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L. Rojas



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    MA 01 - SCLC: Research Perspectives (ID 650)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA 01.02 - Multigene Mutation Profiling and Clinical Characteristics of Small-Cell Lung Cancer in Never-Smokers Versus Heavy Smokers (ID 10335)

      11:00 - 12:30  |  Author(s): L. Rojas

      • Abstract
      • Presentation
      • Slides

      Background:
      Small-cell lung cancer (SCLC) has been occasionally detected in never-smokers as smoking rates decrease worldwide. We investigated the clinical and genetic characteristics of SCLC in never-smokers (Geno1.3-CLICaP)

      Method:
      A cohort of patients diagnosed with SCLC were grouped into smokers (n=10) and ever/never-smokers (n=10). For both groups, somatic mutation profiling was carried out using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes. Epidermal growth factor receptor (EGFR) mutation was confirmed by RT-PCR (Cobas[TM]). The clinical outcomes of the two groups were compared using Kaplan-Meier and Cox proportional models.

      Result:
      Median age was 58 years (r, 46-81), 55% (n = 11) were men, most patients had extended disease (85%) and the dominant tumor involvement site was pleura and lungs (65%). No significant differences were found in age, disease distribution, baseline performance status and cerebral metastases in relation to tobacco exposure. The ORR to first-line therapy were 50% and 90% between smokers and ever/never-smokers, respectively (p=0.032). The median overall survival (OS) was 29.1 months in ever/never-smokers (95%CI 23.5-34.6) versus 17.3 months in smokers (95%CI 4.8-29.7; p=0.0054). Never-smoking history (HR 0.543, 95%CI 0.41-0.80), limited stage disease (HR 0.56, 95%CI 0.40-0.91) and response to first line platinum based chemotherapy (HR 0.63, 95%CI 0.60-0.92) were independently related with good prognosis. Among ever/never smokers main genetic mutations were TP53 (80%), RB1 (40%), CYLD (30%), EGFR (30%), MET (20%), SMAD4 (20%) and BRIP1 (20%). None of the smokers had mutations in EGFR, MET or SMAD4, but there was a greater involvement in RB1 (80%, p=0.04), CDKN2A (30%, p=0.05), CEBPA (30%, p=0.05), FANCG (20%), GATA2 (20%), and PTEN (20%).

      Conclusion:
      Never-smokers with SCLC are increasingly prevalent and have a better prognosis than their smoker counterpart. EGFR, MET and SMAD4 are frequent mutations among SCLCs of ever/never smokers, and RB1, CDKN2A and CEBPA among smokers. Figure 1



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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P1.01-019 - ALK+ Non-Small Cell Lung Cancer Treated with First Line Crizotinib: Patient Characteristics, Treatment Patterns, and Survival (ID 10137)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      This study describes the characteristics, treatment sequencing, and outcomes among locally advanced/metastatic crizotinib-treated ALK+ Non-small cell lung cancer (NSCLC) Hispanic patients.

      Method:
      From June 2014 to June 2017, a retrospective patient review was conducted among several centers from México (n=10), Costa Rica (n=4), Panamá (n=13), Colombia (n=16), Venezuela (n=10), and Argentina (n=20). Participating clinicians identified their ALK+ NSCLC patients who received crizotinib and reported their clinical characteristics, treatments, and survival using a pre-defined case report form. Kaplan-Meier analyses were used to describe overall survival (OS) and progression-free survival (PFS).

      Result:
      73 ALK+ NSCLC patients treated with crizotinib as a first line were included. Median age at diagnosis was 62 years (range, 34-77), 60.3% were female and histological distribution was adenocarcinoma in 93.2%, squamous cell carcinomas in 2.7%, NOS in 2.7% and adenosquamous in 1.4%. Sixty-five patients (89%) were never or former smokers, 52 (71.1%) had ≥2 sites of metastasis and 15 (20.5%) had brain metastasis at diagnosis. Median PFS to treatment with first line crizotinib was 12.3 months (95%CI 9.4-15.3) and overall response rate (ORR) was 52% (CR 6.8% and PR 45.2%). Of those who discontinued crizotinib, 26.1% had brain progression, 35.6% switched to chemotherapy, 14% switched to a different ALK inhibitor and 59% received no further therapy. After starting crizotinib, median OS was 32.5 months (95%CI 25.6-39.4), 42.6 months (95%CI 31.8-53.5) for those who received ceritinib or/and alectinib, and 23.8 months (95%CI 19.0-28.6) among those treated with second line platinum based chemotherapy (p=0.003).

      Conclusion:
      The ORR and PFS observed in Hispanic patients with ALK+ NSCLC treated with first-line crizotinib was similar to that previously described. Limited access to new-generation ALK inhibitors affects OS. Those patients exposed to ceritinib or alectinib demonstrated a significant improvement in OS versus those treated with second-line platinum-based chemotherapy.

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      P1.01-022 - Prediction of Central Nervous System Progression During Crizotinib Treatment in ALK+ NSCLC Among Hispanics (ID 10479)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      Crizotinib has offered patients with non-small cell lung cancer (NSCLC) positive to ALK rearrangements a powerful therapeutical option. Despite the benefit of crizotinib, most patients develop resistance and progression with special emphasis on the central nervous system. Early identification of patients that will present brain metastases could potentially lead to additional interventions preventing relapse. The objective of this study was to identify patients who would present with future CNS relapse after initiation of crizotinib.

      Method:
      A random forest tree model was constructed. Data from Hispanic patients with NSCLC harboring ALK rearrangements treated with crizotinib were collected from the CLICaP database. Clinical variables including age at diagnosis, sex, smoking status, number of metastasis and location and objective response were included. Based on these parameters, progression to central nervous system was predicted.

      Result:
      66 patients were included in the analysis. Median age for the cohort was 55 years old (r, 33-85), 33 (59%) were women, 38 (58%) were never smokers and 29 (44%) presented disease progression during crizotinib treatment while 17 had central nervous system involvement. Median overall survival (OS) was 13.9 months (95%CI 11.6-19.3) in contrast to 8.3 months (95%CI 4.47-13.13) in terms of progression free survival (PFS) after crizotinib initiation. The best predictors for central nervous system progression were age, sex, number of metastasis, objective response to crizotinib and previous CNS involvement. With an AUC of 0.99, a sensitivity of 100% and a specificity of 88%, the model reached an overall accuracy of 97%.

      Conclusion:
      Central nervous system progression after crizotinib treatment can be accurately predicted. Validation for this model in larger cohorts is warranted.

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-055 - Genotyping Squamous Cell Lung Carcinoma Among Hispanics (Geno1.1-CLICaP) (ID 10166)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer subgroup, largely because of a lack understanding of the molecular pathogenesis of the disease. To characterize SCC genomic profile among Hispanics we tested diverse alterations using a validated next generation sequencing (NGS) platform.

      Method:
      We performed sequencing using a comprehensive NGS assay (TruSight Tumor 170) targeting the full coding regions of 170 cancer-related genes on 26 squamous cell lung cancer samples from Hispanic patients. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako) and main clinical outcomes like progression free survival (PFS), overall response rate (ORR), and overall survival (OS) were recorded.

      Result:
      Median age was 67 years (range, 33-83), 53.8% were men and all patients had previous exposure to tobacco (former 69.2%/current 30.8%) with a mean consumption rate of 34-year package. Almost all patients (80.8%) received cisplatin or carboplatin plus gemcitabine as first line with an ORR of 61.5%, a median PFS of 12.0 months (95% CI 10.9-13.2) and OS of 24.8 months (95% CI 20.8-28.7). We found a relatively high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (30.8%) and NOTCH1 (26.9%). In addition, genetic alterations in the NF1 (19.2%), RB1 (15.4%), STK11 (15.4%), SOX2 (11.5%), PTEN (7.7%), KRAS (3.8%) and HRAS (3.8%). Distribution of PD-L1 expression were: negative, 1%, 2-49% and ≥50% in 23.1%, 38.5%, 26.9% and 11.5%, respectively. None of the genetic alterations affected PFS, OS or ORR and PDL1 expression was lower among those who had mutations in TP53 (p=0.037) and PIK3CA (p=0.05).

      Conclusion:
      We identified previously described mutations among Hispanic patients with SCC. Lower PDL1 expression was also found among those who had alterations in TP53 and PIK3CA.Figure 1



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    P1.09 - Mesothelioma (ID 695)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P1.09-013 - Profiling Response to Chemotherapy in Malignant Pleural Mesothelioma Among Hispanics (MeSO-CLICaP) (ID 10430)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.

      Method:
      A series of 53 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested for BAP1 and PI3K mutations and for mRNA expression of TS and EGFR. Immunohistochemistry staining for CD26 (dipeptidyl-peptidase IV, DPP-IV) and Fibulin3 (Fib3) proteins were also performed. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded and evaluated according to biomarkers. Cox model was applied to determine variables associated with survival.

      Result:
      Median age was 58 years (range 36-76), 27 (51%) were men, 89% were current or former smokers, and six patients had previous contact with asbestos. 77% had a baseline ECOG 0-1 and almost all patients (n=52/98%) received cisplatin or carboplatin plus pemetrexed (Pem) as first line; 58% of them were treated with Pem as maintenance for a mean of 4.7 +/-2.8 cycles. 53.5% and 41.5% of patients were positive for CD26 and fibulin-3, while 49% and 43.4% had low levels of EGFR and TS mRNA, respectively. The majority of epithelioid and biphasic types expressed CD26 (p=0.008), Fibulin3 (0.013) and had lower levels of TS mRNA (p=0.008). Mutations in PI3K (c.1173A> G, c.32G> C and c.32G> T) were found in 5 patients and only one patient had a mutation in BAP1 (c.241T> G). First line PFS were significantly longer in CD26+ (p=0.0001), in those with low EGFR mRNA expression (p=0.001), in patients with positive Fib3 (p=0.006) and lower TS mRNA expression (p=0.0001). OS were significantly higher in patients with CD26+ (p=0.0001), EGFR- (p=0.001), Fib3 + (p=0.0002) and low TS mRNA expression level (p=0.0001). Multivariate analysis found that CD26+ (p=0.012), Fib3 (p=0.020) and TS mRNA levels (p=0.05) were independent prognostic factors.

      Conclusion:
      CD26, Fib3 and TS were prognostic factors significantly associated with improved survival in patients with advanced MPM.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.02-063 - EGFR Exon 20 Insertions in Lung Adenocarcinomas: Molecular and Clinicopathologic Characteristics Among Hispanics (Geno1.2-CLICaP) (ID 10406)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      In contrast to other primary EGFR mutations in lung adenocarcinomas, insertions in exon 20 of EGFR have been generally associated with resistance to EGFR tyrosine kinase inhibitors. Their molecular spectrum, clinicopathologic characteristics and prevalence are not well established among Hispanics.

      Method:
      Tumors harboring EGFR exon 20 insertions were identified through a comprehensive screening of 4.500 lung adenocarcinomas from diverse Latin American Countries. Cases were tested for common and uncommon EGFR mutations and KRAS. Almost all cases (n=52) underwent extended genotyping for other driver mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1 by NGS (TruSight tumor[TM]), EGFR amplification, ALK and PDL1 protein expression (D5F3CDx Assay and 22C3 Clone). Clinical outcomes were evaluated using Kaplan-Meier and Cox proportional models.

      Result:
      60 patients were included; median age was 66-yo (r, 24-79), 63.3% were females, most patients had a micropapillary (38.3%) or lepidic (20.0%) adenocarcinomas, 61.7% were never smokers and 36.7% had brain metastasis at diagnosis. 14 patients (23.4%) had common EGFR mutations (del19/L858R) in addition to the exon 20 insertion, 5 (10.0%) had non-common EGFR mutations (G719X /L861Q/S768I) plus the exon 20 insertion, and two cases had additional mutations in PIK3CA and MEK1. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 21.7% of cases. 30% of patients had amplification of the EGFR and 75% had a PDL1 expression level of less than 50%. Overall response rate (ORR) to the first line was 30%, progression free survival (PFS) was 8.3 months (95%CI 6.9-9.6) and OS was 17.4 months (95%CI 16.4-19.5). Prognosis was positively influenced by concomitant presence of common EGFR mutations (p=0.016) and by response to first line therapy (p=0.06).

      Conclusion:
      Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The mean PDL1 expression in this population appears to be higher than in patients with common EGFR mutations, finding that promote the potential use of immunotherapy alone or in combination for this population.

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    P3.08 - Locally Advanced Nsclc (ID 724)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Locally Advanced NSCLC
    • Presentations: 1
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      P3.08-005 - Hereditary Familial Overlap Syndrome with Multiple Synchronous Lung Tumors (ID 10257)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      Here we report the case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDHI) who develop synchronous multiple primary lung adenocarcinomas related to Intra-alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma.

      Method:
      Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcina, one lepidic spread tumor and in STAS area). In the same way, the broad genomic analysis was performed in archival tissue from the previous bone tumor.

      Result:
      Lung tumors were found to harbor PI3KCA (invasive lesions) and a rare in-frame insertion of 6 amino acids in exon 19 of EGFR (lepidic tumor), STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations.

      Conclusion:
      This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline p53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity. Figure 1



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    P3.09 - Mesothelioma (ID 725)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Mesothelioma
    • Presentations: 1
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      P3.09-010b - Predicting Response to First Line Chemotherapy in Pleural Mesothelioma: A Random Forest Tree Model (Meso-CLICaP) (ID 10389)

      09:30 - 16:00  |  Author(s): L. Rojas

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy. Multidisciplinary treatment including surgery, radiation therapy and adjuvant chemotherapy has been established as the cornerstone of management prolonging progression free survival (PFS). Although beneficial, this treatment strategy has morbidity and mortality. Therefore, selection of patients who benefit from this treatment strategy is crucial for maximizing clinical benefit.

      Method:
      A random forest tree model was build for the prediction of response to first line chemotherapy among Hispanic patients with MPM. Variables evaluated included sex, age, ECOG performance status, smoking history, exposure to asbestos and histology. Based on these characteristics, patients were classified by responders (partial or complete response) and non-responders (stable disease or disease progression). In order to validate the results, a random subset of 70% of the sample was used to construct the model and the remaining 30% was utilized as an independent validation cohort. Predictions were compared to each patient’s treatment response and operational characteristics for the validation cohort model and receiver operational curves were computed.

      Result:
      A total of 153 patients were included. Median age was 59 years old (r, 33-84), 60 (39%) were females, 127 (83%) had an ECOG performance score of 0-1 and 127 (83%) had an epithelioid histological subtype. In terms of expositional hazards, 107 (70%) were smokers (24% current/46% former), whereas 61 (40%) presented active exposure to asbestos. In terms of survival, median overall survival (OS) was 25 months (95%CI 23.4-29.4) and median PFS after first line chemotherapy was 6.97 months (95%CI 5.83-8.57). An objective response was observed in 74 patients (48%; complete response in 7/5%). In terms of operational characteristics, the validated model obtained a 0.992 AUC, a sensitivity of 100% and a specificity of 95% for detecting responders and non-responders to first line chemotherapy.

      Conclusion:
      Selection of responders to first line treatment based on clinical variables can accurately be achieved. These results could lead to better selection of Hispanic patients for aggressive and morbid treatments.

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