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Y.I. Garces



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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-018 - Outcomes of lung adenocarcinoma patients with signet ring cell tumors: a three-way evaluation (ID 2884)

      09:30 - 16:30  |  Author(s): Y.I. Garces

      • Abstract

      Background
      Pathologically, signet ring cells (SRC) describe singly dispersed tumor cells with intracytoplasmic mucin vacuoles, which eccentrically displace and compress the nucleus. SRCs are traditionally associated with adenocarcinoma of the gastrointestinal tract and are rare in lung adenocarcinoma (LACA). Patients with primary LACA with SRC features (SRC+) have been associated with poor clinical outcome and ALK gene rearrangement (ALK+). However, the impact of SRC+ on clinical outcome is not well delineated. We systematically studied LACA survival outcomes for the impact of SRC status.

      Methods
      Three distinct groups of surgically treated patients with LACA (n=763) that were followed for ≥5 years were reviewed: never smokers (n=266), 2006-2007 cohort (n=222), and smokers enriched for various degrees of lepidic growth pattern (LGP, n=275). Two pulmonary pathologists reviewed all cases; SRC+ tumors were defined as having >10% SRCs, agreed by both pathologists. SRC+ tumors were TTF1+, and generally cytoplasmic mucin+ and CDX2-. ALK immunostain was performed on all SRC+ cases, and ALK status was confirmed by FISH for cases with any degree of immunoreactivity. Impact of SRC+ on patients’ survival outcomes (overall and disease-free, OS and DFS) were analyzed using Cox models (by hazard ratio, HR) separately for the three groups, with careful evaluation of known prognostic factors: age at diagnosis; gender; smoking status; lung cancer history; tumor subtype; grade and stage; and treatment (surgery, chemotherapy and/or radiation).

      Results
      In the total of 763 patients (61% women, mean age at diagnosis 68 years), 53 (7%) were SRC+. In never smokers (73% women), 9% were SRC+; 33% of the SRC+ were ALK+ vs. 5% among the SRC- cases (p<0.0001). In the 2006-2007 cohort (55% women), 9% were SRC+; in LGP-smokers (54% women), 3% were SRC+. Across all three groups, SRC+ tumors were more likely to occur in men and have higher stage. Univariate analysis showed SRC+ never smokers had shorter survival: median DFS was 2.4 years (vs. 5.2 in SRC- never smokers, p=0.0004), and median OS was 3.7 years (vs. 7.6, p=0.0064). However, multivariate analysis did not confirm a significant impact of SRC+ on survival. In contrast, for the other two groups, crude 5-year survival was 6%-27% decreased in SRC+ cases compared to SRC- cases (none reached statistical significance); however, multivariate analysis revealed a 2-fold higher mortality (HR=2.30, 95% CI=1.01-5.27, p=0.048) for smokers with SRC+ tumors.

      Conclusion
      Based on results from three patient groups, we confirmed that SRC+ is significantly associated with ALK+. Worse survival in patients with SRC+ tumors was observed in never smokers by univariate analysis. A potential negative impact of SRC+ tumors on OS in LGP-smokers was only uncovered after adjusting for known prognostic factors. These results need to be furthered confirmed.

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    PL03 - Presidential Symposium Including Top Rated Abstracts (ID 85)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track:
    • Presentations: 1
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      PL03.05 - An intergroup randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): Results on cetux from RTOG 0617 (ID 1424)

      08:15 - 09:45  |  Author(s): Y.I. Garces

      • Abstract
      • Slides

      Background
      The two primary objectives of RTOG 0617 were to compare the overall survival(OS) differences of 1) standard-dose(SD)(60Gy) versus high-dose(HD)(74Gy) radiotherapy (RT) with concurrent chemotherapy(CT); and 2) the addition of cetux to standard CRT. Cetux is a monoclonal Ab targeting EGFR with activity when combined with CT in metastatic NSCLC and head and neck cancer (HNC), and with RT in locally advanced HNC.

      Methods
      This Phase III Intergroup trial randomized pts in a 2 x 2 factorial design. Concurrent CRT included weekly paclitaxel(45 mg/m2) & carboplatin(AUC=2). Pts randomized to cetux received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. All pts were to receive 2 cycles of consolidation CT. This is the initial report of survival outcome based on cetux. The trial was designed for 450 evaluable patients with 80% power and a 1-sided alpha of 0.0125 to detect a 29% reduction in OS failure for each comparison (RT and cetux).

      Results
      544 pts were accrued, and 419 and 465 are eligible for RT and cetux analyses. Median follow up is 18.7 months. Cetux delivery was acceptable in both the concurrent and consolidation phases. Therapy related ≥Grade 3 non-hematologic toxicity was higher in the cetux group; 70.5% vs 50.7% (p<.0001). Grade 4 and 5 events were 35.8% and 28.2%, respectively. Median survival was 23.1 vs 23.5 months, & 18-month OS rates were 60.8% vs 60.2% on the cetux vs non-cetux arms, respectively (p=0.484, HR=0.99), which crossed a protocol-specified futility boundary for early reporting. As previously reported, median survival times and 18-month OS rates for SD and HD arms were 28.7 vs 19.5 months, and 66.9% vs 53.9% respectively (p=0.0007, HR=1.56). There was no significant interaction between RT dose and the use of cetux. The OS rates for the 4 arms of this trial are shown in Table. An H-score analysis, a measure EFGR positivity, is forthcoming.

      Table: Overall Survival Rates with 95% CI (pts accrued while all 4 arms were open)
      Time 60 Gy 74 Gy 60 Gy + Cetux 74 Gy + Cetux
      12m 78.4% (68.9, 85.4) 62.6% (51.7, 71.6) 80.0% (70.8, 86.6) 74.7% (64.9, 82.2)
      18m 67.9% (57.6, 76.2) 52.3% (41.5, 62.0) 67.1% (56.8, 75.5) 58.0% (47.6, 67.1)

      Conclusion
      In pts receiving CRT for Stage III NSCLC, 74 Gy is not superior to and may be worse than 60 Gy in terms of OS. Cetux provides no survival benefit in the setting of CRT for Stage III NSCLC.

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