Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (18, 3–55) or ovarian (25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. Conclusions: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.

Purpose: Microsatellite stable (MSS) colorectal cancers, in contrast to microsatellite instability–high colorectal cancers, have few mutations and are insensitive to immune checkpoint blockade (ICB). Colorectal cancers treated with targeted agents often acquire a high number of genomic alterations at progression. We asked whether targeted therapy could be used to generate a high tumor mutational burden (TMB) in MSS colorectal cancer and sensitize these tumors to ICB. Experimental Design: In patients with MSS metastatic colorectal cancer treated with targeted therapy, we evaluated baseline and progression TMB and response to ICB for patients whose tumors developed high TMB. We determined types of alterations, mutational signatures, neoantigenicity, and clonality associated with emergent genomic alterations in cases of acquired high TMB. Results: Among 26 cases, nine acquired high TMB at progression. Three of these patients received ICB but none had a response. In the TMB-high cases, we found no induction of tumor-infiltrating lymphocytes or PD-L1 expression. Acquired genomic alterations consisted predominantly of single-nucleotide variants, were enriched for single base substitution 17a/b mutational signature, and did not enhance predicted MHC class I binding. TMB was higher in plasma, driven by highly subclonal acquired alterations, compared with tissue samples, which harbored few resistance alterations. Conclusions: A substantial number of MSS colorectal cancers acquire high TMB following targeted therapy. However, this change is not associated with sensitization to ICB. The high TMB is due to subclonal alterations unique to individual disease sites that are inadequate to elicit a robust antitumor immune response. See related commentary by Parseghian and Eluri, p. 999

Background: The utility of circulating tumor DNA (ctDNA) in addressing challenges of molecular tissue profiling and complementing next-generation sequencing is undefined in pancreas ductal adenocarcinoma. The objective of this study was to assess ctDNA detection rates by stage, disease burden, and metastasis patterns; compare overall survival between ctDNA-positive and ctDNA-negative patients cases; and determine concordance between ctDNA and matched-tissue biopsies. Methods: Patients with pancreas ductal adenocarcinoma who had undergone Next Generation Sequencing by the MSK-ACCESS (Memorial Sloan Kettering – Analysis of Circulating cfDNA to Evaluate Somatic Status) ctDNA assay between 2019 and 2022 were included. Clinical and survival data were abstracted from a prospectively maintained clinical database. Results: A total of 414 patients with pancreas ductal adenocarcinoma: 28% stage I-II, 21% stage III, 51% stage IV. ctDNA detection was highest among patients with advanced disease: 75% stage IV, 38% stage III, 34% stage I-II disease. For stage IV, ctDNA was more frequently detected in patients with at least 2 organs involved vs with less than 2 organs involved (76% vs 38%, P = .025). Higher rates of ctDNA detection were observed in patients with liver metastases vs without (82% vs 52%, P < .001). In the untreated stage IV cohort (n = 120), median overall survival was 10 months for those with detectable ctDNA (95% CI = 6.9 to 14 months) vs 19 months (95% CI = 13 months to not reached) for those with undetectable ctDNA (P = .1). Concordance between ctDNA and matched tissue next-generation sequencing was lower in untreated stage I-III disease, but high for untreated stage IV pancreas ductal adenocarcinoma, including a critical success index of 93.1% of KRAS variants. Conclusion: ctDNA is a promising tool in the detection of somatic variants in pancreas ductal adenocarcinoma. Concordance between ctDNA and tissue is high for patients with untreated metastatic disease, notably for detection of KRAS variants.

Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12C^mut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. Patients with pancreatic cancer and KRAS G12C^mut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12C^mut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m², and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12C^mut (P < .05). Overall survival did not differ between KRAS G12C^mut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. Pancreatic cancer and KRAS G12C^mut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.

Purpose: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. Experimental Design: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). Results: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. Conclusions: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.