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PurposeKRAS mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor KRAS wild-type (WT). We aim to characterize the molecular profiles of KRAS WT PDAC to uncover new pathogenic drivers and offer targeted treatments.Experimental designTumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.ResultsOf the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were KRAS WT. The most frequently mutated gene in KRAS WT PDAC was TP53 (44.5%), followed by BRAF (13.0%). Multiple mutations within the DNA-damage repair (BRCA2, ATM, BAP1, RAD50, FANCE, PALB2), chromatin remodeling (ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2), and cell-cycle control pathways (CDKN2A, CCND1, CCNE1) were detected frequently. There was no statistically significant difference in PD-L1 expression between KRAS WT (15.8%) and MT (17%) tumors. However, KRAS WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; P < 0.05), tumor mutational burden-high (4.5% vs. 1%; P < 0.05), and exhibit increased infiltration of CD8+ T cells, natural killer cells, and myeloid dendritic cells. KRAS WT PDACs exhibited gene fusions of BRAF (6.6%), FGFR2 (5.2%), ALK (2.6%), RET (1.3%), and NRG1 (1.3%), as well as amplification of FGF3 (3%), ERBB2 (2.2%), FGFR3 (1.8%), NTRK (1.8%), and MET (1.3%). Real-world evidence reveals a survival advantage of KRAS WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin.ConclusionsKRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.

Background: Older adults with cancer are at increased risk of treatment‐related toxicities and excess mortality. We evaluated whether a patient‐reported geriatric assessment (GA) based frailty index can identify those at risk of adverse outcomes. Methods: Older adults (≥60 years) enrolled in a single‐institutional prospective registry underwent patient‐reported GA at initial evaluation in our medical oncology clinic. Using deficit accumulation method, we constructed a 44‐item frailty index (CARE‐FI), categorizing patients as robust, pre‐frail, and frail. The primary outcome was overall survival (OS). Secondary outcomes included (a) functional decline at 3 months post‐therapy (b) incident grade ≥3 treatment‐related toxicities at six‐month post‐treatment. We used multivariate Cox and logistic regression models respectively to study the impact of frailty on primary and secondary outcomes. Results: We identified 589 older adults with a median age of 69 years; 55% males and 73% Whites. Overall, 168 (29%) were pre‐frail and 230 (39%) frail. Being frail (vs. robust) was associated with worse OS (Hazards Ratio, HR 1.83, 95% Confidence Interval, CI 1.34–2.49, p < 0.001) after adjusting for age, sex, race/ethnicity, cancer type, cancer stage, and line of therapy. Similarly, frailty was associated with increased risk of functional decline (OR 3.01; 95% CI 1.33–6.81; p = 0.008) and grade ≥3 non‐hematologic toxicities (OR 3.65; 95% CI 1.54–8.69; p = 0.003) but not hematologic toxicities (OR 1.01; 95% CI 0.46–2.22; p = 0.97). Conclusions: Our frailty index using a patient‐reported GA is a robust predictor of survival, functional decline, and treatment related toxicity among older adults with GI malignancies. [ABSTRACT FROM AUTHOR]

Background: Despite recent advances in cancer, racial disparities in treatment outcomes persist, and their mechanisms are still not fully understood. The objective of this study was to examine racial differences in frailty and geriatric assessment impairments in an unselected cohort of older adults with newly diagnosed gastrointestinal (GI) malignancies. Methods: This study used data from the Cancer and Aging Resilience Evaluation Registry, a prospective cohort study that enrolled older adults (≥60 years) with GI malignancies who were presenting for their initial consultation. Participants who had a geriatric assessment completed before chemotherapy initiation and self‐reported as either White or Black were included. Frailty was defined with a frailty index based on the deficit accumulation method. The differences in the prevalence and adjusted odds ratios for frailty and geriatric assessment impairments between Black and White participants were examined. Results: Of the 710 eligible patients who were seen, 553 consented with sufficient data for analyses. The mean age at enrollment was 70 ± 7.1 years, 58% were male, and 23% were Black. Primary cancer diagnoses included colorectal cancer (32%), pancreatic cancer (27%), and hepatobiliary cancer (18%). Black participants were more likely to be frail (50.0% vs 32.7%; P <.001) and report limitations in activities of daily living (27.3% vs 14.1%; P =.001), instrumental activities of daily living (64.8% vs 47.3%; P =.002), and walking 1 block (62.5% vs 48.2%; P =.004). These associations persisted even after adjustments for age, sex, education, cancer type, cancer stage, and comorbidity. Conclusions: Black participants were frailer and reported more limitations in function in comparison with White participants. These findings may partially explain disparities in cancer outcomes and warrant further examination. In an unselected cohort of older adults with newly diagnosed gastrointestinal malignancies, Black participants were frailer and reported more limitations in function in comparison with White participants. An increased prevalence of frailty and functional impairments may partially explain disparities in cancer outcomes and warrants further examination. [ABSTRACT FROM AUTHOR]