Recommendations for the use of next-generation sequencing in patients with metastatic cancer in the Asia-Pacific region: a report from the APODDC working group.

INTRODUCTION: Next-generation sequencing (NGS) diagnostics have shown clinical utility in predicting survival benefits in patients with certain cancer types who are undergoing targeted drug therapies. Currently, there are no guidelines or recommendations for the use of NGS in patients with metastatic cancer from an Asian perspective. In this article, we present the Asia-Pacific Oncology Drug Development Consortium (APODDC) recommendations for the clinical use of NGS in metastatic cancers. METHODS: The APODDC set up a group of experts in the field of clinical cancer genomics to (i) understand the current NGS landscape for metastatic cancers in the Asia-Pacific (APAC) region; (ii) discuss key challenges in the adoption of NGS testing in clinical practice; and (iii) adapt/modify the European Society for Medical Oncology guidelines for local use. Nine cancer types [breast cancer (BC), gastric cancer (GC), nasopharyngeal cancer (NPC), ovarian cancer (OC), prostate cancer, lung cancer, and colorectal cancer (CRC) as well as cholangiocarcinoma and hepatocellular carcinoma (HCC)] were identified, and the applicability of NGS was evaluated in daily practice and/or clinical research. Asian ethnicity, accessibility of NGS testing, reimbursement, and socioeconomic and local practice characteristics were taken into consideration. RESULTS: The APODDC recommends NGS testing in metastatic non-small-cell lung cancer (NSCLC). Routine NGS testing is not recommended in metastatic BC, GC, and NPC as well as cholangiocarcinoma and HCC. The group suggested that patients with epithelial OC may be offered germline and/or somatic genetic testing for BReast CAncer gene 1 (BRCA1), BRCA2, and other OC susceptibility genes. Access to poly (ADP-ribose) polymerase inhibitors is required for NGS to be of clinical utility in prostate cancer. Allele-specific PCR or a small-panel multiplex-gene NGS was suggested to identify key alterations in CRC. CONCLUSION: This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.

Tumor molecular profiling of responders and non-responders following pembrolizumab monotherapy in chemotherapy resistant advanced cervical cancer.

Optimal treatment for advanced cervical cancer after first line chemotherapy remains undefined. Immune checkpoint inhibition with pembrolizumab, a programmed cell death protein 1(PD-1) inhibitor, is under investigation. We analyzed the micro-environmental and molecular genetic profile of tumors from 4 patients with metastatic cervical cancer treated with off-label second-line pembrolizumab in an effort to identify predictive biomarkers. All patients received 2 mg/kg of pembrolizumab, 3-weekly until disease progression. Immunohistochemistry(IHC) for PD-1, PD-L1, CD3 and CD8, as well as next generation sequencing (NGS) for 50 cancer-related genes were performed on tumor samples. All patients tolerated treatment well with no discontinuation of treatment due to toxicity. One patient experienced dramatic and prolonged partial response, and remains stable on pembrolizumab with a progression free survival (PFS) of 21 months at the time of reporting of this series. Three patients experienced disease progression as best response. In the exceptional responder, there was no tumoral expression of PD-L1, however, combined positive score (CPS) for PD-L1 was 1 and we identified somatic mutations in ERBB4(R612W), PIK3CA(E542K) and RB1(E365K). In 2 patients, despite progressive disease defined by RECIST v1.1, symptom stabilization on pembrolizumab was observed. The tumors of both patients had PD-1 expression in ≥1% of stromal lymphocytes. All patients with response or clinical benefit had CPS for PD-L1 ≥ 1. NGS revealed PIK3CA mutations in 3 tumors. Pembrolizumab is a promising therapeutic option in advanced cervical cancer. Further evaluation of biomarkers may guide optimal patient selection.