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E. Stewart
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ORAL 21 - Biology - Moving Beyond the Oncogene to Oncogene-Modifying Genes (ID 118)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:A. Katz, M.S. Tsao
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL21.05 - p53/KRAS Mutation Status Does Not Predict Sensitivity to Chemotherapy in NSCLC PDXs (ID 2459)
11:28 - 11:39 | Author(s): E. Stewart
- Abstract
- Presentation
Background:
The LACE-Bio group assessed the prognostic and predictive values of KRAS and p53 mutations in 1543 completely resected non-small cell lung cancer (NSCLC) tumors. The predictive value of combined KRAS/p53 mutations for survival benefit from adjuvant chemotherapy was evaluated on 49 patients and chemotherapy was deleterious in this group compared to observation (HR 2.49 CI 95% [1.10 – 5.66], p=0.03). Patients with tumors harboring combined KRAS/p53 mutations had a worse outcome when treated with adjuvant chemotherapy compared patient with double wild type (WT) tumors (HR 3.03 (95% CI [1.29 – 7.15], p=0.01, interaction p=0.06). We have compared the chemo-sensitivity of patient derived xenografts (PDXs) with double p53/KRAS mutations, single p53, single KRAS mutation or double WT. 0
Methods:
Surgically resected early stage lung adenocarcinomas (ADC) were implanted into non-obese diabetic severe combined immune deficient (NOD-SCID) mice. Fourteen lung ADC PDXs with various p53/KRAS status were revived and implanted: 11 engrafted and were expanded for comparison of treatment vs control. For each model, 6 replicates were included in treatment and control arms. Chemotherapy (cisplatin 3 mg/kg and vinorelbine 7 mg/kg intraperitoneally weekly) was initiated in the PDXs at tumor volumes of 150 mm[3].
Results:
Four models were p53/KRAS double mutant, 4 p53 mutant, 2 KRAS mutant and 1 double WT. The 4 double mutant PDXs responded to chemotherapy, 2 with reduced (SD) and 2 inhibited (PR) growth. Among the 4 PDXs with p53 mutation only, 2 responded (1 PR and 1 SD) and 2 were resistant. Among the 2 PDXs with KRAS mutation only, 1 had a complete response, but relapsed at treatment arrest and 1 achieved PR. The double WT PDX was highly sensitive to chemotherapy (PR) but also relapsed at treatment arrest.
Conclusion:
Among these 11 PDXs, the p53/KRAS mutation status did not predict chemo-sensitivity to cisplatin/vinorelbine, one of the most active adjuvant chemotherapy regimens in NSCLC. As these PDXs were molecularly profiled, we currently are investigating other biomarkers that might predict their sensitivity or resistance to chemotherapy.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-026 - Second Generation EGFR TKIs Inhibit Tumor Growth in a Chemo-Resistant Squamous Cell Lung Cancer Patient Derived Xenograft Model (ID 1265)
09:30 - 09:30 | Author(s): E. Stewart
- Abstract
Background:
In clinical trials testing the efficacy of first generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), occasional responses were observed in patients with lung squamous cell carcinomas (LSCC) (Shepherd FA, et al. New Engl J Med 2005) and survival benefit was confirmed for erlotinib in a subset analysis of male, ever-smokers with LSCC (Clark GM, et al. Clin Lung Cancer 2006). Currently, the LUX-Lung 8 phase III clinical trial is comparing afatinib versus erlotinib in the second-line setting for LSCC after cisplatin-based chemotherapy (Goss GD, et al. ESMO 2014). Preclinical data indicate that high EGFR protein expression may be predictive of response to erlotinib in EGFR wild type LSCC (Cranston et al, AACR 2013). Herein we assessed and compared the anti-tumor efficacy of different EGFR inhibitors in chemo-resistant squamous cell lung cancer patient derived xenograft (PDX) models with high EGFR expression and EGFR amplification.
Methods:
The cryopreserved PDX model established from a resected early stage LSCC was revived in non-obese diabetic severe combined immunodeficient mice (NOD SCID), expanded and subsequently treated with chemotherapy (cisplatin 3 mg/kg and vinorelbine 7 mg/kg intraperitoneally [IP]), cetuximab 20 mg/kg IP, and daily oral schedules were followed for erlotinib 50 mg/kg, afatinib 20 mg/kg, dacomitinib 3 mg/kg. For each model, 6 mice were used in each of the different treatment and the control arms. Treatment was initiated in the PDXs at a tumor average volume of 150 mm[3].
Results:
The PDX was derived from a 57 year old male, smoker, following right pneumonectomy for a stage IIIB (T4N1M0) LSCC. This patient received adjuvant cisplatin/vinorelbine, but relapsed three weeks after the end of cycle 4 and died a week later. The tumor had a high EGFR expression by immunohistochemistry (H score = 300) and EGFR amplification (clusters) by fluorescent in situ hybridization. The PDX was EGFR wild type by Illumina exome sequencing and OncoCarta[TM ]MassArray mutation screen (Sequenom), also was refractory to cisplatin/vinorelbine. Reduced growth rate (stable disease, SD) was obtained with erlotinib and cetuximab. Treatment with afatinib and dacomitinib resulted in tumor growth inhibition (partial response, PR). The PDX developed resistance to dacomitinib after 100 days of treatment, but continued to be inhibited by afatinib after 215 days of treatment.
Conclusion:
This study shows the efficacy of second generation especially afatinib irreversible EGFR TKIs in a chemoresistant LSCC PDX, with high wild type EGFR expression and EGFR amplification. Our results lend further support to the LUX-Lung 8 trial, and also the use of PDX to model therapeutic responses in lung cancer.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-044 - EGFR and ALK Status Influence Health Utility and Global Quality of Life Scores in Patients with Metastatic Lung Cancer (ID 1613)
09:30 - 09:30 | Author(s): E. Stewart
- Abstract
Background:
EGFR mutations and EML4-ALK rearrangements play important roles in prognosis and response to treatment. While extending survival is a main goal of treatment, improving symptoms, well-being, and quality of life is an equally important priority.
Methods:
At Princess Margaret Cancer Centre, a cross-sectional study evaluated 224 outpatients with metastatic lung cancer who completed demographic and EQ5D-3L questionnaires generating health utility scores (HUS, 0-1) and a visual analogue scale (VAS) slider (0-100). Patients rated their ECOG performance status (0-4), and described their health over the last month from 1 (excellent) to 5 (poor). Results were correlated with clinical and demographic data. Our objective was to compare HUS and global quality of life by mutational status. Patients with EGFR mutations and ALK rearrangements were enriched through targeted enrolment, while patients with neither alteration were selected randomly from the same outpatient clinics.
Results:
94 patients (42%) had an EGFR mutation, 23 (10%) an ALK rearrangement and 107 (48%) had neither (“wildtype”) in their tumor. Participation rate was 87%. Characteristics of the populations were as expected, with higher rates of never smokers in patients with EGFR or ALK alterations (p<0.0001), greater proportion of Asians (p=0.0004), and higher proportion of adenocarcinoma (p<0.0001). Current systemic treatment differed among groups, as the majority of patients with driver mutations were receiving targeted agents at the time of assessment (77% EGFR and 65% ALK vs 7% wildtype). Conversely, wildtype patients were more likely on chemotherapy (6% vs 17% vs 38%) or not on treatment (17% vs 17% vs 47%, p<0.0001). Patients filled questionnaires on average 25 months after initial diagnosis of lung cancer. Patients with EGFR mutations (97%) or ALK rearrangements (100%) were more often ECOG performance status 0-1 at the time of diagnosis of stage IV disease than wildtype individuals (86%, p=0.02). For quality of life analysis, we regrouped the patients with EGFR/ALK alterations (n=117). Their mean HUS was better than for wildtype patients (0.80 vs 0.71, p=0.0003), their mean VAS slider was higher (66.9 vs 60.8, p=0.0381) and their mean self-rated ECOG scores was better (0.90 vs 1.26, p=0.022).
Conclusion:
In a clinical population, patients with metastatic lung cancer harboring EGFR and ALK alterations report superior HUS and global quality of life scores when compared with patients without these molecular changes, during the course of their therapy. This is reflected in higher proportion of patients on active therapy, particularly with molecularly targeted agents, and with improved self-reported performance scores. Health utility values used in economic analyses of metastatic lung cancer patients in clinical practice should be specific for different mutations.
