Clarifying risk-factor associations with quantitative breast tumor features: a pooled analysis of 24 studies.

Risk factors associated with molecular subtypes of breast cancer among indian women: a multicentre matched case-control study.

Estradiol exposure and pancreatic cancer risk: convergent evidence from population-based incidence, pharmacovigilance, and tumor biology

Aim: To evaluate whether estrogen exposure is associated with pancreatic ductal adenocarcinoma (PDAC) risk and to determine whether estrogen signaling influences tumor biology, integrating population-based incidence, pharmacovigilance, and transcriptomic data. Methods: We conducted a multi-modal analysis using four complementary data sources. Population-based incidence was assessed using Surveillance, Epidemiology, and End Results (SEER) multiple-primary standardized incidence ratio (MP-SIR) methodology among female breast cancer survivors, with latency stratification. Pharmacovigilance disproportionality analysis of estradiol-associated pancreatic cancer reports was performed using OpenVigil access to the Food and Drug Administration Adverse Event Reporting System (FAERS), calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), and χ2 statistics. A prospective UK Biobank cohort analysis evaluated self-reported ever use of hormone replacement therapy (HRT) and incident registry-confirmed PDAC using a 5-year landmark and multivariable Cox proportional hazards regression. Tumor transcriptomic associations between estrogen receptor 1 (ESR1) signaling and stromal programs were examined in The Cancer Genome Atlas Pancreatic Adenocarcinoma (TCGA-PAAD) using Spearman correlation and nonparametric group comparisons. Results: In SEER, pancreatic cancer incidence among breast cancer survivors was comparable to the general population (SIR 1.03, 95% CI 1.00–1.07), with no elevation in early or late latency periods. In contrast, pharmacovigilance analysis demonstrated a strong inverse association between estradiol exposure and pancreatic cancer reporting (PRR and ROR 0.095; χ2 = 76.674). In the UK Biobank, 265,572 women contributed 705 incident PDAC events after the 5-year landmark. Ever use of HRT was not significantly associated with PDAC after adjustment for age, body mass index, smoking status, type 2 diabetes, and socioeconomic deprivation (HR 1.16, 95% CI 0.99–1.36; p = 0.059). TCGA analyses revealed a significant positive association between ESR1 expression and inflammatory, tumor-restraining cancer-associated fibroblast programs (p < 1 × 10–6). Conclusions: Estrogen exposure was not associated with a statistically significant reduction in PDAC incidence. Pharmacovigilance and transcriptomic findings support a possible tumor-modifying role for estrogen signaling, whereas the UK Biobank results do not demonstrate a protective association between broadly defined HRT use and PDAC incidence.

High-Penetrance Susceptibility Genes in Hereditary Breast Cancer Syndromes: An Updated Review on Clinical Approach

: Breast cancer remains the most prevalent malignancy worldwide, ranking second in terms of cancer-related mortality. While exposure to modifiable risk factors, variations in screening efficacy, and inaccessibility to early-stage diagnosis contrast, an increased focus has been directed toward the study of its genetic profiles; particularly those attributed to germline pathogenic variants. This narrative review aims to present the major hereditary cancer syndromes associated with an increased breast cancer risk, and to highlight the evidence-based genotype-specific screening and treatment protocols. We examined current published literature and synthesized evidence from randomized controlled trials, observational studies and current clinical guidelines. The significance of genetic testing in breast cancer extends beyond prognostic, diagnostic and risk-assessment utility, with major contributions in therapeutic decision-making. Well-defined criteria for genetic testing are established, encompassing age, familial clustering of cancer, or tumor subtype. The most prevalent hereditary cancer syndrome is the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, driven by mutations in the BRCA1 , BRCA2, and PALB2 genes, while other syndromes, less prevalent but with an increased risk of breast cancer development, like Li-Fraumeni syndrome and Peutz-Jeghers syndrome, arise from mutations in tumor suppressor genes. Despite the contrast in penetrance and risk profiles between the two categories, surveillance should be initiated at early ages, across all syndromes. The therapeutic approach is based on PARP (poly-(adenosine diphosphate–ribose) polymerase (PARP)) inhibitors for BRCA1/2 and PALB2 carriers, while in cases with TP53 mutations, radiotherapy is contraindicated, due to the risk of radiation-induced secondary malignancies. Germline pathogenic variant testing in high-penetrance susceptibility genes serves as the cornerstone of personalized, risk-stratified breast cancer management, enabling prevention, surveillance, and case-specific therapeutic decision-making. The broader integration of multigene panel testing and genetic counselling into routine cancer care remains a fundamental step toward optimizing outcomes across hereditary breast cancer syndromes.

Tumor Characteristics and Event Free Survival in Older and Younger Women with Early Breast Cancer

Background: Age, race, body mass index (BMI), breast density, parity, smoking and alcohol use are associated with increased risk for breast cancer. These factors, as well as tumor characteristics, treatment regimens and comorbidities, are analyzed for associations with five-year event free survival (EFS) in a sample of women with Stage I-III breast cancer who received chemotherapy with curative intent. Methods: EFS was defined in terms of breast cancer recurrence, second primary, metastasis, and overall survival. Analyses were stratified by age (under age 65 vs. over age 65). EFS was estimated using the Kaplan–Meier method and compared using a Cox proportional hazard model. Results: In a sample of 821 women, mean age at diagnosis was 54 years, with 75% White and 22% Black. Younger women had higher proportions of Stage II and III tumors (p = 0.005), larger tumor size (p = 0.0004), and higher breast density (p = 0.003). Five-year EFS was 91% among younger vs. 82% among older women (p = 0.0005). In women aged < 65, there were 48 EFS events, and triple negative patients had significantly worse EFS compared to other subtypes (p = 0.003). Smokers also had worse EFS (p = 0.04). In women aged ≥ 65, there were 26 events, and both tumor size (p = 0.02) and mastectomy (p = 0.03) were significant for EFS. Conclusions: In our sample, triple negative subtype, smoking history, tumor size, and surgery type were significantly associated with shorter EFS. Race, BMI, alcohol use, parity, breast density, radiation treatment, and specific chemotherapy regimen were not significant for EFS in either age group.

Comorbidity patterns and risk of breast cancer: a case–control study exploring interaction with BMI using latent class analysis

Most studies to date have examined individual comorbidities in relation to breast cancer risk but have largely ignored that these conditions often cluster in the same person. Looking at comorbidity patterns rather than isolated diseases may therefore offer a better understanding of breast cancer risk. In this case–control study, latent class analysis (LCA) was performed in the pooled case–control sample based on 10 comorbidities/conditions, including diabetes mellitus, hypertension, coronary heart disease, benign breast disease, breast lump, nipple discharge, history of gynecological tumors, severe lobular hyperplasia of the breast, papillomatous lesions of the breast, and dysfunctional uterine bleeding. Multivariable unconditional logistic regression was then used to examine the association between the identified latent classes and breast cancer risk and to test for potential interaction with body mass index (BMI). The LCA identified three comorbidity patterns in the pooled study sample: a low-comorbidity pattern, a metabolic comorbidity pattern, and a gynecologic–breast comorbidity pattern, accounting for 53.90%, 19.90%, and 26.20% of the study participants, respectively. Compared with the low-comorbidity pattern, both the metabolic comorbidity pattern (aOR = 2.55, 95% CI: 1.69–3.84) and the gynecologic–breast comorbidity pattern (aOR = 3.32, 95% CI: 2.25–4.89) were associated with higher breast cancer risk. Furthermore, a significant interaction was observed between BMI and the metabolic comorbidity pattern, suggesting that the association between this pattern and breast cancer risk varied across BMI categories. These findings suggest that a comorbidity-pattern-based approach can improve the understanding of breast cancer risk. Identifying specific comorbidity or clinical conditions, particularly the metabolic and gynecologic–breast comorbidity patterns, could inform personalized risk stratification and targeted prevention strategies for breast cancer. While BMI modified the association between the metabolic comorbidity pattern and breast cancer risk, no evidence of BMI-related effect modification was observed for the gynecologic–breast comorbidity pattern.

Advancing Evidence of the Associations between specific Benign Breast Diagnoses and Future Breast Cancer Risk.

BACKGROUND Benign breast disease (BBD) increases breast cancer risk; however, associations between specific BBD diagnoses and breast cancer risk are insufficiently studied. METHODS We analyzed 131,075 benign breast biopsy episodes from 1994-2022 identified from eight Breast Cancer Surveillance Consortium registries. Pathological diagnoses were classified into 38 BBDs within 4 categories. For comparison, women with no prior breast biopsy and a negative screening mammogram (N=1,599,694) were identified. Associations of BBDs with invasive breast carcinoma and ductal carcinoma in situ (DCIS) were estimated using Fine-Gray competing risk models. RESULTS Over a median follow-up of 7.5 years, 35,251 invasive breast cancers and 9,743 DCIS cases occurred. Lobular carcinoma in situ was associated with a 5.61-fold (95% confidence interval [CI]: 4.10-7.68) increased risk of invasive carcinoma and an 8.82-fold (95% CI: 5.39-14.4) increased risk of DCIS. Among proliferative changes with atypia BBDs, invasive cancer hazard ratios (HRs) ranged from 2.76-4.85; DCIS HRs, 5.07-8.51. Among proliferative changes without atypia BBDs, invasive HRs ranged from near-null (papillomatosis) to moderate and strong associations (e.g., HR=1.55 for usual ductal hyperplasia and 2.84 for multiple papillomas); DCIS HRs=1.37-5.04. Nonproliferative BBDs were associated with low-to-moderate risk (invasive HRs=0.63 for atrophy to 2.16 for benign breast parenchyma; DCIS HRs=0.66-4.29). Most associations declined with increasing time since biopsy. CONCLUSIONS Associations between BBDs and breast cancer varied widely within commonly used histologic categories. IMPACT Advancing knowledge of specific BBD diagnoses may improve breast cancer risk prediction and support targeted screening and prevention strategies.