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E.M. Berge
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MINI 04 - Clinical Care of Lung Cancer (ID 102)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gaspar, V. Westeel
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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MINI04.08 - Malignant Pleural Effusions Are Predictive of Peritoneal Carcinomatosis in Patients with Advanced EGFR Positive Non-Small Cell Lung Cancer (ID 3191)
17:25 - 17:30 | Author(s): E.M. Berge
- Abstract
- Presentation
Background:
Lung cancer is the most frequent cause of cancer death and metastatic disease at the time of initial diagnosis is common. Peritoneal carcinomatosis (PC) from lung cancer is a rare clinical event with a reported incidence of 1.2% (Satoh et al. 2001). However, there are limited data on what factors predict peritoneal progression in lung cancer. Over the last decade, molecular analysis of NSCLC has provided more detailed classification of patterns of metastatic spread. It has also been shown that oncogene-addicted subsets of NSCLC have different patterns of metastatic spread (Doebele et al. 2012). We investigated whether certain baseline patterns of metastatic spread in patients with advanced EGFR mutation positive (EGFR+) NSCLC can predict subsequent PC.
Methods:
We identified 156 patients with EGFR+ (Exon 19 or L858R) mutations from 2009 - 2014, of which 139 had metastatic NSCLC. 11 patients developed PC. This was defined as the presence of biopsy-proven adenocarcinoma from peritoneal fluid or radiographic patterns consistent with omental metastases. We identified areas of metastatic disease in predefined sites (brain, liver, lung, adrenal, soft tissue and pleura) at the time of diagnosis or metastatic recurrence. We noted if patients developed T790M, a resistance mutation to targeted therapy, in EGFR+ patients. A Fisher-Exact test was used to determine statistical significance between metastatic site and subsequent PC.
Results:Table 1 - Sites of metastasis and presence of T790M mutation in patients with PC and without PC
The presence of a pleural effusion was universal in all 11 EGFR+ patients who subsequently developed PC and this finding was statistically significant (P = 0.0001). 9 out of 11 patients with PC were identified to have a T790M mutation, a finding that was statistically significant (P = 0.0001). Except one patient, all EGFR+ patients developed PC following targeted tyrosine kinase therapy.Metastatic site / mutation PC No PC P value Lung 9.1% 38.6% P = 0.06 Liver 18.2% 15.8% P = 0.689 Bone 36.4% 46.8% P = 0.549 Brain 0% 23.7% P = 0.3570 Adrenal 0% 6.4% P = 0.123 Soft tissue 9.1% 2.2% P = 0.265 Pleural effusion 100% 26.6% P = 0.0001 T790M mutation 81.1% 34.5% P = 0.0001
Conclusion:
The presence of a malignant effusion is highly predictive of developing PC in patients with EGFR+ NSCLC. Although the underlying mechanism of PC is not entirely clear, it may be related to serosal communication with subsequent micrometastatic seeding of the peritoneal cavity. The T790M mutation, the most common acquired resistance mechanism to EGFR kinase inhibitors, was significantly more prevalent in the group that developed PC, although it remains unclear whether this mutation has any causative effect on spread to the peritoneum.
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MINI 13 - Genetic Alterations and Testing (ID 120)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:Y. Koh, R.K. Thomas
- Coordinates: 9/08/2015, 10:45 - 12:15, 205+207
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MINI13.01 - Clinicopathological Profiles of ROS1 Positive Patients Screened by FISH (ID 1450)
10:45 - 10:50 | Author(s): E.M. Berge
- Abstract
- Presentation
Background:
ROS1 fusion variants represent an important subset of oncogenic driver mutations in approximately 0.7 – 3.4% of non-small cell lung cancers. Since the frequency of ROS1 positive lung cancer patients is relatively low, it is unclear whether there are significant clinicopathologic associations for positive cases. Thus far, ROS1 positive patients tend to be younger and never-smokers with tumors displaying adenocarcinoma histology. This study describes a further cohort of ROS1 positive lung cancer patients in an effort to identify clinicopathologic associations.
Methods:
The data represent a retrospective analysis of the clinicopathological profiles of primary and metastatic lung cancer patients tested for ROS1 gene rearrangements by break-apart (BA) FISH at the University of Colorado School of Medicine.
Results:
The cohort consisted of 452 patients enriched for triple-negative (EGFR-, KRAS- and ALK-) non-squamous cell carcinomas screened for ROS1 rearrangements using the BA FISH assay. Nineteen cases (4.2%) were identified as positive for rearrangement, the majority (68%) of which were female, with a mean cohort age of 54.9 years (range 30-79); as compared to negative cases which included 56% female patients (P= 0.1083), and had a mean cohort age of 62.9 (range 21-90) (P= 0.0058). Seventeen out of the 19 ROS1 positive tumors were classified as adenocarcinomas, one was diagnosed as adenosquamous carcinoma, and the histology on one specimen was not otherwise specified (NOS). Among 12 individuals with information on pathologic stage at diagnosis, the majority (75%) were stage IV. The prevalent FISH pattern for rearrangement was a split 5’ and 3’ signal (68%) with the remaining specimens showing primarily single 3’ signals (21%) or a mix of split and single 3’ signals (11%).
Conclusion:
The ROS1 positive tumors in this cohort were primarily classified as adenocarcinomas, diagnosed at an advanced stage, in patients significantly younger and more likely to be women, although the sample set was biased for non-squamous lesions thereby limiting the application of this information to squamous cell lung carcinoma. The higher prevalence of ROS1 positive cases in this cohort compared to unselected cohorts is best explained by the inclusion of specimens with known negative status for EGFR and KRAS mutations and ALK fusions. As such, these data are in agreement with previous descriptions of ROS1 positive cohorts. Screening for ROS1 rearrangements in lung cancer patients displaying adenocarcinoma histology and negative for EGFR, KRAS and ALK activating events should identify a higher frequency of ROS1 rearranged tumors compared to unselected approaches and facilitate this subset of patients to be treated with targeted ROS1 inhibitors.
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MINI 29 - Meta Analyses and Trial Conduct (ID 156)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:D. Morgensztern, M. Redman
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 2a-3b
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MINI29.07 - CNS Disease Enrollment Criteria for NSCLC Drug Trials (ID 908)
19:05 - 19:10 | Author(s): E.M. Berge
- Abstract
- Presentation
Background:
CNS metastases are common in NSCLC, yet clinical trials of new drugs in NSCLC have widely varying inclusion and exclusion criteria in relation to CNS disease. CNS disease that has received local therapy may be dormant, confounding any subsequent drug benefit, whereas untreated CNS disease may reduce PFS if CNS and systemic drug exposure differs. Recently, RANO guidelines propose explicitly explored activity in CNS disease within solid tumor drug trials. The true extent of variation in CNS related enrollment criteria in NSCLC clinical trials has not been documented before.
Methods:
ClinicalTrials.gov was interrogated on September 11, 2014 looking for interventional drug trials including advanced NSCLC. The following characteristics were extracted: 1) trial phase; 2) experimental arm therapy (chemotherapy, targeted therapy, immunotherapy, anti-angiogenic); 3) location (US, International only, US + International); 4) sponsor (Industry, University/IIT, Cooperative Group, NCI); 5) CNS disease allowance (strict exclusion, allowed after local treatment (surgery/radiation), unrestricted/untreated disease allowed). Industry sponsorship was divided into ‘large pharmaceutical’, (top decile by number of sponsored trials) and ‘small pharmaceutical’ (lower 9 deciles). Exclusion of CNS metastasis was treated as a binary variable and grouped as ‘strict exclusion’ vs. ‘allowed CNS metastasis’ (‘allowed with treatment’ and ‘allowed untreated’). Univariable and multivariable logistic regression models were fit to test the association between exclusion of CNS metastasis and trial characteristics. Statistical significance was set at 0.05 with no adjustment for multiple testing.
Results:
Of 735 trials involving NSCLC, 325 (44%) were excluded from analysis mostly because of allowance of early stage NSCLC (50%, n=164), or no active therapy inclusion (45%, n=146). In the remaining 406 trials, patients with CNS metastases were excluded in 58 (14%), allowed after local treatment in 165 (41%), and allowed with no prior treatment in 104 (26%). CNS criteria were not referenced in the available information in 79 (19%) trials which were excluded from further analysis. On univariable analysis, the odds of CNS metastasis exclusion on trial were significantly lower in trials with vs. without targeted therapy (OR 0.44, 95% CI: 0.25-0.78, p=0.005) and significantly higher in trials with vs. without immunotherapy (OR 2.13, 95% CI: 1.06-4.28, p=0.04). No other univariable associations were significant. In multivariable analysis, after adjustment for all other factors, only trials located at international only vs. US only sites had greater odds of exclusion of CNS metastasis (OR 1.64, 95% CI 0.84-3.22; p=0.03).
Conclusion:
Although univariable analysis suggests class of agent may influence trial design, in multivariable analysis trial location was the only variable associated with strict exclusion of CNS metastases. This raises the possibility of exclusion based on historical/cultural rather than scientific factors. With 18% of trials (58/327) excluding all CNS disease and 50% (165/327) only allowing CNS disease if previously treated, less than a third of NSCLC trials permit unequivocal assessment of CNS activity (104/327). Given the high frequency of CNS disease in NSCLC, sponsors should consider consciously tailoring trial designs to more explicitly explore efficacy in this patient population.
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