Landscape of germline BRCA1/BRCA2 variants in breast and ovarian cancer in Peru.

Background: There is an increasing amount of data from Latin America on the characterization of BRCA variants; however, there is limited information from Peru. We conducted a retrospective study to describe germline pathogenic/likely pathogenic(P/LP) variants and variants of uncertain/unknown significance (VUS) in the BRCA1 and BRCA2 genes in Peru, in patients with breast and ovarian cancer, candidates for treatment with poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Methods: The patients were evaluated during the period 2019-2021. Genomic DNA was isolated from peripheral blood samples and targeted sequencing was performed using the Ampliseq BRCA panel. Genetic variant interpretation was carried out in accordance with the recommendations of the American College of Medical Genetics and ClinVar. During this period, 525 patients (143 with breast cancer and 382 with ovarian cancer) were studied. Results: We found that 14.7% (21/143) of breast cancer patients and 20.7% (79/382) of ovarian cancer patients were carriers of P/LP variants in BRCA1/2. The most frequent pathogenic variants detected in BRCA1 were c.2105dupT (BIC: 2224insT, n=12, 18.75%), c.68_69delAG (BIC: 185delAG, n=6, 9.38%), c.140G>T and c.815_824dupAGCCATGTGG (n=5, 7.81%), while in BRCA2 were c.8023A>G (n=6, 16.67%), c.6024dupG (BIC: 6252insG, n=4, 11.11%), and c.9235delG (BIC: 9463delG, n=3, 8.33%). Regarding VUS, we found that 6.99% (10/143) of breast cancer patients and 7.33% (28/382) of ovarian cancer patients were carriers of a VUS in BRCA1/2. For BRCA1, the most frequent VUS was c.93C>G (n=2), and for BRCA2, c.5465A>T (n=4), c.3101T>C (n=3), c.205C>A and c.437T>C (n=2). Conclusion: We found a frequency of 14.7% germline mutations in breast cancer patients and 20.7% in ovarian cancer patients. The most recurrent mutations were BRCA1 c.2105dupT and BRCA2 c.8023A>G. We found that BRCA2 c.8023A>G, c.6024dupG, and c.9235delG were not previously reported in Peruvian patients. BRCA1 c.2344dupA is a novel mutation that has not been previously reported in any database. The frequency of VUS in our cohort was 7.2%.

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.

Distribution of tumor-infiltrating immune cells in glioblastoma.

AIM: Evaluation of features related to infiltrating immune cell level in glioblastoma. METHODS: Tumor-infiltrating lymphocytes (TILs) through H&E staining, and TILs (CD3, CD4, CD8 and CD20) and macrophage (CD68 and CD163) levels through immunohistochemistry were evaluated through digital analysis. RESULTS: CD68 (9.1%), CD163 (2.2%), CD3 (1.6%) and CD8 (1.6%) had the highest density. Higher CD4+ was associated with unmethylated MGMT (p = 0.016). Higher CD8+ was associated with larger tumoral size (p = 0.027). Higher CD163+ was associated with higher age (p = 0.044) and recursive partitioning analysis = 4. Women (p < 0.05), total resection (p < 0.05), MGMT-methylation (p < 0.001), radiotherapy (p < 0.001), chemotherapy (p < 0.001) and lower CD4+ (p < 0.05) were associated with longer overall survival. CONCLUSION: Macrophages are more frequent than TILs. Some subsets are associated with clinical features.

MGMT promoter methylation in Peruvian patients with glioblastoma.

PURPOSE: O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation predicts the outcome and response to alkylating chemotherapy in glioblastoma. The aim of this study is to evaluate the prevalence of MGMT methylation in Peruvian glioblastoma cases. PATIENTS AND METHODS: We evaluated retrospectively 50 cases of resected glioblastoma during the period 2008-2013 at Instituto Nacional de Enfermedades Neoplasicas in Peru. Samples consisted of paraffin embedded and frozen tumour tissue. MGMT-promoter methylation status and the expression level of MGMT gene were evaluated by methylation-specific PCR and real-time PCR, respectively. RESULTS: Unmethylated, methylated and partially methylated statuses were found in 54%, 20% and 26% of paraffin-embedded samples, respectively. Methylation status was confirmed in the Virgen de la Salud Hospital and frozen samples. There was an association between the status of MGMT-promoter methylation and the level of gene expression (p = 0.001). Methylation was associated with increased progression-free survival (p = 0.002) and overall survival (OS) (p < 0.001). CONCLUSION: MGMT-promoter methylation frequency in Peruvian glioblastoma is similar to that reported in other populations and the detection test has been standardised.

Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy.

AIM: To determine influence of neoadjuvant-chemotherapy (NAC) over tumor-infiltrating-lymphocytes (TIL) in triple-negative-breast-cancer (TNBC). METHODS: TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays (TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS: Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response (pCR) (P = 0.0251) and outcome (P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections (ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. Post-NAC lesions with pCR had similar TIL levels than those without pCR (P = 0.6331). NAC produced a TIL decrease in full-face sections (P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival (DFS). Higher counts of CD3 in pre-NAC samples had longer overall-survival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR. CONCLUSION: TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.

[Glioblastoma: Molecular analysis and its clinical implications]. / Glioblastoma: Análisis molecular y sus implicancias clínicas.

Glioblastoma (GB) is the most common and most lethal primary brain tumor. Epidemiologic information indicate that its incidence is lower in Hispanic race. Surgery is the only curative strategy and has recently introduced new strategies that increase resection rates. The use of concurrent chemotherapy with radiotherapy improves survival of patients but is associated with toxicity. Improved understanding of molecular biology of GB allows the identification of predictive biomarkers of response and prognosis as well as therapeutic targets for the development of new therapeutic strategies. Among biomarkers are currently available 1p /19q codeletion, IDH mutation and O6-methylguanine DNAmethyltransferase promoter methylation. The identification therapeutic targets enables the development of new drugs and their evaluation in clinical trials, but none has been prospectively validated in phase III clinical trials.

Glioblastoma: análisis molecular y sus implicancias clínicas / Glioblastoma: molecular analysis and its clinical implications

El glioblastoma multiforme (GB) es el tumor cerebral primario del sistema nervioso central (SNC) más frecuente y más letal en la edad adulta. La evidencia epidemiológica indica que su incidencia es menor en la raza hispana. El tratamiento quirúrgico es la opción terapéutica preferente. Recientemente se han introducido nuevas estrategias que incrementan el volumen de resección. El uso de quimioterapia y radioterapia concurrentes mejora la supervivencia de los pacientes, aunque se asocia a toxicidad. La mejora en la comprensión de la biología molecular del GB ha permitido la identificación de biomarcadores predictivos de respuesta terapéutica y pronóstico, así como la identificación de dianas terapéuticas que han permitido el desarrollo de nuevas estrategias en el tratamiento de estos tumores. Entre los biomarcadores actualmente disponibles se encuentran la codelección 1p/19q, la mutación de IDH y la metilación del promotor O6- metilguanina DNA-metiltransferasa. La identificación de dianas terapéuticas permite el desarrollo de nuevas drogas y su evaluación posterior en ensayos clínicos, aunque ninguna de ellas ha sido validada prospectivamente en ensayos clínicos de fase III.

Glioblastoma (GB) is the most common and most lethal primary brain tumor. Epidemiologic information indicate that its incidence is lower in Hispanic race. Surgery is the only curative strategy and has recently introduced new strategies that increase resection rates. The use of concurrent chemotherapy with radiotherapy improves survival of patients but is associated with toxicity. Improved understanding of molecular biology of GB allows the identification of predictive biomarkers of response and prognosis as well as therapeutic targets for the development of new therapeutic strategies. Among biomarkers are currently available 1p /19q codeletion, IDH mutation and O6-methylguanine DNAmethyltransferase promoter methylation. The identification therapeutic targets enables the development of new drugs and their evaluation in clinical trials, but none has been prospectively validated in phase III clinical trials.

Prognostic factors for patients with newly diagnosed brain metastasis from breast cancer.

AIM: This retrospective study determined features associated with brain metastasis (BM) in women with breast cancer. PATIENTS & METHODS: A total of 215 initially early breast cancer cases were included. We reviewed files and CT scan images of BM. RESULTS: Median age was 47 years and most of our cases were stage III (58.6%), grade III (62.8%), ER negative (62.3%) and nonluminal (59.1%). Median survival after BM was 4 months. Nonluminal, extracranial disease, time to CNS shorter than 15 months, >three brain lesions and poor breast-graded prognostic assessment and recursive partitioning analysis scores were associated with shorter survival. Adding extracranial disease to breast-graded prognostic assessment score also predicted survival after BM. Radiation response was assessed in 57 patients and response tended to be associated with nonluminal phenotype but not with survival. CONCLUSION: Factors associated with both initial tumor and clinical features at BM time are associated with shorter survival in our Latinas population.

Using living cells to transport therapeutic genes for cancer treatment.

One of the key problems in cancer gene therapy is the inefficient delivery of therapeutic transgenes to tumour sites, after the systemic injection of the viral vector. Hence, new vector discovery is extremely important for the improvement of gene therapy results. Previously, mammalian cells were proposed as new vector systems; however with recent advances in stem cell research this modality makes them more suitable candidates. Tumours are composed of both malignant and benign cells. As "benign" cell types are able to form blood vessels, and stroma, it has been hypothesised that exogenously administrated cells of a different kind would preferentially engraft at the stromal tumour site and could deliver cancer gene therapy vectors to tumours.

Uveal vs. cutaneous melanoma. Origins and causes of the differences.

Melanoma is a malignant tumour derived from melanocytes (dendritic cells originated from the neural crest and capable to produce melanin synthesis) that could be established on the skin or less frequently on the uvea. The cellular origin from both kind of melanoma seems to be the same but the melanocytes migrates to the epithelia for cutaneous melanoma, while for uveal melanoma, they migrate to mesodermic tissues. Despite the common origin, both melanomas show extreme differences in their metastatic potential, clinical response to treatments, immune response and genetic alterations. We will describe some of those differences in this review.