Promoter hypermethylation of RARB and GSTP1 genes in plasma cell-free DNA as breast cancer biomarkers in Peruvian women.

BACKGROUND: Promoter hypermethylation is one of the enabling mechanisms of hallmarks of cancer. Tumor suppressor genes like RARB and GSTP1 have been reported as hypermethylated in breast cancer tumors compared with normal tissues in several populations. This case-control study aimed to determine the association between the promoter methylation ratio (PMR) of RARB and GSTP1 genes (separately and as a group) with breast cancer and its clinical-pathological variables in Peruvian patients, using a liquid biopsy approach. METHODS: A total of 58 breast cancer patients and 58 healthy controls, matched by age, participated in the study. We exacted cell-free DNA (cfDNA) from blood plasma and converted it by bisulfite salts. Methylight PCR was performed to obtain the PMR value of the studied genes. We determined the association between PMR and breast cancer, in addition to other clinicopathological variables. The sensitivity and specificity of the PMR of these genes were obtained. RESULTS: A significant association was not found between breast cancer and the RARB PMR (OR = 1.90; 95% CI [0.62-6.18]; p = 0.210) or the GSTP1 PMR (OR = 6.57; 95% CI [0.75-307.66]; p = 0.114). The combination of the RARB + GSTP1 PMR was associated with breast cancer (OR = 2.81; 95% CI [1.02-8.22]; p = 0.026), controls under 50 years old (p = 0.048), patients older than 50 (p = 0.007), and postmenopausal (p = 0.034). The PMR of both genes showed a specificity of 86.21% and a sensitivity of 31.03%. CONCLUSION: Promoter hypermethylation of RARB + GSTP1 genes is associated with breast cancer, older age, and postmenopausal Peruvian patients. The methylated promoter of the RARB + GSTP1 genes needs further validation to be used as a biomarker for liquid biopsy and as a recommendation criterion for additional tests in asymptomatic women younger than 50 years.

A nationwide pilot study on breast cancer screening in Peru.

Introduction: A high prevalence of advanced breast cancer (BC) is a common scenario in Latin America. In Peru, the frequency of BC at Stages III/IV is ≈50% despite implementation of a programme for breast cancer screening (BCS) along the country. We carried out a study to assess the feasibility and develop an instrument to evaluate the knowledge, barriers and perception about BCS in a nationwide pilot study in Peru among candidates for BCS. Methods: We conducted a systematic review of 2,558 reports indexed in PubMed, Scopus, Web of Science, Medline-Ovid and EMBASE, regarding to our study theme. In total, 111 were selected and a 51-items survey was developed (eight items about sociodemographic characteristics). Patients were recruited in public hospitals or private clinics, in rural and urban areas of nine departments of Peru. Results: We surveyed 488 women from: Lima (150), Cajamarca (93), Ica (59), Arequipa (56), Loreto (48), Ancash (38), Junín (15), Puerto Maldonado (15) and Huancavelica (14); 27.9% of them were from rural areas. The mean of age was 53.3 years (standard deviation ± 9.1). Regarding education level, 29.8% had primary, 33.2% secondary and 37.0% higher education. In total, 28.7% of women did not know the term 'mammogram' and 47.1% reported never receiving a BCS (36.9% from urban and 73.5% from rural population). In women that underwent BCS, only 67% knew it is for healthy women. In total, 54.1% of patients had low levels of knowledge about risk factors for BC (i.e. 87.5% of women respond that injuries in the breast produce cancer). Cultural, economic and geographic barriers were significantly associated with having a mammogram where 56.9% of participants considered a cost ≤ 7 USD as appropriate. Mammogram was perceived as too painful for 54.9% of women. In addition, women with a self-perception of low-risk for BC and a fatalistic perception of cancer were less likely to have a BCS. Conclusion: We found that it is feasible to conduct a large-scale study in Peru. The results of this pilot study highlight an urgent need of extensive education and awareness about BCS in Peru.

Characteristics of gastric cancer around the world.

Gastric cancer is one of the most important malignancies in the world due to the high burden of disease and lethality. In this work, we compared the main characteristics of gastric cancer between different regions of the world. We reviewed public repositories to retrieve epidemiological, molecular, clinicopathological, and risk factor data. Eastern Asia presents the highest incidence of gastric cancer, followed by eastern and central Europe. Intestinal histology was more frequent in Caucasians, while gastric tumors located in the cardias were less frequent in Africa and Latin America. TP53, LRP1B, and ARID1A are consistently the most frequently altered genes in all population groups. Gastric cancer is most frequent in men. African patients tend to be younger and have a higher proportion of women patients. Different patterns can be observed in the presentation of gastric cancer between different regions of the world. More research is needed in Latin America and Africa since these populations are underrepresented.

Chip-based digital Polymerase Chain Reaction as quantitative technique for the detection of PIK3CA mutations in breast cancer patients.

Background: PIK3CA is a gene frequently mutated in breast cancer. With the FDA approval of alpelisib, the evaluation of PIK3CA for activating mutations is becoming routinely. Novel platforms for gene analysis as digital PCR (dPCR) are emerging as a potential replacement for the traditional Sanger sequencing. However, there are still few studies on chip-based dPCR to detect mutations in tumor samples. Thus, this cross-sectional study aimed to assess the sensibility of a chip-based dPCR to detect and quantify PIK3CA mutations and compare its performance with Sanger sequencing. Materials and Methods: Tumor samples from 57 breast cancer patients (22 pre-treatment samples, 32 tumors after neoadjuvant chemotherapy, and three lymph nodes) were collected and analyzed by Sanger sequencing and dPCR for the three PIK3CA most relevant mutations (p.E545K, p. H1047R, and p. H1047L). Digital PCR sensitivity, specificity, and overall performance were estimated by contingency tables, receptor operator characteristic (ROC), and area under the curve (AUC). Association of PIK3CA mutations with clinicopathological variables was conducted. Results: Sanger sequencing identified PIK3CA mutations in six patients (10.5%), two with p. H1047R, and four with p. E545K. Digital PCR confirmed those mutations and identified 19 additional patients with at least one mutation. Comparison between dPCR and Sanger sequencing showed a sensitivity of 100% (95% CI 53-100%), and a specificity of 84.2% (95% CI 83-84.2%). Besides, p. H1047R mutation detected by dPCR showed a significant association with breast cancer phenotype (p = 0.019) and lymphatic nodes infiltration (p = 0.046). Conclusions: Digital PCR showed a high sensitivity to detect mutations in tumor samples and it might be capable to detect low-rate mutations and tumor subpopulations not detected by Sanger sequencing.

Prognostic Capability of TNBC 3-Gene Score among Triple-Negative Breast Cancer Subtypes.

Background: Triple-negative breast cancer (TNBC) is a complex and molecularly heterogeneous entity, with the poorest outcome compared with other breast cancer subtypes. Previously, we developed a TNBC 3-gene score with a significant prognostic capability. This study aims to test the 3-gene score in the different TNBC subtypes. Methods: Data from 204 TNBC patients treated with neoadjuvant chemotherapy were retrieved from public datasets and pooled (GSE25066, GSE58812, and GSE16446). After removing batch effects, cases were classified into Lehman's TNBC subtypes and then the TNBC 3-gene score was used to evaluate the risk of distant recurrence in each subgroup. In addition, the association with tumor-infiltrating lymphocyte (TILs) levels was evaluated in a retrospective group of 72 TNBC cases. Results: The TNBC 3-gene score was able to discriminate patients with different risks within the pooled cohort (HR = 2.41 for high vs. low risk; 95%CI: 1.50−3.86). The score showed predictive capability in the immunomodulatory subtype (HR = 4.16; 95%CI: 1.63−10.60) and in the mesenchymal stem-like subtype (HR = 18.76; 95%CI: 1.68−208.97). In the basal-like 1, basal-like-2, and mesenchymal subtypes, the observed differential risk patterns showed no statistical significance. The score had poor predictive capability in the luminal androgen receptor subtype (p = 0.765). In addition, a low TNBC 3-gene score was related to a high level of TIL infiltration (p < 0.001). Conclusions: The TNBC 3-gene score is able to predict the risk of distant recurrence in TNBC patients, specifically in the immunomodulatory and mesenchymal stem-like subtype. Despite a small sample size in each subgroup, an improved prognostic capability was seen in TNBC subtypes with tumor-infiltrating components.

Adjuvant chemotherapy after curative D2 gastrectomy in Latin American patients with gastric cancer.

Background: Gastric cancer (GC) is the fourth most common cause of cancer deaths around the world and the first cause of cancer deaths in Peru; however, there are no prospective trials for adjuvant chemotherapy in GC after curative gastrectomy in this country. The objective of this study was to evaluate the effectiveness of adjuvant chemotherapy in stage II-III gastric cancer patients who underwent D2 gastrectomy. Methods: We included patients with stage II-III gastric cancer who underwent radical gastrectomy and D2 dissection between 2014 and 2016 at our institution. Patients received 3-week cycles of capecitabine (1,000 mg/m2 twice daily on days 1-14) plus oxaliplatin (130 mg/m2 on day 1) for 6 months. Survival curves were estimated with the Kaplan-Meier method, and the Cox proportional hazards model was used to identify prognostic factors for survival. Results: In total, 173 patients were included: 100 (57.8%) patients received adjuvant chemotherapy and surgery (AChS) and 73 (42.2%) surgery alone (SA). Three-year disease-free survival (DFS) was higher in the AChS groups (69%) than in the SA group (52.6%) (p = 0.034). Regarding overall survival (OS), 31 patients (31%) died in the AChS group compared with 34 (46.6%) in the SA group (p = 0.027). In the multivariate analysis, adjuvant chemotherapy was an independent prognostic factor for DFS (HR = 0.60; 95% CI = 0.37-0.97; p = 0.036) and OS (HR = 0.58; 95% CI = 0.36-0.95; p = 0.029). ACh showed consistent benefit in DFS and OS for patients with albumin >3.5 g/dL, lymphovascular and perineural invasion, pT4, pN2-3, pathologic stage (PS) IIIA and IIIB and lymph node ratio (LNR) > 13.1. Conclusion: These data suggest that adjuvant capecitabine and oxaliplatin reduce the recurrence and mortality in patients with stage II-III gastric cancer who underwent D2 gastrectomy. PS IIIA and IIIB and LNR > 13.1 benefited more from receiving adjuvant chemotherapy and poorly cohesive gastric carcinoma did not significantly reduce the rates of survival.

Oncological Care During First Peruvian National Emergency COVID-19 Pandemic: A Multicentric Descriptive Study.

Purpose: The aim of this study is to evaluate the oncological care during the first state of national emergency due to the COVID-19 pandemic in several public cancer hospitals in Peru. Materials and Methods: A multicentric cross-sectional descriptive study was conducted by interviewing adult cancer patients diagnosed and treated between January 2019 and February 2020 from 18 hospitals. This study was carried out in September 2020, the last month of the first state of national emergency. Demographic and clinical characteristics were evaluated, including COVID-19 status and cancer treatment features. Results: A total of 1472 patients were included; the median age was 55 years (range 19-97). Most patients (85.8%, n = 1263) had solid neoplasia, 13.5% (n = 198) hematologic neoplasia, and 0.7% (n = 11) others. SARS-CoV-2 infection was confirmed in 8.6% (n = 126), 1.2% (n = 18) were probable, 1.6% (n = 24) suspected, and 88.6% (n = 1304) negative cases. Overall, 51.6% of patients (n = 759) had cancer treatment delays, 42.5% (n = 626) changed treatment delivery (endovenous to oral systemic therapy), and 12.6% (n = 185) of cases cancer therapy was discontinued. In total, 10.3% (n = 117) of patients whose disease was controlled or in remission, experienced progression of disease during the state of emergency. A total of 6.7% (n = 98) of patients died, of whom 73.5% (n = 72) died from disease progression; 18.4% (n = 18) from SARS-CoV-2 infection and 8.1% (n = 8) from undetermined causes. Patients with hematological malignancies [hazard ratio (HR): 5.11 (95% confidence interval (CI): 1.99-13.07)] and no response to therapy before the onset of the pandemic [5.01 (1.44-17.42)] had an increased risk of death among COVID-19 infected individuals, whereas advanced clinical stage [5.09 (2.37-10.95)] and discontinuation of treatment [3.66 (1.97-6.78)] were risk factors among non-COVID-19 patients. Conclusion: Our study suggests that the COVID-19 pandemic has an adverse impact on the outcomes of Peruvian cancer patients. In our cohort, cancer mortality was higher than COVID-19 disease mortality.

Sex, immunity, and cancer.

The composition of the tumor microenvironment is the complex result of the interaction between tumoral and host factors. Since there are several differences in the regulation of gene circuits between sexes, mainly influenced by sex hormones, the tumor-host interaction presents some differences, leading tumors to evolve under different conditions. Nowadays, it is well known the existence of sexual dimorphism in the regulation of the immune system, where women present an improved immunity to various infectious agents and, on the other hand, a higher incidence of autoimmune diseases than men. In oncology, differences in cancer susceptibility, response to treatment, and clinical outcomes between men and women patients are well known. Recently, sex-specific differences have also been reported in mutations in driver genes and the prognostic value of several biomarkers. Sex has been a widely forgotten biomarker in cancer therapy, but it has recently acquired great relevance due to the different results seen in immunotherapy treatment.

Influence of Sex in the Molecular Characteristics and Outcomes of Malignant Tumors.

BACKGROUND: Sex is frequently underestimated as a prognostic biomarker in cancer. In this study, we evaluated a large cohort of patients and public datasets to determine the influence of sex on clinical outcomes, mutational status, and activation of immune pathways in different types of cancer. METHODS: A cohort of 13,619 Oncosalud-affiliated patients bearing sex-unrelated cancers was followed over a 20-year period. Hazard ratios (HRs) for death were estimated for female vs. male patients for each cancer type and then pooled in a meta-analysis to obtain an overall HR. In addition, the mutational status of the main actionable genes in melanoma (MEL), colorectal cancer (CRC), and lung cancer was compared between sexes. Finally, a gene set enrichment analysis (GSEA) of publicly available data was conducted, to assess differences in immune processes between sexes in MEL, gastric adenocarcinoma (GC), head and neck cancer (HNC), colon cancer (CC), liver cancer (LC), pancreatic cancer (PC), thyroid cancer (TC), and clear renal cell carcinoma (CCRCC). RESULTS: Overall, women had a decreased risk of death (HR = 0.73, CI95: 8%-42%), with improved overall survival (OS) in HNC, leukemia, lung cancer, lymphoma, MEL, multiple myeloma (MM), and non-melanoma skin cancer. Regarding the analysis of actionable mutations, only differences in EGFR alterations were observed (27.7% for men vs. 34.4% for women, p = 0.035). The number of differentially activated immune processes was higher in women with HNC, LC, CC, GC, MEL, PC, and TC and included cellular processes, responses to different stimuli, immune system development, immune response activation, multiorganism processes, and localization of immune cells. Only in CCRCC was a higher activation of immune pathways observed in men. CONCLUSIONS: The study shows an improved survival rate, increased activation of immune system pathways, and an enrichment of EGFR alterations in female patients of our cohort. Enhancement of the immune response in female cancer patients is a phenomenon that should be further explored to improve the efficacy of immunotherapy.

PIK3CA mutation in non-metastatic triple-negative breast cancer as a potential biomarker of early relapse: A case report.

BACKGROUND: Currently, the detection of PIK3CA mutations is of special interest in personalized medicine because it is frequently found in triple-negative breast cancer (TNBC). The PI3KCA mutation is an independent negative prognostic factor for survival in metastatic breast cancer, and its prognostic value in liquid biopsy as a biomarker of treatment and early relapse is under investigation, both for metastatic disease and neoadjuvant scenario with curative intent. CASE SUMMARY: A 54-year-old female patient with TNBC clinical stage IIIA, who, after receiving neoadjuvant chemotherapy (based on anthracyclines and taxanes), surgery, radiotherapy, and adjuvant capecitabine, was detected with a PI3KCA mutation in tissue and peripheral blood (ctDNA in liquid biopsy). After 10 mo, the patient had disease relapse of left cervical node disease. CONCLUSION: The detection of PIK3CA mutation in TNBC after neoadjuvant treatment might be associated with early relapse or rapid disease progression.

Profile of entrectinib in the treatment of ROS1-positive non-small cell lung cancer: Evidence to date.

ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood-brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.

Impact of the Delayed Initiation of Adjuvant Chemotherapy in the Outcome of Triple Negative Breast Cancer.

BACKGROUND: Adjuvant chemotherapy decreases the recurrence risk and improves survival rates; however, it is unclear whether a delayed initiation is associated with adverse outcomes, especially in triple negative breast cancer (TNBC). In this study, we evaluated the influence of the time to start adjuvant chemotherapy (TTC) in the outcomes of TNBC. PATIENTS AND METHODS: We retrospectively analyzed 15 years of data from patients with TNBC who received adjuvant chemotherapy at the Instituto Nacional de Enfermedades Neoplasicas (Lima, Peru). TTC was categorized into 4 groups: ≤ 30, 31 to 60, 61 to 90, and ≥ 91 days. We evaluated overall survival (OS) and distant recurrence-free survival (DRFS). Cox proportional hazard models were used to identify prognostic factors. RESULTS: In total, 687 patients were included. The mean age at diagnosis was 49.1 years (SD, 11.8 years), and most (62.6%) patients had pathologic stage T2. The median TTC was 48.1 days (SD, 27.4 days); 189 (27.5%) received chemotherapy ≤ 30 days; 329 (47.9%), between 31 and 60 days; 115 (16.7%), between 61 and 90 days; and 54 (7.9%) in ≥ 90 days. In the multivariate analysis, a TTC between 31 and 60 days (hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.17-2.72), 61 and 90 days (HR, 2.38; 95%CI, 1.43-3.97), and ≥ 91 days (HR, 2.45; 95% CI, 1.32-4.55) was associated with an increased mortality in contrast with a TTC < 30 days. Although a TTC between 31 and 60 days, 61 and 90 days, and ≥ 91 days was associated with an increased risk of DRFS (HR, 1.86; 95% CI, 1.24-2.79; HR, 2.34, 95% CI, 1.42-3.867; and HR, 3.16; 95% CI, 1.78-5.61, respectively). CONCLUSION: A delaying in TTC ≥ 30 days was associated with poorer outcomes. Our data suggest that several efforts should be conducted to avoid a delayed TTC in patients with TNBC.

Lymph node ratio as best prognostic factor in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy.

Although lymph node status (ypN) is one of the most important prognostic factors of survival, the lymph node ratio (LNR) has emerged as an equitable factor. We aimed to compare the prognostic value of both ypN and LNR in patients with residual triple-negative breast cancer (TNBC) after neo-adjuvant chemotherapy (NAC). This was a retrospective cohort study of patients treated in a tertiary care center during the period 2000-2014. We stratified the population based on LNR (≤0.20, 0.20-0.65, and >0.65) and ypN (N1, N2, and N3) status. The overall survival (OS) and progression-free survival (PFS) were estimated with Kaplan-Meier curves and the log-rank + test. We further compared patient mortality and disease recurrence using multivariate Cox regression analysis. We evaluated 169 patients with a median follow-up of 87 months. At 2 years of follow-up, patients with low-risk LNR compared to those with moderate and high risk had a higher PFS (54% vs 31% vs 18%, respectively; P < .001) and OS (74% vs 64% vs 45%, respectively; P < .001). Moreover, ypN1 patients compared to ypN2 and ypN3 showed similar results in PFS (53% vs 35% vs 19%, respectively; P = .001) and OS (73% vs 69% vs 43%, respectively; P < .001). Compared to the low-risk population, patients with moderate (hazard ratio [HR]: 3.50; 95% confidence interval [CI]: 1.41-8.71) and high risk (HR: 6.90; 95% CI: 2.29-20.77) had a worse PFS. Regarding OS, moderate-risk (HR: 2.85; 95% CI: 1.10-7.38) and high-risk patients (HR: 6.48; 95% CI: 2.13-19.76) showed considerably worse outcomes. On the other hand, ypN staging was not associated with PFS or OS in the multivariate analysis. The LNR is a better prognostic factor of survival than ypN. The LNR should be considered in the stratification of risk after NAC in patients with TNBC.

ALK rearrangements: Biology, detection and opportunities of therapy in non-small cell lung cancer.

The ALK receptor tyrosine kinase (ALK) gene encodes a transmembrane protein rearranged in 2-7% of non-small cell lung cancer (NSCLC) cases. This gene has become the second most studied therapeutic target after EGFR due to the implied therapeutic opportunities. While the diagnostic of ALK rearrangements is well established, small molecules targeting ALK are in constant evolution because tumor cells eventually will develop mechanisms of resistance. In this review we describe the biology of the ALK gene, alterations, epidemiology, diagnostic tests as well as strategies of treatment.

Precision medicine for locally advanced breast cancer: frontiers and challenges in Latin America.

Advances in high-throughput technologies and their involvement in the 'omics' of cancer have made possible the identification of hundreds of biomarkers and the development of predictive and prognostic platforms that model the management of cancer from evidence-based medicine to precision medicine. Latin America (LATAM) is a region characterised by fragmented healthcare, high rates of poverty and disparities to access to a basic standard of care not only for cancer but also for other complex diseases. Patients from the public setting cannot afford targeted therapy, the facilities offering genomic platforms are scarce and the use of high-precision radiotherapy is limited to few facilities. Despite the fact that LATAM oncologists are well-trained in the use of genomic platforms and constantly participate in genomic projects, a medical practice based in precision oncology is a great challenge and frequently limited to private practice. In breast cancer, we are waiting for the results of large basket trials to incorporate the detection of actionable mutations to select targeted treatments, in a similar way to the management of lung cancer. On the other hand and paradoxically, in the 'one fit is not for all' era, clinical and genomic studies continue grouping our patients under the single label 'Latin American' or 'Hispanic' despite the different ancestries and genomic backgrounds seen in the region. More regional cancer genomic initiatives and public availability of this data are needed in order to develop more precise oncology in locally advanced breast cancer.

Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy?

BACKGROUND: There 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. METHODS: We 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). RESULTS: Female 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). CONCLUSIONS: In 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.

Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer.

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.

Mutational analysis of BRCA1 and BRCA2 genes in Peruvian families with hereditary breast and ovarian cancer.

BACKGROUND: Breast cancer is one of the most prevalent malignancies in the world. In Peru, breast cancer is the second cause of death among women. Five to ten percent of patients present a high genetic predisposition due to BRCA1 and BRCA2 germline mutations. METHODS: We performed a comprehensive analysis of BRCA1 and BRCA2 genes by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect large rearrangements in patients from 18 families, which met the criteria for hereditary breast cancer. RESULTS: In this series, we found four pathogenic mutations, three previously reported (BRCA1: c.302-1G>C and c.815_824dup10; BRCA2: c.5946delT) and a duplication of adenines in exon 15 in BRCA1 gene (c.4647_4648dupAA, ClinVar SCV000256598.1). We also found two exonic and four intronic variants of unknown significance and 28 polymorphic variants. CONCLUSION: This is the first report to determine the spectrum of mutations in the BRCA1/BRCA2 genes in Peruvian families selected by clinical and genetic criteria. The alteration rate in BRCA1/BRCA2 with proven pathogenic mutation was 22.2% (4 out 18) and this finding could be influenced by the reduced sample size or clinical criteria. In addition, we found three known BRCA1/BRCA2 mutations and a BRCA1 c.4647_4648dupAA as a novel pathogenic mutation.

In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies.

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.

Repeated observation of immune gene sets enrichment in women with non-small cell lung cancer.

There are different biological and clinical patterns of lung cancer between genders indicating intrinsic differences leading to increased sensitivity to cigarette smoke-induced DNA damage, mutational patterns of KRAS and better clinical outcomes in women while differences between genders at gene-expression levels was not previously reported. Here we show an enrichment of immune genes in NSCLC in women compared to men. We found in a GSEA analysis (by biological processes annotated from Gene Ontology) of six public datasets a repeated observation of immune gene sets enrichment in women. "Immune system process", "immune response", "defense response", "cellular defense response" and "regulation of immune system process" were the gene sets most over-represented while APOBEC3G, APOBEC3F, LAT, CD1D and CCL5 represented the top-five core genes. Characterization of immune cell composition with the platform CIBERSORT showed no differences between genders; however, there were differences when tumor tissues were compared to normal tissues. Our results suggest different immune responses in NSCLC between genders that could be related with the different clinical outcome.