JCO precision oncology最新文献

Purpose: The tumor-agnostic approach has been increasingly adopted in precision oncology. Immunohistochemistry (IHC) is the standard biomarker testing for human epidermal growth factor receptor 2 (HER2)-targeted therapies, whereas next-generation sequencing (NGS) has been widely incorporated in routine clinical practices. Here, we investigated the concordance between NGS-based assays and IHC in HER2 testing. Interfering factors leading to discordant results between the assays were also studied.

Materials and methods: Over 78,000 solid tumors across various types from two independent cohorts in the United States and Japan were investigated for HER2 DNA copy number, mRNA expression, and protein overexpression by whole-exome sequencing (WES), whole-transcriptome sequencing (WTS), and IHC, respectively.

Results: In the US cohort (n = 77,267), HER2 DNA amplification, mRNA overexpression, and IHC-positive (IHC-P) were detected in 4.9%, 10.1%, and 4.7% of the tumors, respectively. Positive results in at least one of the three assays were observed in 10.7% of tumors, while 3.9% were positive for all three assays. Using IHC as a comparator, WTS showed better sensitivity than WES but a lower positive predictive value. These results were consistent in the Japanese cohort (n = 1,225). Although the overall HER2 RNA expression level correlated well with IHC score and DNA copy number, the degree of correlation varied among tumor types. Heterogeneous distribution of IHC-P tumor cells was associated with discordant results between NGS-based assays and IHC.

Conclusion: HER2-positive status in protein, mRNA, and DNA showed concordance in general but varied among tumor types. NGS-based assays, especially WTS, could be a useful predictive tool for HER2 testing in tumor-agnostic settings. Intratumor heterogeneity in HER2 protein expression should be considered when bringing bulk sequencing tests into clinical settings.

Purpose: Neurofibromin 1 (NF1) mutations, the third most common driver mutation in melanoma, occur in approximately 15% of cases and lead to the constitutive activation of the RAF/MAPK pathway, resulting in cell proliferation and survival. MEK inhibitors can inhibit the RAF/MAPK pathway and potentially induce tumor regression.

Patients and methods: We conducted a retrospective study to evaluate the clinical benefit of trametinib in patients with metastatic melanoma harboring an NF1 mutation, using the Institutional Tumor Registry and Melanoma Database. We reviewed the records of all patients with metastatic melanoma whose tumor specimens were analyzed by next-generation sequencing.

Results: Among 231 patients whose melanoma was analyzed by next-generation sequencing, 34 (14.7%) had an NF1 mutation and four were treated with trametinib. The median age was 77 years; two patients had mucosal melanoma, and two had cutaneous melanoma. Three patients had stage IV disease. All four patients were previously treated with anti-PD1 antibodies, and three were also treated with anti-CTLA4 antibodies. Three (75%) patients experienced initial tumor regression, including one prolonged partial response with a progression-free survival (PFS) duration of 18 months. The other two patients discontinued treatment because of intolerable adverse events, and their tumors subsequently progressed on treatment discontinuation. The median PFS duration was 6 months. Interestingly, the patient with the longest response had the highest variant allele frequency (VAF) of NF1, whereas the early progressor had the lowest VAF. Two of the responders had a primary mucosal melanoma.

Conclusion: Despite the small number of patients in our study, our findings suggest the promising activity of trametinib in patients with NF1-mutant melanoma, supporting a rationale for prospective studies of MEK inhibitor therapy.

Purpose: The incidence of young-onset pancreatic cancer (YO-PC) has risen over the past two decades, yet its molecular characteristics and long-term outcomes remain poorly defined.

Methods: We retrospectively evaluated patients with PC treated at a tertiary referral center from 2016 to 2022 who had available molecular data. Patients were classified as YO-PC (≤50 years) or average-onset PC (AO-PC, >50 years). A subset analysis examined outcomes in those who underwent curative-intent pancreatectomy. Primary end points included overall survival (OS) and recurrence-free survival (RFS).

Results: Among 511 patients, 10.9% had YO-PC (n = 56; median age 44 years). Patients with YO-PC more commonly self-identified as non-White compared with patients with AO-PC (41.1% v 26.4%, P = .03). BMI, anatomic stage, and CA19-9 level at presentation were similar between groups. KRAS mutations were the most prevalent somatic alterations in both the YO-PC and AO-PC cohorts (87.0% v 88.0%, P = .83), followed by TP53 (73.5% v 74.1%, P = .93), CDKN2A (14.6% v. 23.6%, P = .20), and SMAD4 (18.2% v 12.9%, P = .34). KRAS-specific allele subtypes were also similar (P = .38). A subset analysis in the surgical cohort (n = 167) yielded similar results. OS was similar for YO-PC and AO-PC (18.7 v 21.7 months; P = .29). In the surgical cohort, OS and RFS for YO-PC and AO-PC were also similar (OS, 31.2 v 47.1 months, P = .34; RFS, 10.3 v 14.7 months, P = .10).

Conclusion: In this single-institution study, patients with YO-PC and AO-PC demonstrated similar clinicopathologic and molecular profiles; however, the study population to date may be underpowered. Routine molecular testing on all patients diagnosed with PC will be critical to better understand its clinical and molecular heterogeneity and to inform design of practice-changing clinical trials.

Purpose: Subprotocol H of the NCI-MATCH trial demonstrated the efficacy of dabrafenib + trametinib in a cohort of patients with BRAF^V600-mutated treatment-refractory solid tumors and myeloma. To confirm the longer-term efficacy and safety of this combination in additional patients, an expansion cohort was added.

Methods: Patients with BRAF^V600-mutated malignancies were eligible; patients with cholangiocarcinoma and low-grade serous ovarian cancer were excluded from the expansion cohort. Patients received dabrafenib 150 mg PO twice daily and trametinib 2 mg PO once daily. The primary end point was to evaluate the objective response rate (ORR); secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival (OS).

Results: The expansion cohort enrolled from October 2020 to January 2023. In total, 36 patients were included in the primary efficacy analysis for the combined cohort, including six patients from the expansion cohort and 30 patients from the original cohort, representing 17 different tumor histologies. Fifty-six percent of patients were female, with a median age of 60. The ORR was 36.1% (13 of 36 [90% CI, 22.9 to 51.2]). The median PFS was 11.4 months, and the median OS was 28.6 months. The 6-month PFS was 67.6% (90% CI, 54.5 to 80.8). In the six molecularly confirmed cases in the expansion cohort, there were two responses, including one complete response in a patient with a pilocytic astrocytoma; an additional two patients without molecular confirmation also had PRs. Three patients (two from the original cohort and one from the expansion cohort) remain on therapy. The safety profile was consistent with previous reports with dabrafenib and trametinib.

Conclusion: This study confirms the clinical benefit of dabrafenib + trametinib in BRAF^V600-mutated solid tumors, supporting the recent tumor-agnostic regulatory approval of this combination.

Purpose: Molecular profiles of sarcomas in Chinese children remain unknown. The Chinese Pediatric Precision Oncology Group (CPPOG) is a prospective precision medicine program aimed at defining tumor molecular profiles in pediatric oncology patients across China, which aids diagnosis and treatment decisions. Herein, we report, to our knowledge, the first data from the CPPOG trial.

Methods: Panel sequencing (830-gene DNA panel and 395-gene RNA panel) was performed on 214 tumors from 210 patients with sarcoma from 11 centers, between April 2021 and January 2022 in China. This study was prospectively analyzed to characterize subtype-specific somatic alterations and pathways. Molecular features among subgroups concerning response to treatment and pathologic characteristics were also identified.

Results: Genomic profiling revealed molecular aberrations in the patients: 88.3% harbored at least one somatic or germline alteration; 51.4% carried gene fusions (including 37 novel fusion variants); 46.3% possessed actionable therapeutic targets; 9.5% exhibited germline variants; and 14.3% had modified diagnoses based on molecular findings. In this study, the most common genetic alterations were TP53 mutation and EWSR1-FLI1 fusion. The most common activated pathways were TP53, PI3K, and RTK-RAS in pediatric sarcomas. Anaplastic embryonal rhabdomyosarcomas had special molecular characteristics, with high TP53, MYCN, and MYCL gene alteration frequencies. The mutation frequencies of TP53 and NRAS were notably higher in patients who had undergone disease progression, relapse, or metastasis. Moreover, MYC, MYCN, and MDM2 alterations were more frequent in tumors with mitotic figures >50/3 mm².

Conclusion: Our study reveals the preliminary molecular landscape of Chinese pediatric sarcomas, indicating that molecular changes may represent different therapeutic responses and pathologic characteristics may correlate with molecular characteristics, suggesting the need for panel sequencing for pediatric sarcoma.

Purpose: Limited validated prognostic biomarkers are available to guide treatment decisions for patients with metastatic clear cell renal cell carcinoma (mccRCC).

Methods: This study used a US-based renal cell cancer clinicogenomic database to analyze the predictive value of genomic alterations in patients treated with immune checkpoint inhibitors (ICI) and antiangiogenic (AA) therapies. Three co-occurring gene clusters (C) were considered: (C1) VHL, SETD2, PBRM1, KDM5C, and NFE2L2; (C2) TP53, TSC1, TERT, and DNMT3A; and (C3) CDKN2A, CDKN2B, BAP1, NF2, and MTAP.

Results: In first line, among 493 patients who underwent systemic therapy, 201 (40.8%) and 172 (34.9%) received AA monotherapy (AAm) and ICI combinations (ICI-C), respectively. TERT, TSC1, and TET2 and C2 were identified as positive predictors of response to ICI-C versus AAm. Conversely, C1 was a predictive marker for enhanced AAm efficacy. Among ICI-C, ICI + AA was more effective than ICI + ICI in patients with SETD2 alterations, and less effective in mutant TSC1.

Conclusion: These findings require prospective validation to confirm their clinical utility.

Purpose: Frontline ovarian cancer treatment protocols involving bevacizumab, poly (ADP-ribose) polymerase inhibitors, and PD-1/PD-L1 inhibitors have failed to improve overall survival (OS) in patients with homologous recombination-proficient (HRP) tumors. To determine mechanistic mutation signatures associated with OS advantage, we constructed a whole-exome sequencing bioinformatic pipeline assay to analyze all 91 patients enrolled in the double-blind randomized placebo-controlled phase II VITAL trial.

Methods: We hypothesized that patients with stage IIIb-IV ovarian cancer who have HRP profile and high clonal tumor mutation burden (cTMB-H) will achieve greater response when undergoing maintenance therapy with gemogenovatucel-T. Our primary objective was assessment of OS using the Kaplan-Meier method among randomly assigned patients receiving either gemogenovatucel-T or placebo.

Results: The median OS in cTMB-H/HRP patients treated with gemogenovatucel-T was 68 months versus 19 months in those treated with placebo (hazard ratio [HR], 0.23; 95% CI, 0.06 to 0.83; 1-sided P = .008). The cTMB-H patients in the non-HRP group did not demonstrate OS advantage (HR, 0.99; 95% CI, 0.39 to 2.47; 1-sided P = .488). No grade 3 treatment-related toxicity was observed in the gemogenovatucel-T group with a follow-up of 8.4 years.

Conclusion: These results demonstrate OS advantage for maintenance treatment of adult females with newly diagnosed, advanced stage IIIb-IV ovarian cancer with HRP status and cTMB-H profile who are in complete response after debulking surgery and frontline platinum-based doublet chemotherapy.

Purpose: In both the early and advanced settings, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for use in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC) in combination with endocrine therapy and increase the duration of invasive disease-free survival and progression-free survival (PFS). The duration of response to these treatments is variable between individual patients, supporting the use of biomarkers to inform treatment. Here, we investigated plasma thymidine kinase activity (TKa) as a continuous prognostic and predictive biomarker of response to CDK4/6 inhibitor-based therapy in early and advanced hormone receptor-positive/HER2- BC.

Materials and methods: TKa levels were assessed longitudinally at baseline, on treatment, and post-treatment on plasma samples from 80 metastatic and 28 high-risk patients receiving CDK4/6 inhibitor-based therapy as the standard of care. Patients were enrolled in the prospective observational Roswell Park Ciclib Study (ClinicalTrials.gov identifier: NCT04526587).

Results: In the metastatic setting, TKa levels in baseline samples were inversely associated with the duration of PFS (hazard ratio, 1.91, P = .03). There was also a reduction in TKa levels from baseline to on-treatment in metastatic disease that displayed longer PFS (≥20 months; 120.7 DiviTum units of activity, DuA v 30.6 DuA, P = .028). Individuals with metastatic disease that displayed shorter PFS (≤8 months) presented with higher TKa values on treatment (220.2 DuA v 30.6 DuA, P = .008) compared with patients with longer PFS. In early-stage high-risk cases, TKa values were lower on treatment compared with baseline (41.4 DuA v 114.8 DuA, P = 3.55e-08).

Conclusion: These findings support further investigation of circulating TKa levels as a continuous prognostic and predictive biomarker of response to CDK4/6 inhibitor-based therapy. Future studies are well-suited to assess definitive TKa cutoff values to inform treatment decisions.

Purpose: A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 (IDH1/2) mutation, which has important prognostic and treatment implications. We evaluated the radiographic features and the sensitivity of magnetic resonance spectroscopy (MRS) and cerebrospinal fluid cell-free DNA (CSF cfDNA) sequencing at detecting IDH1/2 mutations in a cohort of these tumors.

Methods: We identified IDH-mutant brainstem gliomas by retrospective chart review. IDH1/2 mutation was established by biopsy, CSF cfDNA sequencing, and/or the presence of a 2-hydroxyglutarate (2HG) peak by 3-Tesla MRS.

Results: Twenty-one patients with IDH-mutant brainstem gliomas were identified, 57% male with a median age of 26 (6-59) years. All tumors involved the pons and/or abutted the brachium pontis. Although 18 (86%) of 21 were nonenhancing, only one of 21 demonstrated T2-FLAIR mismatch. An IDH1/2 mutation was identified by biopsy in 17 and by CSF cfDNA sequencing in three; in the final patient, an IDH1/2 mutation was inferred by the presence of a 2HG peak. The sensitivity of MRS at identifying 2HG in patients with confirmed IDH1/2 mutations was 64.3% (95% CI, 35.1 to 87.2), which increased to 85.7% (95% CI, 42.1 to 99.6) when the study was performed before treatment. The 2HG peak was absent in all four patients with a repeat MRS after completion of radiation. IDH1/2 mutation was identified in four of seven patients who underwent sequencing of CSF cfDNA. In this cohort, median progression-free survival and overall survival were 57.6 and 90.4 months, respectively. An objective response to radiotherapy was observed in 76%.

Conclusion: IDH-mutant brainstem gliomas have a characteristic clinical and radiographic phenotype. MRS is more sensitive than CSF cfDNA sequencing for noninvasively identifying the presence of an IDH1/2 mutation when performed before radiotherapy.