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S. Zöchbauer-Müller
Moderator of
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 8
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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- Abstract
- Presentation
Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.
Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.
Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.
Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.
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- Abstract
- Presentation
Background:
Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.
Method:
A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).
Result:
No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1
Conclusion:
Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.
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OA 08.03 - Effect of TOP2A and ERCC1 Genes Polymorphism on the Efficacy and Toxicity of Cisplatin and Etoposide Therapy in SCLC Patients (ID 8367)
11:20 - 11:30 | Presenting Author(s): Marcin Nico? | Author(s): P. Krawczyk, A. Rolska-Kopińska, A. Grenda, A. Bożyk, M. Szczyrek, J. Milanowski
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) shows an aggressive course with early metastases to distant organs. The main treatment regimen for SCLC patients involves platinum based chemotherapy (cisplatin or carboplatin) and etoposide. Genetic alternations, as single-nucleotide polymorphisms (SNPs) in TOP2A (topoisomerase II alpha) and in ERCC1 (endonuclease non-catalytic subunit) genes, were tested as a prognostic and predictive factors in patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. However, there is limited data about clinical relevance of these genetic alternations in SCLC. Therefore, we undertook the present retrospective study to determine the influence of SNPs in TOP2A (rs34300454; rs13695; rs11540720) and ERCC1 (rs11615; rs3212986) genes on efficiency and toxicity of chemotherapy with platinum and etoposide in patients with SCLC.
Method:
The studied group included 103 Caucasian SCLC patients (65 male, 38 female, median age 65 ± 7,5 years). We collected detailed clinical-demographical data including: smoking history, environmental/occupational exposure to carcinogens, performance status, disease stage, and the presence of distant metastases. The response to the treatment was carefully monitored according to RECIST criteria, as well as side effects as anemia, neutropenia or weight loss were noted. For SNPs genotyping, we used DNA isolated from peripheral blood leukocytes using Qiamp DNA Mini Kit (Qiagen, Germany) and TaqMan hydrolyzing probes (Applied Biosystem, USA) in real-time PCR technique on Eco Illumina (Illumina, USA) device.
Result:
Patients with C/C genotype in rs13695 of TOP2A gene had significantly lower risk of neutropenia during chemotherapy than C/T heterozygous patients (p=0,01894; χ²=5.51; OR=2,676; 95% CI=1,165-6,143). Patients harbouring homozygous C/C genotype in rs3212986 of ERCC1 gene had significantly higher risk of anaemia during chemotherapy than heterozygous C/A patients (p=0,04531; χ²=4,01; OR=0,417; 95% CI=0,175-0,991). Furthermore, homozygous A/A genotype in rs11615 of ERCC1 gene was associated with significant prolongation of overall survival (12 vs. 9 months) compared to heterozygous G/A genotype of this gene (p=0,0120; χ²=6,3063; HR=1,657; 95% CI=1,0710-2,5633).
Conclusion:
SNPs in ERCC1 and TOP2 genes are associated with the toxicities and overall survival of SCLC patients treated with platinum and etoposide based chemotherapy.
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OA 08.04 - Discussant - OA 08.01, OA 08.02, OA 08.03 (ID 10845)
11:30 - 11:45 | Presenting Author(s): Ikuo Sekine
- Abstract
- Presentation
Abstract not provided
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OA 08.05 - Major Drivers of Chemotherapy and Radiation Utilization for Limited-Stage Small Cell Lung Cancer in the United States (ID 8475)
11:45 - 11:55 | Presenting Author(s): Stephen G Chun | Author(s): T.A. Pezzi, A.S.R. Mohammed, D.L. Schwartz, J.W. Welsh, Ritsuko Komaki, S.M. Hahn, C.D. Fuller
- Abstract
- Presentation
Background:
Small cell lung cancer (SCLC) accounts for 15-30% of newly diagnosed lung cancers. Although chemotherapy and radiation play a vital role in the initial management of limited-stage SCLC, rates of combined modality utilization in the United States have not been comprehensively studied. As such, the National Cancer Database (NCDB) is a valuable resource to understand patterns of care for limited-stage SCLC, as it captures the majority of newly diagnosed thoracic malignancies in the United States.
Method:
All cases of IASLC defined limited-stage SCLC in the United States National Cancer Database (NCDB) were identified from 2004 to 2013. Rates of chemotherapy and radiation utilization were determined along with key factors associated with their use. Kaplan-Meier analysis and multivariable analysis were used to determine factors independently associated with overall survival.
Result:
From 2004 to 2013, there were 70,247 cases with analyzable data in the NCDB that met IASLC criteria for limited-stage SCLC. Of these cases, 40% did not receive radiation and 20% received neither chemotherapy nor radiation. For the irradiated group, the mean radiation dose was 52.8 Gy with a 16.2 Gy interquartile range. On multivariable analysis, being uninsured (OR 0.75, 95% CI 0.67-0.85, p < 0.001), Medicaid (OR 0.79, 95% CI 0.72-0.87, p < 0.001), and Medicare (OR 0.86, 95% CI 0.82-0.91, p < 0.001) were independently associated with a lower likelihood of radiation delivery in comparison to private/managed care insurance (after adjusting for age, tumor stage, and co-morbidity score). The irradiated group had significantly better median survival than the non-radiated group (33 vs. 17 months, p < 0.001). Radiation (HR 0.62, 95% CI 0.6-0.63, p < 0.001) and chemotherapy (HR 0.55, 95% CI 0.54-0.57, p < 0.001) delivery were both independently associated with better survival on multivariable analysis. Adjusted analysis showed that non-academic programs (HR > 1, p < 0.001) and non-private/managed care insurance (HR > 1, p < 0.001) was independently associated with a survival detriment.
Conclusion:
This is the most comprehensive study currently available describing the utilization of combined modality therapy in the initial management of limited-stage SCLC in the United States. A remarkable number of patients received neither radiation nor chemotherapy as part of their initial oncologic treatment. Insurance status was a key determinant of radiation and chemotherapy delivery even after adjusting for potentially confounding factors. Our findings highlight substantial barriers to quality care delivery and challenges in accrual seen for cooperative group clinical trials for limited-stage SCLC.
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OA 08.06 - Exploratory Analysis for Predictors of Benefit of PARP Inhibitor Therapy in Extensive Stage Small Cell Lung Cancer: ECOG-ACRIN 2511 Study (ID 10321)
11:55 - 12:05 | Presenting Author(s): Taofeek K Owonikoko | Author(s): S. Dahlberg, John Poirier, G.L. Sica, Charles M Rudin, Suresh S Ramalingam
- Abstract
- Presentation
Background:
Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. The combination of veliparib (V) with cisplatin/etoposide (CE) doublet as first-line therapy of extensive stage SCLC (ES-SCLC) showed significant signal of efficacy with adjusted PFS HR: 0.63 1-sided p=0.01. There was strata by treatment interaction indicating different efficacy benefit in patient subsets (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets). We explored clinical and tissue-based biomarkers as predictors of benefit from this treatment strategy.
Method:
Post-hoc analysis of clinical data was conducted to identify clinical differences in patients who derived significant benefit from the experimental therapy. Clinical differences were compared between patients in the control and experimental arms within the patient stratum with significant clinical benefit. Similarly, comparison was performed between the strata. Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis using immunohistochemistry to assessSLFN11 and DNA-PK expression. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing biomarker positive to negative patients using a one-sided 0.025 level logrank test.
Result:
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Mutivariable analysis controlling for these imbalances still showed a benefit of veliparib (HR=0.26, p=0.001). Comparison of “in strata” group (N=46) to the “not in strata” group (N=82) showed significant imbalance in pleural effusion (p=0.058); elevated AST (p=0.0099) and bilirubin (p=0.0447). Median PFS was identical at 5.9 mos for both groups while median OS was 10.7 mos (95% CI 8.9-13.2) for “not in strata” subsests vs. 8.8 mos (95% CI 7.8-10.8) for “in strata” with a HR of 1.57 (p=0.027) comparing “in strata” to “not in strata”. Outcome differences based on SLFN11 and DNA-PK expression will be presented at the meeting.
Conclusion:
PFS benefit of PARP inhibitor therapy in extensive stage SCLC patients with elevated LDH and male gender was not associated with any other clinical characteristics.
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OA 08.07 - Pazopanib Maintenance for Extensive Disease Small Cell Lung Cancer: a Randomized, Placebo-Controlled Phase II study (KCSG-LU12-07) (ID 8239)
12:05 - 12:15 | Presenting Author(s): Jong-Mu Sun | Author(s): K.H. Lee, B. Kim, H. Kim, Y.J. Min, S.Y. Yi, H.J. Yun, S. Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
- Abstract
- Presentation
Background:
We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLD).
Method:
This study is a randomized, placebo-controlled, phase II study that enrolled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum combination therapy. Eligible patients were randomly assigned (1:1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).
Result:
Ninety-seven patients were enrolled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n = 48; placebo, n = 47) and were included into the analyses. Grade 3 toxicities for pazopanib maintenance included thrombocytopenia (10.4%, including 1 case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (Hazard ratio [HR] 0.44, 95% CI: 0.29 – 0.69, p < 0.0001). Median PFS longer than 6 months were achieved by 9 patients (18.8%) in pazopanib arm and 2 (4.3%) in placebo. Median overall survival for the pazopanib and placebo arms were 10.6 months and 12.9 months, respectively (HR 1.14, 95% CI: 0.74 – 1.76, p = 0.54).
Conclusion:
Though this study met the primary endpoint of PFS, it failed to translate into improvement of overall survival with pazopanib maintenance. Given the unneglectable toxicity profiles, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.
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OA 08.08 - Discussant - OA 08.05, OA 08.06, OA 08.07 (ID 10846)
12:15 - 12:30 | Presenting Author(s): Karen L Reckamp
- Abstract
- Presentation
Abstract not provided
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