Beatriz Wills

Low correlation between household carbon monoxide and particulate matter concentrations from biomass-related pollution in three resource-poor settings.

Household air pollution from the burning of biomass fuels is recognized as the third greatest contributor to the global burden of disease. Incomplete combustion of biomass fuels releases a complex mixture of carbon monoxide (CO), particulate matter (PM) and other toxins into the household environment. Some investigators have used indoor CO concentrations as a reliable surrogate of indoor PM concentrations; however, the assumption that indoor CO concentration is a reasonable proxy of indoor PM concentration has been a subject of controversy. We sought to describe the relationship between indoor PM2.5 and CO concentrations in 128 households across three resource-poor settings in Peru, Nepal, and Kenya. We simultaneously collected minute-to-minute PM2.5 and CO concentrations within a meter of the open-fire stove for approximately 24h using the EasyLog-USB-CO data logger (Lascar Electronics, Erie, PA) and the personal DataRAM-1000AN (Thermo Fisher Scientific Inc., Waltham, MA), respectively. We also collected information regarding household construction characteristics, and cooking practices of the primary cook. Average 24h indoor PM2.5 and CO concentrations ranged between 615 and 1440 μg/m(3), and between 9.1 and 35.1 ppm, respectively. Minute-to-minute indoor PM2.5 concentrations were in a safe range (<25 μg/m(3)) between 17% and 65% of the time, and exceeded 1000 μg/m(3) between 8% and 21% of the time, whereas indoor CO concentrations were in a safe range (<7 ppm) between 46% and 79% of the time and exceeded 50 ppm between 4%, and 20% of the time. Overall correlations between indoor PM2.5 and CO concentrations were low to moderate (Spearman ρ between 0.59 and 0.83). There was also poor agreement and evidence of proportional bias between observed indoor PM2.5 concentrations vs. those estimated based on indoor CO concentrations, with greater discordance at lower concentrations. Our analysis does not support the notion that indoor CO concentration is a surrogate marker for indoor PM2.5 concentration across all settings. Both are important markers of household air pollution with different health and environmental implications and should therefore be independently measured.

Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy.

We evaluated the association between epithelial–mesenchymal transition (EMT)‐derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 ± 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty‐six percent of the patients were positive for human papilloma virus. Median progression‐free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0–9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11–48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E‐cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E‐cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E‐cadherin: median 14 months, 95% CI: 3–24; negative EGFR + positive E‐cadherin: median 31 months, 95% CI: 14–NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro‐angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer.

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer: Outcomes according to Thymidylate Synthase Expression

Objective To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. Results One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1–32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9–10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2–32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6–12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response. Conclusion Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations

Background Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. Results BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). Methods We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. Conclusions The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.

An international epidemiological analysis of young patients with non-small cell lung cancer (AduJov-CLICaP)

BACKGROUND A proportion of patients with NSCLC is diagnosed at 40 years or younger. These patients tend to be never-smokers, usually present with stage IV adenocarcinoma, and have somatic genomic alterations. Few studies have documented and analyzed epidemiological characteristics of this population. MATERIALS AND METHODS We performed an international epidemiological analysis of 389 young patients with NSCLC. Data was collected from centers participating in the Latin American Consortium for Lung Cancer Research (AduJov-CLICaP). Patients were identified and data was retrospectively collected from different Latin American countries and Canada (Argentina=6, Canada=19, Colombia=29, Costa Rica=9, Mexico=219, Nicaragua=2, Panama=19, Perú=76 and Venezuela=10). The period of study was from 2012 to 2017. Inclusion criteria were: age 40 years or less and a histologically confirmed NSCLC. Clinical data was obtained, and EGFR mutation status and EML4-ALK translocation were collected. RESULTS NSCLC patients aged 40 years or less accounted for approximately 4% of the total NSCLC population. Female patients accounted for 54.5%, while median age was of 37 years. Adenocarcinoma accounted for 86.1% (n=335/389), 72.5% (n=282/389; unknown=5) of patients were non-smokers, and 90.3% (n=351/389) had stage IV disease. Site of metastasis was obtained from 260/351 (unknown=91) stage IV patients (lung metastasis=40.0%, CNS metastasis=35.7%, and bone metastasis=31.5%). OS for the total population was 17.3 months (95%CI=13.9-20.7). OS for EGFRm(+)=31.4months (95%CI=11.6-51.3), EGFRm(-)=14.5months (95%CI=11.0-17.9) (p=0.005). OS for alk(+)=9.8months (95%CI=3.1-16.5) and alk(-)=5.6months (95%CI=3.9-7.3) (p=0.315). CONCLUSIONS Patients aged 40 years or less account for a small but important proportion of NSCLC cases. Younger patients may have different characteristics compared to the older population. EGFRm and EML4-alk translocation frequency is higher than that of the general population.

P1.42 (also presented as PD2.04): PEM/CBP/BEV Followed by Maintenance PEM/BEV in Hispanic Patients With NSCLC: Outcomes According to TS, ERCC1 and VEGF: Track: Advanced NSCLC

The primary and secondary outcomes, Overall Survival (OS) and Progression Free Survival (PFS), respectviely, were evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratios with 95% credible intervals, in an unselected population, as well as by EGFR mutation status, histology, and response to induction. Secondary outcomes were overall survival (OS) and adverse events. Results: Twelve trials evaluating eight maintenance treatments in 3,850 patients were included in NMA. Selected maintenance treatments showed substantial PFS and OS benefits with probabilities 99% and 92% respectively of outperforming no maintenance. Results suggest the following strategy for optimal OS and PFS: (i) switch to or continue pemetrexed or switch to anti-EGFR TKI for nonsquamous patients, (ii) continue gemcitabine for squamous patients, (iii) switch to docetaxel or continue gemcitabine for responders to previous induction, and (iv) switch to or continue pemetrexed or switch to anti-EGFR TKI for patients with stable disease postinduction. Conclusion: Maintenance treatments improve PFS and OS in good performance status patients with stage IIIb/ IV NSCLC not progressing after first-line chemotherapy. Benefits are optimized by targeting specific maintenance treatments to selected patient groups guided by histology and response to previous induction.

O.01: Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP)

PRESIDENTIAL SYMPOSIUM FRIDAY, AUGUST 26 e 08:00 e 09:15 O.01 Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP) Andrés F. Cardona, Oscar Arrieta, Martín I. Zapata, Leonardo Rojas, Beatriz Wills, Hernán Carranza, Noemi Reguart, Carlos Vargas, Jorge Otero, Luis Corrales-Rodriguez, Claudio Martin, Pilar Archila, Mauricio Cuello, Carlos Ortiz, Rafael Rosell Clinical And Translational Oncology Group, Clínica del Country, Bogotá/COLOMBIA, Thoracic Oncology Unit, Instituto Nacional de Cancerología, Mexico DF/MEXICO, Internal Medicine Department, Fundación Santa Fe de Bogotá, BOGOTA/COLOMBIA, Oncology Department, Hospital Universitario San Ignacio, Bogotá/COLOMBIA, Internal Medicine Department, Johns Hopkins Hospital, Baltimore/ UNITED STATES OF AMERICA, Medical Oncology, Hospital Clinic, Barcelona/SPAIN, Medical Oncology, CIMCA / Hospital San Juan de Dios, San José/COSTA RICA, Thoracic Oncology Unit, Instituto Alexander Fleming, CIUDAD DE BUENOS AIRES/ARGENTINA, Foundation for Clinical and Applied Cancer Research, Bogota/COLOMBIA, Hospital De Clínicas, Universidad de la República (UdeLAR), Montevideo/URUGUAY, Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Barcelona/SPAIN Background: Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression. Method: 34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using Journal of Thoracic Oncology Vol. 11 No. 10S: S168-S170 SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for E-cadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M. Results: Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status 80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as firstline treatment and documented mutations were: 60% DelE19 (Del746e750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7e19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2e36.6). There were no differences in PFS according to gender (p1⁄40.10) or type of acquired alteration (p1⁄40.63). Median survival was 32.9 months (CI95% 30.4e35.3), and only the use of postprogression therapy affected OS in multivariate analysis (p1⁄40.05). Conclusion: Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians.

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP)

BackgroundNon-small cell lung cancer (NSCLC) has a 5-year survival of 5–16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role.ObjectiveCompare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp.Patients and MethodsSeventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status.Results30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3–34.6) vs. (11.0, 95% CI 8.2–16.7); p = 0.002] and OS [(37.8, 95% CI 30.9–44.7) vs. (27.1, 95% CI 12.8–41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0–44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4–42.5) (p < 0.001) and longer PFS (p = 0.043).ConclusionAmong Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.

EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP)

OBJECTIVES Contrasting other EGFR mutations (EGFRm) in lung adenocarcinomas, insertions in exon 20 (exon20ins) are generally associated with resistance to targeted therapy, limiting therapeutic options and impoverishing the prognosis compared to other EGFRm. We sought to extensively characterize exon20ins from a large cohort of lung adenocarcinomas in Hispanic patients. MATERIALS AND METHODS This was a region-wide, observational longitudinal cohort study to evaluate characteristics and outcomes of patients with exon20ins in lung adenocarcinoma, based on a secondary analysis of electronic records from the Geno1.2-CLICaP Platform and extended genotype testing. Patients from six Latin-American countries were included (Argentina, Colombia, Costa Rica, Ecuador, Panama, and Mexico). Data obtained included the molecular spectrum (extended genotyping for mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1, as well as for EGFR amplification, ALK and PD-L1 protein expression), clinic-pathologic characteristics, prevalence and outcomes to therapeutic approach. RESULTS AND CONCLUSIONS 4.005 patients diagnosed with stage III/IV lung adenocarcinoma from 2011 to 2016 were initially screened. Among these, 88 patients had a confirmed exon20 in. and were included; median age was 66-years, 62.5% were females, 64% were never smokers and 39% presented with brain metastases. The H773insH variant was the most frequent, making up 21.6% of cases. A common EGFRm was concomitantly found in 36.4% (del19/L858R), and 8% (G719X/L861Q/S768I) of cases. Five cases had additional mutations in PI3K, KRAS and MEK1, 26% had EGFR amplification and 81.7% had PD-L1 expression 1-50%. Overall response rate to first-line therapy was 28% and overall survival was 16.4 months. Prognosis was positively influenced by the concomitant presence of common EGFRm and response to first-line. Our results suggest that patients with EGFR exon20ins have similar clinical characteristics to those with common EGFRm but a poorer prognosis. Last, the mean PD-L1 expression in this population seems higher than for patients with common EGFRm.

Treatment of Complications from Immune Checkpoint Inhibition in Patients with Lung Cancer

Opinion statementImmune checkpoint inhibitors have revolutionized the management of advanced NSCLC. With the intention of generating an anti-tumor immune response, ICIs can also lead to inflammatory side effects involving a wide variety of organs in the body, termed immune-related adverse events. Although no prospective clinical trial exists to guide recommendations for optimal and more specific immunosuppressive treatments rather than corticosteroids, further studies may lead to a more mechanistic-based approach towards these toxicities in the future. In relation to current practice, we recommend adherence to the recent published guidelines which emphasize the importance of early recognition and administration of temporary immunosuppressive therapy with corticosteroids in most cases, depending on the organ system involved, and the severity of toxicity. Recognition of these toxicities is increasingly important as the use of these agents expand within different indications for patients with lung cancers, and to other tumor types.