Annals of Oncology

BackgroundPrecision oncology is predominantly focused on nuclear genomic alterations, while mitochondrial DNA (mtDNA) variation remains largely excluded from routine pharmacogenomic testing. However, mitochondria regulate oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) production, apoptosis, and metabolic reprogramming pathways central to chemotherapy response. Methods468 Complete mitochondrial genomes from Kenyan individuals representing diverse ethnolinguistic groups were analyzed. Seven variants associated with effect on cancer treatment were identified. These include; m.310T>C(D-loop), m.10398A>G (MT-ND3), m.13708G>A (MT-ND5), m.16189T>C, m.13928G>C, m9055G>A and m.16519T>C (D-loop). Allele frequencies and distribution were assessed. ResultsThe coding-region variants (m.10398A>G and m.13708G>A) occur in Complex I subunits and are associated with altered oxidative phosphorylation efficiency and ROS production. The control-region variants (m.16189T>C and m.16519T>C) influence mtDNA replication and copy number. These variants have been implicated in differential response to chemotherapeutic agents including platinum-based therapies and anthracyclines. m.13928G>C sits in the MT-CYB gene and could possibly affect mitochondrial respiratory function; this variant could influence how tumors respond to therapies that rely on apoptosis or ROS generation.m.9055G>A is a MT-ATP6 variant classified as benign in mitochondrial disease but may represent a marker of haplogroup background rather than a direct cancer driver. While m.310T>C itself does not encode a protein, its location in the regulatory D-loop influences mitochondrial function, which can affect how tumor cells respond to chemotherapies that rely on mitochondrial-mediated apoptosis or oxidative stress. ConclusionPharmacogenomics relevant mitochondrial variants are present in the Kenyan population. With the rise of cancer burden in Kenya there is a need carry out more studies to understand the impact of these variations on cancer treatment. This can inform the integration of mtDNA analysis into precision oncology strategies in African populations.

Purpose: Beyond estrogen receptor (ER) positivity, no genomic biomarker reliably identifies ER+ breast cancer patients who derive differential benefit from endocrine therapy (ET). We performed an unbiased genomic screen to discover genes predicting ET response and characterized the top candidate across clinical settings, treatment modalities, and an independent validation cohort. Experimental Design: We screened 240 genes in 1,197 metastatic ET-treated patients from the MSK-CHORD clinical genomics database using Cox proportional hazards regression with false discovery rate (FDR) correction. The top candidate, core-binding factor subunit beta (CBFB), was characterized across four cohorts defined by disease setting (metastatic/adjuvant) and treatment (ET/chemotherapy), with multivariable adjustment, gene-by-treatment interaction testing, left-truncation sensitivity analysis for guarantee-time bias, and external validation in METABRIC (N = 1,499 ER+). Results: CBFB mutations (prevalence, ~5%) were the only gene associated with improved time to progression (TTP). In metastatic ET patients, CBFB-mutated tumors (n = 80) demonstrated significantly longer TTP (hazard ratio [HR], 0.44; 95% CI, 0.29-0.67; P = .0002, FDR q = .010) with no chemotherapy benefit (HR, 1.16; P = .65). The gene-by-treatment interaction was significant (HR, 0.37; P = .009). Effects were robust to multivariable adjustment (HR, 0.46-0.50), independent of histology, and preserved under left-truncated Cox regression (HR, 0.38). In the adjuvant setting, CBFB mutations predicted improved recurrence-free survival (HR, 0.52; 95% CI, 0.31-0.85; P = .010), with no effect under chemotherapy. In METABRIC, CBFB mutations predicted improved ER+ overall survival (HR, 0.52; P = 9.3e-5). Conclusions: CBFB mutations identify ~5% of ER+ breast cancers with exceptional ET benefit. As CBFB is included on all major cancer gene panels, this biomarker requires no additional testing infrastructure for clinical implementation.

BackgroundHigh grade serous ovarian cancer (HGSC) is initially a responsive tumor to platinum (Pt)-based therapy. Pt resistance in HGSC is associated with epigenetic modifications and hypomethylating agents (HMAs) have been studied as carboplatin resensitizing agents. As DNA methylation is detectable in cancer cells and in blood, here we aimed to develop a blood-based methylation signature associated with cancer and cancer recurrence in HGSC. ResultsWe evaluated genome-wide DNA methylation in de-identified peripheral blood mononuclear cells (PBMCs) from women 1) without cancer (controls, n=20); 2) newly diagnosed HGSC (prior to treatment, Pt-naive, n=60) 3) Pt-resistant recurrent HGSC before and after treatment with the novel HMA/DNA methyltransferase inhibitor (DNMTI) guadecitabine (Pt-resistant, n=30). The Pt-resistant patients were enrolled in NCT02901899 clinical trial testing guadecitabine and the PD-1 inhibitor pembrolizumab. DNA extracted from PBMCs was analyzed by using Infinium MethylationEPIC BeadChips. There were 30,369 differentially methylated loci (DMLs) in Pt-naive patients vs. controls (adj. p < 0.05, {beta} >10%), with most loci being demethylated. Enriched pathways in PBMCs from cancer patients included mechanisms of cancer, neutrophil degranulation, and cancer-related signaling pathways (PI3K/AKT, STAT3, HGF, interleukins). The number of DMLs was greater (880 DMLs; adj. p<0.05, {beta}>10%) in Pt-resistant vs. Pt-naive patients, and top enriched pathways associated with Pt-resistant HGSC included pathways in cancer, metabolic pathways, platelet activation, ABC transporters and signaling pathways (calcium, PI3K/AKT, MAPK, Ras, ErbB, Hippo, Wnt). Massive genomewide hypomethylation 5 days after treatment with guadecitabine was observed (13,742 DMLs; adj. p<0.05, {beta}>10%), which persisted 30 days after discontinuation of treatment. Pathways enriched by hypomethylated genes in PBMCs following guadecitabine treatment interestingly included pathways related to neuronal signaling, such as glutaminergic receptor signaling, axonal guidance signaling, synaptic long-term depression, synaptogenesis signaling and serotonin receptor signaling. Deconvolution analysis of the methylome data of PBMCs from Pt-resistant recurrent HGSC before versus after HMA treatment predicted increased naive B cells, memory and naive CD+ T cells, naive CD4+ T cells, and neutrophils and decreased monocytes. ConclusionsWe propose new DMLs associated with Pt-naive versus Pt-resistant HGSC. These findings can lead to new biomarkers for HGSC.

Background Cancer treatment response is highly variable, even among patients with the same tumor type and treatment. Exceptional responders (ERs), who are individuals who experience unusually favorable outcomes, provide critical insights into the biological factors driving treatment success. While prior studies have highlighted the role of somatic changes, the contribution of germline rare variants remains underexplored. This study aimed to uncover the genetic underpinnings of exceptional responses by identifying rare, non-silent and predicted deleterious germline mutations enriched among ERs compared to typical cancer patients. Methods The Network of Enigmatic Exceptional Responders (NEER) project collected clinical and germline whole-genome sequencing (WGS) data from 53 ERs. After quality control procedures and ancestry background checks, 51 ERs were left for final analysis. While non-silent mutations were identified based on allele frequencies and mutation types, multiple pathogenicity predictors were applied for predicted deleterious variants. These were compared to a harmonized and comparable subset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) cohort (n=414) using Fisher's exact tests. Kaplan-Meier survival analysis applied to evaluate prognostic associations in PCAWG patients. Additionally, Fisher's exact tests were conducted stratified by cancer type and treatment regimen to identify potential associations between rare germline variants and therapeutic responses. Results Variants in immune-related genes such as CCL26 and GPRC5D were prevalent, suggesting enhanced immune regulation among ERs. Fourteen genes with non-silent and eight with predicted deleterious mutations showed significantly different frequencies between NEER and PCAWG cohorts (FDR < 0.05). IRX3 emerged as a protective gene enriched in ERs, whereas OR6B2 was associated with poor survival in PCAWG lung cancer patients. Moreover, rare non-silent germline variants in drug target genes were enriched among ERs treated with cisplatin and doxorubicin, implicating altered DNA repair and drug-binding mechanisms in their remarkable outcomes. Conclusions This study reveals a distinctive germline mutation landscape in exceptional cancer responders, marked by immune-related and drug-target-associated variants that may enhance therapy response and prolong survival. The findings highlight potential novel prognostic biomarkers, such as IRX3 and OR6B2, providing a foundation for developing personalized cancer treatments informed by rare genetic variation.

BackgroundTreatment optimization in HPV-associated oropharyngeal cancer (OPSCC) remains challenging, as recent de-escalation trials have shown limited success. Current patient selection strategies based on smoking history and TNM classification are insufficient, highlighting the need for robust, standardized prognostic biomarkers. We report the first validation of the Immunoscore (IS) for prognostic stratification in HPV-associated OPSCC. Patients and methodsWe analyzed 191 HPV-associated (p16+ and HPV DNA/RNA+) OPSCC patients from an international multicenter cohort (2015-2024), comprising a French monocentric retrospective training cohort (N = 48) and three validation cohorts: French monocentric retrospective (N = 48), French multicenter prospective (N = 50), and US multicenter retrospective (N = 45). IS is a standardized digital pathology assay quantifying CD3lJ and CD8lJ densities in tumor cores and invasive margins, with cut-offs defined in the training cohort and validated across cohorts. Associations with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were assessed, alongside 3RNA-seq and sequential immunofluorescence profiling of immune composition. ResultsMedian age 65; 80% male; 74% smokers; 66% T1-2; 82% N0-1 (AJCC8th). IS-High patients demonstrated superior 3-year DFS in the training and validation cohorts 1-3 (all log-rank P < 0.05). Multivariable analysis identified IS-Low as the strongest independent risk factor for DFS (HR 9.03; 95% CI: 4.02-20.31; P < 0.001). The model combining IS with clinical factors showed higher predictive accuracy for DFS (C-index 0.82) than clinical variables alone (0.7; P < 0.0001). Similar findings were observed for TTR and OS. IS-High tumors showed markedly higher enrichment of lymphoid and myeloid immune cell populations, contrasting with immune-poor signatures in IS-Low tumors. ConclusionsIS is a robust biomarker that outperforms standard clinical variables in both prognostic and predictive accuracy. The enriched cytotoxic immune infiltrate in IS-High tumors explains favorable outcomes and supports their suitability for treatment de-escalation. Prospective validation is warranted.

Purpose In resource-limited settings, locally advanced rectal cancer (LARC) often presents at advanced stages. Long-course chemoradiotherapy (LCCRT) remains a cornerstone of neoadjuvant therapy, yet outcome data from such settings remain limited. This study assessed tumor resectability, pathologic response, and factors associated with resectability following neoadjuvant LCCRT at Ethiopias largest tertiary oncology center. Methods A retrospective cohort study was conducted among patients with stage II-III rectal adenocarcinoma (cT3-4 and/or cN+) who completed neoadjuvant LCCRT at Tikur Anbessa Specialized Hospital between 2018 and 2023. Tumor resectability was determined by multidisciplinary team (MDT) assessment. Multivariable logistic regression was used to identify factors associated with post-LCCRT resectability, adjusting for initial T stage, circumferential resection margin (CRM) status, histologic subtype, radiotherapy technique, and neoadjuvant regimen. Results Among 58 eligible patients (median age 45 years; 62% male), 62% had cT4 tumors, 53% had cN2 disease, and 84.5% had involved CRM. The median diagnosis-to-LCCRT interval was 64 weeks (interquartile range [IQR], 37-82). After LCCRT, 27 patients (46.6%) were deemed resectable by MDT assessment; 19 patients (32.8%) ultimately underwent curative-intent surgery (median interval from LCCRT to surgery, 10 weeks; IQR, 7-15). Initial cT3 stage was associated with higher odds of resectability (adjusted odds ratio [AOR], 6.2; 95% CI, 1.06-36.37), whereas receipt of total neoadjuvant therapy was associated with lower odds (AOR, 0.10; 95% CI, 0.02-0.49). No pathologic complete responses were observed. Conclusion In this cohort characterized by advanced disease at presentation and treatment delays, neoadjuvant LCCRT resulted in low resectability and limited pathologic response. To enhance curative potential, concerted efforts are needed to expedite the timely initiation of radiotherapy, optimize multidisciplinary team assessment, and increase surgical capacity.

BackgroundThe management of residual axillary disease after neoadjuvant therapy (NAT) remains controversial, as current recommendations often treat ypN1 breast cancer as a homogeneous entity despite potential prognostic heterogeneity. Evidence supporting uniform axillary surgical strategies across different levels of residual nodal burden is limited. We investigated whether survival associations related to axillary surgical evaluation differ according to residual nodal burden in ypN1 disease, using an adjuvant cohort to validate a SEER-based proxy for surgical extent. MethodsPatients with 1-3 positive lymph nodes were identified in the SEER database (2000-2022) and stratified into neoadjuvant (NAT; n=30,560) and adjuvant (AT; n=197,586) cohorts. Axillary surgical evaluation was categorized as limited (2-3 examined nodes) or extensive ([&ge;]10 examined nodes). Survival was analyzed using Kaplan-Meier methods and log-logistic accelerated failure-time models, adjusted with inverse probability of treatment weighting. ResultsIn the ypN1 cohort, limited axillary evaluation was not associated with inferior overall survival among patients with a single residual positive node (IPTW-adjusted HR: 1.15, p=0.134; time ratio [TR]: 0.86, p=0.184). In contrast, limited evaluation was associated with worse survival in patients with two positive nodes (HR: 1.70, 95%CI 1.54-1.87; TR: 0.58, 95%CI 0.53-0.64). The findings were similar when using breast cancer-specific survival as the endpoint. ConclusionsSurvival associations related to axillary surgical evaluation after NAT vary according to residual nodal burden. Axillary de-escalation appears feasible in patients with a single residual positive node but cannot be extrapolated to those with multiple residual nodes, underscoring heterogeneity within ypN1 disease.

Anal squamous cell carcinoma (ASCC) is a rare malignancy associated with high-risk HPV, with rising incidence among younger adults. While immunotherapy has improved outcomes in metastatic ASCC, treatment for localized disease remains largely unchanged, with high recurrence rates. This study provides comprehensive exome and transcriptome profiling of 40 stage I-III non-metastatic ASCC patients treated with curative chemoradiotherapy (CRT) to identify predictors of treatment response and progression-free survival. Transcriptomic analysis revealed 350 differentially expressed genes between complete responders (CR) and non-complete responders (NCR) (p-value<0.01; FC>2). CR was associated with modulation of immune-related pathways, cytokine production, epidermis development, cell differentiation, and signaling pathways associated with TNFA/NFkB and epithelial to mesenchymal transition. Immune infiltrate analysis showed significant enrichment of CD8+ central memory T cells (p=0.008) in CR cases, correlating with increased tertiary lymphoid structure and improved overall (p=0.0026) and disease-free survival (p=0.0098). Exome-seq identified alterations in novel and known cancer driver genes without association to CRT response, despite high tumor mutational burden (TMB) was significantly associated with shorter overall (p=0.03) and disease-free survival (p=0.027) compared with low TMB cases. These findings highlight the potential of incorporating gene expression signatures (e.g., FDCSP, ALDOB, ADGRB1, SPINK7) alongside immune-related markers into clinical practice to enhance the prediction of treatment response and guide personalized therapies in ASCC. A robust and functionally active immune microenvironment, characterized by specific T and B cell populations and the presence of tertiary lymphoid structures, emerges as a hallmark of complete response and improved survival in ASCC patients undergoing chemoradiotherapy.

PurposeTo develop and validate a multimodal recurrence-risk model integrating histology, genomic testing, and clinical variables. MethodsWe developed AI-Path, a whole-slide image biomarker for recurrence prediction trained in CALGB 9344, and validated it in three independent cohorts: TAILORx, a multi-site Chicago cohort, and the MDX-BRCA cohort. We then integrated AI-Path with Oncotype DX Recurrence Score (RS), tumor size, and nodal status into a Cox model, PathClinRS, fit using 60% of cases from TAILORx, with the remaining 40% held out for validation. The primary end point was distant recurrence-free interval. Performance was assessed using Harrells concordance index (C-index) and Kaplan-Meier analyses. ResultsA total of 12,418 patients were included. In TAILORx, AI-Path outperformed RS for distant recurrence (C-index, 0.682 vs 0.647; P = .038), driven by superior prediction of late recurrence (0.656 vs 0.567; P < .001). In node-negative disease, PathClinRS outperformed RSClin in the TAILORx fitting (0.72 vs 0.70; P = .016) and validation sets (0.74 vs 0.70; P = .004). In node-positive disease, PathClinRS outperformed RSClinN+ in Chicago (0.94 vs 0.74; P < .001) and MDX-BRCA (0.71 vs 0.66; P = .004) cohorts. Compared with NATALEE eligibility, PathClinRS identified nearly twice as many high-risk node-negative patients while maintaining a comparable 10-year distant recurrence risk (16.7% vs 16.6% per NATALEE eligibility in TAILORx fitting; 21.0% vs 19.4% in TAILORx validation). PathClinRS identified 68% of intermediate risk premenopausal patients as low-risk with no evidence of chemotherapy benefit, compared to only 36% identified as low risk by standard clinicopathologic criteria. ConclusionDigital histopathology provides prognostic information complementary to genomic assays and has the potential to personalize therapy beyond existing clinicogenomic tools.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) affects many people receiving taxane treatment for breast cancer. Symptom trajectories vary, with some recovering, and others experiencing persistent, or delayed worsening (coasting) symptoms. The prevalence and predictors of these trajectories remain unclear. This study identified the prevalence and biopsychosocial predictors of CIPN persistence, improvement, and coasting within three months post-treatment. Methods: This secondary analysis included participants treated with taxanes for stage I-III breast cancer who completed the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity-4 (FACT/GOG-NTX-4) at baseline, post-chemotherapy, and three months later. A minimally important difference (MID) from baseline on the FACT/GOG-NTX-4 defined persistence, improvement, coasting, and no MID-CIPN (below the MID threshold at each assessment) trajectories. Baseline assessments included self-reported pain/well-being, sensory, balance, and lower limb physical functioning measures, and sociodemographic and treatment data were collected. Results: Among 102 participants (51.57{+/-}11.24 years), persistence occurred in 34.3%, improvement in 25.5%, coasting in 6.9%, and no MID-CIPN in 33.3%. Compared to no MID-CIPN, older age (OR=1.120; 95%CI: 1.026-1.222), higher expected pain (OR=1.630; 95%CI: 1.082-2.456), and cold hyperalgesia at the foot (OR=1.130; 95%CI: 1.018-1.254) predicted persistence. Lower fatigue predicted improvement (OR=0.904; 95%CI: 0.845-0.968). No predictors were identified for coasting. Conclusion: CIPN trajectories are heterogeneous. Age and pre-treatment pain expectations, cold hyperalgesia, and fatigue differentiate patients with persistent CIPN and those likely to improve from those with no CIPN. Implications for Cancer Survivors: Early identification of individuals at risk for persistent neurotoxicity may support risk stratification and guide targeted supportive care strategies.

PurposeHPV-associated carcinomas (HPV+ cancers) account for 5% of all cancers. Circulating tumor HPV DNA (ctHPVDNA) assays for HPV+ cancer surveillance have limited prognostic utility at the time of cancer diagnosis. While HPV integration into the host genome is a proven tissue-based biomarker predicting poor clinical outcomes, existing clinically utilized ctHPVDNA assays cannot classify the viral physical state. MethodsWe previously developed HPV-DeepSeek, a multi-feature HPV whole-genome sequencing liquid biopsy with 99% diagnostic accuracy at the time of HPV+ oropharynx cancer diagnosis. We test the diagnostic accuracy of HPV-DeepSeek in a cohort of 235 HPV+ cancers across nine anatomic sites and employ a novel blood-based computational classifier to infer HPV genome physical state from plasma, termed HPV-SIGNAL, to assess its prognostic potential. ResultsHPV-DeepSeek demonstrated a sensitivity and specificity of 99%. In 181 eligible samples, HPV-SIGNAL identified four viral physical states: episomal-only (N = 69), episomal-rearranged (N = 48), integrated-mixed (N = 55), and integrated-clonal (N = 9), which were confirmed and further elucidated via three orthogonal tissue and blood approaches. Patients harboring integrated viral states in the blood exhibited significantly worse progression-free survival (HR 3.28, 95% CI 1.63-6.58, p = 0.00084) and overall survival (HR 2.98, 95% CI 1.16-7.64, p = 0.023) compared to patients with episomal states. ConclusionHPV whole-genome sequencing liquid biopsy has high diagnostic accuracy across HPV+ cancer types and can be used to identify and classify HPV physical state from blood. Patients with integrated viral states detected in the blood demonstrated worse progression-free and overall survival, suggesting blood-based HPV physical state classification could be used as a prognostic tool at the time of cancer diagnosis. Translational RelevanceCurrent circulating tumor HPV DNA assays for HPV-associated cancer surveillance have limited prognostic utility at the time of cancer diagnosis. While HPV integration into the host genome is a proven tissue-based biomarker predicting poor clinical outcomes, existing circulating tumor HPV DNA assays cannot classify the viral physical state. Here, we show that HPV-SIGNAL, a novel blood-based computational classifier to infer HPV genome physical state from plasma using output from HPV-DeepSeek, an HPV whole genome sequencing liquid biopsy, accurately identifies and classifies HPV physical state from blood and is prognostic of progression-free and overall survival across HPV-associated cancer types.

Background and ObjectivesIntravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. MethodsPatients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and LimitationsResponders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical ImplicationsDistinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summaryIn this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

A recent randomized clinical trial in non-small cell lung cancer1 confirms what numerous observational studies have reported - time-of-day (ToD) may dramatically influence treatment outcomes in cancer patients2-9. In this recent trial median overall survival (OS) decreased from 28 months in the early ToD arm to 16.8 months in the late ToD arm. We raise the concern that clinical trial outcomes may be influenced by seemingly minor biases in treatment time across arms. We also suggest that by measuring or randomizing treatment-time in clinical trials, we may identify beneficial ToD-dependent treatments that would otherwise be overlooked.

Metabolic dysfunction is increasingly recognized as a risk factor for poor outcomes in breast cancer, but whether incretin-based therapies confer survival benefit beyond weight loss remains unresolved. Using a federated electronic health record platform spanning nearly 29 million patients, we evaluated breast cancer survival after semaglutide and tirzepatide initiation in routine care. In 1:1 propensity-matched pooled-comparator analyses, semaglutide was associated with improved overall survival versus metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitor, and dipeptidyl peptidase 4 (DPP4) inhibitor users, with 54 deaths among 2,433 semaglutide users (2.2%) versus 395 deaths among 2,433 comparators (16.2%) over 24 months (log-rank P < 0.001). Tirzepatide showed a favorable survival association relative to pooled anti-diabetic comparators that did not meet statistical significance (P = 0.24), with 3 deaths among 220 users (1.4%) versus 64 deaths among 220 comparators (29.1%). In a head-to-head propensity-score-matched comparison, overall survival did not differ significantly between semaglutide- and tirzepatide-treated patients with pre-existing breast cancer (2,117 per arm; P = 0.12). In semaglutide-treated patients alive and observable at the 1-year landmark, higher maximum dose achieved was significantly associated with lower post-landmark mortality (P = 0.034), with an event rate of approximately 1.0% in the high-dose group ([&ge;]1.7 mg) versus approximately 4.5% in the low-dose group (0.25-1.0 mg). Despite a linear dose-weight loss relationship for semaglutide, however, weight-loss strata did not separate survival outcomes (global P = 0.22). In tirzepatide-treated patients alive and observable at the same landmark, neither maximum dose achieved nor weight-loss strata separated post-landmark survival (P = 0.98 and P = 0.50, respectively). Structured EHR and AI-based clinical-note analyses further showed significantly lower frequency of documented metastatic disease in semaglutide-treated patients relative to pooled anti-diabetic comparators, including any metastasis (7.0% versus 15.0%, rate ratio 0.5, P < 0.001), bone metastasis (1.0% versus 5.2%, rate ratio 0.2, P < 0.001), and liver, lung, or brain metastases (all P < 0.001). LLM-derived cause-of-death extraction further showed a 60% lower relative proportion of cancer-associated deaths in semaglutide-treated patients (19% of ascertainable deaths) than in matched pooled anti-diabetic comparators (47% of ascertainable deaths), with comparator deaths more often attributed to cancer progression involving metastatic breast cancer, leptomeningeal carcinomatosis, and cancer-driven organ failure. Overall, this study demonstrates that semaglutide use in patients with pre-existing breast cancer is associated with a dose-correlated but weight-loss independent improvement in overall survival. These findings motivate prospective trials of GLP-1 receptor agonists in breast cancer across various stages and treatment settings.

BackgroundCirculating tumor DNA (ctDNA) detection after curative-intent surgery is being used to identify minimal residual disease (MRD) in colorectal cancer (CRC). However, MRD classification is dependent on analytical sensitivity, and the impact of detection threshold on observed post-operative positivity remains incompletely characterized. We evaluated MRD positivity in stage I-III CRC using a CRISPR-based plasma sequencing assay, MUTE-Seq. MethodsPatients were prospectively enrolled and analyzed using customized tumor-informed panels applied to baseline and post-operative plasma samples collected at 4-week and 3-month. We report preliminary results from 39 plasma samples obtained from the first 14 patients. MRD positivity was assessed across multiple hypothetical detection thresholds (1-100 ppm). ResultsAll 14 patients (100%) had detectable mutations at baseline. Mutation-positive call number significantly decreased after surgery (baseline vs 4-week, p = 0.006; baseline vs 3-month, p = 0.004), and ctDNA concentration likewise declined (baseline vs 4-week, p = 0.002; baseline vs 3-month, p = 0.003). Among stage II-III patients, MRD positivity at 4-week was 20% at a 100-ppm threshold but increased to 70% at 10 ppm and 100% at 1 ppm. At 3-month, MRD positivity was 11% at a 100-ppm threshold and 78% at 1 ppm. At both time points, approximately 80% of MRD-positive stage II-III patients harbored ctDNA levels below 100 ppm, and half of these cases were below 15 ppm. Two patients (one stage I and one stage II) developed recurrence; both were MRD-positive at 4-week and demonstrated increasing mutation-positive calls at 3-month, with a median radiologic lead time of 4 months. ConclusionsPost-operative MRD classification in CRC is strongly influenced by analytical sensitivity. A substantial proportion of residual disease signals reside below the conventional ctDNA detection threshold of 100 ppm, supporting the clinical relevance of ultrasensitive ctDNA detection.

BackgroundInvasive lobular breast cancer (ILC) is the most commonly diagnosed special histological subtype of breast cancer (BC). Metastatic ILC (mILC) is less sensitive to FDG-PET imaging and often metastasizes to unusual sites --peritoneum, gastrointestinal (GI) tract, ovaries, urinary tract, and orbit--which may go unrecognized after a long disease-free interval. Some metastatic sites cause nonspecific symptoms, like abdominal/epigastric pain, with numerous published case reports of mILC misdiagnosed as gastric cancer. These atypical BC metastatic sites may lead to late and/or misdiagnosis, thereby delaying effective treatments. ObjectiveWe developed a patient survey to investigate the patient-reported prevalence of delayed diagnosis or misdiagnosis of mILC and their potential impact upon treatment outcomes. MethodsA 45-question survey was developed and piloted with breast cancer researchers, clinical oncologists, and patient advocates. This IRB-approved survey was then distributed to patients with ILC. Analyses including data QC and visualization were conducted in R using descriptive statistics. Incomplete or inconsistent responses were excluded, and summary statistics were stratified by four common mILC sites to highlight subgroup differences. Results525 patient surveys were completed, with 450 patients diagnosed with ILC, and of those 321 diagnosed with mILC. For those with mILC, 33.3% (n=107) were diagnosed with de novo mILC at initial presentation. Of the patients diagnosed with mILC, 32.1% (n=103) presented with other medical conditions at diagnosis. Misdiagnosis was reported by 26.2% (n=84) of patients with mILC, and of these cases, 31% (n=26) had [&ge;]2 misdiagnoses. The top 5 misdiagnoses were bone-related condition (24.7%), benign breast condition (23.4%), another type of BC (7.8%), diagnostic delay (7.8%), and menopause related (5.2%). 44.5% of patients waited [&ge;]1 year for an accurate diagnosis. 49 patients were treated for their misdiagnosis, and 6 received incorrect cancer treatments. The most frequently reported contributors to delayed or misdiagnosis were inconclusive imaging, providers lack of ILC knowledge, and initial misdiagnosis. Of the 321 patients with mILC, 138 (42.9%) reported symptoms before diagnosis; the most common were back pain (16.5%), fatigue/malaise (14.9%), GI symptoms (11.8%), bloating (8.4%), and weight loss (8.1%). Although 40% of patients reported having a mammogram at the time of their initial misdiagnosis, ILC was detected in only 20.5% (24/116) of these cases, and mammography detected only 5 (25%) of the 20 de novo mILC cases. Patients reported additional diagnostic testing within 1-3 months of their initial mammogram, includingbiopsy, ultrasound (US), and MRI. 47.9% of patients were in active BC surveillance after curative intent therapy at the time of their mILC diagnosis; however, no statistical difference was seen in time to diagnosis versus those patients not under surveillance. ConclusionOur survey results underscore the urgent need to improve diagnostic strategies for mILC. Addressing delays and diagnostic errors in mILC is critical to optimizing treatment strategies and improving patient outcomes.

PURPOSE To evaluate cancer risk, age-specific penetrance, and mortality associated with heterozygous pathogenic or likely pathogenic (P/LP) germline PALB2 variants identified through genomic ascertainment and to assess modification by family history of cancer. PATIENTS AND METHODS We conducted a case-control study in two large population-based adult cohorts: the UK Biobank (n=469,580) and Geisinger MyCode (n=167,050). Individuals with heterozygous PALB2 P/LP variants were identified via exome sequencing and compared with non-carriers. Cancer diagnoses and vital status were obtained from linked registry and electronic health record data. We used multivariable logistic regression to estimate odds ratios (ORs) for cancer outcomes and Cox proportional hazards models to estimate hazard ratios (HRs) for all-cause mortality. Age-specific cumulative incidence (penetrance) was estimated using Kaplan-Meier methods. Models were adjusted for birth year, sex (when applicable), smoking status, and body mass index; stratified analyses assessed modification by family history of cancer. RESULTS PALB2 P/LP variant prevalence was 1:571 in UK Biobank and 1:940 in MyCode, with the higher prevalence in the UK cohort driven by the PALB2 p.Trp1038Ter founder variant. Compared with non-carriers, heterozygotes had significantly increased odds of any cancer, female breast cancer, pancreatic cancer, and cancers of ill-defined or secondary sites in both cohorts (P < 0.01). Adjusted hazard ratios for any cancer and female breast cancer ranged from 1.7 to 3.6. All-cause mortality was increased among PALB2-heterozygotes (HR 1.61-1.67), and survival after cancer diagnosis was reduced. Family history further modified cancer risk. CONCLUSION Genomic ascertainment of PALB2-heterozygotes identifies elevated risk for multiple cancers and increased mortality, although risks were lower than estimates from familial ascertainment. These findings inform risk management for individuals identified through genomic screening.

Importance: Enfortumab vedotin (EV) is an antibody-drug conjugate approved for the treatment of locally advanced or metastatic urothelial cancer (la/mUC). Cutaneous adverse events (cAEs) are common during EV therapy, with prior studies suggesting an association between EV-related cAEs and improved survival; however, there is insufficient data to delineate the survival benefit of EV-induced cAEs from those associated with concurrent immune checkpoint inhibitors (ICIs). Objective: This study aims to evaluate the association of EV-induced cAEs and survival, and to characterize the timing and morphology of EV-induced cAEs. Design: We conducted a multi-institutional retrospective study of patients with la/mUC treated with EV between 2020 and 2025. Setting: Multicenter academic referral center. Participants: A total of 449 EV-treated patients were included. Patient characteristics were extracted manually, and likelihood scoring was used to attribute cAEs to either EV or other etiologies. Exposure: EV treatment. Main Outcomes and Measures: We estimated progression-free (PFS) and overall (OS) survival using Kaplan-Meier method. Multivariable time-varying and landmark Cox regression models were used to evaluate associations between EV-induced cAE and survival. Sensitivity analyses were performed at landmarks from 15 to 105 days. Results: Of 449 patients, 206 (45.9%) developed a cAE; 39 (18.9%) were high-grade and 127 (61.7%) were attributed to EV. The most common cAEs were pruritus (41.3%), unspecified and desquamating dermatitis (37.3%), and morbilliform dermatitis (27.7%). Across all treatment groups, survival was longer in patients with EV-induced cAEs. Developing an EV-induced cAE was protective across all examined landmark times, with hazard ratio (HR) 0.60 (95% CI: 0.43-0.82, p<0.001) for PFS and HR 0.46 (95% CI: 0.31-0.67, p<0.001) for OS at primary landmark time of 30 days. Early-onset EV-induced cAEs were protective at all landmark times and high-grade EV-induced cAEs were not associated with worse survival. Conclusions and Relevance: EV-induced cAEs were independently associated with improved PFS and OS in patients with la/mUC, even after accounting for immortal time bias and ICI exposure. Distinguishing EV-induced cAEs from other etiologies in timeline and morphology may help guide oncology and dermatology management.

Immune checkpoint inhibitors such as anti-PD1 antibodies are essential in cancer therapy. Emerging data suggest that lower doses may be effective and more economical, though further evidence is needed. We conducted a retrospective study at Centre Leon Berard to assess the efficacy and safety of low-dose nivolumab (20 mg every three weeks) in patients with advanced cancer, mainly squamous cell carcinomas (SCC). Between 2023 and 2024, 53 patients were treated, with a median age of 74 years; 39.6% were over 80. Most were male (64%) and had ECOG >1 (69.9%). Primary tumor sites included cutaneous SCC (34%), head and neck SCC (32%), and soft tissue sarcoma (15%). After a median follow-up of 8.3 months, median overall survival was 7.5 months. The objective response rate (ORR) was 20.8% overall, rising to 35.3% in cutaneous SCC and 23.5% in head and neck SCC-comparable to standard-dose nivolumab. Toxicity was manageable: 18.7% experienced immune-related adverse events, with only 3.7% grade 3. Low-dose nivolumab demonstrates encouraging efficacy and tolerability in a frail population, supporting its potential role in resource-limited settings. Prospective trials are warranted to confirm these findings in broader populations.

Background: Population-relevant BRCA1/BRCA2 data from Bangladesh are scarce, creating challenges for hereditary breast and ovarian cancer variant interpretation, counseling, and follow-up testing. We examined a clinically referred Bangladeshi cohort to characterize assay-derived BRCA1/BRCA2 short variants, sequencing-depth performance, and copy-number findings in a conservative pilot framework. Methods: Twenty-three de-identified blood-derived DNA samples were assessed using a targeted BRCA1/BRCA2 next-generation sequencing workflow. Downstream analysis used assay-generated short-variant, coverage, and CNV outputs, with coordinates reported on hg19/GRCh37. Short variants were evaluated from high-confidence PASS/VCC-H calls, and CNV review incorporated both target-region and amplicon-level copy-number patterns. Results: After removal of four low-VAF review observations, the primary germline-compatible dataset comprised 304 short-variant observations representing 34 unique variants. Both BRCA1 and BRCA2 contributed comparable variant burdens, while the overall profile was mainly composed of missense and synonymous changes. Six sample-specific heterozygous BRCA1 truncating candidates were observed, including five frameshift variants and one stop-gain variant. Protein-level mapping placed these events across the central-to-C-terminal portion of BRCA1. Sequencing depth was consistently high across the targeted regions, with all 4,255 amplicon-sample measurements exceeding 280x and 99.91% reaching at least 500x. Copy-number analysis highlighted one candidate BRCA1 multi-exon deletion-like event involving exons 15-20 in BCSIR-BRCA-21, with unresolved partial exon 14 involvement. Conclusions: This study provides an initial Bangladesh-focused targeted BRCA1/BRCA2 dataset and identifies candidate short-variant and CNV findings for validation. These findings should be interpreted as analytical candidates only and require confirmatory testing and expert clinical curation before any clinical application. The cohort is referral-enriched and should not be used to infer population prevalence.