As additional biomarkers of clinical significance continue
As additional biomarkers of clinical significance continue to emerge for solid tumors, the applicability and sustainability of single-gene assessment is increasingly questionable, particularly for limited biopsy material. NGS methods provide a highly suitable and cost-effective solution for addressing the evolving needs of comprehensive genotyping [38,39]. Herein, NGS was performed in all 40 cases who had received Crizotinib and we noticed that NGS positive indicated a higher DCR and longer PFS when compared with NGS negative cases. Hence, NGS might be more reliable to pick out optimal candidates for targeted therapy.
The broad scope and flexibility of NGS in specifying and detecting ALK fusions have been well documented by the public literature [40,41]. In this study, among 45 cases that had been assessed by FISH, IHC and NGS concurrently, 8 cases were ALK positive by NGS but negative for either FISH or IHC assays. Their ALK fusion types were: EML4-ALK(5 cases), EML4-ALK + ALK-DIRC3 (one case), EML4-ALK + ALK-AFAP1L1(one case) and ALK-ANO1+IGSF11&TCSC7-ALK(one case). An AFAP1L1 intron2-ALK intron19 fusion gene with unaffected sensitivity to Crizotinib was only detected by NGS. In one FISH-/IHC + case, two novel ALK Doxorubicin partners, ANO1and IGSF11&TCSC7 were identified, highlighting the capability of NGS to detect novel translocation partners not captured by other methodologies. Additionally, the PFS was compared between EML4-ALK variants and rare ALK variants. As a result, no statistic difference was detected between variant sub-types of the fusion gene, indicating the applicability of Crizotinib in various types of ALK fusions, which, however, need further validation by studies with larger samples.
Few studies have focused on the effects of concurrent mutations with ALK fusions on Crizotinib therapy. Based on a comparatively large ALK fusion population, TP53 was found to be the most frequent gene, accounting for nearly the half. Particularly, we validated a higher ORR and a prolonged PFS in TP53 gene wild group compared to TP53 mutation group with the difference approaching statistic significance. The result was in accordance with previous findings that TP53 mutation reduced responsiveness to Crizotinib and worsened prognosis in ALK-rearranged NSCLC patients . Interestingly, Li et al. reported that 5 of 8 EML4-ALK FISH negative but IHC/NGS positive patients had TP53 mutations and speculated a role of TP53 mutation in DNA chromothripsis in some ALK rearrangement events , just as a context-specific role in catastrophic DNA rearrangements in pediatric medulloblastoma and acute myeloid leukemia [44,45]. Therefore, NGS was advantageous in detecting concurrent mutations and investigating their relevance with testing methodologies and prognosis.
Disclosure of potential conflicts of interest
Acknowledgements This work was supported by National Natural Science Foundation of China (Grant No. 81702248) and Zhejiang medical and health science and technology project (Grant No. 2018KY309).
Introduction Lung cancer is a leading cause of death due to cancer in many countries, including Japan . Non-small-cell lung cancer (NSCLC) accounts for 85–90% of lung cancers . Approximately 70% of NSCLC patients are diagnosed with advanced or metastatic disease that is not amenable to surgical resection, and the prognosis remains poor . However, in the previous two decades several new antineoplastic agents have been approved for the treatment of NSCLC in Japan (Fig. 1). In the 1990s, several cytotoxic agents (CAs) were approved, and the role of chemotherapy in the treatment of stage IV NSCLC was established by 1995 . Gefitinib was the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in 2002. Active EGFR mutations were identified in 2004, and the EGFR mutation test has been reimbursed in Japan since 2007 , . Three additional EGFR-TKIs—namely erlotinib, afatinib, and osimertinib—were approved in 2007, 2013, and 2016, respectively.