JCO precision oncology最新文献

Purpose: Molecular markers increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection.

Methods: Clinical variables and somatic mutation data for 20 genes from 641 patients with RMS in the United Kingdom and the United States were used to develop three Cox proportional hazard models for predicting event-free survival (EFS). The Baseline Clinical (BC) model included treatment location, age, fusion status, and risk group. The Gene Enhanced 2 (GE2) model added TP53 and MYOD1 mutations to the BC predictors. The Gene Enhanced 6 (GE6) model further included NF1, MET, CDKN2A, and MYCN mutations, selected through least absolute shrinkage and selection operator regression. Model performance was assessed using likelihood ratio tests and optimism-adjusted, bootstrapped validation and calibration metrics.

Results: The GE6 model demonstrated superior predictive performance compared with the BC model (P < .001) and GE2 model (P < .001). The GE6 model achieved the highest discrimination with a time-dependent area under the receiver operating characteristic curve of 0.766. Mutations in TP53, MYOD1, CDKN2A, MET, and MYCN were associated with higher hazards, while NF1 mutation correlated with lower hazard. Individual prognosis predictions varied between models in ways that may suggest different treatments for the same patient. For example, the 5-year EFS for a 10-year-old patient with high-risk, fusion-negative, NF1-positive disease was 50.0% (95% CI, 39 to 64) from BC but 76% (64 to 90) from GE6.

Conclusion: Incorporating molecular markers into RMS prognosis models improves prognosis predictions. Individualized prognosis predictions may suggest alternative treatment regimens compared with traditional risk-classification schemas. Improved clinical variables and external validation are required before implementing these models into clinical practice.

Purpose: CD276 (B7-H3) is an immunoregulatory protein that plays an important role in the inhibition of T-cell function. CD276 is overexpressed on a variety of human solid cancer cells with limited expression in normal tissues, making it an appealing target for innovative cancer immunotherapy approaches. Pleural mesothelioma (PM) is a highly aggressive disease with a need for new treatment options. Our objective was to investigate the expression of CD276 in the multicenter PM cohort of the European Thoracic Oncology Platform Mesoscape project and correlate the results with annotated clinical data.

Materials and methods: Using tissue microarrays (TMAs), the expression of CD276, assessed using a semiquantitative aggregate H-score method on the membrane (and secondarily in the cytoplasm), was correlated with clinicopathologic characteristics and survival outcome.

Results: CD276 immunohistochemistry results were available for 353 patients, with mostly epithelioid histology (71%). Membranous CD276 expression was present in 86%. High membranous CD276 expression (H-score ≥the median H-score of 120) was significantly more common in females (P = .0029; 71% v 47%) and in epithelioid histology (P < .001; 59% v 29%), whereas no significant association in clinical outcome (overall survival [OS]/progression-free survival) was found. Cross-validation of the TMA method using whole sections revealed a moderate agreement for membranous assessment (Cohen's kappa = 0.47) and a lower agreement for cytoplasm assessment (Cohen's kappa = 0.37). In an exploratory analysis, high cytoplasmic CD276 expression was associated with worse prognosis (OS, log-rank P = .043), but was not significant when adjusting for other clinical variables.

Conclusion: Although no prognostic value of CD276 expression was found, its high membranous expression (86%) in the PM samples of the study supports further research of its potential as a therapeutic target for this disease.

Purpose: Genomic testing is crucial in cancer risk identification, diagnosis, and treatment. However, health care implementation is challenging, even for tests covered by insurance. US payers are important health care participants and may contribute to addressing implementation challenges. We explored whether and how payers consider their role in genomic test implementation, and the perspectives of nonpayer stakeholders on payers' participation.

Methods: We conducted a group interview with private payers (N = 12) to elucidate views on their role in genomic test implementation, implementation challenges, and potential solutions. Subsequently, we conducted individual interviews (N = 10) with nonpayer stakeholders-five cancer advocacy groups and five medical societies working in cancer, examining their reactions to payer input and capturing additional ideas. Qualitative research methods were used to frame the study and analyze results.

Results: Payers considered cancer genomics implementation important and expressed willingness and ability to be involved. They articulated specific challenges relevant to them, including underutilization of covered tests in clinical practice, inequitable test use, and inconsistencies across guidelines, and suggested specific solutions to collaborate on with other stakeholders. Stakeholders viewed payers' participation in implementation as appropriate and feasible, expressed willingness to work with payers where relevant, and concurred with the key challenges noted by payers. Stakeholders' agreement with payers' solutions varied, but they offered additional ideas for addressing challenges.

Conclusion: Both payers and other stakeholders considered payers' role in addressing genomics implementation challenges appropriate and feasible, and offered specific avenues for payer participation. Our findings inform efforts by payers and other stakeholders to address broad health care implementation. They may also help precision oncology professionals, cancer centers, and health systems to frame their own implementation efforts and influence a broader policy and implementation agenda.

Purpose: Current guidelines recommend offering genetic susceptibility testing to individuals with pancreatic cancer regardless of family history, but previous studies have reported only moderate test uptake, highlighting the need for efficient and accessible clinical pathways for delivering pretest genetic education and testing. We evaluated gene testing uptake offered at the point-of-oncology care by a nongenetics provider in an outpatient setting.

Methods: A retrospective chart review was performed of patients with pancreatic cancer treated at the Johns Hopkins Hospital between January 2021 and December 2023. During their initial clinic visit, patients were educated about germline testing by an oncology nurse and provided with educational and instructional handouts and video links, including how to arrange testing (with saliva) with a commercial testing provider. Patients with pathogenic variants and variants of uncertain significance were referred for genetic counseling.

Results: Of the 992 patients seen in the oncology clinic (52.1% male, 75.4% White, 15.4% African American, 6% Asian; median age at diagnosis, 66.9 ± 10.6 years), 90% were offered testing, 77.6% of whom completed it. Factors significantly associated with not going forward with testing included being single, older age, African American, and having advanced-stage disease. Among the tested individuals, 78 (11.3%) had a pathogenic variant identified, including 55 (7.9%) with a pancreatic cancer susceptibility gene variant; of these, 72 (92.3%) were referred for genetic counseling and 50 (69.4%) completed their counseling visit. Testing led to a change in chemotherapy regimen in 28 patients.

Conclusion: The implementation of point-of-care encounters for cancer susceptibility gene testing by an oncology nurse in the outpatient setting yielded a high uptake of testing. Additional approaches are needed to increase testing rates and cancer genetics visits.

Purpose: Immune checkpoint inhibitors (ICIs) are now first-line therapy for most patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), and cetuximab is most often used as subsequent therapy. However, data describing cetuximab efficacy in the post-ICI setting are limited.

Methods: We performed a single-institution retrospective analysis of patients with R/M HNSCC treated with cetuximab, either as monotherapy or in combination with chemotherapy, after receiving an ICI. We extracted objective response rate (ORR), duration of treatment (DOT), and overall survival (OS) and compared them on the basis of patient characteristics. Multivariable models assessed associations between patient and tumor characteristics and outcomes.

Results: We identified 70 patients treated with cetuximab after an ICI. The mean age was 67.6 years, with 60% having virus-associated HNSCC. Overall, the ORR was 21.4%, the median DOT was 1.9 months, and the median OS was 6.3 months. Patients receiving cetuximab with chemotherapy had a higher ORR (27.7% v 8.7%) and longer median DOT but similar OS compared with monotherapy. Virus-independent HNSCC had higher ORR (28.6% v 10.7%), longer DOT (3.3 v 1.2 months; hazard ratio [HR], 0.47 [95% CI, 0.25 to 0.90]), and longer OS (8.1 v 4.6 months; HR, 0.40 [95% CI, 0.19 to 0.83]). In multivariable models, virus-independent disease and negative smoking history were associated with improved OS. Concurrent chemotherapy, age, and sex were not associated with differences in OS. When assessing genomic data, TP53 mutations were associated with improved DOT (HR, 0.33 [95% CI, 0.15 to 0.70]) and OS (HR, 0.38 [95% CI, 0.17 to 0.86]).

Conclusion: Cetuximab-based therapy shows limited efficacy in R/M HNSCC post-ICI, although outcomes were better in virus-independent HNSCC and nonsmokers. The findings may improve prognostication and patient selection for cetuximab after ICI in R/M HNSCC.

Purpose: Although lung cancer is one of the most common malignancies, the underlying genetics regarding susceptibility remain poorly understood. We characterized the spectrum of pathogenic/likely pathogenic (P/LP) germline variants within DNA damage response (DDR) genes among lung cancer cases and controls in non-Hispanic Whites (NHWs) and African Americans (AAs).

Materials and methods: Rare, germline variants in 67 DDR genes with evidence of pathogenicity were identified using the ClinVar database. These P/LP variants were genotyped in a sample of 3,040 lung cancer cases and controls from the Inflammation, Health, Ancestry, and Lung Epidemiology study (NHW: n = 1,915; AA: n = 1,125) and were tested for their association with lung cancer using multivariate logistic regression adjusting for age, sex, pack-years, and race.

Results: We identified 49 unique rare P/LP variants in 21 genes among 156 carriers. Approximately 5.9% of lung cancer cases and 4.2% of controls carried at least one P/LP variant. P/LP variants in DDR genes were more common in lung cancer cases, particularly those diagnosed with adenocarcinoma (odds ratio [OR], 1.46 [95% CI, 1.00 to 2.14]). MUTYH variants were associated with lung cancer overall (OR, 1.82 [95% CI, 1.10 to 3.12]), with the strongest associations among never smokers (OR, 3.37 [95% CI, 1.08 to 10.26]), and in individuals who do not meet current USPSTF screening criteria (OR, 2.85 [95% CI, 1.20 to 7.53]).

Conclusion: Germline variants in DDR genes appear to be associated with lung cancer, particularly when examined by gene subtype and morphologic subtype. MUTYH, a gene historically associated with colorectal and other GI malignancies, emerged as a candidate gene that should be examined in individuals who do not have a significant smoking history.

Purpose: Alterations in human epidermal growth factor receptor 2 (HER2; ERBB2 gene) may be clinically relevant when considering HER2-targeted therapies. We have characterized the breadth of ERBB2 alterations (mutation, fusion, and copy number amplification) in breast cancer and explored the relationship between ERBB2 alterations and prognosis.

Methods: DNA next-generation sequencing (592-gene panel and whole-exome sequencing) and RNA whole-transcriptome sequencing data from 12,153 breast samples were retrospectively reviewed for ERBB2 alterations. Clinicopathologic features were described, including breast cancer subtype, age, and biopsy site. HER2 status was determined according to ASCO guideline recommendations, including HER2-low. Overall survival (OS) data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum tests.

Results: Pathogenic ERBB2 mutations (ERBB2-mut) were identified in 3.2% (N = 388) of tumors overall, most common in liver metastases (113/1,972, 5.7%). ERBB2-mut was more common among breast lobular than ductal (10% v 2.1%; P < .001) and HER2-positive (HER2+)/low tumors (≥3.8% v 1.5% TNBC; P < .05). The most common variant was ERBB2-L755S (1.0% prevalence), enriched in metastatic tumors (1.2% v 0.6% in primary; P < .001). ERBB2 fusions were rare (0.3% prevalence). Coalterations associated with ERBB2-mutated tumors compared with ERBB2 wildtype (WT) included CDH1 (40.0% v 10.2%; P < .001) and ERBB3 (10.6% v 0.8%; P < .001). Of the 10,115 tumor samples with outcome data, ERBB2-mut was associated with worse OS compared with WT.

Conclusion: ERBB2-mut and fusions were observed in all breast cancer subtypes-more commonly in HER2+/low, metastatic, and lobular histology tumors-and associated with poorer prognosis.

Purpose: Fibroblast growth factor receptor 2 isoform IIIb (FGFR2b) protein overexpression is an emerging biomarker in gastric cancer and gastroesophageal junction cancer (GC). We assessed FGFR2b protein overexpression prevalence in nearly 3,800 tumor samples as part of the prescreening process for a global phase III study in patients with newly diagnosed advanced or metastatic GC.

Methods: As of June 28, 2024, 3,782 tumor samples from prescreened patients from 37 countries for the phase III FORTITUDE-101 trial (ClinicalTrials.gov identifier: NCT05052801) were centrally tested for FGFR2b protein overexpression by immunohistochemistry (IHC) and had evaluable results. FGFR2b positivity was defined as both any % tumor cells (TC) and ≥10% TC exhibiting moderate-to-strong (2+/3+) membranous FGFR2b staining. Prevalence was analyzed across patient and sample characteristics.

Results: FGFR2b protein overexpression at any % and ≥10%, 2+/3+ TC positivity was 37.8% (1,428/3,782 [95% CI, 36.2 to 39.3]) and 16.2% (612/3,782 [95% CI, 15 to 17.4]), respectively. Of any %, 2+/3+ TC-positive tumors, 42.9% (612/1,428 [95% CI, 40.3 to 45.4]) were FGFR2b ≥10%, 2+/3+ TC positive. FGFR2b prevalence was not notably different within multiple patient and sample characteristics examined (age, sex, collection method [biopsy v resection], collection site, location of primary tumor, and geographic region).

Conclusion: As of the data cutoff date, we report the largest prevalence assessment of FGFR2b protein overexpression in GC with more than one third (37.8%) of patients with GC exhibiting FGFR2b protein overexpression (any % TC, 2+/3+) by a validated IHC assay. Approximately 16% of patients had FGFR2b protein overexpression in ≥10% of TC. FGFR2b prevalence was similar across geographic regions and within defined patient and sample variables regardless of the level of expression.