Ovarian Suppression: Early Menopause, Late Effects.

PURPOSE OF REVIEW: Pre-menopausal women diagnosed with hormone receptor (HR) breast cancer are candidates for prolonged hypoestrogenism to improve cancer outcomes. However, the disease benefit eclipses the toxicities associated with ovarian function suppression (OFS), which are often under-reported. RECENT FINDINGS: Increased risk of mortality from cardiovascular disease, bone disorders, and metabolic disorders is well reported in women with no history of cancer, after surgical oophorectomy or premature ovarian failure. Vasomotor symptoms, urogenital atrophy, weight gain, sexual dysfunction, cognitive decline, and sleep disturbances contribute to the increased non-compliance associated with OFS, especially in younger women. Balancing the toxicities of prolonged OFS with its benefits should be critically analyzed by providers when making recommendations for their patients. Supportive care to manage multi-system toxicities and to counteract the long-term impact on all-cause mortality should be emphasized by every cancer program. Future studies with OFS should incorporate patient outcomes and strategies for symptom management in addition to focusing on improving disease outcomes.

Promoting informed approaches in precision oncology and clinical trial participation for Black patients with cancer: Community-engaged development and pilot testing of a digital intervention.

BACKGROUND: Black patients with cancer are less likely to receive precision cancer treatments than White patients and are underrepresented in clinical trials. To address these disparities, the study aimed to develop and pilot-test a digital intervention to improve Black patients' knowledge about precision oncology and clinical trials, empower patients to increase relevant discussion, and promote informed decision-making. METHODS: A community-engaged approach, including a Community Advisory Board and two rounds of key informant interviews with Black patients with cancer, their relatives, and providers (n = 48) was used to develop and refine the multimedia digital intervention. Thematic analysis was conducted for qualitative data. The intervention was then pilot-tested with 30 Black patients with cancer to assess feasibility, acceptability, appropriateness, knowledge, decision self-efficacy, and patient empowerment; Wilcoxon matched pairs signed-rank test was used to analyze quantitative data. RESULTS: The digital tool was found to be feasible, acceptable, and culturally appropriate. Key informants shared their preferences and recommendations for the digital intervention and helped improve cultural appropriateness through user and usability testing. In the pilot test, appreciable improvement was found in participants' knowledge about precision oncology (z = -2.04, p = .052), knowledge about clinical trials (z = -3.14, p = .001), and decisional self-efficacy for targeted/immune therapy (z = -1.96, p = .0495). CONCLUSIONS: The digital intervention could be a promising interactive decision-support tool for increasing Black patients' participation in clinical trials and receipt of precision treatments, including immunotherapy. Its use in clinical practice may reduce disparities in oncology care and research. PLAIN LANGUAGE SUMMARY: We developed a digital interactive decision support tool for Black patients with cancer by convening a Community Advisory Board and conducting interviews with Black patients with cancer, their relatives, and providers. We then pilot-tested the intervention with newly diagnosed Black patients with cancer and found appreciable improvement in participants' knowledge about precision oncology, knowledge about clinical trials, and confidence in making decisions for targeted/immune therapy. Our digital tool has great potential to be an affordable and scalable solution for empowering and educating Black patients with cancer to help them make informed decisions about precision oncology and clinical trials and ultimately reducing racial disparities.

Neighborhood Disadvantage, African Genetic Ancestry, Cancer Subtype, and Mortality Among Breast Cancer Survivors.

Importance: Racial disparities in breast cancer (BC) survival arise from multilevel causes, which may exert influence at different stages of BC progression. Clarifying the importance of genetic and social factors could help prioritize interventions. Objective: To jointly examine associations between African genetic ancestry, social environment, and mortality from any cause and BC in Black BC survivors. Design, Setting, and Participants: This population-based cohort study enrolled self-identified Black women aged 20 to 75 years with histologically confirmed BC from June 2005 to May 2019 and followed them up until death or censoring in September 2021. Participants lived in 10 New Jersey counties. Data were analyzed between December 2022 and April 2023. Exposures: A neighborhood socioeconomic status (nSES) index composed of census tract measures (education, income, wealth, employment status, and occupation) was linked to residential addresses at diagnosis. Percentage African ancestry was estimated using the ADMIXTURE program. Main Outcomes and Measures: Sequentially adjusted (age adjusted: age and interview year; fully adjusted: age adjusted with individual SES, lifestyle factors, and comorbidities) logistic regression models were fit to estimate associations with tumor subtypes (estrogen receptor-negative [ER-] vs estrogen receptor-positive [ER+]; triple-negative breast cancer [TNBC] vs luminal A), and Cox models were fit for associations with all-cause mortality (ACM) and breast cancer-specific mortality (BCSM). Models for BCSM were fit using Fine-Gray competing risks models, and robust standard errors were used to account for census tract-level clustering. Results: Among 1575 participants, median (IQR) African ancestry was 85% (76%-90%), and median (IQR) age was 55 (46-63) years. A 10-percentage point increase in African ancestry was associated with higher odds of ER- vs ER+ (adjusted odds ratio [aOR], 1.08; 95% CI, 0.98-1.18) and TNBC vs luminal (aOR, 1.15; 95% CI, 1.02-1.31) tumors, but not with ACM or BCSM. A 1-IQR increase in nSES was associated with lower ACM (adjusted hazard ratio [aHR], 0.76; 95% CI, 0.63-0.93), and the HR for BCSM was less than 1 but not statistically significant (aHR, 0.81; 95% CI, 0.62-1.04) in age-adjusted models, but associations attenuated following further adjustment for potential mediators (individual SES, lifestyles, comorbidities). Conclusions and Relevance: In this cohort study of Black female BC survivors, higher African ancestry was associated with aggressive tumor subtypes. Compared with genetic ancestry, mediating pathways related to social environments may be more important for survival in these patients.

Psychiatric and affective predictors of negative racial attitudes.

Negative Racial Attitudes (NRA) have been identified as major contributors to discrimination and inequalities. Previous studies of predictors of NRA have focused largely on socioeconomic, socialization, social attitudes, and personality characteristics. Yet, the potential links of psychiatric and affective indicators to NRA have received little scientific inquiry. Three-hundred-and-two participants completed measures of explicit, covert, and implicit NRA, along with indices of psychotic-like experiences (PLEs), mood symptoms, affective processing, social attitudes, and personality characteristics. Explicit and covert NRA were significantly correlated with difficulty identifying and describing feelings, use of suppression to regulate emotion, and the PLEs domains of perceptual abnormalities, bizarre experiences, and persecutory ideation, along with social attitudes and personality characteristics. Implicit NRA was not associated with any indicators. Next, employing hierarchical multiple linear regression analyses, the affective and psychiatric indicators accounted 5.2% and 10.4% of the explicit and covert NRA variance, respectively, controlling for previously identified predictors including demographics, social attitudes, and personality characteristics. Our results point to newly identified predictors of NRA including difficulties identifying and describing emotions, use of suppression to regulate emotions, as well as PLEs, specifically perceptual abnormalities. We discuss the implications of the findings to the development and adaptation of anti-racism interventions.

Clinical efficacy of PARP inhibitors in breast cancer.

BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.

Uveitis, a rare but important complication of adjuvant zoledronic acid for early-stage breast cancer.

Bisphosphonates such as zoledronic acid are an important part of adjuvant therapy to reduce the risk of recurrence in early-stage breast cancer. Uveitis remains one of the lesser-known side effects of zoledronic acid; prompt recognition is essential to ensure patients receive appropriate and timely care to help prevent permanent vision loss. We report a case of anterior uveitis in a postmenopausal woman who presented with visual symptoms after receiving the first dose of zoledronic acid. This case report serves to educate and increase awareness of the risk of uveitis in patients who are given zoledronic acid. This is the first and only reported case of zoledronic acid when used in the adjuvant setting for the treatment of breast cancer.

Association of Cigarette Smoking and Alcohol Consumption With Subsequent Mortality Among Black Breast Cancer Survivors in New Jersey.

Importance: There are limited data about how lifestyle factors are associated with breast cancer prognosis among Black or African American women because most of the evidence is based on studies of White breast cancer survivors. Objective: To examine the association of prediagnostic cigarette smoking and alcohol consumption with all-cause mortality and breast cancer-specific mortality in a cohort of Black breast cancer survivors. Design, Setting, and Participants: This population-based cohort study included 1926 Black or African American breast cancer survivors who received a diagnosis from June 6, 2005, to May 21, 2019, identified in 10 counties in New Jersey through rapid case ascertainment by the New Jersey State Cancer Registry. Statistical analysis was conducted from January 1, 2021, to August 1, 2022. Exposures: Information on prediagnostic cigarette smoking, alcohol consumption, and additional covariates was collected during in-person interviews. The covariates examined included smoking status at the time of breast cancer diagnosis (currently smoking at the time of breast cancer diagnosis, formerly smoking, or never smoking), smoking duration (number of years smoking), smoking intensity (cigarettes smoked per day), number of pack-years of smoking, and regular alcohol consumption the year before diagnosis (categorized as nondrinkers, ≤3 drinks per week, or >3 drinks per week). Main Outcomes and Measures: Primary outcomes included breast cancer-specific mortality and all-cause mortality. Results: Among the 1926 women in the study, the mean (SD) age at breast cancer diagnosis was 54.4 (10.8) years. During 13 464 person-years of follow-up (median follow-up, 6.7 years [range, 0.5-16.0 years]), there were 337 deaths, of which 187 (55.5%) were breast cancer related. Compared with never smokers, current smokers at the time of breast cancer diagnosis had a 52% increased risk for all-cause mortality (hazard ratio [HR], 1.52; 95% CI, 1.15-2.02), which was most pronounced for those with 10 or more pack-years of smoking (HR, 1.84; 95% CI, 1.34-2.53). Similar findings were observed for breast cancer-specific mortality (current smokers vs never smokers: HR, 1.27; 95% CI, 0.87-1.85), although they were not statistically significant. There was no statistically significant association between alcohol consumption and all-cause mortality (>3 drinks per week vs nondrinkers: HR, 1.05; 95% CI, 0.73-1.51) or breast cancer-specific mortality (>3 drinks per week vs nondrinkers: HR, 1.06; 95% CI, 0.67-1.67). Conclusions and Relevance: This population-based cohort study of Black breast cancer survivors suggests that current smoking at the time of diagnosis was associated with an increased risk of all-cause mortality, particularly among women with greater pack-years of smoking.

Greater Body Fatness Is Associated With Higher Protein Expression of LEPR in Breast Tumor Tissues: A Cross-Sectional Analysis in the Women's Circle of Health Study.

Background: The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role. Methods: In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons. Results: In multivariable models, we found that increasing BMI (ß = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (ß = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (ß = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (ß = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (ß = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (ß = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found. Conclusions: These findings support an association of increased body fatness - beyond overall body size measured using BMI - with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step.

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: The Search for the Optimal Biomarker.

Triple negative breast cancer (TNBC) is a high-risk and aggressive malignancy characterized by the absence of estrogen receptors (ER) and progesterone receptors (PR) on the surface of malignant cells, and by the lack of overexpression of human epidermal growth factor 2 (HER2). It has limited therapeutic options compared to other subtypes of breast cancer. There is now a growing body of evidence on the role of immunotherapy in TNBC, however much of the data from clinical trials is conflicting and thus, challenging for clinicians to integrate the data into clinical practice. Landmark phase III trials using immunotherapy in the early-stage neoadjuvant setting concluded that the addition of immunotherapy to chemotherapy improved the pathologic complete response (pCR) rate compared to chemotherapy with placebo while others found no significant improvement in pCR. Phase III trials have investigated the utility of immunotherapy in previously untreated metastatic TNBC, and these studies have similarly arrived at inconsistent conclusions. Some studies showed no benefit while others demonstrated a clinically significant improvement in overall survival in the PD-L1 positive population. It is not yet clear which biomarkers are most useful, and assays for these biomarkers have not been standardized. Given the often serious and severe side effects of immunotherapy, it is important and necessary to identify predictive biomarkers of response and resistance in order to enhance patient selection. In this review, we will discuss both the challenges of traditional biomarkers and the opportunities of emerging biomarkers for patient selection.

Clinical and Pharmacologic Differences of CDK4/6 Inhibitors in Breast Cancer.

Targeted therapies such as Cyclin Dependent Kinase 4 and 6 (CDK 4/6) inhibitors have improved the prognosis of metastatic hormone receptor (HR) positive breast cancer by combating the resistance seen with traditional endocrine therapy. The three approved agents currently in the market are palbociclib, ribociclib and abemaciclib. Besides the overall similarities associated with CDK4/6 inhibition, there are differences between the three approved agents that may explain the differences noted in unique clinical scenarios- monotherapy, patients with brain metastases or use in the adjuvant setting. This review article will explore the preclinical and pharmacological differences between the three agents and help understand the benefits seen with these agents in certain subgroups of patients with metastatic HR positive breast cancer.

Association of Body Mass Index, Central Obesity, and Body Composition With Mortality Among Black Breast Cancer Survivors.

IMPORTANCE: Obesity disproportionately affects Black women, who also have a higher risk of death after a breast cancer diagnosis compared with women of other racial/ethnic groups. However, few studies have evaluated the association of measures of adiposity with mortality among Black breast cancer survivors. OBJECTIVE: To assess the association of measures of adiposity with survival after a breast cancer diagnosis among Black women. DESIGN, SETTING, AND PARTICIPANTS: This prospective population-based cohort study comprised 1891 women with stage 0 to IV breast cancer who self-identified as African American or Black and were ages 20 to 75 years. The New Jersey State Cancer Registry was used to identify women living in 10 counties in New Jersey who were recruited from March 1, 2006, to February 29, 2020, and followed up until September 2, 2020. EXPOSURES: Measures of adiposity, including body mass index, body fat distribution (waist circumference and waist-to-hip ratio), and body composition (percent body fat and fat mass index), were collected during in-person interviews at approximately 10 months after breast cancer diagnosis. MAIN OUTCOMES AND MEASURES: All-cause and breast cancer-specific mortality. RESULTS: Among 1891 women, the mean (SD) age at breast cancer diagnosis was 54.5 (10.8) years. During a median follow-up of 5.9 years (range, 0.5-14.8 years), 286 deaths were identified; of those, 175 deaths (61.2%) were associated with breast cancer. A total of 1060 women (56.1%) had obesity, and 1291 women (68.3%) had central obesity. Higher adiposity, particularly higher waist-to-hip ratio, was associated with worse survival. Women in the highest quartile of waist-to-hip ratio had a 61% increased risk of dying from any cause (hazard ratio [HR], 1.61; 95% CI, 1.12-2.33) and a 68% increased risk of breast cancer death (HR, 1.68; 95% CI, 1.04-2.71) compared with women in the lowest quartile. The risks of all-cause and breast cancer-specific death were similarly high among women in the highest quartile for waist circumference (HR, 1.74 [95% CI, 1.26-2.41] and 1.64 [95% CI, 1.08-2.48], respectively), percent body fat (HR, 1.53 [95% CI, 1.09-2.15] and 1.81 [95% CI, 1.17-2.80]), and fat mass index (HR, 1.57 [95% CI, 1.11-2.22] and 1.74 [95% CI, 1.10-2.75]); however, the risk was less substantial for body mass index (HR, 1.26 [95% CI, 0.89-1.79] and 1.33 [95% CI, 0.84-2.10]). In analyses stratified by estrogen receptor status, menopausal status, and age, a higher waist-to-hip ratio was associated with a higher risk of all-cause death among women who had estrogen receptor-negative tumors (HR, 2.24; 95% CI, 1.14-4.41), women who were postmenopausal (HR, 2.15; 95% CI, 1.28-3.61), and women who were 60 years or older at diagnosis (HR per 0.10-U increase, 1.76; 95% CI, 1.37-2.26). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, central obesity and higher adiposity were associated with higher all-cause and breast cancer-specific mortality among Black breast cancer survivors. Simple measures of body fat distribution and body composition were found to be useful tools for identifying Black women with a higher risk of death after a breast cancer diagnosis.

Receptor-Defined Breast Cancer in Five East African Countries and Its Implications for Treatment: Systematic Review and Meta-Analysis.

PURPOSE: Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) are determinants of treatment and mortality for patients with breast cancer (BC). In East Africa, the estimated 5-year survival (37.7%) is far lower than the US average (90%). This meta-analysis investigates BC receptor subtypes within five East African countries to ascertain cross-country patterns and prioritize treatment needs. METHODS: From a PubMed search, January 1, 1998-June 30, 2019, for all English-only BC articles for Ethiopia, Kenya, Rwanda, Tanzania, and Uganda, eligible studies had receptor distributions for female BC samples ≥ 30 patients. Outcomes were proportions of ER+, PR+, and HER2-positive (HER2+), and/or molecular subtypes. Data included study characteristics and mean or median patient age. Using metaprop, Stata 16, we estimated pooled proportions (ES) with 95% CIs and assessed heterogeneity. RESULTS: Among 36 BC studies with receptor data, 21 met criteria. Weighted mean age was 47.5 years and median, 48. Overall ES were as follows: 55% for ER-positive (ER+) (95% CI, 47 to 62), 23% for HER2+ (95% CI, 20 to 26), and 27% for triple-negative BC (TNBC) (95% CI, 23 to 32). CONCLUSION: We found differences between countries, for example, lower distribution of TNBC in Ethiopia (21%) compared with Uganda (35%). ER+, the dominant BC subtype overall at 55%, emphasizes the need to prioritize endocrine therapy. Overall proportions of HER2+ BC (with or without ER+ or PR+), 23%, approached proportions of TNBC, 27%, yet HER2 testing and treatment were infrequent. Testing and reporting of receptor subtypes would promote delivery of more effective treatment reducing the mortality disparity.

Gene expression of adipokines and adipokine receptors in the tumor microenvironment: associations of lower expression with more aggressive breast tumor features.

PURPOSE: Limited epidemiologic data are available on the expression of adipokines leptin (LEP) and adiponectin (ADIPOQ) and adipokine receptors (LEPR, ADIPOR1, ADIPOR2) in the breast tumor microenvironment (TME). The associations of gene expression of these biomarkers with tumor clinicopathology are not well understood. METHODS: NanoString multiplexed assays were used to assess the gene expression levels of LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 within tumor tissues among 162 Black and 55 White women with newly diagnosed breast cancer. Multivariate mixed effects models were used to estimate associations of gene expression with breast tumor clinicopathology (overall and separately among Blacks). RESULTS: Black race was associated with lower gene expression of LEPR (P = 0.002) and ADIPOR1 (P = 0.01). Lower LEP, LEPR, and ADIPOQ gene expression were associated with higher tumor grade (P = 0.0007, P < 0.0001, and P < 0.0001, respectively) and larger tumor size (P < 0.0001, P = 0.0005, and P < 0.0001, respectively). Lower ADIPOQ expression was associated with ER- status (P = 0.0005), and HER2-enriched (HER2-E; P = 0.0003) and triple-negative (TN; P = 0.002) subtypes. Lower ADIPOR2 expression was associated with Ki67+ status (P = 0.0002), ER- status (P < 0.0001), PR- status (P < 0.0001), and TN subtype (P = 0.0002). Associations of lower adipokine and adipokine receptor gene expression with ER-, HER2-E, and TN subtypes were confirmed using data from The Cancer Genome Atlas (P-values < 0.005). CONCLUSION: These findings suggest that lower expression of ADIPOQ, ADIPOR2, LEP, and LEPR in the breast TME might be indicators of more aggressive breast cancer phenotypes. Validation of these findings are warranted to elucidate the role of the adipokines and adipokine receptors in long-term breast cancer prognosis.

Immunohistochemical analysis of adipokine and adipokine receptor expression in the breast tumor microenvironment: associations of lower leptin receptor expression with estrogen receptor-negative status and triple-negative subtype.

BACKGROUND: The molecular mechanisms underlying the association between increased adiposity and aggressive breast cancer phenotypes remain unclear, but likely involve the adipokines, leptin (LEP) and adiponectin (ADIPOQ), and their receptors (LEPR, ADIPOR1, ADIPOR2). METHODS: We used immunohistochemistry (IHC) to assess LEP, LEPR, ADIPOQ, ADIPOR1, and ADIPOR2 expression in breast tumor tissue microarrays among a sample of 720 women recently diagnosed with breast cancer (540 of whom self-identified as Black). We scored IHC expression quantitatively, using digital pathology analysis. We abstracted data on tumor grade, tumor size, tumor stage, lymph node status, Ki67, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) from pathology records, and used ER, PR, and HER2 expression data to classify breast cancer subtype. We used multivariable mixed effects models to estimate associations of IHC expression with tumor clinicopathology, in the overall sample and separately among Blacks. RESULTS: Larger proportions of Black than White women were overweight or obese and had more aggressive tumor features. Older age, Black race, postmenopausal status, and higher body mass index were associated with higher LEPR IHC expression. In multivariable models, lower LEPR IHC expression was associated with ER-negative status and triple-negative subtype (P < 0.0001) in the overall sample and among Black women only. LEP, ADIPOQ, ADIPOR1, and ADIPOR2 IHC expression were not significantly associated with breast tumor clinicopathology. CONCLUSIONS: Lower LEPR IHC expression within the breast tumor microenvironment might contribute mechanistically to inter-individual variation in aggressive breast cancer clinicopathology, particularly ER-negative status and triple-negative subtype.

Prediagnostic Allostatic Load as a Predictor of Poorly Differentiated and Larger Sized Breast Cancers among Black Women in the Women's Circle of Health Follow-Up Study.

BACKGROUND: Few studies have empirically tested the association of allostatic load (AL) with breast cancer clinicopathology. The aim of this study was to examine the association of AL, measured using relevant biomarkers recorded in medical records before breast cancer diagnosis, with unfavorable tumor clinicopathologic features among Black women. METHODS: In a sample of 409 Black women with nonmetastatic breast cancer who are enrolled in the Women's Circle of Health Follow-Up Study, we estimated prediagnostic AL using two measures: AL measure 1 [lipid profile-based-assessed by systolic and diastolic blood pressure (SBP, DBP), high-density lipoprotein, low-density lipoprotein, total cholesterol, triglycerides, and glucose levels; waist circumference; and use of diabetes, hypertension, or hypercholesterolemia medication] and AL measure 2 (inflammatory index-based-assessed by SBP, DBP, glucose, and albumin levels; estimated glomerular filtration rate; body mass index; waist circumference; and use of medications previously described). We used Cohen's statistic to assess agreement between the two AL measures and multivariable logistic models to assess the associations of interest. RESULTS: AL measures 1 and 2 moderately agreed (κ = 0.504). Higher prediagnostic AL predicted higher grade (poorly differentiated vs. well/moderately differentiated) using AL measure 1 [OR = 2.16; 95% confidence interval (CI), 1.18-3.94] and AL measure 2 (OR = 1.60; 95% CI, 1.02-2.51), and larger tumor size (≥2 cm vs. <2 cm; OR = 1.58; 95% CI, 1.01-2.46) using AL measure 2 only. CONCLUSIONS: Elevated prediagnostic AL might contribute to more unfavorable breast cancer clinicopathology. IMPACT: Addressing elevated prediagnostic levels of AL has potentially important clinical implications.

Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention.

Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53-null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFß. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.

A TGFß-miR-182-BRCA1 axis controls the mammary differentiation hierarchy.

Maintenance of mammary functional capacity during cycles of proliferation and regression depends on appropriate cell fate decisions of mammary progenitor cells to populate an epithelium consisting of secretory luminal cells and contractile myoepithelial cells. It is well established that transforming growth factor-ß (TGFß) restricts mammary epithelial cell proliferation and that sensitivity to TGFß is decreased in breast cancer. We show that TGFß also exerts control of mammary progenitor self-renewal and lineage commitment decisions by stringent regulation of breast cancer associated 1 (BRCA1), which controls stem cell self-renewal and lineage commitment. Either genetic depletion of Tgfb1 or transient blockade of TGFß increased self-renewal of mammary progenitor cells in mice, cultured primary mammary epithelial cells, and also skewed lineage commitment toward the myoepithelial fate. TGFß stabilized the abundance of BRCA1 by reducing the abundance of microRNA-182 (miR-182). Ectopic expression of BRCA1 or antagonism of miR-182 in cultured TGFß-deficient mammary epithelial cells restored luminal lineage commitment. These findings reveal that TGFß modulation of BRCA1 directs mammary epithelial cell fate and, because stem or progenitor cells are thought to be the cell of origin for aggressive breast cancer subtypes, suggest that TGFß dysregulation during tumorigenesis may promote distinct breast cancer subtypes.

Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer.

INTRODUCTION: Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC). METHODS: The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus. RESULTS: We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis. CONCLUSION: Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT01127763.