JCO precision oncology最新文献

Purpose: To investigate whether hormone receptor-positive, human epidermal growth factor receptor 2-low (HR+HER2-low) versus HR+HER2-zero early breast cancers have distinct genomic and clinical characteristics.

Methods: This study included HR+, HER2-negative early breast cancers from patients enrolled in the phase III, randomized BIG 1-98 and SOFT clinical trials that had undergone tumor genomic sequencing. Tumors were classified HR+HER2-low if they had a centrally reviewed HER2 immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization and HR+HER2-zero if they had an HER2 IHC score of 0.

Results: A total of 1,795 tumors were evaluable for this study (BIG 1-98 n = 520, SOFT n = 1,275). The frequency of HER2-low tumors was 37% and 21% in the postmenopausal BIG 1-98 and premenopausal SOFT cohorts, respectively. There were no significant differences in clinicopathologic variables between HER2-low and HER2-zero groups which was consistent across both trials. There was no significant difference in risk of distant recurrence for patients with HER2-low tumors versus HER2-zero tumors (5-year % distant recurrence-free 94.0% v 92.8%, P = .61, in BIG 1-98; 89.4% v 92.7%, P = .31, in SOFT, respectively). Somatic genomic profiles were similar with the exception of MAP3K1 mutations which were more frequent in HER2-zero tumors (BIG 1-98 19% v 5%, SOFT 11% v 6%). Both ERBB2 copy number and ERBB2 gene expression abundance were significantly higher in HER2-low tumors compared with HER2-zero tumors; however, the absolute difference was small. Correlation between ERBB2 copy number values and gene expression was modest (r = 0.17).

Conclusion: In two large clinical trials with centrally reviewed HER2 IHC, our findings do not support HER2-low breast cancer as a distinct clinical or biologic entity among HR+HER2- early breast cancers. Absolute differences in median ERBB2 copy number levels or gene expression are small and of unclear biologic relevance.

Purpose: Considerable genetic heterogeneity is currently thought to underlie hereditary prostate cancer (HPC). Most families meeting criteria for HPC cannot be attributed to currently known pathogenic variants.

Methods: To discover pathogenic variants predisposing to prostate cancer, we conducted a familial case-control association study using both genome-wide single-allele and identity-by-descent analytic approaches. Sequence of high-risk haplotype carriers was used for variant detection. Candidate pathogenic variants were tested for association with prostate cancer across independent biobanks for replication of observations.

Results: Pathogenic variants within WNT9B were associated with familial prostate cancer and observations replicated within four of four independent biobanks. WNT9B E152K carried 2.5-fold risk and reached genome-wide significance under meta-analysis, collectively encompassing a half million patients. WNT9B Q47R was also associated with prostate cancer with genome-wide significance among Finns, for which identity-by-descent analyses confirmed a founder effect. WNT9B shares an unexpected commonality with the previously established prostate cancer risk genes HOXB13 and HNF1B: they are each required for embryonic prostate development. With this recognition, we further evaluated two additional genes known to cause Mendelian genitourinary developmental defects, KMT2D and DHCR7. These too were nominally associated with prostate cancer under meta-analyses.

Conclusion: WNT9B and additional genes that are required for early genitourinary development are also involved in the later development of prostate cancer.

Purpose: MAP2K1/MEK1 mutations are potentially actionable drivers in cancer. MAP2K1 mutations have been functionally classified into three groups according to their dependency on upstream RAS/RAF signaling. However, the clinical efficacy of mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) for MAP2K1-mutant tumors is not well defined. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi.

Methods: We interrogated American Association for Cancer Research (AACR) GENIE (v13) to analyze solid tumors with MAP2K1 mutations. We performed a systematic review and meta-analysis of published reports of patients with MAP2K1-mutant cancers treated with MAPKi according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The primary end point was progression-free survival (PFS), and secondary end points were overall treatment response rate (ORR), duration of response (DOR), and overall survival.

Results: In the AACR GENIE data set, class 2 MAP2K1 mutations (63%) were more prevalent than class 1 (24%) and class 3 (13%) mutations (P < .0001). Co-occurring MAPK pathway-activating mutations were more likely to occur in class 1 versus class 2 or 3 MAP2K1-mutant tumors (P < .0001). Our systematic meta-analysis of the literature identified 46 patients with MAP2K1-mutant tumors who received MAPKi. In these patients, ORR was 28% and median PFS was 3.9 months. ORR did not differ according to MAP2K1 mutation class or cancer type. However, patients with class 2 mutations experienced longer PFS (5.0 months) and DOR (23.8 months) compared with patients with class 1, 3, or unclassified MAP2K1 mutations (PFS 3.5 months, P = .04; DOR 4.2 months, P = .02).

Conclusion: Patients with class 2 MAP2K1 mutations represent a novel subgroup that may derive benefit from MAPKi. Prospective clinical studies with novel MAPKi regimens are warranted in these patients.

Purpose: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. TIPN prediction is challenging although patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to identify protein predictors of TIPN and paclitaxel pharmacokinetics (PK).

Methods: This is a retrospective analysis of a prospective study of females with early-stage breast cancer receiving weekly paclitaxel. TIPN was assessed using the sensory subscale of the European Organisation for Research and Treatment of Cancer QLQ-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 (CIPN8). A blood sample was collected within 10 minutes before the end of the first paclitaxel infusion to measure plasma proteins using liquid chromatography-mass spectrometry and to estimate maximum systemic paclitaxel concentration (C_max). A second sample was collected approximately 24 hours after the first infusion to estimate paclitaxel time above threshold (T_c>0.05). Linear mixed-effect and regression models were used to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α = .0006.

Results: Data from 36 participants were included in the analysis testing associations of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories (P = .0002). No proteins were associated with either C_max or T_c>0.05 (all P > .0006).

Conclusion: Complement C3 concentration at the end of initial paclitaxel infusion may be useful for identifying patients with breast cancer and potentially other tumor types who could benefit from TIPN prevention strategies to improve long-term treatment outcomes.

Purpose: Metastatic spread of non-small cell lung cancer (NSCLC) to the brain is a commonly occurring and challenging clinical problem, often resulting in patient mortality. Systemic therapies including immunotherapy have modest efficacy in treating brain metastases. Moreover, the local immune environment of brain metastases remains poorly described. This study aims to understand the genomic and immune landscape of NSCLC brain metastases.

Methods: A total of 3,060 patients with NSCLC sequenced with the Strata Select assay on the Strata Oncology Platform were analyzed. Genomic alterations, tumor mutation burden (TMB), PD-L1 expression, and immune gene expression were compared across different tissue sites and histologies and within brain metastases.

Results: A significant increase in TMB was observed in the brain metastasis samples compared with nonbrain metastasis samples. Mutations in TP53, KRAS, and CDKNA2A were more prevalent within the brain metastasis cohort compared with other tissue locations. In addition, PD-L1 expression was significantly decreased within brain metastasis samples compared with other sites. The overall immune landscape within the brain metastasis samples was largely reduced compared with primary lung samples. However, an immune-enriched brain metastasis cohort was identified with higher expressions of PD-L1 and other immune-related genes.

Conclusion: The overall TMB is increased within brain metastases compared with primary lung and other metastasis sites and is associated with a markedly diminished overall immune landscape. The identification of an immune-enriched brain metastasis subgroup suggests potential heterogeneity within the brain metastasis patient cohort, which might have implications for the development of targeted therapies.

Purpose: Biliary tract cancers (BTCs) include intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancers. BTCs have a number of genomic alterations, including isocitrate dehydrogenase 1 (IDH1) mutations, fibroblast growth factor receptor 2 (FGFR2) rearrangements, and ERBB2 amplifications. Therapies targeting these alterations have shown clinical benefit in patients with BTCs in the United States. However, molecular differences between races in BTCs are largely unknown. In particular, the genomic profiles of African American (AA) patients with BTCs have been infrequently reported. We sought to identify key genomic differences between AA and Caucasian patients with BTCs in the United States in the Foundation Medicine and American Association for Cancer Research (AACR) GENIE databases.

Methods: BTC patients from AA and Caucasian patients from the Foundation Medicine and AACR GENIE databases were retrospectively reviewed. BTCs were divided into ICC, ECC, and GBCs in the Foundation Medicine database. BTCs were divided into cholangiocarcinomas and GBCs in the AACR GENIE database.

Results: The mean age of AA patients with BTCs was lower compared with Caucasians. TP53 and FGFR2 alterations were significantly more frequent in AA patients compared with Caucasian patients with BTCs. IDH1 mutations in Caucasian patients with BTCs were double that of AA patients.

Conclusion: The results of this study suggest that significant genomic differences exist between races and warrant further investigation.

Purpose: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have shown promise in treating HER2-amplified metastatic colorectal cancer (mCRC). Identifying optimal biomarkers for treatment decisions remains challenging. This study explores the potential of artificial intelligence (AI) in predicting treatment responses to trastuzumab plus pertuzumab (TP) in patients with HER2-amplified mCRC from the phase II TRIUMPH trial.

Materials and methods: AI-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis were applied to the prescreening cohort (n = 143) and the TRIUMPH cohort (n = 30). AI analyzers determined the proportions of tumor cells (TCs) with HER2 staining intensity and the densities of various cells in TME, examining their associations with clinical outcomes of TP.

Results: The AI-powered HER2 QCS for HER2 immunohistochemistry (IHC) achieved an accuracy of 86.7% against pathologist evaluations, with a 100% accuracy for HER2 IHC 3+ patients. Patients with ≥50% of TCs showing HER2 3+ staining intensity (AI-H3-high) exhibited significantly prolonged progression-free survival (PFS; median PFS, 4.4 v 1.4 months; hazard ratio [HR], 0.12 [95% CI, 0.04 to 0.38]) and overall survival (OS; median OS, 16.5 v 4.1 months; HR, 0.13 [95% CI, 0.05 to 0.38]) compared with the AI-H3-low (<50% group). Stratification among patients with AI-H3-high included TME-high (all lymphocyte, fibroblast, and macrophage densities in the cancer stroma above the median) and TME-low (anything below the median), showing a median PFS of 1.3 and 5.6 months for TME-high and TME-low respectively, with an HR of 0.04 (95% CI, 0.01 to 0.19) for AI-H3-high with TME-low compared with AI-H3-low.

Conclusion: AI-powered HER2 QCS and TME analysis demonstrated potential in enhancing treatment response predictions in patients with HER2-amplified mCRC undergoing TP therapy.

Purpose: Precision medicine plays an important role in the treatment of patients with advanced melanoma. Despite its high incidence in White patients, advanced melanoma is rare in Asian countries, hampering prospective clinical trials targeting the Asian population. This retrospective study aimed to elucidate the real-world molecular diagnoses and outcomes of Japanese patients with melanoma using comprehensive genome profiling (CGP).

Materials and methods: Patients with melanoma who completed standard anticancer medical treatments (including those expected to complete the treatments) underwent CGP, which is covered by the National Health Insurance. We analyzed the results and clinical annotations of 569 patients registered before August 2023 in a national database.

Results: Skin, mucosal, and uveal melanomas accounted for 64%, 28%, and 7% of cases, respectively. Patients with BRAF, NRAS, NF1, and KIT variants represented 25%, 20%, 17%, and 17%, respectively. Eighty-two percent of BRAF, 97% of NRAS, 69% of NF1, and 54% of KIT were actionable alterations (ie, BRAF classes I, II, and III, NRAS Q61, G12, G13, NF1 loss-of-function, KIT gain-of-function variants). BRAF V600E/K variants occurred in 22% of skin and 2% of mucosal melanomas, but not in uveal melanomas. The mean tumor mutation burden in cutaneous melanomas was 4.2 variants/Mb. Patients previously treated with BRAF-targeted therapy harbored amplifications of BRAF and cell cycle genes more frequently than therapy-naive patients. Thirty-six patients (6.3%) were treated following the molecular tumor board (MTB) recommendations.

Conclusion: Actionable gene alterations in BRAF, NRAS, NF1, and KIT are common in Japanese patients with melanoma. However, few patients were treated according to the MTB recommendations, suggesting that there is an unmet need to increase accessibility to gene-matched clinical trials in Japan.