Context: Breast cancer is increasing in prevalence in parallel with rising rates of obesity worldwide. Obesity is recognized as a leading modifiable risk factor for the development of breast cancer; however, this association varies considerably by clinicopathologic features, and the underlying mechanisms are complex.Evidence Acquisition: Pubmed literature search using combinations of “obesity,” “breast cancer risk,” “diet,” “exercise,” “weight gain,” “weight loss,” “adipose tissue inflammation,” “crown-like structure,” “immune markers,” “metformin,” “gliflozins,” “SGLT-2i,” “GLP1-RA,” and related terms.Evidence Synthesis: Elevated body mass index and weight gain are associated with increased risk of postmenopausal, hormone receptor–positive breast cancer. Emerging evidence suggests that adverse measures of body composition in individuals of any weight can also confer increased breast cancer risk. Mechanistically, various factors including altered adipokine balance, dysfunctional adipose tissue, dysregulated insulin signaling, and chronic inflammation contribute to tumorigenesis. Weight loss and more specifically fat mass loss through lifestyle and pharmacologic interventions improve serum metabolic and inflammatory markers, sex hormone levels, and measures of breast density, suggesting a link to decreased breast cancer risk.Conclusion: Incorporating markers of metabolic health and body composition measures with body mass index can capture breast cancer risk more comprehensively. Further studies of interventions targeting body fat levels are needed to curb the growing prevalence of obesity-related cancer.

Invasive lobular carcinoma (ILC) represents approximately 10-15% of all breast cancers and is defined by a unique discohesive morphology due to loss of E-cadherin. Despite its prevalence, ILC has been historically underrepresented in clinical and translational research, contributing to diagnostic, therapeutic, and prognostic uncertainties. This narrative review, conducted by the Invasive Lobular Carcinoma Research Group, synthesizes current evidence on ILC with expert perspectives to inform future research and clinical strategies. We highlight the distinct biology of ILC, including characteristic genomic alterations (e.g., CDH1, PIK3CA, ERBB2 mutations) and its relationship with endocrine sensitivity and limited immune infiltration. Diagnostic challenges are underscored by ILC's subtle imaging presentation and underestimation of tumor extent on mammography and ultrasound, with MRI and contrast-enhanced mammography offering improved accuracy. The review discusses evolving surgical approaches, axillary staging considerations, and radiotherapy strategies, with an emphasis on adapting techniques to ILC's infiltrative growth. Endocrine therapy remains central for hormone receptor-positive ILC, with emerging evidence supporting CDK4/6 inhibitors and extended endocrine therapy in high-risk cases. Investigational therapies targeting ILC-enriched mutations and synthetic lethality mechanisms (e.g., ROS1 inhibition in CDH1-deficient tumors) hold promise for personalized treatment. This comprehensive review identifies knowledge gaps and advocates for histology-specific clinical trials, biomarker-driven treatment strategies, and tailored imaging and surgical techniques to improve outcomes for patients with ILC.

The KEYNOTE-522 (KN522) regimen for neoadjuvant treatment of triple negative breast cancer (TNBC) utilized q3week dosing for doxorubicin plus cyclophosphamide (AC); however, dose-dense AC (ddAC) has demonstrated superior overall survival (OS) compared to q3week AC in anthracycline and taxane-based regimens. We performed a retrospective analysis assessing the use of ddAC in KN522 and the impact of sequencing ddAC before or after carboplatin/paclitaxel (CbT) plus pembrolizumab on multiple outcomes. 128 patients with TNBC were included. Overall pathologic complete response (pCR) rate of 56%. Sequencing of ddAC vs CbT first showed no difference in pCR rate (ddAC 55% vs. CbT 58%, p = 0.77). However, ddAC first compared to CbT first correlated with a significant increase in the incidence of overall treatment delays (ddAC 70% vs. CbT 51%, p = 0.03), with cytopenias most frequent (ddAC 59% vs. CbT 31%, p = 0.001). ddAC in a modified KN522 regimen is safe, tolerable, and effective. Efficacy is comparable regardless of chemotherapy sequencing, but ddAC first is significantly associated with higher rates of treatment delays and cytopenias.

• Endometrial mesonephric-like adenocarcinoma (MLA) is a rare and aggressive subtype of epithelial endometrial cancer. • KRAS mutations are characteristic in patients with endometrial MLA. • We report two cases of KRAS-mutated endometrial MLA with excellent and durable responses to lenvatinib and pembrolizumab. • Tumors with KRAS mutations may be particularly sensitive to lenvatinib, but this warrants further study.

Hyperinsulinemia is an independent risk factor for cancer mortality. Insulin-lowering dietary strategies such as calorie restriction (CR), low-carbohydrate or ketogenic diets (KD), and intermittent fasting (IF) are aimed at reducing systemic stores of nutrients utilized by cancer cells, attenuating insulin-related growth signaling, and improving obesity-related metabolic parameters. In this narrative review, we searched the published literature for studies that tested various insulin-lowering diets in metastatic cancer in preclinical and clinical settings. A total of 23 studies were identified. Of these, 14 were preclinical studies of dietary strategies that demonstrated improvements in insulin levels, inhibition of metastasis, and/or reduction in metastatic disease burden in animal models. The remaining nine clinical studies tested carbohydrate restriction, KD, or IF strategies which appear to be safe and feasible in patients with metastatic cancer. These approaches have also been shown to improve serum insulin and other metabolic parameters. Though promising, the anti-cancer efficacy of these interventions, such as impact on tumor response, disease-specific-, and overall survival, have not yet been conclusively demonstrated. Studies that are adequately powered to evaluate whether insulin-lowering diets improve cancer outcomes are warranted.