JCO precision oncology最新文献

Purpose: Copanlisib, a pan-class phosphatidylinositol 3-kinase (PI3K) inhibitor with activity predominantly against the PI3K-delta and PI3K-alpha isoforms, has shown promising results in preclinical cancer models with PTEN loss. Herein, we report the activity and safety data from the Z1G and Z1H subprotocols, which included patients with PTEN loss, of the National Cancer Institute Molecular Analysis for Therapy Choice trial.

Methods: Patients with complete loss of cytoplasmic and nuclear PTEN as determined by immunohistochemistry regardless of PTEN mutation or deletion status were included in subprotocol Z1G, and patients with a deleterious mutation in the PTEN gene and retained expression of PTEN were included in subprotocol Z1H. Copanlisib was given intravenously over 1 hour at a dose of 60 mg on days 1, 8, and 15 in a 21-day-on and 7-day-off schedule in 28-day cycles. Patients continued treatment until disease progression or unacceptable toxicity.

Results: Overall, 49 patients (20 patients in Z1G and 29 in Z1H) were included in the primary efficacy analyses. The objective response rates in both cohorts were 0% (Z1G; 90% CI, 0 to 13.9) and 3.4% (Z1H; 90% CI, 0.2 to 15.3), respectively. The median progression-free and overall survival durations were 1.8 months (90% CI, 1.4 to 3.9 months) and 13.7 months (90% CI, 6.8 to 18.3 months) for the Z1G cohort and 1.8 months (90% CI, 1.8 to 2.1 months) and 9.0 months (90% CI, 5.4 to 13.3 months) for the Z1H cohort, respectively.

Conclusion: Our results do not support the antitumor activity of single-agent copanlisib in tumors with PTEN loss regardless of mutation or deletion status or PTEN deleterious mutations with PTEN expression.

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: 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: Clinical risk assessment models can identify patients with hereditary cancer susceptibility, but it is unknown how multigene cancer syndrome prediction models compare with syndrome-specific models in assessing risk for individual syndromes such as Lynch syndrome (LS). Our aim was to compare PREMMplus (a 19-gene cancer risk prediction model) with PREMM5 (a LS gene-specific model) for LS identification.

Methods: We analyzed data from two cohorts of patients undergoing germline testing from a commercial laboratory (n = 12,020) and genetics clinic (n = 6,232) with personal and/or family histories of LS-associated cancer. Individual PREMMplus and PREMM5 scores were calculated for all patients. Using a score cutoff of $\ge$2.5%, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) for identifying LS with each model. Overall ability to discriminate LS carriers from noncarriers was measured using receiver operating characteristic (ROC)-AUC.

Results: PREMMplus had higher sensitivity than PREMM5 in the laboratory- (63.7% [95% CI, 57.0 to 70.0] v 89.2% [95% CI, 84.4 to 93.0]) and clinic-based cohorts (60.8% [95% CI, 52.7 to 68.4] v 90.5% [95% CI, 84.8 to 94.6]). NPV was ≥98.8% for both models in both cohorts. PREMM5 had superior discriminatory capacity to PREMMplus in the laboratory- (ROC-AUC, 0.81 [95% CI, 0.77 to 0.84] v 0.71 [95% CI, 0.67 to 0.75]) and clinic-based cohorts (ROC-AUC, 0.79 [95% CI, 0.75 to 0.84] v 0.68 [95% CI, 0.64 to 0.73]).

Conclusion: Both PREMM5 and PREMMplus demonstrated high NPVs (>98%) in LS discrimination across all patient cohorts, and both models may be used to identify individuals at risk of LS. The choice of which model to use can be based on the goals of risk assessment and patient population.

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.

Purpose: This study aimed to assess (1) the prognostic value of circulating tumor DNA (ctDNA) and (2) the ability of ctDNA to detect recurrence compared with standard surveillance in curatively resected early-stage biliary tract cancer (BTC).

Methods: This retrospective, multicenter cohort study evaluated serial ctDNA testing for surveillance in patients with early-stage BTC after curative resection. We evaluated the relapse-free survival (RFS) by ctDNA positivity. The sensitivity of ctDNA in detecting a confirmed recurrence of BTC, defined as a biopsy-proven or true progression by radiographic tumor dynamics, was evaluated. The lead time was calculated from the first ctDNA detection to the confirmed recurrence.

Results: A total of 56 patients with curatively resected stage I-III BTC were included in this study, with a median follow-up of 12.8 months from the date of surgery. ctDNA detection during the molecular residual disease window period (median RFS, 6.6 months v not reached; hazard ratio [HR], 26 [95% CI, 2.6 to 265]; P < .0001) and during the surveillance period (median RFS, 19.3 months v not reached; HR, 20 [95% CI, 2.6 to 153]; P < .0001) were associated with poorer RFS. Sixteen patients had confirmed recurrence. ctDNA identified recurrence in 93.8.% (15/16) of the recurred patients with an average lead time of 3.7 months. Carbohydrate antigen 19-9 levels did not show any significant correlation with RFS (HR, 1.17 [95% Cl, 0.24 to 5.71]; P = .844) in contrast to ctDNA.

Conclusion: The findings from our real-world cohort study revealed the (1) promising value of ctDNA as a prognostic biomarker for relapse in curatively resected BTC and (2) potential early detectability of recurrence by ctDNA compared with standard surveillance.

Purpose: The SPARTAN trial demonstrated that the addition of apalutamide to androgen deprivation therapy improves outcomes among patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). We applied a previously reported digital histopathology-based multimodal artificial intelligence (MMAI) algorithm to estimate clinical outcomes in SPARTAN.

Methods: Patients with available hematoxylin and eosin-stained slides from the primary tumor were included. Histopathology slides were digitized. MMAI scores ranging from 0 to 1 were generated from digital histopathology and baseline clinical parameters. Patients were categorized into MMAI non-high-risk and high-risk groups using previously validated cutoffs. Kaplan-Meier estimates were calculated for metastasis-free survival (MFS), second progression-free survival (PFS2), and overall survival (OS); comparisons were performed using Cox proportional hazards regression for treatment arms and MMAI risk. The interaction between treatment arm and risk group was evaluated using a Cox proportional hazards model.

Results: The study included 420 evaluable patients after excluding those with missing clinical data or inadequate histopathology images. Of these, 63% (n = 266) were MMAI high risk and 37% (n = 154) were non-high risk. MMAI risk score was associated with shorter MFS (hazard ratio [HR], 1.72; P < .005), PFS2 (HR, 1.57; P < .005), and OS (HR, 1.41; P = .02). MMAI high-risk patients receiving apalutamide demonstrated significant improvement in MFS (HR, 0.19; P < .005), PFS2 (HR, 0.47; P < .005), and OS (HR, 0.6; P = .01). The interaction between MMAI risk score and treatment for MFS (P = .01) and PFS2 (P = .03) was significant, indicating greater benefit from apalutamide treatment in MMAI high-risk patients.

Conclusion: MMAI is a prognostic marker in nmCRPC and may serve as a predictive biomarker with high-risk patients deriving the greatest benefit from treatment with apalutamide. These results represent the first extension of an MMAI classifier to patients with castration-resistant prostate cancer, warranting additional validation.