Use of Ras effector RASSF1A promoter gene methylation and chromosome 9p loss of heterozygosity (LOH) to predict progression-free survival (PFS) in perioperative chemotherapy (CT) phase III trial IFCT-0002 in resectable non-small cell lung cancer

Abstract

7500 Background: IFCT-0002 phase 3 trial compared two timings of CT in early lung cancer, all before surgery (PRE) versus PERIoperative, and two CT regimens, CDDP-Gem vs. CBDCA-Pac. 528 patients were randomized. Early results showed no difference between the two CT regimens for response rate or tolerance, but a better compliance in PRE vs. PERI arm. We hypothesized that molecular markers could help to define the subgroups that did not beneficiate from CT. Methods: Molecular alterations in key pathways regulating G1/S transition or apoptosis were screened. TP53, EGFR and K-RAS mutations, RASSF1A, DAPK, ECAD, FHIT, TIMP3 and p16 promoter gene methylation, 3p, 17p and 9p LOH were evaluated in 178 patients with snap-frozen tissue collected at time of surgery. Results: K-ras mutations identified in 16.3% of patients, was the only molecular alteration associated with the absence of tumor response to chemotherapy (crude RR = 2.13 95%CI [1.11–4.55], p=0.019). However, K-ras mutations were not associated with PFS (p=0.89). RASSF1A promoter gene methylation found in 22.2% of patients was not mutually exclusive with K-Ras mutations. Although not associated with tumor response, RASSF1A promoter gene methylation (adjusted HR = 2.34 95%CI [1.46–3.75], p=0.0013) and 9pLOH (adjusted HR = 2.28 95%CI [1.25–4.15], p=0.015) predicted a worse PFS independently of T, Stage, PS and histology, with respectively 14 vs. 64 months and 18 vs. 36 months of median PFS. Alterations of both RASSF1A and 3p LOH, or RASSF1A plus FHIT methylation or 3p LOH, also predicted a worse PFS (respective adjusted HR 2.46 and 2.22, p= 0.024 and 0.031). There only was a non significant trend for alterations of both p53 and 17p, predicting a worse PFS (18 vs. 36 months of median PFS, p=0.13), with a negative impact for disruptive p53 mutations. Conclusions: This study showed a negative prognostic impact for alterations of RASSF1A in early lung cancer. In resectable patients receiving neoadjuvant CT, a limited set of apoptosis or proliferation alterations could represent strong negative prognostic factors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly France Eli Lilly