JCO precision oncology最新文献

Purpose: Platinum-based chemotherapy and surgery are pivotal in managing ovarian cancer (OC), yet prognosis remains poor, and early biomarkers for platinum resistance are needed. The neoadjuvant setting provides an opportunity to evaluate tumor responsiveness to platinum chemotherapy in vivo. This study evaluated whether early measures of platinum response combined with molecular alterations could predict surgical outcomes and survival in patients with OC treated with neoadjuvant chemotherapy (NACT).

Methods: The CHIVA study enrolled stage III/IV OC patients eligible for three cycles NACT with or without nintedanib, followed by interval debulking surgery. Archival samples underwent extensive sequencing to detect clinically relevant variants and copy number alterations and calculate genomic instability (GIS). Early chemotherapy response measures-cancer antigen 125 kinetics by KELIM, major pathologic response, GIS status, tumor infiltrating lymphocytes (TILs) abundance, and genomic alterations-were correlated with surgery completeness and survival.

Results: Among 127 patients, the overall response rate was 44%, and the complete cytoreduction (CC0) rate was 54.8%. Homologous recombination deficiency (HRD) was identified in 56% of patients and was associated with better survival. The median progression-free survival was 21.4, 20.5, and 14.4 months in the BRCAmut, BRCAwt/GIS-high, and BRCAwt/GIS-low subgroups, respectively (P = .001). Unfavorable KELIM predicted lower objective response rate, CC0, and shorter survival, while low intraepithelial TILs (ieTILs) correlated with poor outcomes. Multivariate analysis confirmed KELIM, HRD status, and ieTILs as independent biomarkers. CCNE1 amplifications, observed in 20% of patients, were associated with moderate chemotherapy sensitivity.

Conclusion: HRD status, KELIM, and TILs are key independent biomarkers in advanced OC. CCNE1 amplifications, although typically associated with platinum resistance, were linked to moderate chemotherapy sensitivity, defining an intermediate prognostic subgroup.

Purpose: Neoadjuvant chemotherapy is a key component of curative treatment in advanced colorectal cancer (CRC). However, 30%-40% of patients show progression on treatment, underscoring the need for predictive tools to guide up-front treatment selection. Scalable and reproducible methods for patient stratification remain limited. MicroOrganoSpheres (MOS) are droplet-encapsulated 3D tumor models that allow for high-throughput functional drug testing. Here, we evaluate the potential of tumor-derived MOS to predict response to chemotherapy in patients with CRC.

Methods: MOS droplets were generated from 37 primary and/or metastatic tumor samples collected from 21 patients. MOS response to chemotherapy was quantified using AI-based imaging analysis and compared with clinical response (RECIST/disease-free survival [DFS]) and lesion-specific outcomes (pathologic response/percent tumor volume change).

Results: MOS chemoprediction assay showed high reproducibility (coefficients of variation ≤ 2.5%). MOS drug sensitivity recapitulated patient response with 83% accuracy in the full sample cohort and 100% accuracy when derived from primary tumors. Patients with sensitive MOS showed longer DFS. Individual MOS analysis revealed preservation of intratumor heterogeneity in vitro and enabled identification of drug-resistant clones.

Conclusion: MOS technology offers a scalable and robust functional precision medicine platform with potential to guide clinical decision making in CRC. The platform accurately predicts patient response to chemotherapy and provides insights into intrapatient and intratumor heterogeneity.

Purpose: Patients with unresectable pancreatic cancer (URPC) have poor prognoses and heterogeneous responses to systemic chemotherapy. Existing staging systems show limited accuracy for prognostic assessment. We aimed to develop and validate a radiopathomics signature for pancreatic cancer (RPSPC) to estimate overall survival (OS) and evaluate chemotherapy benefit.

Methods: Ninety-eight patients with URPC were enrolled retrospectively and divided into training (n = 69) and validation (n = 29) cohorts. Radiomics features were extracted from contrast-enhanced computed tomography, and pathomics features were obtained from biopsy-derived whole-slide images. RPSPC was developed to predict OS, and its association with OS was assessed. Hyperparameters were optimized by five-fold cross-validation in the training cohort. The concordance index (C-index) and the AUC were calculated in both cohorts. Patients were stratified into high- and low-RPSPC groups to assess chemotherapy benefit.

Results: RPSPC was independently associated with OS in the training cohort (hazard ratio [HR], 2.636; P = .003). The nomogram incorporating RPSPC and carbohydrate antigen 19-9 level achieved C-indices of 0.793 in the training cohort and 0.792 in the validation cohort. For 1-year survival prediction, the nomogram exhibited AUCs of 0.906 and 0.859 in the training and validation cohorts, respectively. In the total cohort, patients with high RPSPC had significant survival benefit from systemic chemotherapy (HR, 0.492; P = .020), whereas patients with low RPSPC did not have significant survival benefit (HR, 0.621; P = .176).

Conclusion: RPSPC could serve as an independent prognostic factor for patients with URPC and might help identify those who benefit from chemotherapy.

Purpose: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of targeted agents in patients with advanced cancer and genomic alterations. Results of four cohorts of patients with ATM-altered tumors treated with olaparib are reported: colorectal cancer (CRC), lung cancer (LC), pancreatic cancer (PC), and other solid tumors (histology-pooled, HP).

Methods: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16 weeks duration. For histology-specific cohorts, Simon's two-stage design was based on a null DC rate of 15% versus 35% (power = 0.85; α = .10). For the HP cohort, the hypothesized null DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points were OR, progression-free survival, overall survival, duration of response or SD, and safety.

Results: Patients with CRC (n = 30), LC (n = 20), PC (n = 28), or other advanced cancers (n = 38) with ATM alterations were enrolled. The DC rates were 23% (one-sided 90% CI, 8 to 100; P = .38), 45% (one-sided 90% CI, 32 to 100; P = .0004), 28% (one-sided 90% CI, 14 to 100; P = .14), and 25% (one-sided 90% CI, 16 to 100), respectively. The null hypothesized 15% DC rate was rejected for the LC and HP cohorts but not the CRC and PC cohorts. Twenty of 116 patients (17%) experienced treatment-related grade 3 adverse events (AE) or serious AEs.

Conclusion: Olaparib met the prespecified criteria to declare a signal of activity in patients with ATM-altered cancer within the LC and HP cohorts but not the CRC or PC cohorts.

Purpose: Multidisciplinary molecular tumor boards (MTBs) have demonstrated improved clinical outcomes in various malignancies. Sequential next-generation sequencing (NGS) is widely performed at the time of recurrence, which may lead to multiple MTB reviews. This study assessed the clinical benefit of multiple MTB reviews for sequential NGS.

Methods: A retrospective cohort review was performed to compare patients reviewed once at a single-institution MTB and those reviewed multiple times for the same diagnosis with sequential NGS between January 2016 and December 2023. Demographics were compared, and regression and survival analysis was performed.

Results: In all, 3,702 patients were included, 3,446 (91.6%) were reviewed once, and 256 (8.4%) were reviewed multiple times. Patients reviewed once had higher proportion of actionable findings (52.7% v 44.5%, P = .01) compared with those reviewed multiple times at initial review. Approximately half of the patients at their second (47.3%) and third or more (62.5%) reviews had actionable findings. The mean time on recommended targeted therapy for patients reviewed multiple times was 8.24 months (standard deviation [SD], 9.34; range, 0.07-42.4), and the mean time on recommended immunotherapy was 7.02 months (SD, 9.47; range, 0.1-39.2). Patients with multiple MTB reviews had a 30% lower risk of death compared with those reviewed once, even after controlling for primary site, age, presence of actionable NGS findings, and stage (hazard ratio, 0.7, 95% CI, 0.55 to 0.89; P = .004).

Conclusion: Sequential NGS identified actionable findings in approximately 50% of those with multiple reviews, and many patients stay on recommended therapy for at least 6 months. Patients with sequential NGS and multiple reviews have a survival advantage, and although this may be due to therapy sensitivity, it reflects the importance of NGS testing and usefulness of MTB in interpreting those results.