There were 3 presentations on genomics from the Biomarkers II session that I thought noteworthy for extending the understanding of genotype driver mutations in lung ADC.
O016.01 is an update from the U.S. Lung Cancer Mutation Consortium (LCMC) on 911 patients registered to date who have undergone comprehensive testing for currently known driver mutations in NSCLC. KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, and NRAS have been testing using multiplexed assays, whilst ALK rearrangements and MET amplification have been assessed using FISH (which are reported in a separate abstract from the conference).
Multiplexed assays have been completed in 420 patients and a genetic alteration has been identified in >50%. All patients had advanced stage (3B or 4) ADC. The median age of this population is 61 years and 59% are women. There was no significant difference in the age between those patients with tumors associated with identifiable mutations and those having tumors without mutations. Neither did gender or smoking history show any significant association with mutation status.
This is very interesting early data from this project that contrasts the clinical observations of driver mutations being associated with female gender and never (or light) smoking history. This data also supports mutation testing for all patients with lung ADC, at least in advanced stage patients who might be considering erlotinib therapy or enrollment into a clinical trial testing other “targeted” agents.
O016.05 was a presentation of another high profile project, the Lung Cancer Mutation Analysis Project (LC-MAP) from Memorial Sloan Kettering Cancer Center. The authors presented their 2-year results of comprehesive mutation analysis of 1231 NSCLC (ADC=896, other non-SQC=49). Evidence of driver mutations was found in 56% of tumors as follows: KRAS 30%, EGFR 20%, ALK-EML4 7%, HER2 5%, PIK3CA 1%, BRAF 1%, MEK1 0.2%, AKT1 0.1%.
This study provides some preliminary benchmarking data to discuss with clinicians, although I would provide a caveat that there is likely to be a referral bias (since this is a single-institutional study from one of the world’s most reknown cancer centers) that overestimates the frequency of driver mutations in ADC.
Finally, O016.06 is another presentation from the MSKCC that examined the prognostic impact of driver mutations in lung ADC with respect to smoking history. There is important background that puts this study in context, namely, the demonstration of an independent dose-dependent relationship between smoking history and survival in patients with advanced stage NSCLC with never-smokers living 50% longer than smokers (Janjigian et al., Cancer 2010). The authors reviewed 301 consecutive never smokers and 373 consecutive smokers with lung ADC who underwent testing for EGFR and KRAS mutations and ALK rearrangements between May 2009 and May 2010.
They found statistically significant differences in the frequency of these mutations between never smokers and smokers: KRAS mutations in 4% of never smokers vs. 43% smokers (P<0.0001); EGFR mutations in 37% of never smokers vs. 14% smokers (P<0.0001); ALK rearrangements in 12% of never smokers vs. 2% smokers (P<0.0001). By multivariate analysis, there were significant survival differences between never smokers with EGFR mutations vs. KRAS mutations (HR for death 4.2, favoring EGFR mutations) and between never smokers with EGFR mutations vs. ALK rearrangements (HR for death 0.31, favoring ALK rearrangements). But, within a given genotype, there were no significant survival differences between never smokers vs. smokers.
This is very interesting data suggesting that the prognostic impact of smoking is driven by the type of mutation (at least in those patients in whose tumor has a detectable driver mutation). Integration of smoking history with the type of mutation detected should refine estimation of the overall prognosis of patients with lung ADC.