JCO precision oncology最新文献

In clinical trials, the initial step typically involves assessing a new drug's toxicity profile, aiming to identify a tolerable dose level for subsequent studies. In phase I trials, the primary objective is to determine the maximum tolerated dose, defined as the highest dose associated with an acceptable level of toxicity. Numerous methods have been developed to guide dose escalation and de-escalation decisions during trial conduct. Among these approaches, the calibration-free odds (CFO) design has demonstrated superior operating characteristics and has emerged as one of the most effective approaches for dose finding. To facilitate the application of the CFO design in clinical trial practice, an R package and a Shiny app have been released. This study presents CFO decision tables in Excel files to further remove the barrier of applying the CFO design to real trials. Anyone involved in the trial conduct can implement the CFO design with no difficulties. During the trial, dose movement decisions can be made simply by referring to the cumulative data (including numbers of patients treated and observed toxicities) and the pregenerated decision tables, without any additional statistical calculation. This approach significantly enhances the usability of the CFO design and reduces the operational complexity associated with its implementation in clinical trials. The Excel CFO decision tables can be downloaded from CFO Shiny App.

Purpose: We performed spatial transcriptomics of estrogen receptor (ER)-negative, ER-low, and ER-high tumor regions of breast cancers that were intermediate (10%-60%) ER-positive by immunohistochemistry to better understand the intratumor heterogeneity in ER expression and to elucidate whether cells of different molecular subtypes (ie, Luminal A [LumA], Luminal B [LumB], human epidermal growth factor receptor 2-enriched, or Basal-like) can coexist in the same tumor.

Methods: Digital spatial profiling was performed on 10 ER-heterogeneous (10%-60% ER+) and 10 ER-high (>60% ER+) primary breast cancers using the NanoString GeoMx platform with the Human Whole Transcriptome Atlas probe set.

Results: LumA and LumB molecular subtypes were intermixed, but there were no Basal-like populations in these ER-heterogeneous tumors. The ER-negative (ER-) regions were LumB-like and showed lower expression of ESR1 and endocrine therapy sensitivity gene signatures but higher expression of immune-related genes and higher recurrence scores, indicating a more endocrine-resistant but chemotherapy-sensitive phenotype. We also found that ESR1 strongly positive cells enriched after preoperative chemotherapy in clinical trial tissues.

Conclusion: This study demonstrates mixed Lum-A and Lum-B molecular subtypes within ER-intermediate primary breast cancers and reveals that ER- tumor cell populations have molecular features of endocrine resistance but chemotherapy sensitivity. These findings may explain the worse clinical outcomes of patients with ER-heterogeneous breast cancers and suggest benefit from combined endocrine and chemotherapy strategies.

Purpose: Delta-like ligand 3 (DLL3) is an emerging target across neuroendocrine cancers, but remains underexplored in gastroenteropancreatic neuroendocrine neoplasms (GEP NENs), including poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP NECs) and well-differentiated neuroendocrine tumors (NETs). We aimed to define the landscape of DLL3 expression and feasibility of DLL3-targeted imaging in this population.

Patients and methods: We completed DLL3 immunohistochemistry (IHC) on 379 tumor samples from patients with GEP NENs, analyzing associations between DLL3 IHC positivity, clinicopathologic features, and outcomes. [⁸⁹Zr]Zr-DFO-SC16.56 DLL3 immuno-positron emission tomography-computed tomography (immunoPET-CT) imaging was performed in six patients with DLL3 IHC-positive advanced GEP NENs.

Results: Among GEP NECs, DLL3 expression was identified in 55/78 (71%) tumors, was enriched for small cell histology, and did not demonstrate prognostic significance. Among well-differentiated gastroenteropancreatic neuroendocrine tumors, DLL3 expression was identified in 5/235 (2%) of grade 1-2 and 25/66 (40%) grade 3 (G3) tumors, most commonly G3 pancreatic NETs (PanNETs; 22/52, 43%), with univariate analysis revealing increased mortality risk among patients with DLL3-positive advanced G3 PanNETs (hazard ratio 3.27 [95% CI, 1.09 to 9.78]). Between May 28, 2024, and February 10, 2025, six patients with DLL3 IHC-positive GEP NENs underwent [⁸⁹Zr]Zr-DFO-SC16.56 immunoPET-CT imaging, which delineated DLL3-avid tumor lesions in five of six patients (two of two GEP NECs, three of four G3 PanNETs). Tumor-specific uptake of [⁸⁹Zr]Zr-DFO-SC16.56 varied between patients, with maximum standard uptake values ranging from 7.4 to 36.7, with four of six cases demonstrating DLL3 avidity in ≥50% of tumor lesions.

Conclusion: DLL3 is expressed on a majority of GEP NECs and on a subset of high-grade PanNETs marked by poor outcomes. Functional imaging suggests DLL3 as a promising therapeutic target in both GEP NECs and high-grade PanNETs.

Purpose: Renal cell carcinoma (RCC) that metastasizes to the pancreas (RCC-PM) is a rare but known phenomenon. These patients have been described to have indolent disease and longer overall survival than patients with metastasis to other sites. We investigated the genomic landscape and outcomes for patients with RCC-PM.

Methods: We used two cohorts for this study: (1) a Tempus cohort (TC) to investigate the genomic landscape and (2) a Stanford cohort (SC) where we include disease course and outcomes in addition to the genomic landscape. All patients included underwent testing with commercial next-generation sequencing (NGS) platform (Tempus AI, Inc, Chicago, IL.). For the TC, we compared the genomic landscape based on tissue samples that underwent molecular analysis (DNA and RNA sequencing and immune cell subtypes) from RCC tumors metastatic to the pancreas, liver, lung, or brain. For SC, patients from 2000 to 2024 with RCC-PM had a tumor tissue sample undergo NGS testing, and we report baseline characteristics, NGS, treatment history, and outcomes.

Results: Between the TC and SC, we identified 83 patients with RCC-PM. Compared with other sites of metastasis, RCC-PM had enrichment in PBRM1 mutations, similar tumor mutational burden but lower rates of infiltrating B cells and PD-L1 positivity compared with other metastatic sites. In the SC, patients demonstrated long and indolent disease courses, but without clear genomic predictors of benefit to tyrosine kinase inhibitors or immunotherapies.

Conclusion: Our study furthers RCC with pancreatic metastasis as a good clinical prognostic marker. We also identified enrichment of angiogenic signatures, such as PBRM1 mutations and potential suppression of an immunogenic environment. However, despite these findings, no systemic treatment strategy had significantly better outcomes.

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.