Giovanni Selvaggi

The biology of epidermal growth factor receptor in lung cancer.

The prognostic significance of epidermal growth factor receptor (EGFR) expression in lung cancer and, more importantly, its ability to predict response to anti-EGFR therapies, are currently subjects of active research. In a meta-analysis, EGFR overexpression confirmed a worse prognosis (HR 1.13) in eight studies using immunohistochemistry, although cutoff values were generally selected arbitrarily by investigators. Most applied clinical research on the EGFR has been focused on the overexpression of the receptor, whereas less research has addressed the potential role of other mechanisms of increased signaling or of nonmembrane-bound events. The emerging concept of EGFR signaling reveals a multilayered network that allows for horizontal interactions and permits multiple combinatorial responses that may explain the specificity of cellular outcomes to receptor activation. New technologies such as nucleotide arrays and proteomics will help to elucidate the issue by providing information on how EGFR signaling may affect the expression of genes and proteins in cancer cells.

Thymidylate Synthase But Not Excision Repair Cross-Complementation Group 1 Tumor Expression Predicts Outcome in Patients With Malignant Pleural Mesothelioma Treated With Pemetrexed-Based Chemotherapy

PURPOSE The relationship between thymidylate synthase (TS) expression and outcome in patients with malignant pleural mesothelioma (MPM) treated with pemetrexed (P) was retrospectively evaluated. PATIENTS AND METHODS Sixty histologically confirmed patients with MPM previously treated with P and platinum (45 of 60) or as single agent (15 of 60) were retrospectively considered. Eighty-one control patients with MPM not P-treated were also evaluated. TS and excision repair cross-complementation group 1 (ERCC1) gene expression levels were evaluated by real-time polymerase chain reaction and by immunohistochemistry using the H-score. RESULTS Median TS H-score value was 90 (range, 5 to 240). A significant correlation between low TS protein expression and longer time to progression (TTP; 17.9 v 7.9 months; hazard ratio [HR], 2.05, 95% CI, 1.19 to 3.77; P = .02) or overall survival (OS; 30 v 16.7 months; HR, 2.38; 95% CI, 1.15 to 4.91; P = .019) was found when patients were divided according to median H-score. Conversely, TS mRNA levels were not significantly correlated with outcome. In platinum-treated patients (n = 45), no correlation was found with survival according to ERCC1 median H-score, but patients in the lower tertile had a significantly shorter survival (HR, 3.06; 95% CI, 1.08 to 8.69; P = .035). In control MPMs, TS had no prognostic role. At multivariate analysis, TS protein levels were the only independent prognostic factor for both TTP (HR, 2.71; 95% CI, 1.13 to 6.49; P = .02) and OS (HR, 6.91; 95% CI, 1.90 to 25.07; P = .003). CONCLUSION In patients with MPM treated with P-based chemotherapy, low TS protein levels are predictive of improved TTP and OS. The role of TS assessment is worth of prospective validation in future studies on MPM.

PS01.58: A Phase 3 Trial of Nivolumab, Nivolumab Plus Ipilimumab, or Placebo Maintenance for Extensive-Stage SCLC After First-Line Chemotherapy: Topic: Medical Oncology

The reported prevalence of ALK rearrangement in NSCLC ranges from 2%-7%. The primary standard diagnostic method is fluorescence in situ hybridization (FISH). Recently, immunohistochemistry (IHC) has also proven to be a reproducible and sensitive technique. Reverse transcriptase-polymerase chain reaction (RT-PCR) has also been advocated and most recently the advent of targeted Next-Generation Sequencing (NGS) for ALK and other fusions has become possible. This study compares ALK evaluation with all 4 techniques in resected NSCLC from the large ETOP Lungscape cohort. 96 cases from the ETOP Lungscape iBiobank, with any ALK immunoreactivity were examined by FISH, central RT-PCR and NGS. H-score>120 defines IHC-positivity. RNA was extracted from the same formalin-fixed, paraffin-embedded tissues. For RT-PCR, primers covered the most frequent ALK translocations. For NGS, the Oncomine™ Solid Tumour Fusion Transcript Kit was used. The concordance was assessed using the Cohens kappa coefficient (two-sided alpha≤5%). NGS provided results for 77 out of the 95 cases tested (81.1%), while RT-PCR for 77 out of 96 (80.2%). Concordance occurred in 55 cases out of the 60 cases tested with all 4 methods (43 ALK-negative, 12 ALK-positive). Using ALK co-positivity for IHC and FISH as gold standard, we derive sensitivity for RT-PCR/NGS 70.0%/85.0%, with specificity 87.1%/79.0%. Combining either RT-PCR or NGS with IHC, the sensitivity remains the same, while the specificity increases to 88.7% and 83.9% respectively. NGS evaluation with the Oncomine™ Solid Tumour Fusion transcript kit and RT-PCR proves to have high sensitivity and specificity advocating their use in routine practice. For maximal sensitivity and specificity, ALK status should be assessed using two techniques and a third one in discordant cases. We therefore propose a customizable testing algorithm. These findings significantly influence existing testing paradigms and have clear clinical and economic impact.