Borad, Mitesh J

PURPOSE Deficient mismatch repair/microsatellite instability (dMMR, MSI-H) in biliary tract cancers (BTCs) is observed in 1%-5% of tumors. MSI-H across solid tumors has demonstrated durable response to immune checkpoint inhibitors (ICIs) regardless of the anatomic location. Here, we describe clinical outcomes and surgical conversion of MSI-H BTC treated with ICIs. Patients and Methods We conducted a multicenter, retrospective analysis of BTC patients with dMMR/MSI-H between 2017 and 2024 at Mayo Clinic, University of Michigan, and University Hospitals Seidman Cancer Center. Outcomes of interest were surgical resection rate, rate of pathologic response, 2-year overall survival (OS; time from initiation of treatment to death/last follow-up), and time to treatment discontinuation (TTD; time from initiation of treatment to cessation because of any cause). Analyses were descriptive. RESULTS Thirty patients with MSI-H BTC were identified: 19 with cholangiocarcinoma, three with gallbladder cancer, and 8 with BTC undefined. The median age at diagnosis was 61.5 years (range, 26-86). Twenty-six (86.7%) patients had advanced stage at diagnosis. Twenty-seven patients (90%) received first-line systemic therapy, and 13 (48.1%) continued onto second line. Six patients (23.1%) were restaged to resectable from advanced disease after ICI therapy and underwent resection; all remained recurrence-free at last follow-up. Of these six patients, 3 (50%) achieved a pathologic complete response. Among those receiving first-line therapy, the median TTD was 9.9 months (95% CI, 5.7 to 14.5 months) and the 2-year OS was 73% (95% CI, 56% to 94%). CONCLUSION ICI therapy in patients with MSI-H BTC demonstrated durable response and downstaged some BTC to a resectable stage. dMMR/MSI-H should be performed up-front to guide treatment decisions.

PURPOSE EGFR alterations occur in a subset of biliary tract cancers (BTCs) and are often linked to disease progression and poor prognosis, yet targeted approaches remain underexplored. ERRFI1 , encoding the epidermal growth factor receptor (EGFR) inhibitor MIG6, is mutated in various cancers, including BTC, representing a potential predictive biomarker. We investigated whether loss of ERRFI1 function may enhance sensitivity to EGFR-targeted tyrosine kinase inhibitors (TKIs), presenting a potential therapeutic opportunity. METHODS This is a retrospective multicenter study of patients with BTC harboring ERRFI1 alterations. Data were extracted from electronic health records following institutional approval. ERRFI1 alterations were classified based on the alteration type, variant allele frequencies were documented, and coalterations were analyzed. Treatment outcomes including response, time to progression (TTP), overall survival (OS), safety profiles, and tumor marker kinetics were noted. RESULTS Fourteen BTC patients with ERRFI1 mutations were identified in our database; the median age was 50 years, 64% were males; all cases were intrahepatic cholangiocarcinomas. Common coalterations included IDH1 (36%), TP53 (29%), and ARID1A (29%). All patients received gemcitabine-cisplatin as first-line treatment, and 79% received immune checkpoint inhibitors. Eight patients (57%) received EGFR TKIs. Best responses to EGFR therapy included three partial responses (2 responses lasting >20 months), four stable diseases, and one progressive disease. The median TTP was 7 months (95% CI, 6 to 21 months). Treatment was well-tolerated: toxicities included rash (n = 2), transaminitis (n = 1), and diarrhea (n = 1). The median OS was 20 months (95% CI: 8-36 months); 50% remained alive at last follow-up. CONCLUSION ERRFI1 mutations represent actionable biomarkers in BTC, with EGFR-targeted therapy demonstrating meaningful clinical benefit in this heavily pretreated population. These findings support integration of ERRFI1 testing into routine molecular profiling of BTC and other EGFR-driven malignancies.

Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune–based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.

PURPOSE Hepatopancreatobiliary (HPB) cancers—including hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), pancreatic ductal adenocarcinoma (PDAC), and gallbladder cancer—are aggressive malignancies with limited treatment options and poor prognosis. The emergence of personalized liquid biopsy technologies, particularly bespoke circulating tumor DNA (ctDNA), offers new opportunities for improving clinical management. Traditional methods like imaging and tumor markers may miss early recurrence or evolving disease. This study explores the real-world application of ctDNA in HPB cancers, focusing on its use for surveillance, diagnostic clarification, treatment monitoring, and recurrence detection. Methods We retrospectively analyzed the use of a personalized ctDNA assay (Signatera, Natera) in 54 patients with HPB cancers at a single academic cancer center. The cohort included PDAC (22/54), HCC (11/54), and CCA (21/54). ctDNA was assessed longitudinally for surveillance, treatment monitoring, or diagnostic clarification. Concordance with imaging and tumor markers, as well as lead time to recurrence detection, was descriptively analyzed. RESULTS ctDNA was evaluable in 37/54 patients (84.6%), with ctDNA positivity in 22/37 (59.5%). Success rates by tumor type were 16/22 (72.7%) in PDAC, 10/11 (90.9%) in HCC, and 11/21 (52.4%) in CCA. ctDNA concordance with imaging was observed in 69/85 assessments (72.6%) and with tumor markers (carbohydrate antigen 19-9 or alpha fetoprotein) in 39/95 (41%). Clinical applications included disease surveillance (21/54, 38.9%), treatment monitoring (24/54, 44.4%), and diagnostic clarification (16/54, 29.6%). In patients with recurrence, ctDNA detected disease before imaging in several cases, with a median lead time of 28 days (range, 1 month to 7 months). CONCLUSION Personalized ctDNA testing demonstrated meaningful utility across HPB cancers, enabling early recurrence detection and guiding clinical decision making as a complementary tool in multidisciplinary care.

PURPOSE Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy. METHODS A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data. RESULTS In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden. CONCLUSION Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

PURPOSE Gastroesophageal carcinoma (GEC) is increasingly managed using biomarker-guided therapies. Although both tissue DNA (tDNA) and circulating tumor DNA (ctDNA) testing are used clinically, the concordance of genomic alterations between primary tumors, metastatic sites, and liquid biopsy remains incompletely understood. METHODS We retrospectively analyzed 345 patients with GEC who underwent ctDNA testing at Mayo Clinic. tDNA next-generation sequencing and immunohistochemistry (IHC) for human epidermal growth factor receptor 2 (HER2)/erb-b2 receptor tyrosine kinase 2 ( ERBB2 ) and mismatch repair (MMR) were collected. Concordance was evaluated between ctDNA and tDNA, ctDNA and IHC, and across all three modalities, using 60-day and 30-day intervals. RESULTS Among 345 patients with ctDNA testing, 186 had tDNA testing, and 310 underwent IHC. ctDNA testing showed a shorter turnaround time than tDNA (median 6 v 13 days). The most frequent alteration in ctDNA, primary tDNA, and metastatic tDNA was TP53. Concordance between ctDNA and primary tDNA was ≥78.8% for key genes; between ctDNA and metastatic tDNA, it was ≥84.8%. IHC-ctDNA concordance was higher in metastatic tumors, with 91.1% for HER2/ ERBB2 and 97.7% for mismatch repair (MMR)/microsatellite instability (MSI) compared with 81.1% and 95.8%, respectively, in primary tumors. Triplet concordance for MSI/MMR was 97.6% in primary tumors and 100% in metastatic tumors, while ERBB2 /HER2 showed 84.4% and 93.9% concordance, respectively. ctDNA temporal heterogeneity analysis revealed 14 patients with fluctuating ERBB2 status and 3 with fluctuating MSI-H status. CONCLUSION ctDNA testing demonstrates high concordance with tDNA and IHC and offers faster turnaround. Given its minimally invasive nature and strong concordance with tissue-based testing, ctDNA is a reliable tool for genomic profiling and longitudinal monitoring in GEC.

ABSTRACT The limited efficacy of current therapies against cholangiocarcinoma (CCA) necessitates the development of novel treatment strategies. Src family kinases (SFKs) contribute significantly to tumor progression and resistance in CCA. Therefore, we investigated the novel, first-in-class SFK ‘OFF’ inhibitor NXP900 in diverse preclinical CCA models, including those with acquired resistance. This study evaluated the therapeutic effects of NXP900 and detailed adaptive molecular responses to SFK inhibitor therapy. We also aimed to identify biomarkers predictive of drug sensitivity using integrated multiomic profiling and develop strategies to overcome resistance. NXP900 inhibited YAP activity through direct inhibition of tyrosine phosphorylation and indirect activation of the Hippo pathway via LATS. These effects were associated with decreased tumor cell viability in CCA cell lines and several in vivo models. Notably, IDH -mutant patient-derived xenograft CCA models were particularly sensitive to NXP900. NXP900 also synergized with gemcitabine/cisplatin chemotherapy, enhancing antitumor efficacy in both in vitro and in vivo models. Multiomic analyses combining transcriptomics, global proteomics, and phosphoproteomics identified molecular features associated with primary response and acquired resistance. IL13RA-AKT signaling was upregulated in resistant models; NXP900 sensitivity could be restored with AKT or IL13RA2 inhibition. Together, these findings demonstrate the therapeutic potential of NXP900 as a novel YAP inhibitor in CCA and support further investigation in a clinical trial. Graphical Abstract

Abstract Purpose: Mutant IDH1 (mIDH1) defines a therapeutically targetable subtype of intrahepatic cholangiocarcinoma (ICC), with the mIDH1 inhibitor ivosidenib approved for advanced disease. A subset of patients experiences prolonged disease stabilization; however, the molecular basis for eventual progression remains poorly defined. Experimental Design: We performed molecular profiling of matched baseline and postprogression circulating tumor DNA (ctDNA) samples from patients with mIDH1 ICC enrolled in the ClarIDHy phase III trial. Functional studies were conducted to characterize candidate resistance mechanisms. Results: Longitudinal ctDNA analysis of 18 patients treated with ivosidenib for &gt;6 months revealed emergent genomic alterations in multiple cases. Acquired mutations in mitogen-activated protein kinase (MAPK) pathway genes (KRAS, NRAS, MAP2K1, NF1) were identified in five cases, with instances of concurrent alterations and/or high variant allele fractions (VAF). Additional candidate resistance events included a secondary IDH1 mutation and a hotspot IDH2 mutation, detected at low VAF in the same patient. Functional studies showed that these IDH mutations conferred sustained 2-hydroxyglutarate production and ivosidenib resistance, whereas MAPK activation blunted gene expression induced by ivosidenib plus IFNγ, a key therapeutic output of mIDH1 inhibition. In parallel, baseline ctDNA profiling of 81 patients revealed that ARID1A mutations and elevated mIDH1 VAF were associated with reduced clinical benefit. Conclusions: MAPK pathway alterations represent a recurrent mechanism of resistance to mIDH1 inhibition in ICC, whereas emergent IDH1/IDH2 mutations appear infrequent. Functional data suggest that MAPK-mediated resistance may involve impaired IFN signaling. These results support MAPK-directed combination strategies and highlight the utility of ctDNA profiling to identify predictive and resistance biomarkers in mIDH1-driven ICC.

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.

Abstract Purpose: Isocitrate dehydrogenase (IDH) 1/2–isoform inhibitors have clinical efficacy in IDH1/IDH2-mutated neoplasms. However, primary resistance and secondary resistance limit their therapeutic potential. LY3410738, an oral, brain-penetrant, dual IDH1/IDH2-mutated isoform-selective inhibitor, was designed to overcome resistance. Patients and Methods: This global, multicenter, open-label, phase I study of patients with IDH-mutant solid tumors evaluated LY3410738 as monotherapy (dose escalation) for advanced solid tumors in combination with cisplatin–gemcitabine (CISGEM) for newly diagnosed cholangiocarcinoma or with durvalumab for relapsed/refractory cholangiocarcinoma (dose expansion; NCT04521686). Primary objectives were the maximum tolerated dose, recommended phase II dose, and preliminary antitumor activity. Safety, pharmacokinetics, inhibition of D-2-hydroxyglutarate, and ctDNA were assessed. Results: Overall, 119 patients received LY3410738 alone (N = 94) or in combination with CISGEM (N = 19) or durvalumab (N = 6). No dose-limiting toxicities were observed; the maximum tolerated dose was not determined. Common adverse events included nausea, vomiting, and decreased appetite. Overall response rates of 5.2% and 11.1% and disease control rates of 56.9% and 63.0% were observed for patients with relapsed/refractory IDH1- or IDH2-mutant cholangiocarcinoma or IDH1-mutant glioma, respectively. D-2-hydroxyglutarate normalization was rapid and durable. In dose-expansion cohorts, combination treatments were tolerable, with one dose-limiting toxicity in the durvalumab cohort. LY3410738 plus CISGEM demonstrated a response rate of 42.1%, a median duration of response of 8.1 months, and a median progression-free survival of 10.2 months for patients with newly diagnosed IDH-mutant cholangiocarcinoma. Conclusions: LY3410738 demonstrated largely cytostatic antitumor activity in IDH1- or IDH2-mutated cholangiocarcinoma and IDH1-mutated gliomas. LY3410738 plus CISGEM exhibited favorable antitumor activity in patients with treatment-naïve IDH-mutated cholangiocarcinoma, warranting further exploration as a treatment strategy.