprised of eight genes was also associated with increased risk of recurrence among all women (HR = 1.11, 95% CI = 1.04–1.19) and among white (HR = 1.14, 95% CI = 1.03–1.27) and black (HR = 1.11, 95% CI = 1.02–1.20) women. Conclusions Racial differences in gene expression may contribute to the survival disparity observed between black and white women diagnosed with breast cancer

<html>Pubertal and adult windows of susceptibility to a high animal fat diet in <i>Trp53-null</i> mammary tumorigenesis</html>

Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk

Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status

Abstract Introduction Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk. Methods We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status. Results We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors. Conclusions Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors