JCO precision oncology最新文献

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.

Purpose: Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers.

Patients and methods: Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical Oncology (ESMO) recommendations for germline follow-up of tumor variants in CPGs were assessed.

Results: Both tumor and germline reports were completed for 1,167 patients (87.5% of enrolled). A total of 295 tumor reports (25%) included 361 CPG variants of which 70 variants (19.4%) were found in the germline sample. Three additional germline-only CPG variants resulted in 73 (6.3%) of 1,167 germline reports containing variants across 21 CPGs previously associated with pediatric and/or adult cancers. Among frequently mutated CPGs in tumors, concurrent germline findings ranged from 8/32 NF1 (25.0%) and 25/163 TP53 (15.3%) to zero of 27 ALK and 18 PTEN tumor variants. ESMO guidelines recommended clinical follow-up for 110 (30.5%) of 361 tumor CPG variants which included 40 (57.1%) of 70 germline variants.

Conclusion: Coordinated germline and tumor panel testing was feasible and revealed P/LP CPG variants in 6.3% of the Pediatric MATCH cohort. Tumor variant fraction, germline association of CPG with tumor type, and adult-oriented guidelines were not predictive of germline status, emphasizing the need for systematic germline follow-up after tumor genomic testing for pediatric patients.

Purpose: The impact of first recurrence site on outcome after resection of intrahepatic cholangiocarcinoma (IHC) is ill-defined, as are the genomic underpinnings of recurrence and outcomes.

Methods: Resected patients with IHC at two institutions with genomic data were included. Sites of first recurrence (SOFR) were classified as liver only (LO), extrahepatic (EH) only, or simultaneous liver and extrahepatic (SIM). Overall survival (OS) was calculated from the time of recurrence.

Results: Between 1993 and 2021, 318 patients met inclusion criteria; 232 (73%) recurred. SOFR were LO = 93 (40%), EH = 80 (34%), and SIM = 59 (26%). Median OS from recurrence was similar in the LO (33 [26, 42] months) and EH groups (33 [23, 46] months) but much lower in SIM (12 [9.8, 18] months; P < .001). Moderate/poor tumor differentiation, lymphovascular invasion, N1 disease, perineural invasion, and time to recurrence (all P < .05) were associated with SIM; only positive resection margin predicted LO (P = .007). No individual genomic or pathway alterations predicted SOFR; however, for all recurrers, TP53mut (n = 51, 22%; hazard ratio [HR], 2.0 [1.4 to 2.9]; P = .002), CDKN2Adel (n = 34, 15%; HR, 3.4 [95% CI, 2.2 to 5.3]; P < .001), CDKN2B (n = 25, 11%; HR, 3.2 [95% CI, 2.0 to 5.0]; P < .001), and KRASmut (n = 25, 11%; HR, 2.5 [95% CI, 1.6 to 4.0]; P = .002) were associated with worse OS. On multivariable analysis, SIM (HR, 2.5 [95% CI, 1.7 to 3.5]; P < .001), N1 status (HR, 1.8 [95% CI, 1.2 to 2.6]; P = .004), and alterations in the high-risk genotype (TP53mut, CDKN2Adel or KRASmut; n = 84, 36%; HR, 2.4 [95% CI, 1.7 to 3.3]; P < .001) were independent predictors of poor OS.

Conclusion: Recurrence after resection of IHC is common, and the liver was the most common site (66%). Clinicopathologic and genomic factors had limited ability to predict SOFR. Although LO and EH were associated with similar OS, SIM recurrences had dramatically worse OS. Adjuvant strategies targeting liver recurrence may improve outcomes after resection of IHC.

Purpose: Translocation-associated sarcomas (TASs) encompass a wide spectrum of pathologic entities and clinical behavior. Driven by the oncogenic fusion, TASs typically show a stable genome and a low tumor mutational burden (TMB), with infrequent secondary genetic alterations (SGAs). Although oncogenic/likely oncogenic SGAs have been associated with an aggressive clinical course in certain histotypes, a comprehensive comparative study of their clinical impact across TAS histotypes has not been performed to date.

Materials and methods: Herein, we investigate the genomic landscape of 632 TASs, spanning the most common histotypes: Ewing sarcoma (ES, n = 196), desmoplastic small round cell sarcoma (DSRCT, n = 115), solitary fibrous tumor (SFT, n = 87), synovial sarcoma (SS, n = 75), etc. All tumors were tested on a clinically validated, matched tumor-normal DNA-targeted next-generation sequencing panel, with confirmed gene fusion partners. Both gene-level and arm-level copy number alterations were assessed and correlated with survival.

Results: Overall, oncogenic SGAs were detected in 51% of patients, with the highest incidence in myxoid liposarcoma (MLS, 88%). Patients with oncogenic SGA had a higher TMB and were associated with distant metastasis and/or progression-free survival (PFS) in ES, SFT, SS, and MLS in the localized group. TP53 mutations were the most common oncogenic SGAs across histotypes, with SFT and ES showing the highest rate (26% and 11%) and associated with worse PFS and disease-specific survival (P < .01). TP53 mutations in ES (P < .01) and SFT (P = .045) and TERT promoter mutations in SFT (P < .001) and MLS (P = .049) correlated with metastasis in the localized group.

Conclusion: Overall, oncogenic SGA correlated with a worse survival in certain TAS types.

Purpose: Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy associated with an exceptionally poor prognosis. A limitation in its standard-of-care management is the absence of practical molecular tools for monitoring disease progression. Circulating tumor DNA (ctDNA) has emerged as a promising biomarker with potential applications in prognostication, early detection of cancer recurrence, refined evaluation of treatment response, and improved disease surveillance.

Materials and methods: We analyzed serial plasma samples from 81 patients with SCLC using a 105-gene hybrid capture-based next-generation sequencing liquid biopsy assay at three key time points: diagnosis, postchemotherapy, and clinical relapse.

Results: Extensive-stage (ES) patients demonstrated significantly higher median baseline maximum variant allele frequency (VAF_max) compared with limited-stage cases. Notably, limited-stage patients with VAF_max >40% experienced outcomes similar to those with ES disease. Across the cohort, median VAF_max values declined from 53.30% at baseline to 0.15% during remission and then rose to 38.65% at relapse, reflecting initial therapeutic sensitivity followed by disease recurrence that remained unremitting. Baseline VAF_max correlated with the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Moreover, disease-free survival (DFS), defined as the time to relapse from the date of clinical response (evaluated post-4-cycle chemotherapy), was significantly associated with baseline VAF_max and a decline in VAF_max of <99.89% at remission. Relapse genomic profiles largely mirrored baseline alterations, although some patients showed novel mutations.

Conclusion: Median ctDNA VAF_max was strongly associated with OS, PFS, DFS, and ORR. Importantly, patients with detectable residual alterations at completion of prescribed chemotherapy exhibited a markedly shorter DFS, less than that of patients with lower detectable residual alterations, highlighting the potential utility of ctDNA in risk stratification and the value of early trial enrollment for high-risk subgroups.