Post-therapy emergence of an NBN reversion mutation in a patient with pancreatic acinar cell carcinoma.

Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

ATR inhibitor, camonsertib, dose optimization in patients with biomarker-selected advanced solid tumors (TRESR study).

BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus dose/schedule optimization requires extended follow-up to assess prolonged treatment effects. METHODS: Long-term safety/tolerability and antitumor efficacy of three camonsertib monotherapy dose levels/schedules were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on/4 off (160 3/4; the preliminary recommended phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on/1 off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating-tumor-DNA (ctDNA)-based molecular response rate. RESULTS: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (HR = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. CONCLUSION: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering significantly reduced anemia incidence without any compromise to efficacy.

Loss of the DNA Repair Gene RNase H2 Identifies a Unique Subset of DDR-Deficient Leiomyosarcomas.

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In the TCGA database, RNASEH2B homozygous deletions (HomDels) were found in 6% (5/80) of LMS cases, with a higher proportion in U-LMS (15%; 4/27) compared with ST-LMS (2%; 1/53). Using the SNiPDx targeted-NGS sequencing assay to detect biallelic loss of function in select DDR-related genes, we found RNASEH2B HomDels in 54% (19/35) of U-LMS cases with RNase H2 loss by IHC, and 7% (3/43) HomDels in RNase H2 intact cases. No RNASEH2B HomDels were detected in ST-LMS. In U-LMS patient cohort (n = 109), no significant overall survival difference was seen in patients with RNase H2 loss versus intact, or RNASEH2B HomDel (n = 12) versus Non-HomDel (n = 37). The overall diagnostic accuracy, sensitivity, and specificity of RNase H2 IHC for detecting RNA-SEH2B HomDels in U-LMS was 76%, 93%, and 71%, respectively, and it is being developed for future predictive biomarker driven clinical trials targeting DDR in U-LMS.