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.
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.
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.
This document offers practical guidance on the clinical utility of NGS in specific cancer indications from an Asian perspective.
•Clinical adoption of NGS is heterogeneous in the APAC region due to diversity in access, practice guidelines, and funding.•The APODDC group recommends routine NGS testing for daily practice in patients presenting with advanced NSCLC.•Routine multigene NGS testing is not recommended in metastatic GC, cholangiocarcinoma, NPC, BC, and HCC.•In research centres with molecular screening programs, NGS can enhance understanding of promising targets in OC.•Allele-specific PCRs or a small-panel, multiplex-gene NGS testing was suggested to identify key alterations in CRC.
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.
•1 of 4 patients receiving second line pembrolizumab, experienced dramatic and durable response.•All patients with response or clinical benefit had CPS for PD-L1 ≥ 1.•Germline BRCA1 mutation was detected in 1 patient, but she was a non-responder.•All tumors had somatic mutation in PIK3CA or PTEN.
Background Epithelial ovarian cancer (EOC) mortality rates have remained unchanged in 30 years. The most common EOC subtype, high-grade serous ovarian carcinoma (HG-SOC), can be divided into four ...subgroups on the basis of molecular characteristics. The C5 subgroup is defined by MYCN pathway activation and carries a poor prognosis. The commonly used EOC cell lines are poor models of HG-SOC, whereas patient-derived xenografts (PDX) retain pathological and immunohistochemical features of primary tumour, providing a valuable preclinical resource for therapeutic exploration. Methods Fourteen “C5-like” HG-SOC PDX were generated from tumour tissue transplanted into NOD/SCIDIL2R γ null mice. Three were from a consecutive cohort of HG-SOC PDX identified by qRT-PCR of the MYCN pathway and the rest from a separate cohort by gene expression analysis. Molecular analysis done included qRT-PCR for MYCN, HMGA2 , LIN28B, and sequencing of DNA repair genes. In-vivo response to cisplatin (intraperitoneal on days 1, 8, and 18) is underway, because platinum response provides prognostic information. Tumour volume is measured twice weekly and mice with tumours larger than 0.7 cm3 are euthanised. PDX are deemed sensitive if response is maintained for 100 or more days; resistant if they had stable disease or relapsed in less than 100 days; and refractory if they progressed on treatment. Investigation of in vivo response to compounds targeting the MYCN pathway is underway and each response is considered in light of molecular phenotype. Findings Preliminary data revealed six “C5-like” PDX overexpressed LIN28B and eight overexpressed MYCN . Three overexpressed CCNE1 (drug resistance marker) and three PDX harboured mutations in DNA repair genes (marker of platinum sensitivity). Two PDX were sensitive to cisplatin, two were resistant, four were refractory, and one showed mixed response. Interpretation This cohort of “C5-like” HG-SOC PDX depicts molecular complexity and treatment response heterogeneity. Use of these molecularly annotated PDX to demonstrate novel effective therapies targeting the MYCN pathway will inform clinical trial design.
We previously showed that OCCC can be classified into 4 molecular subgroups based on their irGES profiles with distinct clinicopathological characteristics and prognostic outcomes. A combined ...analysis of samples from 3 independent centres was performed to investigate the prognostic relevance of the irGES profiles in a larger cohort of OCCC patients.
Immune-related gene profiling was performed on 255 FFPE OCCC samples collected from 3 centres (NUH, Singapore, Saitama, Japan, and Edinburgh, UK) using the nanoString nCounter PanCancer Immune Profiling Panel. Unsupervised hierarchical clustering analysis was performed and correlated with clinical outcome. MMR protein levels were assessed by immunohistochemistry.
Total of 255/264 samples from 3 independent cohorts were successfully profiled. Median age at diagnosis was 57 yrs. 137 (53.7%) were stage 1 (Singapore 46.9%, Saitama 65.8%, Edinburgh 50.6%) with 113 (44.3%) Stages 2-4 (Singapore 47.9%, Saitama 34.2%, Edinburgh 49.4%) and 5 (1.9%) missing data. 68.8%, 80.3% and 80.7% of pts from Singapore, Saitama and Edinburgh respectively, received adjuvant treatment. Median PFS for OCCC pts from Singapore, Saitama and Edinburgh were 27, 29.2 and 31.9 mths, respectively. Median OS were 33.5, 35.1 and 41.6 mths respectively for pts from Singapore, Saitama and Edinburgh. Based on irGES, 4 distinct molecular subgroups of OCCCs were consistently identified and reproducible. The PD-1 high subgroup was observed to have poorer 3yr OS rate (52% vs 57% vs 73% vs 74%, p=0.05) and a trend towards poorer 3 year PFS rate (42% vs 58.7% vs 51% vs 65%, p=0.12) compared to the CTLA4, ProA and AP subgroups respectively. A similar trend was observed when pts were stratified based on stage and whether they received adjuvant treatment. MMR expression levels were noted to be deficient in 6.3% and 5.1% of pts from Singapore and Saitama, respectively and were not significantly associated with any irGES group.
Clinical outcomes, based on irGES profiles, appeared to be similar across Asian and Caucasian OCCC pts. 4 molecular subgroups based on their irGES profiles were consistently identified between 3 independent cohorts with distinct prognostic outcomes.
The authors.
NUHS Clinician Scientist Programme-Residency (NCSP-R) Grant NMRC -Centre grant scheme Yong Siew Yoon fellowship grant Clinician Scientist Award (IMAC) CSA-NMRC grant Nicola Murray Foundation.
C. Gourley: Honoraria (self), Advisory / Consultancy: Roche, AstraZeneca, Tesaro, Nucana, Clovis, Foundation One, Sierra Oncology, Cor2Ed; Research grant / Funding (self): AstraZeneca, Novartis, Aprea, Nucana, Tesaro; Licensing / Royalties: PCT/US2012/040805, PCT/GB2013/053202, 1409479.1, 1409476.7 and 1409478.3. D.S. Tan: Honoraria (self): Roche, Bayer, MSD, Genmab, AstraZeneca, Merck Serono, Tessa Therapeutics, Novartis; Research grant / Funding (institution): Bayer, Karyopharm, AstraZeneca. R. Huang: Spouse / Financial dependant: ACT genomics Singapore. All other authors have declared no conflicts of interest.
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