Lung cancer : journal of the International Association for the Study of Lung Cancer
-
Standard management of stage II non-small cell lung cancer (NSCLC) is surgery, often followed by adjuvant chemotherapy. However, some patients do not undergo surgery for various reasons. The optimal non-surgical management of stage II NSCLC is undefined. We surveyed Canadian oncologists to understand current practices. ⋯ Most lung cancer physicians manage inoperable stage II NSCLC patients with curative intent, but consensus on how to optimally employ radiotherapy and/or chemotherapy is lacking. Future prospective, randomized trials are warranted.
-
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatic effects on EGFR-mutant non-small-cell lung cancer (NSCLC). However, most patients experience disease recurrences, approximately half of which are T790M-mediated. Monitoring EGFR status with re-biopsy has spatiotemporal limitations. ⋯ Monitoring ctDNA is useful in evaluating treatment responses and monitoring driver oncogene status in NSCLC. ctDNA revealed clonal heterogeneity and genetic processes of cancer evolution in individual patients. The simple presence of the T790M mutation may be insufficient to confer EGFR-TKI resistance to tumor cells.
-
Review Case Reports
K-RAS mutations indicating primary resistance to crizotinib in ALK-rearranged adenocarcinomas of the lung: Report of two cases and review of the literature.
The paradigm of mutually exclusive alterations among oncogenic drivers in non-small-cell lung cancer (NSCLC) is challenged by the increasing evidence of detection of two or more driver alterations in the same tumor using highly-sensitive molecular assays. We report here two cases of ALK-rearranged adenocarcinomas harboring concomitant exon 2 K-RAS mutations (G13D and Q61H). The patients, a 49-year-old smoker man and a 59-year-old non-smoking woman, experienced a rapid disease progression and primary resistance to crizotinib. ⋯ Among 8 similar cases receiving crizotinib previously reported (4 in first line and 4 in second line), 1 had a partial response, 1 stable disease and 6 disease progression. One patient still had progression disease when switching to ceritinib. At the end, K-RAS mutations seem to represent a negative predictive marker in ALK-rearranged adenocarcinomas treated with ALK inhibitor.
-
Since the discovery of sensitizing EGFR mutations as a predictive marker of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), the field of targeted therapy in non-small cell lung cancer (NSCLC) has been revolutionized. Patients harbouring these sensitizing mutations treated with EGFR TKI have derived significant clinical outcome when compared with standard platinum based chemotherapy doublets. However disease progression invariably occurs at a median of about 9-13 months from initiation treatment, if acquired resistance commonly due to the development of EGFR T790M mutation. ⋯ Acquired resistance to third generation EGFR TKIs has been reported including EGFR C797S. Given its non-invasive nature, plasma ctDNA is being explored as a possible approach to detect T790M mutation and to also inform on novel molecular mechansims of tertiary resistance to third generation EGFR TKIs. An understanding of the mechanisms of acquired resistance to the third-generation EGFR TKIs will greatly aid in the development of the next generation of EGFR TKIs.
-
Many acquired resistant mutations to the anaplastic lymphoma kinase (ALK) gene have been identified during treatment of ALK-rearranged non-small cell lung cancer (NSCLC) patients with crizotinib, ceritinib, and alectinib. These various acquired resistant ALK mutations confer differential sensitivities to various ALK inhibitors and may provide guidance on how to sequence the use of many of the second generation ALK inhibitors. We described a patient who developed an acquired ALK F1174V resistant mutation on progression from crizotinib that responded to alectinib for 18 months but then developed an acquired ALK I1171S mutation to alectinib. ⋯ Sequential tumor re-biopsy for comprehensive genomic profiling (CGP) is important to appreciate the selective pressure during treatment with various ALK inhibitors underpinning the evolution of the disease course of ALK+NSCLC patients while on treatment with the various ALK inhibitors. This approach will likely help inform the optimal sequencing strategy as more ALK inhibitors become available. This case report also validates the importance of developing structurally distinct ALK inhibitors for clinical use to overcome non-cross resistant ALK mutations.