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BackgroundAlthough early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1).Methodology and Principal FindingsWe performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04).ConclusionsOverexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

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In this prospective randomized study, first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median, 32 v 31 weeks), duration of response (48 v 39 weeks), and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE, and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned, a trend of superiority over CMF was observed, which was of borderline significance. Due to the lack of survival advantage and to toxicity, this combination is not recommended for routine clinical use. However, its high level of activity should be taken into account for further research.

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Background: Endogenous retrovirus (ERV) elements represent genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that ERV transcription has been associated with increased immunogenicity in cancers. This study focused on the identification of an ERV signature for predict PD-1 blockade response in advanced clear cell renal cell carcinoma (ccRCC).Methods: We obtained ERV mRNA profiles from 3 clinical trials of the anti-PD-1 antibody nivolumab in advanced ccRCC (named RCC_CheckMate), and The Cancer Genome Atlas database (TCGA-KIRC). Identify innate immunity-related ERVs in all the cohorts. Univariate Cox proportional hazards regression analysis and LASSO Cox model were performed to identify and construct the prognostic ERV signature. Timedependent receiver operating characteristic, the Kaplan-Meier curve was used to assess the prognostic capacity of the ERV signature.Results: In this study, the RCC_CheckMate cohort included 181 advanced ccRCC patients from CheckMate 009 (NCT01358721), CheckMate 010 (NCT01354431), and CheckMate 025 (NCT01668784). RCC_CheckMate cohort was divided into the train (n¼129 pts) and test cohort (n¼52 pts). This study identified a prognostic signature based on 27 innate immunity-related ERV mRNAs. In the train cohort, the median OS in the high-and low-risk groups was 20.7 vs 46.3 months (HR¼0.36 (0.23 -0.57); P ¼ 4e-06), respectively. In the test cohort, the median OS in the high-and low-risk groups were 16.9 vs NR (not reach) months (HR¼0.31 (0.15 -0.65); P ¼ 0.001). In order to validate ERV signature at independently cohort, 83 advanced RCC patents selected from TCGA-KIRC, the median OS in the high-and low-risk groups were 15.1 vs 30.6 months (HR¼0.55 (0.33 -0.89); P ¼ 0.01). In all the advanced ccRCC patients, the low-risk group showed significantly better survival compared with the high-risk group.Conclusions: Our study established a novel ERV signature which works as a valid predictive and prognostic biomarker for immunotherapy-treated advanced ccRCC patients.Clinical trial identification: Pseudonymized individual participant data from Check-Mate 009 (NCT01358721), CheckMate 010 (NCT01354431) and CheckMate 025 (NCT01668784).