JCO precision oncology最新文献

Purpose: Analyses in oncology frequently include Cox proportional hazards models for survival outcomes, but reported results typically only include hazard ratios and respective inference. Cox model predictions of survival functions may help to provide a greater clinical meaning from fitted Cox models for precision oncology research.

Patients and methods: We created a publicly available software library, shinyCox, that can generate user-friendly interactive applications to visualize survival outcome predictions of fitted Cox models. To illustrate the benefits of this software, we analyzed data from AML02 and AML08, randomized clinical trials for pediatric patients with AML. Building on a recent article, we assessed how baseline factors and a pharmacogenomics score (ACS10) can affect the predicted overall survival (OS) and event-free survival (EFS) between patients assigned to induction regimens of clofarabine plus cytarabine or daunorubicin and etoposide combined with low-dose cytarabine or high-dose cytarabine.

Results: Our model outcome prediction visualization application highlights previously reported associations of ACS10 with EFS and OS, while also providing a better understanding of how other prognostic factors amplify or mitigate prognostic implications of ACS10. It is informative to better understand the practical clinical outcomes in terms of predicted survival probabilities to complement the insights gained from hazard ratio tables.

Conclusion: Using shinyCox, we generated visualization applications that let us identify complex relationships between the ACS10 score, age, and the predicted OS and EFS probabilities after AML therapy. This article shows how shinyCox will facilitate model interpretation and accelerate the development of personalized therapies in oncology.

Purpose: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of hepatocellular carcinoma (HCC), yet current screening strategies overlook the genetic complexity of MASLD. We hypothesized that capturing this complexity through a multitrait polygenic approach could improve HCC prevention.

Methods: Using genome-wide association data for 10 MASLD-related traits in individuals of European ancestry, we constructed a meta-polygenic risk score (metaPRS) in the UK Biobank. We evaluated its performance in HCC prediction and its utility in stratified screening. Risk advancement period (RAP) analysis estimated how much earlier individuals in different genetic risk groups reach comparable risk levels.

Results: The metaPRS that incorporated genome-wide variants achieved a C-statistic of 0.686 for HCC prediction, outperforming existing PRSs. Individuals in the top 20% of genetic risk had a 5.33-fold higher HCC risk than those in the bottom 20%. RAP analysis showed that high-risk individuals reached the HCC risk threshold 11.91 years earlier than the intermediate group, whereas low-risk individuals reached it 5.49 years later, suggesting a shift in recommended screening age from 65 to 43 years. Genetic stratification by the metaPRS also improved the predictive performance of noninvasive fibrosis scores (eg, Forns score). Combining high genetic risk with an elevated Forns score yielded a 10-year HCC risk of 2.68%, compared with 0.01% in the lowest-risk group-reducing the number needed to screen from 7,918 to 27.

Conclusion: The MASLD-related metaPRS supports effective population risk stratification and enables a layered HCC screening strategy combining genetic risk profiling with targeted clinical assessment.

Purpose: Incidence rates of early-onset colorectal cancer (CRC) have risen globally, with younger birth cohorts-individuals born after 1960-experiencing higher rates. However, whether somatic mutation profiles vary across birth cohorts remains unclear. This study examines differences in the mutational landscape of CRC by birth cohort.

Methods: Colorectal tumors that underwent somatic next-generation sequencing (NGS) for 154-168 genes in an in-house laboratory between 2015 and 2022 were retrospectively identified. Microsatellite instability status was determined by NGS as either microsatellite stable (MSS) or microsatellite instability-high (MSI-H). Patients with hereditary cancer syndromes or inflammatory bowel disease were excluded. Genes were then grouped according to their molecular pathway. Associations between somatic mutations and birth cohorts were assessed using univariable and multivariable logistic regression. Associations were adjusted for CRC stage, location, neoadjuvant chemo/radiotherapy, and age.

Results: Overall, 369 patients with CRC were identified. The median birth year was 1955 (IQR, 1947-1963) and the median age at diagnosis of CRC was 62.9 (IQR, 52.9-70.8). Twenty (5.4%) had MSI-H tumors and were analyzed separately from MSS tumors. Patients with MSI-H tumors had an earlier birth year than patients with MSS (median 1946 v 1956, P < .001), but this association was not significant after adjusting for confounders (P = .722). No correlation between tumor mutational burden and birth year was identified after controlling for confounders (P = .427). There were no statistically significant differences in mutation prevalence or pathway-level alterations by birth cohort.

Conclusion: In this study, mutational landscape of CRC did not differ by birth cohort, suggesting that the observed shifts in CRC incidence across generations are unlikely to be driven by changes in tumor genomics. However, larger studies are needed to validate these findings.

Purpose: We aimed to synthesize evidence on factors associated with implementation of biomarker testing and strategies to improve its clinical uptake in cancer care.

Methods: MEDLINE, EMBASE, and CENTRAL databases were searched until July 7, 2024. We used the Theoretical Domains Framework to report factors associated with implementation of biomarker testing from clinicians' and patients' perspectives and identify strategies to improve its clinical uptake.

Results: We included 77 studies: 47 studies reported factors from clinicians' perspective, 33 studies reported patients' perspective, 23 studies reported implementation strategies, and seven studies evaluated effectiveness of interventions to facilitate implementation and improve uptake. Clinicians reported inconsistent knowledge and skills related to interpreting results of biomarker testing, making treatment recommendations, and communicating findings of uncertainty and its implications for patients. Patients reported gaps in their knowledge about biomarker testing, how it related to treatment, and the research processes. Long turnaround times, lack of coverage by health insurance plans, and logistical constraints also impaired implementation. Concerns associated with inappropriate use of biomarker testing in unvalidated populations, safety and efficacy profiles of the corresponding immuno-oncology agents, lack of access to corresponding trials, and setting potentially unrealistic expectations for patients regarding their prognosis were highlighted. There are scarce data on strategies and interventions to facilitate implementation and improve uptake of biomarker testing. Setting up an institutional tumor board, multidisciplinary team coordination, and formal ongoing education were the most frequently reported strategies to facilitate implementation. Educational interventions were reported to be feasible, acceptable, and increased knowledge.

Conclusion: This review highlights many factors that are amenable to aid implementation and clinical uptake. However, there is a need to evaluate strategies addressing uncertainties and barriers.

Purpose: Salivary gland cancers (SGCs) are rare and comprise multiple histologic entities. In the recurrent or metastatic (R/M) setting, there is limited evidence for effective systemic anticancer treatment for most subtypes, affecting prognosis and quality of life. Molecular analysis of SGCs holds promise to more accurately classify SGC subtypes and to determine novel therapeutic targets.

Materials and methods: Fifteen patients with R/M SGC underwent tumor biopsy and blood sampling to perform whole-genome sequencing (WGS) of tumor and germline as part of their standard-of-care management. Small somatic mutations, structural alterations, copy number variation, and mutational signatures were processed using WGS pipelines alongside germline testing. Alterations were correlated to clinical features and fed back to clinical team to inform treatment decisions.

Results: WGS quality control was acceptable in 14 of 15 patients (adenoid cystic carcinoma [AdCC, n = 10], salivary duct carcinoma ex pleomorphic adenoma [n = 1]; clear cell myoepithelial carcinoma [n = 1]; epithelial-myoepithelial carcinoma [n = 1]; and acinic cell carcinoma [n = 1]). Genomic rearrangements/fusions were present in 12 of 14. Rearrangements involving MYB and or NFIB were identified in 8 of 10 patients with AdCC. One patient harbored a clinically actionable FGFR1-pleomorphic adenoma gene 1 fusion and responded to fibroblast growth factor receptor-targeted therapy, in addition to enabling histologic reclassification. Other fusions included EWSR1-ATF1 and CRTC1-MAML2, which also aided definitive histologic classification. Small somatic alterations were identified in all but one patient. There were no pathogenic germline mutations.

Conclusion: WGS in SGC is achievable in clinically relevant timeframes, providing genomic information for deeper understanding of disease pathophysiology, to clarify histologic subtype and can identify actionable genomic targets which may not be found through routine sequencing technologies. Further use of WGS has the potential to improve care for patients with SGC.

Purpose: Growing use of multigene panels (MGPs) is increasing the number of patients identified with multiple pathogenic germline variants (PGVs) in cancer predisposition genes. This study characterizes the landscape of patients with multiple PGVs and identifies clinical settings where multiple PGVs affect management.

Materials and methods: This is a single-institution retrospective cohort analysis comprising patients seen in the Department of Clinical Genetics and consented to the Risk Assessment Program (RAP) Registry who were evaluated with a MGP and found to have multiple PGVs.

Results: All patients tested between January 1, 2014, and January 1, 2024, and found to have multiple PGV are included. Sixty-four patients (64/7,961, 0.8%) from 58 families carried multiple PGVs, 22/64 (34%) patients carried at least two PGVs in high- or moderate-risk genes, and 33/64 (52%) carried at least two PGVs that result in potential management changes. Five percent (30/557) of all patients with a PGV in BRCA1 or BRCA2 also carried an additional PGV, while 7% (19/284) of patients with a PGV in a mismatch repair (MMR) gene also carried an additional PGV. Ten patients from nine unrelated families had both a PGV in BRCA1 or BRCA2 as well as a PGV in an MMR gene.

Conclusion: Although the overall percentage of patients undergoing clinical genetic testing with multiple PGVs is small, a significant fraction of these patients could benefit from medical management changes because of the identification of multiple PGVs.

Purpose: To investigate tumor mutation variations across different racial/ethnic groups to better understand implications for targeted cancer therapies.

Methods: A retrospective analysis of 5,045 patients at University of New Mexico Comprehensive Cancer Center who underwent tumor genetic testing between January 2015 and April 2022 was conducted. Data were standardized from internal genetic tests, FoundationOne, and Guardant next-generation sequencing panels. Chi-square tests, one-way analysis of variance, and negative binomial regression estimated differences in mutation rates across race/ethnicity, adjusting for cancer type, age, testing year, and number of genes screened. Primary outcomes included tumor mutation rates and their variation across racial/ethnic groups. Specific focus was placed on mutation frequencies in common genes, and association between race/ethnicity and mutations detected, adjusted for covariates.

Results: Among 5,045 patients-Hispanic/Latino (30%), American Indian (5.7%), Asian/Hawaiian Native (1.9%), Black (1.5%), non-Hispanic White (41%), and other/unknown (19.7%)-mutations were identified most commonly for Asian/Hawaiian Native individuals, with a rate of 0.068 mutations per gene screened (95% CI, 0.051 to 0.090), followed by White individuals (rate = 0.061, 95% CI, 0.051 to 0.072). Fewest mutations were identified for Black individuals, with a rate of 0.045 mutations per gene screened (95% CI, 0.033 to 0.061). Single-gene comparisons suggested BRAF mutations to be most prevalent in non-Hispanic Whites (5.8%, P = .015) while EGFR mutations were most common in Asian/Hawaiian Native patients (10.53%, P = .005).

Conclusion: This study highlights substantial heterogeneity in tumor mutations across racial/ethnic groups while emphasizing the need for wider understanding of genomics and tailored approaches in cancer treatment. Findings underscore the need for equitable genomic testing, tailored therapies, and inclusive cancer care. Further research is necessary to bridge existing disparities, ensuring comprehensive, personalized cancer treatment for all patients.

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 five cohorts of patients with BRCA1/2-mutated solid tumors treated with olaparib are reported: breast cancer (BC), biliary tract cancer (BTC), lung cancer (LC), uterine cancer (UC), and other solid tumors (histology-pooled [HP]).

Methods: Eligible patients had advanced 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 complete or partial response or stable disease (SD) of at least 16-weeks duration. For histology-specific cohorts, Simon two-stage design is based on a null DC rate of 15% versus 35% (power = 0.85; α = .10). Cohorts that were closed before achieving the planned stage II sample size were analyzed using a one-sided exact binomial test. 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 objective response, progression-free survival, overall survival, duration of response or SD, and safety.

Results: Patients with BC (n = 28), BTC (n = 19), LC (n = 25), UC (n = 15), or other advanced cancers (n = 32) with BRCA1/2 alterations were enrolled. The DC rates with one-sided 90% CI were 69% (55-100, P < .001), 50% (32-100, P = .0008), 41% (26-100, P = .0025), 47% (28-100, P = .0036), and 41% (29-100), respectively. The null hypothesized 15% DC rate was rejected for all cohorts. Thirty-six of 119 patients experienced treatment-related grade 3-4 adverse events (AEs) or serious AEs.

Conclusion: Olaparib met prespecified criteria to declare a signal of activity in patients with various advanced BRCA1/2-altered solid tumors.

Purpose: Uncertainty persists regarding the optimal interval between D2 gastrectomy and initiation of adjuvant chemotherapy (AC) for stage II to III gastric cancer (GC). We investigated whether delaying treatment beyond 6 weeks compromises overall survival.

Materials and methods: Using multicenter observational data (2010-2022), we emulated a pragmatic noninferiority target trial to compare AC initiation at ≤6 versus 7-12 weeks postgastrectomy. Eligible patients had received curative-intent surgery for stage II to III GC. The AC regimen comprised platinum-based agents plus fluoropyrimidines. The primary end point was 5-year all-cause mortality from surgery to death or administrative censoring (30 June 2025). The Clone-censor-weighting approach was used, and inverse probability weighting achieved balance across baseline and postoperative time-varying covariates (standardized mean difference <0.1). Weighted pooled logistic regression estimated cumulative mortality; risk differences (RDs) and risk ratios (RRs) were computed from 500 bootstrap samples. The prespecified noninferiority margin was an absolute 10% increase in 5-year mortality.

Result: Among 1,637 eligible patients, 35.9% initiated AC within 6 weeks (median 37 days), whereas 17.5% began between 7 and 12 weeks postoperatively. Delayed initiation (7-12 weeks) met the noninferiority criterion: the absolute RD in 5-year mortality was -0.52% (95% CI, -7.95 to 7.41), with the upper confidence limit below the 10% margin. The noninferiority finding was robust to weight trimming and to alternative imputation strategies. No significant difference in mortality was observed across clinically relevant subgroups.

Conclusion: Initiating AC 7-12 weeks after D2 gastrectomy appeared to be noninferior to initiation within 6 weeks with respect to 5-year mortality in stage II to III GC; however, residual confounding cannot be excluded and the findings require validation in further studies.