Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Alzheimer Disease and Related Dementia Following Hormone-Modulating Therapy in Patients With Breast Cancer.

Importance: Hormone-modulating therapy (HMT) is a widely accepted treatment for hormone receptor-positive breast cancer, although its cognitive effects, including a potential link to Alzheimer disease and related dementias (ADRD), remain understudied. Objective: To investigate the association between HMT for breast cancer treatment and risk of developing ADRD in women aged 65 years or older. Design, Setting, and Participants: This cohort study used a comprehensive dataset from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database to identify patients who did and did not receive HMT treatment within 3 years after the initial diagnosis of breast cancer and assessed their risk of developing ADRD in later life. Individuals with a preexisting diagnosis of ADRD or receiving HMT before the diagnosis of breast cancer were excluded. This study was performed from June 2022 through January 2024. Exposure: Receipt of HMT. Main Outcomes and Measures: Risk of ADRD associated with HMT; associations of risk with age, self-identified race, and HMT type. Risk was measured using hazard ratios (HRs) with 95% CIs and adjusted for potential confounders such as demographic, sociocultural, and clinical variables. Results: Among 18 808 women aged 65 years and older diagnosed with breast cancer between 2007 and 2009 (1266 Black [6.7%], 16 526 White [87.9%], 1016 other [5.4%]), 12 356 (65.7%) received HMT within 3 years after diagnosis, while 6452 (34.3%) did not. The most common age group in both samples was the 75 to 79 years age group (HMT, 2721 women [22.0%]; no HMT, 1469 women [22.8%]), and the majority of women in both groups self-identified as White (HMT, 10 904 women [88.3%]; no HMT, 5622 women [87.1%]). During an average of 12 years of follow-up, 2926 (23.7%) of HMT users and 1802 (27.9%) of non-HMT users developed ADRD. HMT was associated with a 7% lower relative risk of ADRD overall (HR, 0.93; 95% CI, 0.88-0.98; P = .005). The association decreased with age and varied by race. The reduction in ADRD risk associated with HMT was greatest for women aged 65 to 74 years who self-identified as Black (HR, 0.76; 95% CI, 0.62-0.92). This association decreased among women aged 75 years or older (HR, 0.81; 95% CI, 0.67-0.98). Women aged 65 to 74 years who self-identified as White had an 11% relative risk reduction (HR, 0.89; 95% CI, 0.81-0.97), but the association disappeared for women aged 75 years or older (HR, 0.96; 95% CI, 0.90-1.02). Other races showed no significant association between HMT and ADRD. Age- and race-based associations also varied by HMT type. Conclusions and Relevance: In this retrospective cohort study, hormone therapy was associated with protection against ADRD in women aged 65 years or older with newly diagnosed breast cancer; the decrease in risk was relatively greater for Black women and women under age 75 years, while the protective effect of HMT diminished with age and varied by race in women. When deciding to use HMT for breast cancer in women aged 65 years or more, clinicians should consider age, self-identified race, and HMT type in treatment decisions.

Variables affecting CA15.3 tumor antigen expression and antibodies against it in female National Health and Nutritional Survey (NHANES) participants.

BACKGROUND: Cancers of ductal origin often express glycoprotein mucin 1 (MUC1), also known as CA15.3, with higher levels leading to poorer prognosis. Conversely, anti-MUC1 antibodies develop in some patients leading to better prognosis. We sought to identify epidemiologic factors associated with CA15.3 antigen or antibody levels. METHODS: Levels of CA15.3 antigen and anti-CA15.3 IgG antibodies were measured in archived sera from 2302 mostly healthy women from the National Health and Nutritional Survey (NHANES); and epidemiologic predictors of their levels were examined using multivariate and correlational analyses. RESULTS: Among racial groups, Black women had the highest level of CA15.3 antigen and lowest levels of antibodies. Increasing BMI and current smoking were associated with low anti-CA15.3 antibody levels. Low CA15.3 antigen levels were seen in oral contraceptive (OC) users and high levels in women who were pregnant or lactating at the time of blood collection, with the latter group also having high antibody levels. Past reproductive events associated with high antigen levels included: later age at menarche, having given birth, and history of endometriosis. Lower antigen levels were seen with increasing duration of OC use. Anti-CA15.3 antibody levels decreased with an increasing estimated number of ovulatory years. CONCLUSION: Key determinants of CA.15.3 antigen or antibody levels include: race, BMI, smoking, later menarche, childbirth, number of ovulatory cycles, and endometriosis. IMPACT: This study supports the premise that known epidemiologic factors affecting risk for or survival after MUC1-expressing cancers may, at least partially, operate through their association with CA15.3 antigen or antibody levels.

Characterization of latently infected EBV+ antibody-secreting B cells isolated from ovarian tumors and malignant ascites.

Introduction: Intra-tumoral B cells mediate a plethora of immune effector mechanisms with key roles in anti-tumor immunity and serve as positive prognostic indicators in a variety of solid tumor types, including epithelial ovarian cancer (EOC). Several aspects of intra-tumoral B cells remain unclear, such as their state of activation, antigenic repertoires, and capacity to mature into plasma cells. Methods: B lymphocytes were isolated from primary EOC tissue and malignant ascites and were maintained in cell culture medium. The stably maintained cell lines were profiled with flow cytometry and B cell receptor sequencing. Secreted antibodies were tested with a human proteome array comprising more than 21,000 proteins, followed by ELISA for validation. Originating tumor samples were used for spatial profiling with chip cytometry. Results: Antibody-secreting B lymphocytes were isolated from the ovarian tumor microenvironment (TME) of four different EOC patients. The highly clonal cell populations underwent spontaneous immortalization in vitro, were stably maintained in an antibody-secreting state, and showed presence of Epstein-Barr viral (EBV) proteins. All originating tumors had high frequency of tumor-infiltrating B cells, present as lymphoid aggregates, or tertiary lymphoid structures. The antigens recognized by three of the four cell lines are coil-coil domain containing protein 155 (CCDC155), growth factor receptor-bound protein 2 (GRB2), and pyruvate dehydrogenase phosphatase2 (PDP2), respectively. Anti-CCDC155 circulating IgG antibodies were detected in 9 of 20 (45%) of EOC patients' sera. Tissue analyses with multiparameter chip cytometry shows that the antibodies secreted by these novel human B cell lines engage their cognate antigens on tumor cells. Discussion: These studies demonstrate that within the tumor-infiltrating lymphocyte population in EOC resides a low frequency population of antibody-secreting B cells that have been naturally exposed to EBV. Once stably maintained, these novel cell lines offer unique opportunities for future studies on intratumor B cell biology and new target antigen recognition, and for studies on EBV latency and/or viral reactivation in the TME of non-EBV related solid tumors such as the EOC.

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.