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L. Corrales-Rodriguez



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    P1.01 - Poster Session 1 - Cancer Biology (ID 143)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.01-005 - EGFR and KRAS mutations in patients having lung adenocarcinoma associated with human papilloma virus infection (ID 2626)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      Many studies have reported the presence of human papilloma virus (HPV) primary oncoproteins in lung cancer patients. Their detection depends on histological and geographical patterns and seems to be associated with the response obtained to EGFR inhibitors.

      Methods
      Information regarding 84 patients suffering lung adenocarcinomas and EGFR mutations and another 48 patients lacking them (including 7 KRAS carriers) was explored for the presence of HPV16 in paraffin-embedded tumour tissue using INNO-LiPA PCR-based assays. The results were correlated with clinical characteristics and multiple outcomes, including response rate, progression-free survival (PFS) and overall survival (OS).

      Results
      Mean age was 59.9 years (+/- 12.2) and HPV16 infection positivity was 39% (N=52). HPV was predominant in females (N=42; p=0.032), no differences being found regarding histological pattern (p=0.72) or having a background of smoking (p=0.54). 62% of the patients had EGFR exon 19 deletions and 22.6% the L858R mutation. Changes in exon 19 were positively related to the presence of HPV16 (p=0.043), differently to the exon 21 mutation (p=0.3). Overall response rate to tyrosine -kinase inhibitors in EGFR mutation carriers’ was 65%, stable disease was 31% and clinical benefit 86.5%. Positive differences were found for response according to HPV virus status (p=0.03). PFS rate was greater in patients who were EGFR+/HPV+ compared to the EGFR+/HPV- population (p=0.014). Likewise, OS was longer for the EGFR+/HPV+ population compared to the EGFR+/HPV- population (34 months versus 24 months; p=0.0001). OS was also longer for HPV+ patients in the absence of EGFR mutations (p=0.001). The presence of HPV also discriminated OS in the small cohort of KRAS+ patients.

      Conclusion
      The present study has documented a high HPV positivity rate in Hispanic patients suffering lung adenocarcinoma. The presence of viral DNA can thus be presumed to be a positive prognostic factor for EGFR and KRAS mutated patients, thereby leading to considering infection as a dominant part of carcinogenesis amongst non-smokers in Latin America.

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-019 - Common and uncommon EGFR mutations and their impact on response to EGFR tyrosine-kinase inhibitors and platinum-based chemotherapy in non-small cell lung cancer (NSCLC): Latin-American Consortium for the Investigation of Lung Cancer (CLICaP) (ID 1728)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      An association has been well-established between common EGFR mutations and response to reversible and irreversible direct EGFR tyrosine-kinase inhibitors (EGFR-TKIs); however, there is a significant lack of information about the impact of uncommon mutations on outcomes such as overall response (OR), progression-free survival (PFS) and overall survival (OS) rates after being exposed to EGFR-TKIs or platinum-based chemotherapy (CT).

      Methods
      Information regarding 186 NSCLC patients from three Latin-American countries was analysed. Tests were made for EGFR and KRAS mutations; the clinical and pathological characteristics and the presence of common and uncommon EGFR mutations were considered according to OR, PFS and OS rates concerning EGFR-TKIs and CT.

      Results
      79.5% of the patients had common EGFR mutations and 20.5% uncommon mutations, including complex alterations. Lepidic and acinar histological subtypes were associated with higher common EGFR mutation frequency (p= 0.010). Patients having an OR to EGFR-TKIs treatment also had an OR to CT (p< 0.001). Patients harbouring common EGFR mutations had greater sensitivity to EGFR-TKIs than those having uncommon mutations (63.8% [IC 95% 51.1-76.5] vs 32.4% [20.0-44.7] p< 0.0001). Median PFS regarding EGFR-TKIs (16.4 [12-21.1] vs 4.1 months [1.9-5.9]) and CT (16 [10.9-21] vs 4.3 months [0.9-12.9]) was better in patients having common EGFR mutations compared to patients carrying uncommon mutations. The median OS of patients treated with EGFR-TKIs that harbored common EGFR mutations (37.3 months [33.2-41]) was longer compared to those patients who harbored uncommon mutations (17.4 months [12.9-21.8]).

      Conclusion
      Our findings suggest that patients with EGFR uncommon mutations, could receive platinum-based chemotherapy as first line of treatment and EGFR-TKIs can be reserved as second or third line treatment options.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-021 - Retrospective analysis of the prevalence of NSCLC driver mutations in unselected samples. (ID 3365)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      Much of the recent improvement in lung cancer outcomes owes to the advent of the Lung Cancer Mutation Consortium. We aimed to assess thequality of the pathologic specimens and to study the prevalence of each of the most clinically relevant driver mutations in a non-referred population with non-squamous, non-small cell lung cancer (NS-NSCLC) treated in a tertiary center in the province of Quebec characterized by a high prevalence of smokers (25% of adult population).

      Methods
      Consecutive patients with pathologically proven NS-NSCLC diagnosed or treated in our institution between January 2006 and June 2009 inclusively were accrued. Patients whose diagnosis is based uniquely on a positive cytology or whose diagnostic material was not available were excluded. Specimens were tested for ALK translocations (by IHC and FISH), for EGFR mutations in exons 19 and 21 by PCR (fragment analysis and qPCR) and for mutations in KRAS codons 12 and 13 by PCR-RFLP. ALK-FISH and ALK-IHC results were analyzed in a blinded manner.

      Results
      A total of 1017 consecutive patients were screened. We excluded 209 patients who had only cytologic material, 55 patients who had no residual material and 197 patients who had insufficient tissue. Analysis was possible on 556 patients. The median age of the analyzed population was 64 years and male gender frequency was 45.5%. Compared to our entire cohort, metastatic cases were significantly under-represented in the analyzed population 27.3% vs. 79.1% for local disease (p<0.0001). The distribution according to stage and year of diagnosis along with that related to overall eligible population as well as the percentage of each of the 3 driver mutations status in the specimens analyzed so far are shown in the table below:

      Local disease analyzable / overall Loco-regional analyzable / overall Metastatic analyzable / overall Total analyzable / overall
      2006 - 2007 188/227 (82.8%) 66/147 (44.9 %) 55/207 (26.6 %) 311/583 (53.3 %)
      2008 - Mid 2009 161/214 (75.2%) 50/96 (52.1 %) 36/126 (28.6 %) 247/436 (56.7 %)
      Total 349/441 (79.1%) 116/243 (47.7%) 91/333 (27.3 %) 556/1017 (54.7 %)
      Mutation results: Local disease positive/total analyzed Loco-regional positive/total analyzed Metastatic positive/total analyzed Total positive/total analyzed
      KRAS codon 12 76/216 (35.2%) 20/55 (36.4%) 17/54 (31.5%) 113/325 (34.8%)
      KRAS codon 13 7/216 (3.2%) 2/55 (3.6%) 2/54 (3.7%) 11/325 (3.1%)
      KRAS mutated 83/216 (38.4%) 22/55 (40%) 19/54 (35.2%) 124/325 (37.9%)
      EGFR exon 19 11/128 (8.6%) 2/42 (4.8%) 4/39 (10.3%) 17/209 (8.1%)
      EGFR exon 21 6/128 (4.7%) 3/42 (7.1%) 1/39 (2.6%) 10/209 (4.8%)
      EGFR mutated 17/128 (13.3%) 5/42 (11.9%) 5/39 (12.8%) 27/209 (12.9%)
      ALK-FISH 2/264 (0.8%) 0/90 (0%) 1/69 (1.4%) 3/423 (0.7%)
      ALK – IHC* 1/277 (0.4%) 0/97 (0%) 1/75 (1.3%) 2/453 (0.4%)
      *One ALK-FISH positive case was IHC negative on repeated testing.

      Conclusion
      Our study shows that adequate tumor sampling is a challenge when performing retrospective molecular biology studies, creating a bias of adequate tissue availability in favor of more localized stages of disease. Nonetheless, our study shows a lower percentage of EGFR/ALK mutations and a higher percentage of KRAS mutations than that reported by the LCMC and other groups. This may be related to the non-selected, regional distribution and smoking habits of our study population. Prospective studies on the molecular diagnosis of NS-NSCLC will refine epidemiologic features of the different genetic subtypes of this disease.

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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-043 - Results of a Multidisciplinary Team in the Management of Non-Small Cell Lung Cancer in a Developing Country (ID 3041)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      Lung cancer has the highest cancer-related mortality in the World. In developing countries, mortality rates tend to be higher due to deficits of diagnostic and professional resources, and long time intervals between patient’s symptoms and the initiation of treatment. Multidisciplinary teams improve the care of patients with NSCLC, but this practice is not common in developing countries. In Costa Rica more than 90% of cancer patients are treated in a public hospital where resources are limited. To improve patient care a weekly multidisciplinary thoracic oncology meeting was organized in Hospital San Juan de Dios, one of Costa Rica’s three adult general hospitals. This hospital is responsible for the management of more than 40% of Costa Rica’s cancer patients.

      Methods
      A multidisciplinary team including Medical Oncology, Pneumology, Pathology, Thoracic Surgery, Radiology and Radiation Oncology started to meet in a weekly basis since November 2011. All patients with a possible lung cancer in the hospital were evaluated by the team and recommendations were given. Data of patients with NSCLC seen by the multidisciplinary team during 2012 was compared to a historic data of NSCLC patients diagnosed in the same hospital between 2003 and 2008 when there was no multidisciplinary team involved in patient care. Exclusion criteria included insufficient clinical information. Epidemiologic data was analyzed and survival curves were obtained.

      Results
      In the periods 2003-2008 and 2012, 92 and 39 patients respectively with NSCLC were included for analysis. Epidemiologic results are summarized in Table 1 and overall survival is plotted in Figure 1. Figure 1 Figure 2

      Conclusion
      The inclusion of a multidisciplinary team in the management of NSCLC lead to an earlier diagnosis and increased survival of patients. This approach should be considered in the management of NSCLC patients in a developing country.

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    P2.21 - Poster Session 2 - Diagnosis and Staging (ID 170)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.21-010 - EGFR mutation frequency in patients diagnosed with NSCLC from Costa Rica (ID 3459)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      Histological differentiation in NSCLC has been addressed recently due to the importance regarding prognosis and treatment options. Adenocarcinoma is considered the most frequent histology and recent guidelines recommend the EGFR mutation testing. Epidemiological characteristics of EGFR mutation positive patients have been widely described in Caucasian and Asian population. Given the differences between these populations, it is important to evaluate the epidemiology in other populations. More than 90% of Costa Rica’s population is treated in a government-based hospital. Hospital San Juan de Dios (HSJD) attends approximately a 40% of Costa Rica’s population. Starting at the end of 2011, all patients with lung adenocarcinoma are evaluated for EGFR mutations.

      Methods
      We conducted a retrospective analysis of all patients diagnosed with NSCLC in HSJD between January and December 2012. A total of 42 patients were diagnosed with a NSCLC but 2 patients were excluded from the study due to insufficient clinical information. Epidemiologic data was obtained and EGFR mutation status was analyzed.

      Results
      The NSCLC population analyzed had a median age of 68 y (41-87 y). The most frequent histology reported was adenocarcinoma. All adenocarcinomas were analyzed for EGFR mutations (exon 18, 19, 20, and 21). 33.3% of adenocarcinoma patients had an EGFR mutation. Smoking history was statistically associated with the occurrence of an EGFR mutation. Patient characteristics are summarized in Table 1.

      Table 1: Characteristics of patients diagnosed with NSCLC in HSJD-Costa Rica during 2012
      Total NSCLC population n=40 Adenocarcinoma population n=27 EGFR mut positive population n=9
      Median age 68 y (41-87 y)
      Sex p=0.504
      M (%) 24 (60) 15 (55.6) 4 (44.4)
      F (%) 16 (40) 12 (44.4) 5 (55.6)
      Smoking history (PY) p=0.022
      Non smoker (%) 14 (35) 12 (44.4) 7 (77.8)
      5-20 (%) 3 (7.5) 3 (11.1) 0
      21-40 (%) 4 (10) 1 (3.7) 0
      41-60 (%) 9 (22.5) 4 (14.8) 1 (11.1)
      >60 (%) 10 (25) 7 (26) 1 (11.1)
      Adenocarcinoma histology (%) 27 (67.5)
      Stage of diagnosis
      I-II 3 (7.5) 2 (7.4) 0
      IIIA 9 (22.5) 4 (14.8) 0
      IIIB 5 (12.5) 2 (7.4) 0
      IV 23 (57.5) 19 (70.4) 9 (100)
      % EGFR mutation positive 22.5 33.3
      % of type of EGFR mutation
      Exon 18 0 0 0
      Exon 19 17.5 25.9 77.8
      Exon 20 2.5 3.7 11.1
      Exon 21 2.5 3.7 11.1

      Conclusion
      In Costa Rica, the incidence of EGFR mutations in adenocarcinoma patients tends to be higher to that of the Caucasian population and lower than the Asian population. This incidence might be similar in other Latin American countries. Epidemiological characteristics of EGFR mutation positive patients are similar to that reported in the literature.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-045 - E-Cadherin and vimentin as biomarkers of clinical outcomes among EGFR+ lung adenocarcinoma (LA) patients treated with erlotinib (CLICaP) (ID 3025)

      09:30 - 16:30  |  Author(s): L. Corrales-Rodriguez

      • Abstract

      Background
      Epithelial-mesenchymal transition (EMT) has been known to play a key role in stromal invasion of lung adenocarcinoma. Loss of E-cadherin and acquisition of vimentin are two critical steps in EMT, that are induced by Snail-1 and TWIST upregulation associated with overexpression of epidermal growth factor receptor (EGFR). However, roles of EMT-related proteins in EGFR mutants have not been fully elucidated. We investigated the inmunoexpression of EMT-related proteins in EGFR lung adenocarcinoma to demonstrate their key roles in tumor progression.

      Methods
      E-Cadherin and vimentin expression was assessed in 84 patients with EGFR+ LA to determine if these markers had the potential to predict clinical outcomes in patients treated with Erlotinib. The percentage of tumor cells with grades 0, 1, 2, or 3 membrane staining of E-Cadherin and cytoplasmic staining of vimentin was measured. We selected previously reported cut-off points shown to provide optimal stratification: ≥40% of tumor cells with staining of +2 and +3 for E.cadherin and ≥10% of tumors cell with any staining for vimentin. Overall response rates (ORR), clinical benefit (CB), time to progression (TTP), and overall survival (OS) were estimated, as well as variables that influenced OS.

      Results
      Mean age was 59.6 years (SD +/- 13.1) and 79.8% of patients were women. Mutations of EGFR, L858R and G719X in exon 19 were present in 61%, 31% and 6% respectively. Vimentin expression was strong in 9.5% (n=8) and E-cadherine expression was weak in 51.2%, moderate in 23.8% and strong in 23.8%. Highest positivity of E-Cadherin was related to exon 19 deletion (p=0-001) but not to L858R mutations (p=0.14). Strong vimentin reactivity was associated with history of smoking (p=0.03). OS was 12.3 [10-14], 27.0 [23-31],26.1 [20-32] and 33.5 [30-36] months when E-cadherine expression was negative, weak, moderate and strong (p=0.05). OS was 33 months [31-35] in vimentin-negative and 8.2 months [6-10] in vimentin-positive (p=0.001). Similar trends were observed for progression-free survival and response rate.

      Conclusion
      E-Cadherin and vimentin are valuable predictive biomarkers for EGFR+ patients. These results warrant further research on EMT in selected populations exposed to erlotinib.