Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site

Abstract

IMPORTANCEAlthough profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach.OBJECTIVE To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP.DESIGN, SETTING, AND PARTICIPANTS This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan.INTERVENTIONS RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. MAIN OUTCOMES AND MEASURESThe primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. RESULTSOf 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months.CONCLUSIONS AND RELEVANCE This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP.

Successful Alectinib Treatment for Carcinoma of Unknown Primary with EML4-ALK Fusion Gene: A Case Report

“…Furthermore, several patients with ERBB2 amplification, BRAFV600E mutation, KIF5B-ALK fusion, NCOA4-RET fusion, FGFR2/3 fusion, and IRF2BP-NTRK1 fusion showed a response to matched specific kinase inhibitors [12]. In a trial conducted by Hayashi et al, precision therapy, based on NGS (molecular targeted therapy), was performed for CUP [6]. EGFR mutations (E709G, L861Q, R776C, and G719C) were detected in five of the ninety-seven patients in their trial.…”

“…The current treatment strategy for CUP is a site-specific therapy, based on histopathological features, determined through immunohistochemistry [3][4][5], or gene expression and gene alterations, detected by next-generation sequencing (NGS). Hayashi et al reported that genetically matched molecular targeted therapy, based on site-specific treatment evaluated by NGS, could be used to treat patients with CUP, a type of cancer, whose prognosis is unfavorable [6]. In the CUPISCO trial, anaplastic lymphoma kinase (ALK) rearrangement was detected in 0.7% of the cases [7].…”

Clinical benefit for clinical sequencing using cancer panel testing

“…These findings will contribute to the identification of the appropriate timing and clinical stage at which clinical sequencing should be performed according to tumor type. Considering that some patients with refractory solid tumor (such as rare tumors and pancreato-biliary cancer) experience impressive responses to targeted therapy following genetic tests [11,12,28], we recommend that clinical sequencing for those patients be performed at an earlier stage (i.e., at the time of tumor diagnosis or prior to standard chemotherapy).…”

Synthetic lethality-mediated precision oncology via the tumor transcriptome

“…There have been significant advances in precision oncology, with an increasing adoption of sequencing tests that identify targetable mutations in cancer driver genes. Aiming to complement these efforts by considering genome-wide tumor alterations at additional ''-omics'' layers, recent studies have begun to explore the utilization of transcriptomics data to guide cancer patients' treatment (Beaubier et al, 2019;Hayashi et al, 2020;Rodon et al, 2019;Tanioka et al, 2018;Vaske et al, 2019;Wong et al, 2020). These studies have reported encouraging results, testifying to the potential of such approaches to comple-ment mutation panels and increase the likelihood that patients will benefit from genomics-guided precision treatments.…”