JCO precision oncology最新文献

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: 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.

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: RAS mutation is a key biomarker of anti-epidermal growth factor receptor (EGFR) antibody resistance in colorectal cancer (CRC). However, the clinical impact of RAS amplification on the efficacy of anti-EGFR therapy remains unclear. This study aimed to characterize RAS-amplified CRC and evaluate the sensitivity of these tumors to anti-EGFR antibodies.

Methods: We conducted a retrospective observational study using the Center for Cancer Genomics and Advanced Therapeutics database in Japan, which includes clinical and genomic data from patients who underwent comprehensive genomic profiling. We analyzed the data from 9,135 patients with unresectable colorectal adenocarcinoma (CRA) who underwent FoundationOne CDx testing.

Results: RAS amplification was identified in 2.1% (188/9,135) of patients with CRA. Among 1,649 patients with RAS wild-type CRA who received first-line chemotherapy with anti-EGFR antibodies, those with RAS amplification had a lower overall response rate (ORR) and a shorter time to treatment failure (TTF) compared with those without RAS amplification (ORR, 37.5% [21/56] v 52.9% [843/1,593]; median TTF, 195 days [95% CI, 129 to 224] v 274 days [95% CI, 258 to 293]; P = .023 and P = .005, respectively). By contrast, among 4,858 patients treated with bevacizumab, no significant differences were observed in ORR (37.3% [31/83] v 37.1% [1,772/4,775]; P = .964) or TTF (median, 231 days [95% CI, 175 to 273] v 259 days [95% CI, 252 to 270]; P = .445).

Conclusion: RAS amplification is a rare alteration that may confer resistance to anti-EGFR antibodies. Assessing RAS amplification status may help guide the appropriate use of anti-EGFR antibodies in clinical practice.

The presence of circulating tumor DNA (ctDNA) in patients indicates post-treatment molecular residual disease (MRD). Given the complexity of ctDNA-based MRD detection tests, consensus on analytical validation (AV) criteria is needed. To address this, the Blood Profiling Atlas in Cancer (BLOODPAC) Consortium's MRD AV Working Group evaluated existing protocols to develop standardized guidance for tumor-informed assays. Protocols pertaining to blood collection tube types, quantitative output, tissue processing, tumor or matched normal sequencing, software, and clinical validation were considered out of scope. After alignment on objectives and assumptions, study designs on the basis of best practices in the field, available assay validation guidance documents, and unique performance challenges for tumor-informed MRD assays were authored. Each protocol contains introduction, experimental design, statistical analysis, and an example data presentation per the US Food and Drug Administration (FDA) Center for Devices and Radiological Health standard format. Biostatisticians were consulted to define minimal test requirements, sample size, and appropriate statistical analyses. The protocols were submitted to the FDA via the presubmission process for formal written feedback followed by a meeting. BLOODPAC's generic protocols for the AV of tumor-informed ctDNA assays for MRD are designed to provide test developers with a core baseline of standardized AV protocols such that methods described can be adapted and applied for any tumor-informed MRD assay irrespective of technology, panel design algorithm, or workflow component. These protocols aim to optimize test developers' presubmission reviews with the FDA, ensuring productive meetings while enabling reviewers to streamline feedback. As always, test developers are encouraged to communicate with FDA directly around their particular AV methods.