MutS Homologue 2 and the Long-term Benefit of Adjuvant Chemotherapy in Lung Cancer

Abstract

Purpose: We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial.Experimental design: We tested the interaction between MSH2 and the allocated treatment (chemotherapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01.Results: MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from chemotherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for chemotherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). A similar decrease was noted when combining MSH2 and P27 (P = 0.01). Chemotherapy prolonged overall survival in the combined low MSH2/low ERCC1 subgroup (HR, 0.65; 95% CI, 0.47-0.91; P = 0.01) and in the combined low MSH2/low P27 subgroup (HR, 0.65; 95% CI, 0.46-0.93; P = 0.01).

Tumor Heterogeneity and Permeability as Measured on the CT Component of PET/CT Predict Survival in Patients with Non–Small Cell Lung Cancer

“…This is particularly true in stage 3A disease, in which outcome remains variable (4). Moreover, the selection and benefit of surgical patients for neoadjuvant/adjuvant treatment is also unclear (20)(21)(22)(23)(24). It is important that the possible survival benefits of chemoradiation are balanced by the adverse effects of toxicity to the patient.…”

Molecular mechanisms of cisplatin resistance

“…According to accepted viewpoints, MMR proteins would attempt to repair cisplatin adducts, fail, and hence transmit a proapoptotic signal (Vaisman et al, 1998). In line with this model, MSH2 and MLH1 are often mutated or underexpressed in the context of acquired cisplatin resistance (Aebi et al, 1996;Drummond et al, 1996;Brown et al, 1997;Fink et al, 1998), although NSCLC patients with high MSH2 expression who do not undergo cisplatin treatment upon tumor resection have a better prognosis than patients with low MSH2 levels (Kamal et al, 2010). This apparent discrepancy simply reflects the intrinsic difference between naive, previously untreated tumors (for which high MSH2 levels constitute a good prognostic indicator) and cancers that have acquired resistance upon cisplatin exposure (which are often associated with reduced MSH2 expression).…”

“…This apparent discrepancy simply reflects the intrinsic difference between naive, previously untreated tumors (for which high MSH2 levels constitute a good prognostic indicator) and cancers that have acquired resistance upon cisplatin exposure (which are often associated with reduced MSH2 expression). Thus, at least in some clinical settings, a high DNA repair capacity appears to protect against tumor relapse (Kamal et al, 2010) but may prevent patients to benefit from DNA-damaging agents. Of note, defects in MLH1 and MSH6 (another component of the MMR system) are associated with increased level of translesion synthesis, the phenomenon whereby DNA synthesis is not blocked but proceeds beyond cisplatin adducts (Bassett et al, 2002).…”

How close are we to customizing chemotherapy in early non-small cell lung cancer?

“…This was also noted when MSH2 expression was combined with that of p27 Kip1 , suggesting that MSH2 immunostaining was a superior predictive biomarker when considered jointly with either of the two other variables. Similar to the prognostic role of other DNA-excision-repair proteins, high MSH2 levels predicted a significantly longer survival in patients on the observation arm [Kamal et al 2010].…”