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.

Structured AbstractO_ST_ABSPurpose/ObjectivesC_ST_ABSThe role of postmastectomy radiotherapy (PMRT) in patients with pathologic N1 (pN1) breast cancer, including triple-negative breast cancer (TNBC), remains controversial in the era of modern systemic therapy. We evaluated the association between PMRT and recurrence-free survival (RFS) and overall survival (OS) and identified prognostic factors in a contemporary single-institution pN1 cohort. Materials/MethodsWe retrospectively reviewed female patients with pT1-2N1M0 breast cancer treated with mastectomy between 2016 and 2022. RFS and OS were estimated using Kaplan-Meier methods and compared by PMRT status with log-rank testing. Univariable Cox proportional hazards models assessed associations between clinical factors--including tumor laterality, receptor subtype (TNBC vs non-TNBC), nodal burden, and adjuvant therapies--and survival outcomes, with subgroup analyses by PMRT status and receptor subtype. ResultsFifty-seven patients were included; 22 (38.6%) received PMRT. With a median follow-up of 85 months, PMRT was not associated with improved RFS (median 133 vs 120 months; p=0.256) or OS (not reached vs 195 months; p=0.154). Hormone therapy was significantly associated with improved RFS (HR 0.43; p=0.026) and OS (HR 0.13; p=0.003), while having 2-3 positive lymph nodes predicted worse RFS (HR 2.86; p=0.007). No significant differential benefit from PMRT was observed in patients with TNBC or non-TNBC disease. ConclusionsPMRT was not associated with a survival benefit in this pN1 cohort, including patients with TNBC. Interpretation is limited by modest sample size and statistical power. Outcomes appeared driven by tumor biology, nodal burden, and systemic therapy, supporting individualized PMRT decision-making.

PurposeSquamous non-small cell lung cancer (sq-NSCLC) is a distinct subtype of NSCLC. This exploratory, phase II study investigated the feasibility and efficacy of a four-cycle perioperative regimen combining serplulimab with a taxane (paclitaxel or nab-paclitaxel) and carboplatin in patients with resectable stage II-IIIA sq-NSCLC. MethodsThis investigator-initiated, single-arm, phase II exploratory trial (NCT05775796) enrolled patients with histologically confirmed, resectable clinical stage II-IIIA squamous NSCLC. Patients received 2-3 cycles of neoadjuvant serplulimab plus taxane-carboplatin, followed by curative-intent surgery and 1-2 cycles of adjuvant treatment. The primary endpoint was major pathological response (MPR). Secondary endpoints included pathological complete response (pCR), R0 resection rate, overall response rate (ORR), safety, event-free survival (EFS), and overall survival (OS). ResultsA total of 30 patients without actionable driver mutations were enrolled and 29 underwent surgery. The median age was 65 years, and most were male smokers (n=28, 93.33%). An R0 resection was achieved in 28 patients (93.33%), and the MPR and pCR rates were 76.67% and 50.00%, respectively. Based on radiological assessments during the neoadjuvant phase, the ORR was 73.33% (95% CI: 54.11-87.72). Grade 3 and more treatment-related adverse events were predominantly hematologic and were generally manageable. Long-term EFS and OS data are not yet mature. Additionally, exploratory minimal residual disease analysis using circulating tumor DNA (ctDNA) in 27 patients showed a strong correlation between ctDNA clearance and pCR (p=0.004), suggesting ctDNA as a promising biomarker for immunochemotherapy response. ConclusionsA four-cycle perioperative regimen of serplulimab combined with taxane-carboplatin demonstrated promising MPR and pCR rates with an acceptable safety profile in resectable sq-NSCLC patients. Long-term follow-up and future phase III trials are warranted to confirm survival benefits.

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.

BackgroundThe genetic architecture of Breast Cancer (BC) in Arab populations remains largely understudied, limiting the precision of current prevention and screening programs. The Emirati Genome Program (EGP), one of the worlds first nation-wide sequencing initiatives, offers an unprecedented opportunity to delineate inherited BC risk across an entire population. MethodsWe analyzed 436,780 EGP individuals, including 229,309 women, integrating whole-genome sequencing (WGS) with electronic health records (EHRs). We quantified the prevalence and penetrance of pathogenic and likely pathogenic (P/LP) variants across 13 NCCN-recommended BC genes, evaluated the performance of established polygenic risk scores (PRS), and reconstructed >48,000 pedigrees to measure familial aggregation. ResultsP/LP variants were identified in 0.84% of women, accounting for 5.2% of BC cases (mean age of 45.9{+/-}11.1 years). Highly penetrant BRCA1 c.4065_4068del (p.Asn1355fs) and BRCA2 c.2808_2811del (p.Ala938Profs) variants showed age-specific cumulative risks of 37.6% and 31% by age 60, respectively, and allele frequencies up to tenfold higher in the Emirati population than in global reference datasets. The European-derived PRS model (PGS000004) demonstrated strong performance, advancing 10-year BC risk onset by a decade for women in the top decile. Family-based PRS discriminated affected from unaffected individuals, revealing higher polygenic risk even within sister pairs. Integration of monogenic, polygenic, and familial data defined a national framework for risk stratification, identifying disease-free women potentially eligible for targeted prevention. ConclusionsNation-scale genome sequencing reveals, for the first time, the comprehensive landscape of inherited BC susceptibility within a Middle Eastern population. The integration of monogenic, polygenic, and familial data establishes a national framework for genomic risk stratification--transforming population genomics into a foundation for precision prevention and early detection in the UAE and beyond.

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.

BackgroundSingle-cell-based analyses of high-grade serous ovarian carcinoma (HGSOC) survival have largely ignored adipocytes, which are fragile and under-represented in single-cell references. Adipocytes are known active components of the tumor microenvironment in many cancers, and HGSOC tumors frequently metastasize to the omentum, a lining of adipose tissue. MethodsWe created a composite reference that combines single-nucleus adipose profiles with published HGSOC single-cell data to deconvolve 588 bulk RNA-seq tumours from the Schildkraut cohorts. We used stage-stratified Cox models to quantify the association between intratumoural adipocyte fractions and overall survival while adjusting for age, body mass index (BMI), race, and residual disease. We also evaluated associations with deconvolved immune, stromal, and epithelial cell groups. ResultsA 10% increase in estimated tumor adipocyte content was associated with a 41% increase in the hazard of death (HR = 1.41, 95% CI 1.18-1.70, p = 0.0002) after adjusting for age, BMI and race (n=566). A 10% increase in immune cell proportion was associated with favorable survival (HR = 0.82, 95% CI 0.69-0.97, p = 0.024). Stromal and epithelial macro-fractions were not associated with survival. Associations with adipocyte and immune cell type proportions were unchanged in models additionally controlling the other cell type proportions. Results were similar after additionally adjusting for residual disease after debulking surgery. ConclusionsAdipocytes may be a tumor-intrinsic factor associated with adverse outcomes in HGSOC. Quantifying adipocyte burden using bulk RNA-seq could enhance risk stratification and guide the development of adipocyte-targeted therapies.

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.

BackgroundLeptomeningeal disease (LMD) is a serious complication of metastatic breast cancer (MBC) with poor survival. This single-institution retrospective study compares overall survival (OS) among MBC patients with LMD based on CSF parameters (glucose, protein, and WBC count) MethodologyMBC patients who were diagnosed with LMD between 2010-2023 at Wilmot Cancer Institute were screened for eligibility. Only those with available data on CSF glucose, protein, and WBC count were included. OS was assessed via the Kaplan-Meier method and compared using the log-rank test. Cox models were used for multivariate analysis. ResultsOut of 69 patients with MBC LMD, 28 had CSF data and were included in the final analysis. The CSF cytology-positive cohort had significantly lower glucose levels vs the CSF cytology-negative cohort [median (IQR) 40 (18-58) vs 64 (53-92) mg/dl, p=0.006]. Median CSF WBC count was significantly higher in the CSF cytology positive cohort vs the CSF cytology negative cohort [median (IQR) 13 (6-44) vs. 2(2-4)cells/mm3, p=0.001]. When stratified by CSF cytology results and CSF glucose levels, the CSF cytology negative, glucose-low group was associated with the worst OS, while the CSF cytology negative, normal/high glucose group was associated with the best OS(p=0.03) in an unadjusted analysis. Multivariate analysis confirmed that low CSF glucose was independently associated with poorer survival [HR 4.64 (1.71, 13.2)]. Neither CSF protein levels nor CSF WBC counts were significantly associated with OS in unadjusted and multivariate analyses. ConclusionLow CSF glucose was associated with worse OS than normal/high CSF glucose. There was insufficient evidence to suggest that CSF protein or CSF WBC counts were associated with OS.

Recurrence scores based on a 21-gene assay are clinically useful for predicting prognosis and chemotherapy benefit in postmenopausal node-positive breast cancer patients, but its performance in premenopausal patients is inconsistent. Here, we evaluated Ataraxis Breast RISK (ATX), an AI test that predicts recurrence risk, and compared it with the genomic assay. ATX identified high risk patients misclassified as low risk by the genomic assay and therefore may refine selection of patients for adjuvant chemotherapy.

BackgroundOlder age and comorbidities complicate initial therapy in non-small-cell lung cancer (NSCLC), as platinum ineligibility has not been systematically characterized. MethodsAll 2592 patients presenting with metastatic NSCLC between 2018-2023 at Thoraxklinik Heidelberg were analyzed. ECOG status (PS), comorbidities, molecular testing, therapy, toxicities, and outcomes were verified from individual patient records. ResultsAmong 1306 patients with PD-L1 0-49%, systemic therapy was initiated in 74%. With availability of monoimmunotherapy, the treatment rate for patients with PD-L1[&ge;]50% (n=507) was higher by 5% (p=0.01), while best supportive care (BSC) by own choice was reduced (1.8% vs. 4.5%, p=0.005) more than medical BSC (mBSC 14.6% vs. 17.8%, p=0.11), and early death remained unchanged (ca. 4%). Initial suitability for systemic therapy was documented for 70% of cases eventually receiving mBSC after deterioration associated with comorbidities, metastatic burden, longer workup duration, or radiotherapy upfront (all p<0.001). The atezolizumab Summary of Medicinal Product Characteristics (SmPC) criteria, i.e. >80 years, or PS [&ge;]3, or comorbidities with PS [&ge;]2 or with age [&ge;]70, were fulfilled by 38% of patients (n=501) and associated with a >3-fold higher risk of BSC or early death (230/501), as well as significantly higher toxicity under platinum and shorter survival, which for a platinum dose ratio [&le;]60% across 4 cycles (9% of 1306) was similar to that with single-agent chemotherapy (median 5.1 months, p<0.001). SmPC criteria correlated better than comorbidity scores with foregoing platinum, but predictive performance for individual patients remained modest (AUC 0.71, p<0.001). ConclusionsThe high initial attrition of approximately 25% in NSCLC could improve with availability of monoimmunotherapy, but requires optimized, faster patient workflows for better mitigation. Adoption of the SmPC criteria could support a priori identification of patients at risk for mBSC or platinum overtreatment to enhance utilization of monoimmunotherapy and other novel platinum-free first-line options in the future. HighlightsO_LIA high initial attrition of approximately 25% is caused by deterioration after histologic diagnosis in advanced NSCLC. C_LIO_LIMonoimmunotherapy and optimized workflows may facilitate treatment for ca. 15% additional stage IV NSCLC patients. C_LIO_LISmPC criteria indicate cases at higher risk for BSC (>3x) or platinum overtreatment (i.e. platinum dose ratio [&le;]60%). C_LIO_LISmPC patients receiving platinum have higher toxicity and shorter survival than non-SmPC patients. C_LIO_LIImproved therapeutic allocation will be essential for utilization of any novel platinum-free option in the future. C_LI

Head and neck cancer (HNC) is highly prevalent in South-Asia, driven by additional region-specific exposures such as chewing tobacco and betel nut. Despite therapeutic advances, five-year survival rate remains around 50-60%, underscoring urgent need to identify novel therapeutic targets and improve disease-free survival. This study was designed to identify both somatic and germline drivers contributing to HNC pathogenesis. Through whole-exome sequencing of 103 patients, we detected mutations in known HNC drivers (TP53, CDKN2A, NOTCH1) as well as novel hotspots in several genes, including TRIM48, MAP3K19, and CDC20. A recurrent hotspot mutation (p.A187T) in POLQ gene was identified in patients with high tumor mutation burden and was absent in both TCGA and ICGC cohorts. Among known hotspots, the MYC p.T73A mutation was highly prevalent, occurring in over 50% of patients. As MYC is considered an "undruggable" target, alternative strategies targeting upstream regulators such as BRD4 with specific inhibitors may hold promise for South-Asian HNSCC patients harboring the p.T73A mutation. Copy-number variation analysis further revealed EGFR amplification and TP73 deletion in the majority of patients, highlighting additional layers of genomic dysregulation. Comparative genomic analyses showed no recurrent mutations in epigenetic regulators (ARID2, EP300, KMT2B/MLL2, KMT2D/MLL4, NSD1, and TET1). We report p.S456L germline variant in SDHA consistently among South-Asian cohorts. Patients with p.S456L mutation were younger than those without it, reflecting typical epidemiological signature of a genetic variant that increases susceptibility. Systematic molecular characterization of recurrent mutations is required to elucidate mechanism of action of these variants and to find actionable therapeutic targets.

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.

ObjectiveCervical cancer is caused by human papillomavirus (HPV) infections; however, there are no molecularly defined subtypes, and few approved targeted therapies. We defined molecular subtypes and tested targeted agents. MethodsPublic datasets were analyzed; cell lines were treated with drugs; and donor T cells and their proliferation were measured. ResultsWe define three molecular subtypes: I, Wild type for PIK3CA/no YAP1 amplification; II, PIK3CA mutation/no YAP1 amplification; III, PIK3CA WT/YAP1 amplification. Patients with YAP1-amplified cervical cancer have poorer survival. The PI3K-specific inhibitors Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit the proliferation of multiple PIK3CA-mutated cervical cancer cell lines, but not a PIK3CA wild-type (WT) line. The pan-AKT inhibitor, Capivasertib (AZD5363), suppressed some but not all tested PIK3CA-mutated cell lines and one PIK3CA-wt cell line (SiHa). Alpelisib inhibits the expression of the HPV16 E7 oncoprotein, CD274/PD-L1, YAP1, and EGFR genes, only in PI3K-mutated cell lines. Treatment of an HPV16-positive, HLA-A2, PIK3CA mutant cell line (CaSki) with T cells (NexImmune), specific to HPV16 tumor antigens inhibited in a T cell: target cell ratio-dependent manner. BYL-719, in combination with donor T cells, enhances cytotoxicity against CaSki cells. Furthermore, pretreatment with BYL-719 and removing the drug, followed by treatment with donor T cells, had the maximum effect. ConclusionsOur study revealed molecular inhibitors targeting mutant PIK3CA cervical cancer. When combined with immune therapies, these agents may improve outcomes of advanced HPV16 cancers. Further research on targeted therapies will improve the prognosis of patients with cervical cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/26344562v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@d56c22org.highwire.dtl.DTLVardef@1ae5edforg.highwire.dtl.DTLVardef@d697d9org.highwire.dtl.DTLVardef@8b6483_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentified 3 molecular subtypes of CC based on PIK3CA and YAP1 amplification status C_LIO_LICervical cell lines with PIK3CA mutation are suppressed by targeted inhibitors C_LIO_LIPI3K inhibitors Alpelisib/Inavolisib selectively block PIK3CA-mutant cells C_LIO_LIPIK3CA mutation is associated with higher expression of the checkpoint CD274/PD-L1 C_LIO_LIPI3K inhibitors cooperate with donor-derived T cells to kill cervical cells C_LI

BackgroundA retrospective study in Nature recently reported improved overall survival (OS) when COVID-19 mRNA vaccination was administered around initiation of immune checkpoint inhibitor (ICI) therapy. Whether this association depends on vaccination timing relative to ICI treatment remains unclear. MethodsWe conducted a single-centre retrospective cohort study of patients receiving palliative-intent ICI therapy at a UK tertiary cancer centre (October 2014-December 2025). Two vaccination exposure definitions were evaluated: (1) vaccination within 100 days of the first ICI cycle (initial window); and (2) vaccination from 100 days before the first ICI cycle to 100 days after the final ICI cycle (extended window). OS was analysed using Kaplan-Meier methods and Cox models relative to unvaccinated patients. ResultsAmong 2109 patients, 515 (24.4%) received [&ge;]1 COVID-19 vaccine dose. Under the initial window, mRNA vaccination was associated with a longer OS in the all-tumours cohort only (HR 0.76; 95% CI 0.58-0.99; p=0.04). Under the extended window, mRNA vaccination was associated with longer OS in the all-tumours cohort (HR 0.58; 95% CI 0.46-0.75; p<0.0001), including melanoma (HR 0.35; 95% CI 0.18-0.69; p=0.002) and kidney cancer (HR 0.47; 95% CI 0.28-0.79; p=0.004), but not NSCLC. In an era-restricted analysis limited to patients receiving ICI therapy from 2020 onwards, the all-tumours association persisted (HR 0.76; 95% CI 0.59-0.98; p=0.04) with no significant tumour-specific associations. ConclusionsCOVID-19 mRNA vaccination was associated with improved OS, with magnitude and tumour specificity dependent on vaccination exposure definition. Prospective studies are required to assess causality and tumour-specific effects.

Somatic mutations and the tumor immune microenvironment in breast tumors are important predictors of treatment response and survival, yet data for Hispanic/Latina (H/L) women are limited. Here we analyzed whole exome sequencing data from tumor/normal pairs and RNAseq data from 748 H/L women and 388 non-Hispanic White (NHW) women. Overall, the somatic profiles in tumors from H/L women were similar to NHW women. However, somatic mutations in genome organizer CTCF were significantly more common in H/L women. We also found that tumor microenvironment immune ecotypes CE9 and CE10, characterized by increased lymphocyte infiltration and more favorable prognosis, were more common among women with higher Indigenous American ancestry. Finally, we found that a germline APOBEC3A/B copy-number deletion was more prevalent in H/L than in NHW and was associated with the COSMIC APOBEC mutational signatures and with CE10 ecotype. Overall, these results suggest that ancestry differences may provide insights into specific mutation and immune profiles.

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.

BackgroundTamoxifen is a cornerstone of endocrine treatment for hormone receptor-positive breast cancer, reducing recurrence and breast cancer-specific mortality. However, its use is associated with a small, yet clinically relevant, increase in uterine cancer. As diagnosis of this cancer remains symptom-triggered, it is essential for patients to be aware of this risk and report symptoms promptly for optimal outcomes. We therefore assessed risk awareness among breast cancer survivors while exploring their attitudes towards potential future endometrial surveillance strategies. MethodsOver a 10-month period, a web-based survey was conducted among breast cancer survivors with/without tamoxifen treatment. The mixed-format questionnaire included closed-ended questions and optional free-text comments. Quantitative data were summarized descriptively and analyzed statistically; qualitative responses were reviewed thematically to contextualize survey findings. ResultsOf 163 respondents, 154 breast cancer survivors were included in the analysis, 128 of whom had received tamoxifen. Among tamoxifen-associated participants, 60% reported insufficient awareness of the associated uterine cancer risk, and half expressed uncertainty about the adequacy of the current symptom-triggered endometrial evaluation. Despite this, acceptance of tamoxifen therapy was high; only one patient declined treatment over concerns about side effects. Almost all participants (96%) were willing to adopt endometrial surveillance methods, if developed and validated. ConclusionAs evaluation of tamoxifen-associated uterine pathology is symptom-triggered, our data highlight the need for improved and standardized risk communication to promote timely symptom recognition, reporting, and diagnostic evaluation. Moreover, our findings support incorporating patient-reported preferences into the development of future endometrial detection strategies to improve survivorship care.

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.