JCO precision oncology最新文献

Purpose: The prognostic significance of isolated tumor cells (ITCs) in lymph nodes remains uncertain, and immunohistochemistry (IHC) is not consistently used for their detection. We aimed to evaluate the clinical relevance of ITCs and assess whether omission of IHC leads to nodal understaging by comparing outcomes across node-negative patients with and without IHC-confirmed negativity.

Materials and methods: In this retrospective population-based cohort study, we analyzed SEER data from 2010 to 2015, including 127,494 women with invasive breast cancer. Nodal status was classified as N0, N0(i-), N0(i+), or N1mi. Breast cancer-specific survival (BCSS) was evaluated using univariable and multivariable Fine-Gray competing risk regression. Overall survival (OS) was assessed using univariable and multivariable flexible parametric survival models (FPSMs). Models were adjusted for age, tumor grade, histologic subtype, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 status, T stage, race, surgery, chemotherapy, radiation, marital status, number of lymph nodes examined, and year of diagnosis. Subgroup analysis was performed among patients who received both chemotherapy and radiation.

Results: Compared with N0(i-), both N0(i+) and N0 were significantly associated with worse BCSS (adjusted subdistribution hazard ratio [SHR], 1.40 [95% CI, 1.23 to 1.60]; P < .001 and 1.09 [95% CI, 1.03 to 1.16]; P = .003, respectively). N0(i+) also had worse BCSS than N0 (adjusted SHR, 1.28 [95% CI, 1.13 to 1.46]; P < .001). For OS, N0(i+) and N0 showed higher mortality risks compared with N0(i-) in the multivariable FPSM (HR, 1.15 [95% CI, 1.06 to 1.25]; P = .001 and 1.10 [95% CI, 1.07 to 1.14]; P < .001, respectively), with no significant difference between N0(i+) and N0 (HR, 1.05 [95% CI, 0.97 to 1.13]; P = .26). In patients receiving both chemotherapy and radiation, N0(i+), compared with N0(i-), remained associated with worse OS (HR, 1.26 [95% CI, 1.02 to 1.56]; P = .03), whereas BCSS differences were not statistically significant.

Conclusion: ITCs are associated with worse BCSS and OS despite classification as node-negative. Omitting IHC may obscure their detection. Incorporating IHC into routine nodal evaluation may enhance prognostic assessment and guide treatment decisions.

Purpose: Although KRAS mutations represent the primary oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), the association between codon-specific alterations and patient outcomes remains poorly elucidated, largely because of a lack of data sets coupling genomic profiling with rich clinical annotations across disease stages.

Materials and methods: We used American Association for Cancer Research's GENIE Biopharma Consortium Pancreas v1.2 data set to test the association of codon-specific KRAS mutations with clinicogenomic features and patient outcomes in patients with PDAC diagnosed with localized (stages I to III) and advanced disease (stage IV). Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods.

Results: Among 1,032 eligible patients, 949 (92%) exhibited mutant KRAS. These mutations were predominantly observed at G12D (n = 390, 41%), G12V (n = 305, 32%), and G12R (n = 149, 16%). In the group of patients who presented with localized disease, those with G12V mutation had notably longer survival compared with G12D mutation (P = .03). By contrast, patients with G12V mutation who presented with metastatic disease experienced shorter OS compared with those with G12R (P = .04) and G12D mutations (P = .04). Furthermore, no significant differences were observed in the frequencies of coaltered driver genes, including TP53, CDKN2A, and SMAD4, across the different KRAS mutations.

Conclusion: These findings demonstrated that codon-specific KRAS mutations affect PDAC outcomes differently based on disease stage at diagnosis. As studies testing KRAS inhibitors continue to emerge and mature, the prognostic variability of individual KRAS mutations must be carefully considered to avoid confounding and ensure accurate evaluation of therapeutic efficacy in early-phase studies.

Advancements in profiling technologies have deepened our understanding of cancer biology, particularly in non-small cell lung cancer (NSCLC). Genomic data have demonstrated profound clinical impact, enabling the rational design of therapeutics and achieving excellent clinical outcomes for patients with oncogene-addicted disease. While proteomics, transcriptomics, epigenetics, metabolomics, and microbiomics have also generated a wealth of data in NSCLC, their clinical impact is comparatively limited. The increasing use of multiomic profiling has the capacity to change this paradigm, offering new opportunities for improving patient care, particularly for those with non-oncogene-addicted (NOA) NSCLC. This review will summarize the current landscape of multiomic research in NSCLC, emphasizing the potential role in precision oncology. Each omic field is discussed in turn, describing potential clinical applications and challenges of each. In addition, the developing fields of spatial-omic and integrated multiomics, which are becoming increasingly important in understanding cancer biology, are discussed. NSCLC samples have been extensively profiled across different omic technologies, revealing a range of biomarkers associated with prognosis or response to therapy and potential drug targets, many of which are being investigated. While the patient groups analyzed differ between studies, most are performed on early-stage resection samples, and many studies do not stratify results by genomic status, limiting our understanding of NOA-NSCLC. In addition, while many studies independently analyze several omics, fewer use multiomic integration algorithms. Despite significant research into spatial-omic and multiomics in NSCLC, only genomics has significantly affected NSCLC clinical care, leaving an unmet need in NOA-NSCLC. However, nongenomic technologies have significant potential for precision oncology, particularly when used alongside multiomic integration to discover biomarkers or to identify future precision medicine targets.

Purpose: Approximately one in three patients with appendiceal cancer (AC) is diagnosed before age 50 years. Early-onset appendiceal cancer (EOAC) exhibits distinct clinicopathologic and demographic features compared with late-onset disease, suggesting potential biological differences. However, the molecular differences remain poorly understood. This study aims to compare EOAC and late-onset AC (LOAC, ≥50 years) mutational profiles and evaluate their impact on overall survival (OS).

Methods: A retrospective analysis was conducted using the Memorial Sloan Kettering-Metastatic Events and Tropisms database. Patients were stratified by age at the time of surgery into EOAC and LOAC groups. Logistic regression was used to assess differences in mutational profiles between these two groups. Findings were validated using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange project. Kaplan-Meier survival analysis and multivariable Cox proportional hazard models were used to evaluate associations with survival.

Results: The study included 200 patients with appendiceal adenocarcinoma (median age: 55 years, IQR, 47-68), of whom 70 (35%) had EOAC and 130 (65%) had LOAC. Patients with EOAC had higher odds of harboring PIK3CA mutations compared with LOAC (17.1% v 7.7%; odd ratio, 2.65; P = .04), which was consistent when combined with the GENIE data set (12.3% v 5.9%; P < .01). PIK3CA mutations were exclusively observed in patients with metastatic disease (11.8%) and were more common in adenocarcinoma not otherwise specified (NOS) than mucinous tumors (63.6% v 36.4%; P = .04). In multivariable analysis, PIK3CA mutations were independently associated with worse OS (hazard ratio, 2.62 [95% CI, 1.32 to 5.20]; P < .01).

Conclusion: PIK3CA mutations are more common in EOAC and independently associated with worse OS. These findings suggest incorporating PIK3CA mutation status into prognostic assessments and warrant further investigation of PIK3CA inhibitors as a potential therapeutic strategy for appendiceal adenocarcinoma.

Purpose: Anal adenocarcinoma (AD) is a rare GI malignancy with no established standard treatment. Little is known about genomic alterations (GAs) and their therapeutic implications in advanced anal AD. Here, we compared the genomic profiles of advanced anal AD and advanced rectal AD.

Methods: We retrospectively extracted data from patients with advanced anal or rectal AD who underwent comprehensive genomic profiling (CGP) and were registered at the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB).

Results: From June 2019 to April 2023, 45 patients with anal AD and 1,915 patients with rectal AD were enrolled into the C-CAT database. TP53 (88.9%) and KRAS (51.1%) were the most common GAs in anal AD. Compared with rectal AD, anal AD showed significantly higher frequencies of ERBB3 (22.2% v 1.8%), MYC (20.0% v 8.4%), and BRCA2 (6.7% v 1.5%) alterations and a significantly lower frequency of APC mutations (8.9% v 84.6%). TMB-high status (≥10 mutations/Mb) was observed in 6.7% of anal AD cases, whereas no MSI-high tumors were identified in this group. At least one druggable GA (excluding RAS, BRAF V600E, ERBB2, and MSI) was detected in 40.0% of patients with anal AD. Druggable GAs were identified in genes related to the MAPK pathway, DNA damage response pathway, and other oncogenic pathways.

Conclusion: Advanced anal AD exhibited a distinct genomic profile compared with advanced rectal AD. CGP is a useful approach for identifying druggable GAs in advanced anal AD to expand therapeutic opportunities.

Purpose: Homologous recombination deficiency (HRD) results in DNA instability in tumor cells and contributes to tumor pathogenesis. Although HRD-directed therapies are established in other cancers, their role in skin cancers remains unclear. Given the poor response to standard therapies in skin cancer subtypes like acral and mucosal melanoma, we aimed to characterize the prevalence of HRD across skin cancer subtypes, evaluate its correlation with immune checkpoint inhibitor (ICI) response biomarkers, and assess its prognostic relevance in patients treated with immunotherapy (IO).

Methods: A total of 2,508 patients with skin cancer underwent molecular profiling including whole-exome sequencing, whole-transcriptome sequencing, and immunohistochemistry. HRD status was defined by a high loss of heterozygosity (LOH-high) or mutations in homologous recombination repair (HRR) genes. Associations between HRD and established ICI biomarkers (tumor mutational burden, PD-L1, deficient mismatch repair/microsatellite instability-high, immune cell fractions, and transcriptomic signatures) were assessed. Survival outcomes on ICI therapy were assessed in cutaneous melanoma using insurance claims data.

Results: Overall, among the melanoma subtypes, mucosal and acral melanoma had a greater prevalence of LOH-high than cutaneous (30.9% v 13.1% v 8.3%, P < .001). Generally, LOH-high in skin cancer did not correlate with mutations in HRR genes. Additionally, there was no significant association in ICI response biomarkers and HRD among patients with skin cancers. Furthermore, HRD was not associated with a prognostic advantage following IO (hazard ratio, 0.981 [CI, 0.80 to 1.20]; P = .854).

Conclusion: HRD defines a biologically distinct subset of skin cancers and is not predictive of ICI response or improved outcomes. The high prevalence of HRD in acral and mucosal melanoma highlights the need to investigate HRD-directed therapies strategies in this distinct cohort, such as poly (ADP-ribose) polymerase inhibitors or platinum-based therapies.