A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population.

BACKGROUND: Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC. METHODS: A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes. RESULTS: EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1-2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79-15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92-15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55-5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7-15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18-3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49-5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22-4.80) p = 0.011 respectively]. CONCLUSION: EGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy.

Modifying factors of PD-L1 expression on tumor cells in advanced non-small-cell lung cancer.

BACKGROUND: Programmed death ligand-1 (PD-L1) expression predicts immunotherapy utility in nononcogenic addictive lung adenocarcinoma (ADC). However, its reproducibility and reliability may be compromised outside clinical trials. This study aimed to evaluate factors associated with PD-L1 expression in lung ADC. METHODS: This observational study assessed 547 tumor samples with advanced lung ADC from January 2016 to December 2020 in a single cancer institution. Tumor samples were stained by at least one approved PD-L1 clone, SP263 (Ventana) or 22C3 (Dako), and stratified in tumor proportion score (TPS) <1%, 1-49%, or ≥50%. RESULTS: Of all the tumor samples, positive PD-L1 staining was higher in poorly differentiated tumors (67.3% vs. 32.7%, p < 0.001). Analytical factors associated with a PD-L1 high expression (TPS ≥ 50%) were the SP263 clone (19.6% vs. 8.2%, p < 0.001), time of archival tumor tissue <12 months (15.3% vs. 3.8%, p = 0.024), whenever the analysis was performed in the most recent years (2019-2020) (19.0% vs. 8.3%, p < 0.001), and whenever the analysis was performed by pathologists in the academic setting (Instituto Nacional de Cancerologia, INCan) (19.9% vs. 11.9%, p = 0.001). In the molecular analysis, EGFR wild-type tumors had an increased proportion of PD-L1 positive and PD-L1 high cases (60.2% vs. 47.9%, p = 0.006 and 17.4% vs.8.5%, p = 0.004). A moderate correlation (r = 0.69) in the PD-L1 TPS% was observed between the two different settings (INCan vs. external laboratories). CONCLUSION: Clinicopathological factors were associated with an increased PD-L1 positivity rate. These differences were significant in the PD-L1 high group and associated with the academic setting, the SPS263 clone, time of archival tumor tissue <12 months, and a more recent period in the PD-L1 analysis.

Prevalence and Molecular Profile of Breast Carcinoma Using Immunohistochemistry Markers in Mexican Women.

BACKGROUND: In Mexico, breast cancer is the leading cause of death by malignant tumors in women aged 20 and older. The World Health Organization estimates that 69% of deaths caused by breast cancer occur in developing countries. Little is known about the prevalence of breast carcinoma in Mexico and its molecular subclassification. METHODS: This retrospective cross-sectional study included patients who underwent a mastectomy (single, radical or lumpectomy) or a breast tumor biopsy (core-needle or excisional) from January 2002 to December 2018. The primary purpose of the study was to determine the prevalence and molecular profile of breast in comprehensive cancer center in Mexico and compare our results with those published in the US. This study was approved by our scientific and bioethical committee. RESULTS: The final analysis included 379 patients. The youngest patient was 23 years old and the oldest patient was 89; the mean age at diagnosis was 54.63 years. Patients of 40 years old or younger accounted for 48 of the cases (12.66%) and those older than 40 accounted for 331 of the cases (87.33%). The molecular subclassification showed luminal A subtype in 139 cases (36.67%), luminal B subtype in 143 cases (37.73%), human epidermal growth factor receptor 2-positive carcinomas in 32 cases (8.44%) and triple-negative carcinomas in 65 cases (17.15%). Diabetes mellitus was present in 43 patients (11.34%), hypertension in 78 patients (20.58%), obesity in 82 patients (21.63%) and 66 patients reported being treated with exogenous hormone therapy (17.41%). CONCLUSIONS: Breast carcinoma occurs at an earlier age in Mexican women compared to women in the US. Hormone-positive tumors were found to be more prevalent in older patients, while high-grade tumors were more frequently identified in younger patients.

Association of Carcinoembryonic Antigen Reduction With Progression-free and Overall Survival Improvement in Advanced Non-small-cell Lung Cancer.

BACKGROUND: Non-small cell lung cancer elevates serum carcinoembryonic antigen (CEA). CEA determinations are not recommended currently. This study aims to identify the correlation between reducing serum CEA levels with progression-free survival (PFS) and overall survival. METHODS: This study assessed at baseline and in every scheduled visit serum CEA levels throughout first-line therapy. A sensitivity and specificity analysis identified the best cut-off point and correlated it with progression-free survival and overall survival. Multivariate Cox proportional hazard models were conducted. RESULTS: We assessed 748 patients with elevated serum CEA levels at diagnosis. A ≥20% decrease from baseline was associated with a 2-fold median survival compared with patients with lower decreases (20.5 months vs 9.1 months; hazard ratio, 0.53; 95% confidence interval, 0.44 to -0.64; P < .001). CEA sensitivity and specificity to predict survival was 79.8% and 59.8%, respectively. A ≥10% decrease in CEA concentrations was associated with longer progression-free survival (7.7 months vs 5.9 months; hazard ratio, 0.71; 95% confidence interval, 0.57 to -0.88; P = .001) in those treated with chemotherapy, and in patients under tyrosine kinase inhibitors (11.9 months vs 7.3 months; hazard ratio, 0.63; 95% confidence interval, 0.47 to -0.83; P = .0001) and a ≥20% decrease. CONCLUSION: In patients with metastatic non-small cell lung cancer with an elevated baseline CEA level, the percentage decrease of CEA concentrations above the threshold during the first-line therapy was associated with more prolonged survival and progression-free intervals. Serum CEA determinations are a feasible, noninvasive option for monitoring and prognosis.

Myoepithelial Carcinoma Arising in a Plasmacytoid Myoepithelioma of the Parotid Gland Synchronized with Melanoma: A Case Report and Review of the Literature.

Myoepithelial carcinoma, also known as malignant myoepithelioma, is considered an extremely rare (0.45-1%) malignant salivary gland neoplasm. Approximately 100 cases have been reported in the English-language literature on myoepithelial carcinoma. The majority of the myoepitheliomas described in the literature have been benign, and the malignant counterpart is considered rare (<1%). Such a tumor may appear de novo or rarely develop from a preexisting pleomorphic adenoma (<20%), and in exceedingly rare cases (<0.5%), it has arisen from a benign myoepithelioma (i.e., plasmacytoid myoepithelioma). To our knowledge, no case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma has been reported to date. The treatment of myoepithelial carcinoma has been mainly surgical, including wide excision with free margins, with or without nodal dissection. The roles of chemotherapy and radiotherapy have not yet been established. We report a case of myoepithelial carcinoma of the parotid gland arising in a plasmacytoid myoepithelioma synchronized with melanoma in a 40-year-old woman. In our case, a complete response was achieved with surgery followed by adjuvant chemotherapy based on carboplatin and paclitaxel concurrent with radiotherapy.

Impact of the Type of Analgesic Therapy on Postsurgical Complications of Patients with Kidney Cancer Undergoing Nephrectomy.

BACKGROUND: The treatment of kidney cancer usually involves surgery, and in some cases systemic therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to control postsurgical pain in patients undergoing nephrectomy for renal cancer. Nevertheless, the association between these drugs and adverse postsurgical outcomes, including deterioration of renal function, is not fully established. METHODS: This retrospective cohort study included patients >18 years old with kidney cancer undergoing nephrectomy between January 2006 and January 2018. The primary endpoint was to determine the impact of postsurgical analgesic therapy (NSAIDs vs. acetaminophen) on renal function and postsurgical complications. This study was approved by our scientific and bioethical committee. RESULTS: One hundred patients were included in the final analysis. Clear-cell renal-cell carcinoma was the most frequent histologic subtype. Adequate acute pain control was accomplished in 91% of the patients during hospitalization. Twenty percent of the patients presented postsurgical complications. Bleeding-related complications were the most frequent (9%), followed by surgical-site infection (6%) and acute renal injury (6%). The administration of NSAIDs was not related to any postsurgical complication in comparison with the use of acetaminophen (21.3 vs. 17.9%, respectively). The length of hospital stay did not differ between patients treated with NSAIDs and those treated with acetaminophen (the average stay was 4 days for both groups, p = 0.32). CONCLUSION: The use of NSAIDs was not related to acute kidney injury, postsurgical complications, or prolonged hospital stay in patients with renal cancer undergoing nephrectomy.

Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer.

BACKGROUND: Previous population-based studies have demonstrated an association between metformin use and improved survival among diabetic patients with cancer. We sought to analyze the effects of diabetes and its treatment in terms of the survival of patients with lung cancer. METHODS: Overall, 1106 patients with non-small cell lung cancer (94.3 % with stage IV disease) were included. The outcomes were compared between the patients with (n = 186) and without diabetes (n = 920). The characteristics associated with antidiabetic treatment and proper glycemic control (defined as a mean plasma glucose <130 mg/dL) were examined at diagnosis. The overall survivals (OSs) of the different patient populations were analyzed using Kaplan-Meier curves, and a multivariate Cox proportional hazard model was used to determine the influences of the patient and tumor characteristics on survival. RESULTS: The OS for the entire population was 18.3 months (95 % CI 16.1-20.4). There was no difference in the OSs of the diabetic and non-diabetic patients (18.5 vs 16.4 months, p = 0.62). The diabetic patients taking metformin exhibited a superior OS than did those on other antidiabetic treatments (25.6 vs 13.2 months, p = 0.017). Those with proper glycemic control had a better OS than did those without proper glycemic control and the non-diabetics (40.5 vs 13.2 and 18.5 months, respectively, p < 0.001). Both the use of metformin (HR 0.53, p < 0.0001 and HR 0.57, p = 0.017, respectively) and proper glycemic control (HR 0.49, p < 0.0001 and HR 0.40, p = 0.002, respectively) were significant protective factors in all and only diabetic patients, respectively. CONCLUSIONS: The diabetic patients with proper glycemic control exhibited a better OS than did those without proper glycemic control and even exhibited a better OS than did the patients without diabetes mellitus. Metformin use was independently associated with a better OS.