C-Kit Expression Is Associated with KRAS Mutation in Lung Adenocarcinoma
Alexandra E Kovach, Veronica Klepeis, Eugene J Mark, Dora Dias-Santagata, A John Iafrate, Mari Mino-Kenudson. Massachusetts General Hospital, Boston, MA
Background: Effective treatments for primary lung adenocarcinoma with KRAS mutation remain elusive. Further investigation into the biology of these tumors is needed, including identification of associated markers. The proto-oncogene c-kit that encodes a tyrosine kinase receptor c-kit is not commonly mutated or amplified in lung adenocarcinoma, but our experience with a small number of cases suggests that c-kit protein overexpression may be associated with KRAS mutation. We sought to examine c-kit expression levels in a large cohort of lung adenocarcinomas in the context of KRAS mutation status, clinical profiles, and patient outcomes.
Design: Three-hundred nine cases of stage I and II primary lung adenocarcinoma resected at our institution were immunohistochemically stained with c-kit on tissue microarrays. c-kit cytoplasmic and/or membranous intensity was scored as 2 (strong), 1 (weak), or 0 (negative) and multiplied by the percentage of positive cells, for overall scores of 0 to 200; cases scoring 25 or greater were deemed positive. For the 148 most recent cases (resections since 2008, cohort 1), mutational analysis data was available from an in-house clinical SNaPshot assay of common cancer-associated genes, and these results were compared with c-kit expression. Detailed clinicopathologic and outcome data were obtained for the additional 161 cases (resected before 2007, cohort 2) and compared with c-kit expression.
Results: In cohort 1, 38 cases had EGFR mutations, 46 had KRAS mutations, and 64 were wild-type for both (NENK). c-kit was positive in 2/38 EGFR mutants (5%), 20/46 KRAS mutants (43%), and 15/64 NENK (23%). c-kit expression was more common in cases with KRAS mutation compared to those with EGFR mutation (p<0.0001), NENK (p=0.026), or wild type for KRAS (p=0.0009). Cohort 2 consisted of 57% females, mean age at diagnosis of 67 years, 87% clinical stage I, and an acinar pattern as the most common predominant histology (51%). The average follow-up time was 5.3 years (range 0-16 years). The 5-year disease-free survival for c-kit-positive versus negative cases was 39% and 40%, respectively. Gender, age, clinical stage, and predominant histology also appeared unrelated to c-kit expression.
Conclusions: Lung adenocarcinoma with KRAS mutation appears enriched in c-kit overexpression by immunohistochemistry, raising the possibility of inhibiting c-kit signaling pathway as a treatment option for this population. The finding that c-kit expression was not associated with survival may be a function of the generally favorable prognosis of this early-stage cohort, and further investigation is needed in advanced stage disease.
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 299, Tuesday Morning