BackgroundThere are well-known differences in gender outcome in non-small cell lung cancer (NSCLC) and other cancers. In this work, we evaluated several randomised clinical trials to explore the gender influence in the outcome of patients with NSCLC treated with targeted therapy and immunotherapy.MethodsWe performed a series of meta-analysis to compare the gender outcome in the routine setting for overall survival and progression-free survival (PFS) in phase III randomised clinical trials comparing EGFR inhibitors versus chemotherapy (OPTIMAL, LUX-lung 3, LUX-lung 6, EURTAC, ENSURE and WTJOG); ALK inhibitors versus chemotherapy (ASCEND 4, ASCEND 5, PROFILE 1014 and NCT009323893) and anti-PD1 checkpoint inhibitors versus chemotherapy (CheckMate 017, CheckMate 026, CheckMate 057, KEYNOTE 010 and KEYNOTE 024).ResultsFemale patients with NSCLC have a reduced risk of death compared with men (HR=0.73; 95% CI 0.67 to 0.79; p<0.00001). Women had a better benefit from EGFR inhibitors than men (HR=0.34; 95% CI 0.28 to 0.40; p<0.00001 vs HR=0.44; 95% CI 0.34 to 0.56; p<0.00001, respectively). The benefit from ALK inhibitors was similar for both genders (HR=0.51; 95% CI 0.42 to 0.61; p<0.00001 vs HR=0.48; 95% CI 0.39 to 0.59; p<0.00001, for women and men, respectively). Anti-PD1 inhibitors significantly improved the PFS in male patients when compared with chemotherapy (HR=0.76; 95% CI 0.68 to 0.86; p<0.00001); in contrast, women showed no benefit in 5/5 randomised trials (HR=1.03; 95% CI 0.89 to 1.20; p=0.69).ConclusionsIn this exploratory study, some targeted treatments were influenced by gender. Despite differences in outcomes that could be attributed to different histology, EGFR and smoking status, gender should be evaluated more deeply as prognostic variable in patients with NSCLC.

DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR, it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.DDIT4 gene (for DNA-damage-inducible transcript 4), also known as REDD1 or RTP801, encodes a protein product that is induced by a variety of stress conditions and whose major function is to inhibit mTORC1 by stabilizing the TSC1-TSC2 inhibitory complex [1][2][3] .Despite inhibition of mTOR pathway is a current strategy in the treatment of cancer, paradoxically, several in vitro and in vivo studies indicate that DDIT4 have a protective role against apoptosis, where a knockdown of this gene lead to increased levels of dexamethasone-induced cell death in murine lymphocytes without effect in glucocorticoid-induced cell death in primary thymocytes 4,5 .A recent study by Celik et al., reported that DDIT4 may be used as a surrogate pharmacodynamic marker of ezrin inhibitors compound activity 6 . Only two previous reports describe the prognostic value of DDIT4. Jia et al. 7 , evaluated DDIT4 protein expression (assessed by immunohistochemistry) in 100 primary ovarian tumors describing that a high DDIT4 expression is related to a shorter disease-free survival (P = 0.020) and overall survival (P = 0.023) 7 . In the other hand, our group screened 449 genes related with triple negative breast cancer aggressiveness and found that a high DDIT4 expression was an independent factor associated with a shorter

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited options of targeted therapy. Recent findings suggest that the clinical course of TNBC may be modified by the presence of tumor-infiltrating lymphocytes (TILs) and chemokine’s expression, such as CCL5. Diverse studies have shown that CCL5 suppresses anti-tumor immunity and it has been related to poor outcome in different types of cancer while in other studies, this gene has been related with a better outcome. We sought to determine the association of CCL5 with the recruitment of TILs and other immune cells. With this aim we evaluated a retrospective cohort of 72 TNBC patients as well as publicly available datasets. TILs were correlated with residual tumor size after neoadjuvant chemotherapy (NAC) and CCL5 expression. In univariate analysis, TILs and CCL5 were both associated to the distant recurrence free survival; however, in a multivariate analysis, TILs was the only significant marker (HR = 0.336; 95%IC: 0.150–0.753; P = 0.008). CIBERSORT analysis suggested that a high CCL5 expression was associated with recruitment of CD8 T cells, CD4 activated T cells, NK activated cells and macrophages M1. The CD8A gene (encoding for CD8) was associated with an improved outcome in several public breast cancer datasets.

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (þ) tumors; however, the factors contributing to this observation are unknown. Genomewide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2 þ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P ¼ 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2 þ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. Significance: The positive association between Indigenous American genetic ancestry and HER2 þ breast cancer suggests that the high incidence of HER2 þ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.

Residual disease after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is related with poor prognosis; however, the risk of recurrence after 3 years from surgery, becomes similar to other breast cancer subtypes indicating that TNBC is composed of tumours of different prognosis. To evaluate genes related to TNBC aggressiveness in the outcome of TNBC resistant to NAC, we profiled 82 samples of residual tumours whose expression for 449 genes was quantified with NanoString. The validation set (GSE25066) consisted of 113 TNBC cases with residual disease. The stepwise multivariate survival analysis performed by the Cox proportional hazards mode selected CCL5, DDIT4 and POLR1C as independent prognostic factors for distant recurrence-free survival (DRFS). We developed a three-genes signature using the regression coefficients for each gene (−0.393×CCL5+0.443×DDIT4+0.490×POLR1C). The median score in the discovery set (0.1494) identified two subgroups with different DRFS (P<0.001). The median score in the validation set was 0.0024 and was able to discriminate patients with different DRFS (P=0.002). In addition, the three-genes signature was a prognostic factor in TNBC patients regardless their response to NAC (data set GSE58812; P=0.001) and in patients with oestrogen-receptor-negative tumours (data set GSE16446; P=0.041). Here we describe a prognostic signature based on expression levels of CCL5, DDIT4 and POLR1C. The knowledge about the involvement of these genes in chemotherapy resistance could improve the therapeutic strategies in TNBC.