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Shailesh Agarwal,1 Lisa Pappas,2 Jayant Agarwal3 1Department of Surgery, University of Michigan, Ann Arbor, MI, 2Huntsman Cancer Institute, Biostatistics Core, 3Department of Surgery, Division of Plastic Surgery, University of Utah, Salt Lake City, UT, USA Background: Utilization of bilateral mastectomy for unilateral breast cancer is increasing despite cost and surgical risks with conflicting reports of survival benefit. Current studies evaluating death after bilateral mastectomy have included patients treated both with breast conservation therapy and unilateral mastectomy. In this study, we directly compared breast cancer–specific death of patients who underwent bilateral or unilateral mastectomy for unilateral breast cancer using a matched cohort analysis.Methods: This was an observational study of women diagnosed with unilateral breast cancer from 1998 through 2002, using the Surveillance, Epidemiology, and End Results (SEER) database. A 4-to-1 matched cohort of patients was selected including 14,075 patients. Mortality of the groups was compared using Cox proportional hazards models for cause-specific death. Results: A total of 41,510 patients diagnosed with unilateral breast cancer were included. Unilateral mastectomy was performed in 93% of patients, while bilateral mastectomy was performed in the remaining 7% of patients. When 4-to-1 matching was performed, 11,260 unilateral mastectomy and 2,815 bilateral mastectomy patients were included. Patients with bilateral mastectomy did not have a significantly lower hazard of breast cancer–specific death when compared with patients with unilateral mastectomy (hazard ratio: 0.92 vs 1.00, p=0.11).Conclusion: Bilateral mastectomy did not provide a clinically or statistically significant breast cancer–specific mortality benefit over unilateral mastectomy based on a matched cohort analysis of a nationwide population database. These findings should be interpreted in the context of patient preference and alternative benefits of bilateral mastectomy. Keywords: breast cancer, contralateral prophylactic mastectomy, bilateral mastectomy, survival, logistic regression, matched cohorts

BACKGROUND: Video capsule endoscopy (VCE) may be useful for surveillance of small-bowel polyps in patients with familial adenomatous polyposis (FAP). OBJECTIVE: To compare VCE to standard endoscopy for diagnosing small-bowel polyps in a defined segment of small bowel (proximal to a tattoo) and the entire examined small bowel. DESIGN: Prospective. SETTING: Single tertiary referral center. PATIENTS: Participants with FAP (n = 32). The majority were selected for their high number of proximal small-bowel polyps and prior endoscopic tattoo placement in the proximal small bowel. INTERVENTIONS: VCE (interpreted by 2 readers), push enteroscopy (PE), and lower endoscopy (LE) to count and measure small-bowel polyps. RESULTS: In the defined segment, VCE detected a median of 10.0 (interquartile range [IQR], 5.0-19.0) and 9.0 (IQR, 6.0-16.0) polyps for each reader compared with a median of 41.0 (IQR, 19.0-64.0) polyps on PE (P = .002). Agreement between the 2 methods was fair (kappa = 0.34, 0.36). Agreement between VCE and PE was poor to fair (kappa = 0.10, 0.22) for estimating the size of the largest polyp and poor (kappa = -0.20, -0.27) for detecting large polyps (> or =1 cm). In the entire examined small bowel, VCE diagnosed a median of 38.0 (IQR, 10.5-71.5) and 54.0 (IQR, 13.0-100.0) polyps for each reader compared with a median of 123.0 (IQR, 38.5-183.0) for combination endoscopy (PE and LE) (P < .001). Agreement between the 2 methods was fair to moderate (kappa = 0.21, 0.56). LIMITATIONS: Participants selected for high polyp burden, and results may not be applicable to all patients with FAP. CONCLUSIONS: VCE underestimates the number of small-bowel polyps in persons with FAP and does not reliably detect large polyps. [ABSTRACT FROM AUTHOR]

Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E) and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC) markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu (HER2) protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH). Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC) ≥ 0.9). Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B) subtypes (92%), but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74%) and Luminal A tumors were less likely to have high proliferation (11% vs 77%). Seventy-seven percent (30/39) of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57%) and HER2-E (30%) subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as shown in a multivariate analysis. Conclusions The standard immunohistochemical panel for breast cancer (ER, PR, and HER2) does not adequately identify the PAM50 gene expression subtypes. Although there is high agreement between biomarker scoring by protein immunohistochemistry and gene expression, the gene expression determinations for ESR1 and ERBB2 status was more prognostic.

Abstract Background During pregnancy the mammary epithelium undergoes a complex developmental process which culminates in the generation of the milk-secreting epithelium. Secretory epithelial cells display lactogenic differentiation which is characterized by the expression of milk protein genes, such as beta-casein or whey acidic protein (WAP). Transcription factors AP-2alpha and AP-2gamma are downregulated during lactation, and their overexpression in transgenic mice impaired the secretory differentiation of the mammary epithelium, resulting in lactation failure. To explore whether the downregulation of AP-2alpha and AP-2gamma is of functional significance for lactogenic differentiation, we analyzed the expression of the AP-2 family members during the lactogenic differentiation of HC11 mammary epithelial cells in vitro. Differentiation of HC11 cells was induced following established protocols by applying the lactogenic hormones prolactin, dexamethasone and insulin. Findings HC11 cells express all AP-2 family members except AP-2delta. Using RT-PCR we could not detect a downregulation of any of these genes during the lactogenic differentiation of HC11 cells in vitro. This finding was confirmed for AP-2alpha and AP-2gamma using Northern analysis. Differentiating HC11 cells displayed lower expression levels of milk protein genes than mammary glands of mid-pregnant or lactating mice. Conclusion The extent of lactogenic differentiation of HC11 cells in vitro is limited compared to mammary epithelium undergoing secretory differentiation in vivo. Downregulation of AP-2 transcription factor genes is not required for lactogenic differentiation of HC11 cells but may functionally be involved in aspects of lactogenic differentiation in vivo that are not reflected by the HC11 system.

Abstract Background Surgical treatment of peripheral vascular disease (PVD) in dialysis patients is controversial. Methods We examined the post-operative morbidity and mortality of surgical revascularization or amputation for PVD in a retrospective analysis of United States Renal Data System. Propensity scores for undergoing amputation were derived from a multivariable logistic regression model of amputation. Results Of the Medicare patients initiated on dialysis from Jan 1, 1995 to Dec 31, 1999, patients underwent surgical revascularization (n = 1,896) or amputation (n = 2,046) in the first 6 months following initiation of dialysis were studied. In the logistic regression model, compared to claudication, presence of gangrene had a strong association with amputation [odds ratio (OR) 19.0, 95% CI (confidence interval) 13.86–25.95]. The odds of dying within 30 days and within1 year were higher (30 day OR: 1.85, 95% CI: 1.45–2.36; 1 yr OR: 1.46, 95% CI: 1.25–1.71) in the amputation group in logistic regression model adjusted for propensity scores and other baseline factors. Amputation was associated with increased odds of death in patients with low likelihood of amputation (< 33rd percentile of propensity score) and moderate likelihood of amputation (33rd to 66th percentile) but not in high likelihood group (>66th percentile). The number of hospital days in the amputation and revascularization groups was not different. Conclusion Amputation might be associated with higher mortality in dialysis patients. Where feasible, revascularization might be preferable over amputation in dialysis patients.

Background: Mutant-selective inhibitors of KRAS G12C (KRAS G12C i) have demonstrated efficacy in KRAS G12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRAS G12C i and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms., Methods: To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from post-progression cell-free DNA samples in patients treated with KRAS G12C i at two US cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors., Results: A total of 143 patients were analyzed. Most patients had non-small cell lung cancer (NSCLC, n=68) or colorectal cancer (CRC, n=58) and were treated with single-agent KRAS G12C i (n=109) or combined with anti-EGFR antibodies (n=30). RAS/MAPK alterations emerged in 46% of patients (n=66), with 39% developing ≥1 new KRAS alteration (n=56) and 23% (n=33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%) and NRAS/HRAS mutations (8%). Notably, the proportion of patients with ≥1 acquired RAS/MAPK alteration was significantly higher in CRC compared to NSCLC (69% vs. 26%, p<0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan-KRAS-In-1 effectively targeted KRAS activating mutations, and the RAS(ON) multi-selective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations., Conclusion: Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRAS G12C i detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations., (Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis., Patients and Methods: Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test., Results: A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001)., Conclusions: Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies., (© The Author(s) 2024. Published by Oxford University Press.)

Biliary tract cancers demonstrate profound therapeutic resistance, and broadly effective therapies for refractory disease are lacking. We conducted a single-arm, second-line phase II trial combining DKN-01, a humanized monoclonal antibody targeting Dickkopf-1 (DKK-1), and nivolumab to treat patients with advanced biliary tract cancer (NCT04057365). No objective responses were seen. To identify mechanisms of treatment failure, we analyzed paired pre-treatment and on-treatment biopsies using scRNA-seq and constructed a detailed molecular classification of malignant and immune cells. We annotated five biliary tract cancer malignant cell states: classical, basal, mesenchymal, neural-like, and endothelial-like. Neural-like and endothelial-like states, which drive therapeutic resistance in other cancers, have not previously been described in BTC. Malignant cell states co-varied with distinct immune cell states, revealing diverse mechanisms of myeloid and T-cell mediated immune suppression, including M2 myeloid and terminally exhausted T cell programs that were induced by DKN-01/nivolumab. Here, we provide the first systematic classification of functionally annotated cell states in biliary tract cancer and provide new insight into resistance mechanisms to an immunotherapy combination that can inform the next generation of trials., Competing Interests: MP has served as a consultant for Third Rock Ventures. LP has served as a consultant for Astellas. DGD has received research funding support from Bayer, Bristol-Myers Squibb, Exelixis and Surface Oncology. NH holds equity in and advises Danger Bio/Related Sciences, is on the scientific advisory board of Repertoire Immune Medicines and CytoReason, owns equity in and has licensed patents to BioNTech and receives research funding from Bristol Myers Squibb and Calico Life Sciences. DTT has received consulting fees from ROME Therapeutics, Sonata Therapeutics, Leica Biosystems Imaging, PanTher Therapeutics, and abrdn. DTT is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, Inc., which is not related to this work. DTT is on the advisory board with equity for ImproveBio, Inc. DTT has received honorariums from Astellas, AstraZeneca, Moderna, and Ikena Oncology that are not related to this work. DTT receives research support from ACD-Biotechne, AVA LifeScience GmbH, Incyte Pharmaceuticals, Sanofi, and Astellas which was not used in this work. DTT’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. AM has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, ManaT Bio, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is currently a part-time Entrepreneur in Residence at Third Rock Ventures, is an equity holder in ManaT Bio, Asher Biotherapeutics and Abata Therapeutics, and has received research funding support from Bristol-Myers Squibb. AM’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. All other authors have nothing to disclose.