Citations

Abstract Introduction: The HER2-targeted doublet, tucatinib and trastuzumab, recently received FDA approval for previously treated HER2-positive metastatic colorectal cancer (mCRC). While the intensity of HER2 IHC staining and ERBB2 amplification have been proposed as potential markers of response, our understanding of the role of the tumor microenvironment remains limited. Methods: The phase II MOUNTAINEER Trial (NCT03043313) enrolled patients for tucatinib plus trastuzumab based on HER2 positivity (IHC or NGS amplification). Patients from cohort A with available HER2 IHC and H&E slides were included in this analysis. Previously validated AI-based models (Lunit SCOPE uIHC and SCOPE IO) were used to quantify the percentage of HER2 3+ stained tumor cells (AI-H3+) and the densities of tumor infiltrating lymphocytes (TILs) in the cancer epithelium (iTIL) and stroma (sTIL). Results: The analyzed cohort (N=30) had an objective response rate (ORR) of 43.4% and median progression-free survival (PFS) of 8.0 months. AI-H3+ percentage showed a strong, dose-dependent association with an ORR of 57.1%, 66.6%, and 80.0% for tumors with AI-H3+ ≥10% (n=14), ≥25% (n=12), and ≥50% (n=10), respectively. This benefit extended to PFS, with the ≥50% cohort reporting a PFS HR of 0.17 (P=0.002) compared to tumors with AI-H3+ <50%. Tumors with below median iTIL or sTIL had significantly shorter PFS. Notably, tumors with sTIL density in the bottom quantile had an ORR of 0% and PFS HR of 4.40 (P=0.002) despite including cases with high AI-H3+. TIL densities and AI-H3+ percentage were not correlated. Conclusion: These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting. Citation Format: Mitsuho Imai, John H. Strickler, Woochan Hwang, Kara Bonneau, Andrew B. Nixon, Jongchan Park, Chang Ho Ahn, Tanios Bekaii-Saab, Takayuki Yoshino. HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2-positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7735.

Abstract Background: Adhering to 2018 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) Cancer Prevention Recommendations is reportedly associated with better survival among long-term colon cancer survivors (likely affected by immortal time bias). Thus, it is important to validate survival benefits by assessing adherence shortly after diagnosis, and further investigation is needed to examine its association with chemotherapy outcomes. Methods: Using an NCI-sponsored adjuvant chemotherapy trial conducted in patients with stage III colon cancer (CALGB/SWOG 80702; NCT01150045), we included 1,666 patients who returned valid Willett food frequency questionnaires (FFQ) at chemotherapy initiation and derived WCRF/AICR scores accordingly (higher score suggesting higher adherence). The primary outcome was disease-free survival (time from FFQ completion to recurrence or death), and secondary outcomes were reduced relative dose intensity (RDI; <85% suggesting worse completion) and severe toxicities (grade ≥3 for any chemotherapy-related toxicity). To estimate the associations of WCRF/AICR scores (quartiles) with survival and chemotherapy outcomes, we conducted multivariable Cox proportional hazards regression for disease-free survival and multivariable logistic regression for reduced RDI and severe toxicities. Results: Compared to those in the lowest quartile of the WCRF/AICR score, patients in the highest quartile had significantly better disease-free survival (hazard ratio: 0.75 [0.58, 0.98], Ptrend = 0.02) and lower risk of reduced RDI (odds ratio [OR]: 0.74 [0.54, 1.00], Ptrend = 0.03), but not for severe toxicities (OR: 1.24 [0.93, 1.67], Ptrend = 0.11). Conclusions: In patients with stage III colon cancer, higher adherence to WCRF/AICR recommendations was associated with better survival and chemotherapy completion, but not for severe toxicities. Funding: https://acknowledgments.alliancefound.org Citation Format: En Cheng, Chao Ma, Qian Shi, Anthony F. Shields, Peter T. Campbell, Ardaman P. Shergill, Katherine A. Guthrie, Felix Couture, Philip Kuebler, Pankaj Kumar, Benjamin Tan, Smitha S. Krishnamurthi, Kimmie Ng, Eileen M. O'Reilly, Justin C. Brown, Philip A. Philip, Jeffrey A. Meyerhardt. Associations of WCRF/AICR recommendations with survival and chemotherapy outcomes in colon cancer: CALGB/SWOG 80702 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5038.

Abstract Introduction: Lung cancer rates differ across rural and urban areas, but few studies have evaluated rural-urban differences across the risk-screening continuum. We examined smoking, cessation interventions, and lung cancer screening patterns across the rural-urban continuum in a geographically defined area over 10 years. Materials and Methods: A retrospective cohort study (2014-2023) was conducted using clinical data from the Rochester Epidemiology Project, derived from healthcare encounters in a 27-county region of the midwestern United States. Patients ages 40-80 were included. We used Rural-Urban Commuting Area codes to assign residence as urban, rural, or highly rural. We examined yearly smoking prevalence, cessation intervention (pharmacotherapy, counseling), and low-dose computed tomography (LDCT) lung cancer screening. Results: Over the 10-year study period, the sample size ranged from 305,530 to 340,411 people annually with 36-38% urban, 56-57% rural, and 6-7% highly rural. Current smoking prevalence declined from 14 to 12% over the 10-year period (range=12-16%; p=0.06) and was consistently lower in urban areas (range=10-14%) than rural (range=12-17.0%) and highly rural areas (range=12-18%; p=<0.001). Among individuals who currently smoked with no history of lung cancer, yearly smoking cessation intervention ranged from 16% to 23%, increasing over the 10-year period (p=<0.001). Cessation medication (varenicline, bupropion, or nicotine replacement) prescription consistently increased overall over time but remained higher in urban than rural and highly rural areas (p=<0.001). Cessation counseling rates also increased overall over time and were similar between urban and rural areas and lower in highly rural areas (p=<0.001). Among people who had ever-smoked aged 50-80 years with no diagnosis of lung cancer, LDCT screening increased from 0.0% to 3.1% over the study period. Increases were higher in urban areas (0.0-3.6%) and similar in rural and highly rural areas (0.0-2.8% and 0.0-2.9%, respectively; p=<0.001). Among people who currently smoked, LDCT screening also increased over the study period (0.0-6.4%), with higher increases in urban (0.1-8.0%) than rural (0.0-5.7%) or highly rural (0.1-6.1%) areas (p=<0.001). After the new screening guidelines in 2021, rates in all areas increased year-on-year. Conclusion: In this cohort, we found that smoking prevalence, cessation interventions, and lung cancer screening improved from 2014-2023 across the rural-urban continuum. Unfortunately, smoking prevalence remained higher and cessation interventions and screening rates lower in rural compared to urban areas. The persistent patterns underscore the need for strategies to overcome barriers for rural residents and improve lung cancer prevention and early detection in all areas. Citation Format: Brianna Tranby, Paul A. Decker, Jiang Ruoxiang, David Midthun, Lori C. Sakoda, Melinda C. Aldrich, Debra Friedman, Adoma Manful, Oindrila Bhattacharyya, Christi Patten, Chyke A. Doubeni. Patterns of tobacco use, cessation interventions, and lung cancer screening in rural vs. urban areas over time; a 10-year retrospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5045.

Abstract Prognostic indices such as the CLL International Prognostic Index (CLL-IPI) and the International Prognostic Score for Early-stage CLL (IPS-E) can predict time to first treatment (TTFT) in patients with early-stage CLL. Their ability to predict risk of infection - a leading contributor to morbidity and mortality in CLL - remains uncertain. The CLL-TIM is a machine-learning model developed in Europe that integrates clinical, laboratory, and infection-related data to predict TTFT or infection risk within 2-years of diagnosis, Receiver Operating Characteristic - Area Under the Curve (ROC-AUC) 0.74; Agius et al., Nat Comm 11, 363 2020. We conducted the first validation of CLL-TIM in a US cohort of newly diagnosed CLL patients and compared its performance with the CLL-IPI and IPS-E indices. Adults with newly diagnosed CLL (2000-2020) were identified through the Rochester Epidemiology Project using International Classification of Disease (ICD) codes; all diagnoses were confirmed. We replicated the variable selection from the original CLL-TIM model and applied it to our cohort. The primary endpoint was a 2-year composite of either TTFT or incident infection (defined as having blood cultures drawn). Model performance was evaluated using ROC-AUC consistent with the original CLL-TIM methods. CLL-IPI and IPS-E performance was assessed using time-dependent ROC-AUC; pairwise differences in discrimination were tested using DeLong. We identified 454 CLL patients with a median age of 72 years [range, 30-97], 166 (37%) were female, Rai Stage was 0-II in 399 (92%) patients. IGHV genes were unmutated in 130/305 (42%) patients and TP53 disruption (either del17p by FISH or TP53 mutation) was present in 24/329 (8%) patients. At 2-years, 55 (12%) patients received CLL therapy, and 56 (12%) patients had an infection. The 2-year composite endpoint was observed in 94 (21%) patients. The ROC-AUC was 0.74 (95% CI 0.68-0.80) for CLL-TIM, 0.69 for CLL-IPI (95% CI 0.63-0.75, p=0.11 compared to CLL-TIM) , and 0.68 for IPS-E (95% CI 0.62-0.74, p=0.02 compared to CLL-TIM). We also evaluated the ROC-AUC using all the prognostic models for each individual endpoints. The corresponding ROC-AUC for TTFT at 2 years were 0.79, 0.74, and 0.76 for CLL-TIM, CLL-IPI, and IPS-E, respectively; and for infection at 2 years were 0.68, 0.57, and 0.52, respectively. This is the first validation of the CLL-TIM in a US-based cohort of newly diagnosed CLL patients. Although the CLL-TIM model exceeded the minimally meaningful discrimination threshold (AUC >0.7) for individual patient-level risk prediction, there was no statistical difference in AUC between CLL-TIM and CLL-IPI, suggesting either model can predict the composite endpoint at 2 years. Most of the observed discrimination was driven by prediction of TTFT rather than infection, underscoring the need to develop more infection-specific risk models for newly diagnosed CLL. Citation Format: Raphael Mwangi, Tait D. Shanafelt, Soren Basnet, Emily L. West, Owen Keegan, Timothy G. Call, Yao Yuan, Bryan Alexis Vallejo, Paul J. Hampel, Lindsey E. Roeker, Yucai Wang, Saad J. Kenderian, Sara J. Achenbach, Aaron D. Norman, Kari G. Rabe, Neil E. Kay, James R. Cerhan, Curtis A. Hanson, Susan L. Slager, Sameer A. Parikh. Validation of the CLL treatment infection model (CLL-TIM) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4228.

Abstract Peritoneal Carcinomatosis (PC) is a metastatic cancer of the lining of the abdominal cavity, most often originating from the gastrointestinal or gynecological tracts. PC occurs in approximately 20% of colorectal cancer and 60% of ovarian cancer cases, with estimated 5-year survival rates as low as 6%. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a locoregional drug delivery modality administered via a minimally invasive laparoscopic approach. PIPAC shows promise in the treatment of peritoneal metastasis in early trials on colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery. The spatial organization of the tumor microenvironment (TME) and the complex cellular interactions within profoundly shape biology and treatment response. Spatial transcriptomics offers an opportunity to characterize TME heterogeneity in its native architecture, allowing the identification of biomarkers, interactions, and gene expression programs as well as resistance mechanisms and new potential targets. We performed image-based spatial transcriptomic profiling of 152 tissue samples, including 50 pre-treatment and 65 post-treatment metastatic tumors and 17 pre-treatment and 20 post-treatment tumor-adjacent normal tissue samples from 19 patients who participated in a Phase I trial on Oxaliplatin PIPAC. Through a comprehensive characterization of transcriptional profiles of a total of 1,249,711 cells, as well as cellular neighborhood and ligand-receptor interactions, we describe the heterogeneity of PC in its spatial context. We have further characterized treatment-driven changes in pre- and post-treatment tumors of a subset of 7 patients who underwent PIPAC with mitomycin IP. Through cell-based niche and proximity analyses, we identify distinct shifts in the composition and architecture of treated tumors. Most notably, treatment resulted in an 87% decrease in the number of malignant cells, as well as an expansion of the plasma-barrier niche and an increased number of immune infiltrates. Further analysis revealed distinct differences in the abundance of specific cancer-associated fibroblast and immune subsets, demonstrating changes in TME architecture. Overall, our results provide an invaluable characterization of PC in CRC and AC, garnering new insight into their architecture, cellular composition, and cell-cell interactions at baseline and in response to regional chemotherapy. Further analyses and follow-up studies can identify and validate new, actionable biomarkers to target these hard-to-treat tumors. Citation Format: Heini Maaret Natri, Arianna L. Williams-Katek, Muhammad Talha Waheed, Tiana Li, Marwan Fakih, Mingye Feng, Amit Merchea, Sue Chang, Richard L. Whelan, Danielle Deperalta, Thanh H. Dellinger, Nicholas Banovich, Mustafa Raoof. Spatial transcriptomic profiling of peritoneal metastases identifies multicellular programs in patient tumors undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3958.

Abstract Background: Tumor angiogenesis drives treatment resistance by fostering an immunosuppressive microenvironment. VEGF inhibitors (VEGFi) target the vasculature, while immune checkpoint inhibitors (ICI) do not address this mechanism directly. Quantitative Vessel Tortuosity (QVT) Score is a radiomic biomarker of vascularity previously shown to be associated with ICI response. Here, we introduce QVT Subscore, an interpretable panel that isolates distinct vascular attributes (e.g., branching, curvature, radius), enabling treatment-specific insight into vascularity MoA and vascular normalization. Methods: QVT Subscores are derived by grouping the 910 QVT features comprising QVT Score into six biological categories, summarized by principal component analysis. The panel was evaluated in 557 patients from the phase 3 SWOG S0819 trial and a real-world ICI monotherapy cohort (n=147). QVT score/subscore changes from baseline to first on-treatment CTs were assessed by paired t-test and substratified by objective response (OR). Results: While the mono-chemotherapy showed no vascularity changes, VEGFi regimens reduced QVT Score, with Branch and Curvature Subscores decreasing significantly but Vessel Volume unchanged. In contrast, ICI recipients exhibited significant increases in QVT Score and 5/6 Subscores, showing opposite changes to VEGFi in four subscores and differing effects on vessel Radius and Volume. VEGFi produced the greatest vascularity decrease in patients achieving OR, with milder decreases in non-OR. For ICI, OR showed negligible QVT change, while vascularity significantly increased in non-OR across all subscores except Radius. Conclusions: The QVT Subscore panel captures granular tumor vascular remodeling from different treatments, providing mechanistically grounded insights into clinical trial arm performance. Future work will assess the panel’s potential for identifying regimens that benefit from adding VEGFi. Citation Format: Haojia Li, Pushkar Mutha, Young Kwang Chae, Kai Zhang, Liam Il-Young Chung, Amogh Hiremath, Rhea Chitalia, Justin Yau, Omid Haji-Maghsoudi, Trishan Arul, Vamsidhar Velcheti, Anant Madabhushi, Nathaniel Braman. QVT Subscore: An interpretable radiomic panel of tumor vascularity reveals treatment-specific mechanisms-of-action (MoA) in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3751.

Abstract Background: CLL incidence differs by ancestry, with higher rates in individuals of European ancestry (EA) than African ancestry (AA). The contribution of epigenetic variation to these disparities remains unclear. We investigated chromatin accessibility, histone modifications, and gene expression in CLL patients of EA and AA to identify ancestry-associated epigenetic signatures. Methods: ATAC-seq was performed on blood clonal B cells from 15 AA and 51 EA patients; CUT&Tag profiling of six histone marks (H3K4me1, H3K4me3, H3K27ac, H3K9me3, H3K27me3, H3K36me3) was done in 8 AA and 12 EA cases; RNA-seq was generated for all samples. Ancestry was genetically confirmed. Differential regions were linked to genes using ENCODE and Hi-C datasets. Results: ATAC-seq revealed 4,955 regions with increased and 3,000 with decreased accessibility in AA vs EA (fold change >2, FDR ≤0.05). Regions with increased accessibility mapped to 2,313 genes; 599 were upregulated and enriched in TNF-α/NF-κB (p=1.40E-53) and apoptosis pathways (p=6.90E-11). Regions with decreased accessibility linked to 1,953 genes; 317 were downregulated, enriched in interferon-γ response (p=1.04E-03) and IL-6/JAK/STAT3 signaling (p=6.41E-03). Histone profiling showed ancestry-specific changes across all marks. For H3K27ac (active enhancer), 68 genes with a decreased signal in AA were downregulated and enriched in interferon-γ (p=1.55E-06) and IL-6/JAK/STAT3 (p=9.62E-05) pathways. Increased H3K27me3 (repressive histone modification) in AA affected 399 genes enriched in IL-6/JAK/STAT3 (p=8.13E-09) and interferon-γ (p=2.48E-05) pathways. These findings suggest coordinated regulation by active and repressive chromatin states. Conclusions: Despite limited sample size, this study suggests differences between AA and EA ancestries may exist in epigenetic signatures in CLL, implicating chromatin accessibility and histone modifications in pathways relevant to tumor biology. These signatures may also contribute to the differences in CLL incidence by ancestry. Future studies with more patients and functional validation experiments are needed to clarify the role of these epigenetic differences in CLL pathogenesis. Citation Format: Zhiquan Wang, Huihuang Yan, Mingma Sherpa, Daniel Bihnam, Cristine Allmer, Chantal McCabe, Daniel O’Brien, Dennis P. Robinson, James R. Cerhan, Neil E. Kay, Sameer A. Parikh, Esteban Braggio, Susan Slager. Ancestry-associated epigenetic differences in chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5064.

Abstract Background: Approximately 70% of breast cancers are estrogen receptor-positive (ER+), and endocrine therapies, including selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs), are standard-of-care. However, interpatient variability in treatment response and relapse remains substantial, suggesting underlying germline pharmacogenomic factors that modify ER signaling. Here, we mapped ER pharmacogenomic eQTLs to identify germline variants that modulate transcriptional responses to estradiol (E2) and tamoxifen (Tam). Methods: We treated 30 genotyped lymphoblastoid cell lines (LCLs) with vehicle, E2, Tam, or E2+Tam and performed RNA-seq to quantify ligand-induced expression fold changes. Using MatrixEQTL, we identified SNP-gene PGx-eQTLs (cis, ±200 kb), requiring evidence of ER transcriptional specificity via (i) reversal by dual treatment, and (ii) overlap with ER ChIP-seq binding annotations. Clinical relevance was assessed by linkage to breast cancer GWAS datasets, including NSABP, MA.27, and M3. Chromatin regulatory states were annotated (ChromHMM), and transcription factor motif enrichment was performed from SNP-centered ±200 bp regions. Results: Distinct PGx-eQTL architectures were identified for E2 and Tam, with partial overlap in ligand-responsive loci. ER PGx-eQTL variants were predominantly enriched in enhancer chromatin and co-localized with canonical ER-binding motifs. Integrative analysis with GWAS of breast cancer outcomes highlighted multiple drug-response-associated loci, including rs311392-MRPL15 and rs7953325-SYCP3. High MRPL15 expression was linked to shorter relapse-free survival, whereas high SYCP3 expression correlated with improved outcomes. Additional loci derived from a GWAS catalog for cancer and hormone phenotypes included rs2850247-SIK2 and rs11673604-LSM4, where higher SIK2 expression was associated with improved relapse-free survival and higher LSM4 expression with poorer outcomes. Conclusions: We identified ligand-dependent ER PGx-eQTLs that mechanistically connect germline regulatory variants to transcriptional response heterogeneity and clinical endocrine therapy outcomes. These SNP-gene relationships represent potential biomarkers for precision endocrine therapy selection and may reveal endocrine-dependent therapeutic vulnerabilities. Citation Format: Martin Meng, Huanyao Gao, August John, Arnab Ghosh, Shreya Indulkar, Liewei Wang, . Estrogen receptor-mediated pharmacogenomic eQTLs as predictors of endocrine therapy response in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3610.

Abstract Background: Early-onset gastrointestinal (GI) cancers are increasing globally, yet the genomic basis for age-related differences across multiple tumor types remains poorly defined. We leveraged AACR Project GENIE v18.0 (N≈34,000 GI tumors) to characterize molecular distinctions by age in colorectal, pancreatic, small bowel, and anal cancers with sufficient early-onset representation. Methods: Clinical and genomic data were extracted and tumors classified into early-onset (<50 years) and late-onset (≥50 years). Mutation frequencies were compared by cancer type and age group, focusing on recurrent drivers, DNA repair, Wnt signaling, RAS/MAPK, chromatin remodeling genes, and targetable alterations. Results: Early-onset colorectal cancer (N=5,724) showed increased Wnt/β-catenin pathway alterations: APC (+4.9%), TCF7L2 (+4.1%), and TP53 (+5.0%), while late-onset tumors (N=15,807) were enriched for BRAF (−5.4%), RNF43 (−1.9%), and GNAS (−1.1%), indicating divergent tumorigenic pathways. Early-onset pancreatic cancer (N=890) exhibited significantly lower frequencies of canonical drivers—KRAS (−24.7%), TP53 (−15.6%), CDKN2A (−6.9%), SMAD4 (−6.0%)—with enrichment of MEN1 (+3.5%), TSC2 (+3.0%), ATRX (+2.0%), DAXX (+1.9%), and CTNNB1 (+2.4%), consistent with fusion-driven, hereditary, and chromatin remodeling biology. Small bowel cancer (N=99) in early-onset patients demonstrated enrichment in DNA damage response and MAPK/RAS genes including BRCA2 (+7.2%), NF1 (+7.4%), FBXW7 (+8.8%), FLT4 (+6.5%), ARAF (+6.4%), and ALK (+5.1%), whereas late-onset tumors (N=538) were enriched for KDR (−5.1%) and MGA (−5.2%). Early-onset anal cancer (N=62) showed elevated MGA (+7.8%), WHSC1/NSD2 (+6.9%), PBRM1 (+6.2%), FANCA (+5.2%), ERCC5 (+6.2%), and MSH6 (+5.9%), highlighting chromatin remodeling and DNA repair pathways potentially related to HPV biology; late-onset tumors (N=464) had enrichment in ATM (−5.6%), PTEN (−5.5%), STK11 (−5.2%), APC (−5.2%), and KMT2C (−5.0%), reflecting age-associated genomic instability. Conclusions: This pan-GI age-stratified analysis reveals distinctive oncogenic programs in early-onset GI cancers characterized by Wnt/TP53-driven colorectal, fusion- and chromatin remodeling-driven pancreatic, DNA damage response/MAPK-driven small bowel, and chromatin-immune DDR signatures in anal cancers. These findings underscore the need for age-tailored precision oncology and support routine genomic profiling in early-onset GI malignancies to identify targetable alterations enriched in younger patients. Citation: AACR Project GENIE Consortium. AACR Project GENIE: Powering Precision Medicine Through an International Consortium. Cancer Discov. 2017;7(8):818-831. (Data: GENIE Release 18.0-public)Acknowledgement: AACR and Project GENIE registry Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Mosalem M. Osama, Hani M. Babiker. Distinct age associated genomic landscapes in colorectal, pancreatic, small bowel, and anal cancers: A pan gastrointestinal analysis of 34,000 tumors from AACR Project GENIE v18.0 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4105.

Abstract Background: PARP inhibitors are restricted to a subset of BRCA-associated cancers, but homologous recombination repair (HRR) deficiency signifies a broader genomic vulnerability that may extend therapeutic opportunities across diverse malignancies. We utilized AACR Project GENIE v18.0-public to define the pan-cancer prevalence of HRR gene alterations. Methods: Somatic mutation and clinical sample data from GENIE v18.0-public were analyzed. HRR genes included BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51B/C/D, RAD51L1, BARD1, BRIP1, and core FANC genes. HRR alteration rates were calculated by tumor type using unique samples; only de-identified aggregate results are reported. Results: Among 101,240 tumors, HRR gene alterations were frequent in multiple non-BRCA-associated cancers. Highest rates were seen in sialoblastoma (100%), large cell medulloblastoma (50%), malignant glomus tumor (50%), lung cancer (46.0%), infantile fibrosarcoma (42.9%), liver (40%), kidney (40%), non-melanoma skin (36.9%), colorectal (36.6%), melanocytoma (34.2%), biliary tract (33.3%), bladder (31.5%), and ovarian/fallopian tube (30.2%). Notably, lung, bladder, hepatobiliary, renal, gastrointestinal, and some sarcoma subtypes showed HRR mutation prevalence equal or higher than current PARP indications, yet lack FDA approval. Conclusions: HRR alterations are widespread across solid tumors, often surpassing rates in cancers eligible for PARP treatment. These findings support expanding tumor-agnostic HRR genomic testing beyond BRCA-linked malignancies and warrant prospective trials of PARP inhibitors in HRR-enriched tumor types such as lung, bladder, hepatobiliary, renal, gastrointestinal, and pediatric/rare cancers. Impact: Large-scale genomic profiling from AACR Project GENIE demonstrates that HRR gene alterations are common across diverse solid tumors, with prevalence in multiple cancer types surpassing those currently eligible for PARP inhibitor therapy. These findings support broad implementation of HRR genomic testing in routine molecular diagnostics and provide a rationale for expanding PARP inhibitor use beyond BRCA-associated malignancies. The data justify prospective tumor-agnostic clinical trials of PARP inhibitors in HRR-enriched cancers such as lung, bladder, hepatobiliary, renal, gastrointestinal, and select pediatric and rare tumors; this could transform therapeutic decision-making and accelerate development of synthetic lethality-based targeted therapies Citation: AACR Project GENIE Consortium. Cancer Discov. 2017;7(8):818-831 Acknowledgement: AACR and Project GENIE Citation Format: Ahmed Abdelhakeem, Nency Ganatra, Dina Elantably, Tayo Adeoye, Nayef H. Abdel-Razeq, Osama M. Mosalem, Hani M. Babiker. Pan cancer enrichment of homologous recombination repair (HRR) gene alterations in 101,240 tumor samples from AACR Project GENIE: Implications for tumor-agnostic PARP inhibitor expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4106.