JCO precision oncology最新文献

Purpose: Hematopoietic cell transplantation (HCT) is considered the only curative treatment for patients with myelodysplastic syndrome (MDS), with disease relapse (REL) as the major cause of post-HCT failure. We aimed to conduct a comprehensive genomic screening of prognostic biomarkers associated with post-HCT disease relapse.

Methods: In this retrospective, cohort study, we analyzed whole-genome sequencing data from 494 non-Hispanic White patients with MDS who received HCT in the Center for International Blood and Marrow Transplant Research network. Genomic prognostic biomarkers were determined by cause-specific Cox regression multivariable models, with additional sensitivity analyses on unrelated transplant subcohorts and different competing outcomes. Their clinical significance on post-HCT risk stratifications was further evaluated via random survival forest models with optimism-bias adjusted bootstrap procedure.

Results: Ten novel genomic biomarkers associated with relapse were identified, including somatic mutations in two genes (HNRNPA3 and TENM2), one locus (HSPC324) with a burden of rare germline single-nucleotide variants (SNVs), six loci harboring common SNVs, and one region harboring a structural variant (SV). For prognostic performance comparisons, the combined model that included these novel genomic biomarkers showed significant improvement of concordance indices (0.747 [95% CI, 0.705 to 0.786]) for predicting post-HCT disease relapse, compared with 0.547 (95% CI, 0.503 to 0.595) in the baseline model (Revised International Prognostic Scoring System [IPSS-R] + hypomethylating agents + graft-versus-host disease prophylaxis). Especially, the combined model showed superior risk stratifications for low or intermediate IPSS-R MDS patients with divergent post-HCT outcomes.

Conclusion: Our results suggest that SNVs and SVs beyond recurrent somatic mutations and cytogenetic abnormalities may play important roles in determining post-HCT relapse risk stratification in patients with MDS.

Purpose: Frontline ovarian cancer treatment protocols involving bevacizumab, poly (ADP-ribose) polymerase inhibitors, and PD-1/PD-L1 inhibitors have failed to improve overall survival (OS) in patients with homologous recombination-proficient (HRP) tumors. To determine mechanistic mutation signatures associated with OS advantage, we constructed a whole-exome sequencing bioinformatic pipeline assay to analyze all 91 patients enrolled in the double-blind randomized placebo-controlled phase II VITAL trial.

Methods: We hypothesized that patients with stage IIIb-IV ovarian cancer who have HRP profile and high clonal tumor mutation burden (cTMB-H) will achieve greater response when undergoing maintenance therapy with gemogenovatucel-T. Our primary objective was assessment of OS using the Kaplan-Meier method among randomly assigned patients receiving either gemogenovatucel-T or placebo.

Results: The median OS in cTMB-H/HRP patients treated with gemogenovatucel-T was 68 months versus 19 months in those treated with placebo (hazard ratio [HR], 0.23; 95% CI, 0.06 to 0.83; 1-sided P = .008). The cTMB-H patients in the non-HRP group did not demonstrate OS advantage (HR, 0.99; 95% CI, 0.39 to 2.47; 1-sided P = .488). No grade 3 treatment-related toxicity was observed in the gemogenovatucel-T group with a follow-up of 8.4 years.

Conclusion: These results demonstrate OS advantage for maintenance treatment of adult females with newly diagnosed, advanced stage IIIb-IV ovarian cancer with HRP status and cTMB-H profile who are in complete response after debulking surgery and frontline platinum-based doublet chemotherapy.

Purpose: Molecular profiles of sarcomas in Chinese children remain unknown. The Chinese Pediatric Precision Oncology Group (CPPOG) is a prospective precision medicine program aimed at defining tumor molecular profiles in pediatric oncology patients across China, which aids diagnosis and treatment decisions. Herein, we report, to our knowledge, the first data from the CPPOG trial.

Methods: Panel sequencing (830-gene DNA panel and 395-gene RNA panel) was performed on 214 tumors from 210 patients with sarcoma from 11 centers, between April 2021 and January 2022 in China. This study was prospectively analyzed to characterize subtype-specific somatic alterations and pathways. Molecular features among subgroups concerning response to treatment and pathologic characteristics were also identified.

Results: Genomic profiling revealed molecular aberrations in the patients: 88.3% harbored at least one somatic or germline alteration; 51.4% carried gene fusions (including 37 novel fusion variants); 46.3% possessed actionable therapeutic targets; 9.5% exhibited germline variants; and 14.3% had modified diagnoses based on molecular findings. In this study, the most common genetic alterations were TP53 mutation and EWSR1-FLI1 fusion. The most common activated pathways were TP53, PI3K, and RTK-RAS in pediatric sarcomas. Anaplastic embryonal rhabdomyosarcomas had special molecular characteristics, with high TP53, MYCN, and MYCL gene alteration frequencies. The mutation frequencies of TP53 and NRAS were notably higher in patients who had undergone disease progression, relapse, or metastasis. Moreover, MYC, MYCN, and MDM2 alterations were more frequent in tumors with mitotic figures >50/3 mm².

Conclusion: Our study reveals the preliminary molecular landscape of Chinese pediatric sarcomas, indicating that molecular changes may represent different therapeutic responses and pathologic characteristics may correlate with molecular characteristics, suggesting the need for panel sequencing for pediatric sarcoma.

Purpose: Limited validated prognostic biomarkers are available to guide treatment decisions for patients with metastatic clear cell renal cell carcinoma (mccRCC).

Methods: This study used a US-based renal cell cancer clinicogenomic database to analyze the predictive value of genomic alterations in patients treated with immune checkpoint inhibitors (ICI) and antiangiogenic (AA) therapies. Three co-occurring gene clusters (C) were considered: (C1) VHL, SETD2, PBRM1, KDM5C, and NFE2L2; (C2) TP53, TSC1, TERT, and DNMT3A; and (C3) CDKN2A, CDKN2B, BAP1, NF2, and MTAP.

Results: In first line, among 493 patients who underwent systemic therapy, 201 (40.8%) and 172 (34.9%) received AA monotherapy (AAm) and ICI combinations (ICI-C), respectively. TERT, TSC1, and TET2 and C2 were identified as positive predictors of response to ICI-C versus AAm. Conversely, C1 was a predictive marker for enhanced AAm efficacy. Among ICI-C, ICI + AA was more effective than ICI + ICI in patients with SETD2 alterations, and less effective in mutant TSC1.

Conclusion: These findings require prospective validation to confirm their clinical utility.

Purpose: Young patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative tumors often exhibit poor outcomes. This study evaluated whether BRCA mutation contributes to prognosis by comparing oncologic outcomes according to BRCA status.

Materials and methods: We conducted a retrospective study of a prospective institutional cohort. Among 1,025 patients 40 years and younger with ER-positive, HER2-negative breast cancer who underwent BRCA1/2 testing, 967 patients were included (excluding low ER expression). Ninety-eight patients (10.1%) were BRCA mutation carriers. Propensity score matching (1:4) and multivariate Cox regression were performed using covariates differing between groups.

Results: BRCA mutation carriers showed more aggressive features. They had worse distant metastasis-free survival (DMFS) compared with noncarriers (hazard ratio [HR], 2.40, P < .001), with a greater risk in late DMFS beyond 5 years (HR, 3.50, P < .001). These findings persisted after adjustment (DMFS HR, 1.76, P = .038, late DMFS HR, 2.84, P = .009). Overall survival was not significantly different. Bone was the most common first site of metastasis in BRCA carriers, whereas noncarriers more frequently showed metastasis to multiple sites. In exploratory subgroup analysis, luminal A-like BRCA carriers consistently showed the poorest survival among the four subgroups.

Conclusion: In luminal-type YBC excluding low ER expression, BRCA carriers demonstrated more aggressive features and significantly worse distant metastasis outcomes. These findings support the need for long-term surveillance and consideration of tailored treatment strategies, including PARP inhibitors, in this high-risk population.

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.