Clinical Benefits of Olaparib in Mexican Ovarian Cancer Patients With Founder Mutation BRCA1-Del ex9-12.

Background: Ovarian cancer (OC) is gynecologic cancer with the highest mortality rate. It is estimated that 13-17% of ovarian cancers are due to heritable mutations in BRCA1 and BRCA2. The BRCA1 (BRCA1-Del ex9-12) Mexican founder mutation is responsible for 28-35% of the cases with ovarian cancer. The aim was to describe the PFS of OC patients treated with olaparib, emphasizing patients carrying the Mexican founder mutation (BRCA1-Del ex9-12). Methods: In this observational study, of 107 patients with BRCAm, 35 patients were treated with olaparib from November 2016 to May 2021 at the Ovarian Cancer Program (COE) of Mexico; patient information was extracted from electronic medical records. Results: Of 311 patients, 107 (34.4%) were with BRCAm; 71.9% (77/107) were with BRCA1, of which 27.3% (21/77) were with BRCA1-Del ex9-12, and 28.1% (30/107) were with BRCA2 mutations. Only 35 patients received olaparib treatment, and the median follow-up was 12.87 months. The PFS of BRCA1-Del ex9-12 was NR (non-reach); however, 73% of the patients received the treatment at 36 vs. 11.59 months (95% CI; 10.43-12.75) in patients with other BRCAm (p = 0.008). Almost 50% of patients required dose reduction due to toxicity; the most frequent adverse events were hematological in 76.5% and gastrointestinal in 4%. Conclusion: Mexican OC BRCA1-Del ex9-12 patients treated with olaparib had a significant increase in PFS regardless of the line of treatment compared to other mutations in BRCA.

Impact of metabolic syndrome on the risk of endometrial cancer and the role of lifestyle in prevention.

Endometrial cancer is the second gynecological cancer with the highest global incidence. Among many associated risk factors, metabolic syndrome is an important and preventable one. It comprises a group of conditions that often occur together: central adiposity, hyperglycemia, arterial hypertension, and atherogenic dyslipidemia. This review aimed to describe the epidemiological and biological relationship between metabolic syndrome and endometrial cancer, focusing on the role of lifestyle in prevention. A literature search was carried out in the PubMed database. 4824 publications were screened, and 123 were included for this review. The association between metabolic syndrome and endometrial cancer has been described. Chronic adipose tissue inflammation and insulin resistance are involved in the development of obesity, particularly visceral adiposity. These changes promote the ideal environment for the development of endometrial cancer. Strategies based on lifestyle modifications may be effective for the prevention of metabolic syndrome and consequently endometrial cancer. Some of these modifications include adopting a diet rich in fruits, vegetables, whole grains, and legumes, depending to the accessibility of these foods for each region. Avoiding ultra-processed foods and increasing daily physical activity were also some suggested modifications. We propose that women be screened for metabolic syndrome to establish early treatment and to possibly prevent endometrial cancer. Clinical trials designed to prove the effect of lifestyle modifications on the prevention of endometrial cancer are needed.

Impact of detecting plasma EGFR mutations with ultrasensitive liquid biopsy in outcomes of NSCLC patients treated with first- or second-generation EGFR-TKIs.

BACKGROUND: Few trials have evaluated the utility of liquid biopsies to detect epidermal growth factor receptor mutations (EGFRm) at the time of response evaluation and its association with the clinical characteristics and outcomes of non-small-cell lung cancer (NSCLC) patients. OBJECTIVE: This study aimed to evaluate, in a real-world clinical setting, the prevalence of plasma EGFRm and its association with the clinical characteristics, response and survival outcomes of NSCLC patients under treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). METHODS: This observational study enrolled advanced or metastatic NSCLC patients, with confirmed tumor EGFRm, receiving treatment with first- or second-generation EGFR-TKIs. Blood samples for the detection of plasma EGFRm were collected at the time of response evaluation and processed using the Target Selector™ assay. The main outcomes were the detection rate of plasma EGFRm, median Progression-Free Survival (PFS) and Overall Survival (OS) according to plasma EGFR mutational status. RESULTS: Of 84 patients, 50 (59.5%) had an EGFRm detected in plasma. After a median follow-up of 21.1 months, 63 patients (75%) had disease progression. The detection rate of plasma EGFRm was significantly higher in patients with disease progression than in patients with partial response or stable disease (68.3% versus 33.3%; P< 0.01). PFS and OS were significantly longer in patients without plasma EGFRm than among patients with plasma EGFRm (14.3 months [95% CI, 9.25-19.39] vs 11.0 months [95% CI, 8.61-13.46]; P= 0.034) and (67.8 months [95% CI, 39.80-95.94] vs 32.0 months [95% CI, 17.12-46.93]; P= 0.006), respectively. A positive finding in LB was associated with the presence of ⩾ 3 more metastatic sites (P= 0.028), elevated serum carcinoembryonic (CEA) at disease progression (P= 0.015), and an increase in CEA with respect to baseline levels (P= 0.038). CONCLUSIONS: In NSCLC patients receiving EGFR-TKIs, the detection of plasma EGFRm at the time of tumor response evaluation is associated with poor clinical outcomes.

Validation of the QLQ-EN24 instrument for the assessment of health-related quality of life for women with endometrial cancer in México.

PURPOSE: The impact of disease activity or treatments on health-related quality of life (HRQL) is crucial in Oncology, but adequate instruments for this assessment are scarce. Our aim is to validate the Mexican-Spanish version of the QLQ-EN24 questionnaire to evaluate HRQL in women with endometrial cancer (EC). METHODS: This is a prospective study of Mexican women with EC, attending a single cancer centre, who responded the QLQ-C30 and QLQ-EN24 instruments; usual psychometric analysis were performed as well as the association of HRQL scales and relevant clinical data. Correlation analysis was performed with the Spearman's method, reliability analysis with the Cronbach's alpha, known-group comparisons with the Kruskal-Wallis test, and survival analysis with the Kaplan-Meier method and Log-rank test. RESULTS: One hundred and eighty-nine women with EC were assessed. Most functional scales reported high values, and most symptom scales, low. Questionnaire compliance rates were high and internal consistency tests demonstrated adequate convergent and divergent validity. Cronbach's α coefficients of the five multi-item scales the QLQ-EN24 instruments were from 0.659 to 0.887. Scales of the QLQ-C30 and QLQ-EN24 instruments distinguished among clinically distinct groups of patients, particularly based on serum albumin levels. The Urological symptoms, Gastrointestinal symptoms, Body image, Pelvic pain and Taste change scales were significantly associated with OS. CONCLUSION: The Mexican-Spanish version of the QLQ-EN24 questionnaire is reliable and valid for the assessment of HRQL in patients with EC and can be broadly used in multi-national clinical trials. However, conclusions derived from scales evaluating sexual function should be handled carefully.

Clinical Evaluation of BRCA1/2 Mutation in Mexican Ovarian Cancer Patients.

Ovarian cancer (OC) is an important cause of gynecologic cancer-related deaths. In Mexico, around 4700 new cases of OC are diagnosed per year and it represents the second cause of gynecological cancer mortality with more than 2700 deaths. Germline mutations in BRCA1/2 genes are present in 13-18% of OC cases. Few studies have evaluated the presence of mutations in BRCA genes in a population of OC Mexican patients and their relationship with clinical response and survival rates. A total of 179 OC patients were studied by molecular testing for BRCA1/2 through next-generation sequencing and multiplex ligation-dependent probe amplification. Recurrence-free survival (RFS) was estimated by the Kaplan-Meier method. BRCA mutation was detected in 33% of patients. A percentage of 66.1% were BRCA1 mutated and 33.9% were BRCA2 mutated. BRCA1 mutation carriers had a worst RFS compared with BRCA2 mutation carriers (37.6 [29-46.2] vs 72.7 [38.4-107.2]; P = 0.030). The most common mutation for BRCA1 was ex9-12del (28.2%) (Mexican founder mutation). The Mexican founder mutation had a better RFS than other BRCA1 mutations (86.1 [37.2-135.1] vs 34.5 [20.7-48.2]; P = 0.033). The presence of BRCA2 mutations in the ovarian cancer cluster region (OCCR) had a significantly better RFS than mutations in breast cancer cluster regions (BCCR) and not-related risk region (NRR) (NR vs 72.8 [39-106.6] vs 25.8 [8.3-43.2]; P = 0.013). These results demonstrate that the prevalence of BRCA1/2 positive patients in OC Mexican patients are the highest reported. Patients with mutations in BRCA2 have a better prognosis than those mutated in BRCA1. The Mexican founder mutation has an important role in clinical outcomes. These results highlight the importance to test all the HGSP (high-grade serous papillary) OC patients with or without cancer family history (CFH) in Mexican population.

Experiencia con el uso de olaparib en pacientes con cáncer de ovario.

INTRODUCTION: More than the twenty percent of ovarian cancers are hereditary, and most have BRCA mutations. The 30% of Mexican patients with the BRCA1 mutation have the BRCA1 gene exon 9-12del deletion founder mutation (BRCA1 ex9-12del). BRCA-mutated tumors are more sensitive to PARP inhibitors such as olaparib. OBJECTIVE: To show the clinical experience on the use of olaparib at Instituto Nacional de Cancerología in Mexico. METHOD: Ovarian cancer patients treated with olaparib from November 2016 to December 2018 were studied, and their characteristics, clinical response, progression-free survival (PFS) and toxicities were described. RESULTS: Nineteen patients were assessed, with BRCA1 mutation being found in 78.9%, out of which 21.1% were carriers of the ex9-12del founder mutation. The median of PFS was 12 months; for patients treated on second and third line it was > 15 months, and for those treated with a fourth and subsequent line it was 8.3 months. Patients with the founder mutation had better results. Toxicities were like those reported in previous studies. CONCLUSIONS: Olaparib offers greater PFS benefit as maintenance therapy after a first and second relapse. Patients with founder mutation have had sustained PFS.

INTRODUCCIÓN: Más del 20 % de los cánceres de ovario puede ser hereditario y la mayoría tiene mutaciones BRCA. El 33 % de las pacientes mexicanas con mutación BRCA1 tiene la mutación fundadora deleción del exón 9-12del del gen BRCA1 (BRCA1 ex9-12del). Los tumores BRCA mutados son más sensibles a inhibidores PARP como olaparib. OBJETIVO: Mostrar la experiencia clínica del uso de olaparib en el Instituto Nacional de Cancerología de México. MÉTODO: Se estudiaron las pacientes con cáncer de ovario tratadas con olaparib de noviembre de 2016 a diciembre de 2018 y se describieron sus características, respuesta clínica, supervivencia libre de progresión y toxicidades. RESULTADOS: Se evaluaron 19 pacientes, 78.9 % presentó mutación BRCA1, del cual 21.1 % era portador de la mutación fundadora ex9-12del. La mediana de supervivencia libre de progresión global fue de 12 meses, para las pacientes tratadas tratadas con olaparib de mantenimiento posterior a segunda y tercera línea fue de > 15 meses y para las de cuarta línea o más fue de 8.3 meses. Las pacientes con mutación fundadora presentaron mejores respuestas. Las toxicidades fueron similares a las de estudios con el uso de olaparib. CONCLUSIONES: Olaparib ofrece mayor beneficio en supervivencia libre de progresión como tratamiento de mantenimiento después de la primera y segunda recaída. Las pacientes con mutación fundadora han tenido respuesta sostenida.

Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer.

Polymorphonuclear-MDSC (PMN-MDSC) have emerged as an independent prognostic factor for survival in NSCLC. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone. We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3+, CD3+CD4+ and CD3+CD8+), neutrophils (CD66b+) and polymorphonuclear-MDSC (PMN-MDSC; CD66b+CD11b+CD15+CD14-) as well as the concentration of 14 plasma cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-α, IFN-γ) in 90 treatment-naïve NSCLC patients and 25 healthy donors (HD). In contrast to HD, NSCLC patients had a higher percentage of PMN-MDSC and neutrophils (P < 0.0001) but a lower percentage of CD3+, CD3+CD4+ and CD3+CD8+ cells. PMN-MDSC% negatively correlated with the levels of IL1-ß, IL-2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSC. Patients with low PMN-MDSC (≤ 8%) had a better OS (22.1 months [95% CI 4.3-739.7]) than patients with high PMN-MDSC (9.3 months [95% CI 0-18.8]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. In sum, our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1ß, IL-27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses.

Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients.

Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co-inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD-1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and response to therapy. In this prospective observational study, plasma cytokine levels and PD-1, PD-L1 and PD-L2 expression was evaluated in circulating CD3+, CD3+CD4+ and CD3+CD8+ cells from 70 treatment-naïve patients with advanced NSCLC (Stage IIIB and IV) and from 10 healthy donors. The primary objective was to assess OS according to PD-1, PD-L1, PD-L2 expression status on PBMCs and lymphocyte subsets. Our results indicate that the percentage of PD-L1+CD3+, PD-L1+CD3+CD8+ PD-L2+PBMCs, PD-L2+CD3+, PD-L2+CD3+CD4+ cells was higher in patients than in healthy donors. Survival was decreased among patients with a high percentage of either PD-1+PBMCs, PD-1+CD3+, PD-L1+CD3+, PD-L1+CD3+CD8+, PD-L2+CD3+, PD-L2+CD3+CD4+, or PD-L2+CD3+CD8+ cells. IL-2 and TNF-α showed the strongest association with PD-L1 and PD-L2 expression on specific subsets of T-lymphocytes. Our findings suggest that increased PD-1/PD-L1/PDL-2 expression in PBMCs, particularly in T-cells, may be an additional mechanism leading to tumor escape from immune control. This study is registered with ClinicalTrials.gov, number NCT02758314.

CD47 overexpression is associated with decreased neutrophil apoptosis/phagocytosis and poor prognosis in non-small-cell lung cancer patients.

BACKGROUND: Non-small-cell lung cancer (NSCLC) patients often exhibit neutrophilia, which has been associated with poor clinical outcomes. However, the mechanisms that lead to neutrophilia have not been fully established. CD47 is an antiphagocytic molecule that promotes neutrophil recruitment. METHODS: Blood was collected from 50 treatment-naive patients with advanced NSCLC and from 25 healthy subjects. The frequency of CD66b+ cells and the expression of CD47 were determined by flow cytometry. Neutrophil apoptosis was determined by 7-amino-actinomycin D/Annexin V-APC staining. Phagocytosis was assessed by flow cytometry. Reactive oxygen species production after phorbol 12-myristate 13-acetate treatment was quantified by 2',7'-dichlorofluorescein fluorescence. Pro-inflammatory plasma cytokines were quantified using a cytometric bead array assay. RESULTS: The percentage of circulating neutrophils was significantly higher in patients than in controls (P<0.001). Patient-derived neutrophils had a higher oxidative potential than those of controls (P=0.0286). The number of neutrophils in late apoptosis/necrosis was lower in patients than in controls (P=0.0317). Caspase 3/7 activation was also lower in patients than in controls (P=0.0079). CD47 expression in whole-blood samples and in the neutrophil fraction was higher in NSCLC patients than in controls (P=0.0408 and P<0.001). Patient-derived neutrophils were phagocytosed at a lower rate than those of controls (P=0.0445). CD47 expression in neutrophils negatively correlated with their ingestion by macrophages (P=0.0039). High CD47 expression was associated with a lower overall survival. CONCLUSIONS: Increased CD47 expression on the surface of neutrophils was associated with a delay in neutrophil apoptosis and with an impairment in their phagocytic clearance by macrophages, suggesting that CD47 overexpression may be one of the underlying mechanisms leading to neutrophilia in NSCLC patients.