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N. Rekhtman
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 2
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.05 - Can Tumor Spread through Air Spaces (STAS) in Lung Adenocarcinomas Be Predicted Pre- and Intraoperatively? (ID 6026)
14:50 - 14:56 | Author(s): N. Rekhtman
- Abstract
- Presentation
Background:
We and others have reported the prognostic impact of tumor spread through air spaces (STAS) in lung adenocarcinomas. The goal of this study is to investigate preoperative predicting factors for STAS and to determine whether STAS can be detected by intraoperative frozen section analysis.
Methods:
In a cohort of 874 patients with small (≤2cm) stage I adenocarcinoma (1995-2012), we reviewed preoperative computed tomography (CT) and positron emission tomography (PET) scans. According to the 2016 Fleischner Society’s criteria, radiological whole tumor size, consolidation size, as well as C/T ratio (consolidation/whole tumor diameter) were determined using thin slice (<3mm) CT scans where available (n=174). Clinico-radiological prediction of STAS was evaluated by logistic regression model. Using the frozen section slides with adequate adjacent lung parenchyma surrounding tumor without artifact (n=48), the presence of STAS was evaluated by five pathologists who are unaware of the radiological findings or the pathological information on permanent slides. The kappa statistic was calculated to measure the agreement between two pathologists.
Results:
In univariable model for predicting STAS, current smoker, larger consolidation tumor size, C/T ratio, and SUVmax were significant variables. In multivariable model, current smoker and C/T ratio were independent risk factors for the presence of STAS (p=0.027 and p<0.001, respectively; Table 1a). The sensitivity and the specificity of frozen section for prediction of STAS were 71% (95% confidence interval: 52-91%), 92.4% (81-100%) respectively, and the accuracy was 80% (71-89%). The kappa statistics were 0.40-0.74 (Table 1b) with 8/10 being moderate or substantial agreement.
Conclusion:
Smoking status and C/T ratio were independent predictors for the presence of STAS in patients with small lung adenocarcinomas. Frozen section prepared with adequate surrounding normal lung tissue may help identify STAS intraoperatively. Figure 1
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MA12.06 - Tumor Spread through Air Spaces (STAS) in Lung Squamous Cell Cancer is an Independent Risk Factor: A Competing Risk Analysis (ID 6051)
14:56 - 15:02 | Author(s): N. Rekhtman
- Abstract
- Presentation
Background:
Tumor spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma, however, the incidence of and prognostic importance of STAS have not yet been defined in squamous cell carcinoma (SCC).
Methods:
In a cohort of 445 patients with p-stage I-III lung SCC, cumulative incidence of recurrence and lung cancer-specific death (LCSD) was evaluated by competing risks analysis and overall survival (OS) by Cox models.
Results:
76% of patients were >65 years of age. 273 patients died during follow up, one third (91, 33.3%) died of lung cancer whereas two thirds died of competing events or unknown cause. STAS was present in 132 (30%). The cumulative incidence of any, distant, and locoregional recurrence as well as LCSD were significantly higher in patients with STAS compared to those without STAS (Figure), whereas there was no statistically significant difference in OS. STAS was an independent predictor for both recurrence and LCSD in multivariable analysis (p=0.034 and 0.016, respectively, Table).
Conclusion:
STAS was present in one third of resected lung SCC and it was an independent predictor of recurrence and LCSD, supporting our proposal that STAS is a clinically important pattern of invasion and not an artifact. Figure 1 Figure 2
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.05 - A Phase 2 Study of Cabozantinib for Patients with Advanced RET-Rearranged Lung Cancers (ID 5731)
11:35 - 11:45 | Author(s): N. Rekhtman
- Abstract
- Presentation
Background:
RET rearrangements are actionable drivers found in 1-2% of non-small cell lung cancers. We previously reported the efficacy and safety of the multikinase RET inhibitor cabozantinib in 16 patients with RET-rearranged lung cancers in the first stage of our Simon two-stage phase 2 clinical trial (overall response rate 38%; Drilon, ASCO 2015). This study has since completed accrual of both stages, now with 26 patients treated with cabozantinib.
Methods:
This was an open-label, single center, phase 2 trial (NCT01639508). Eligibility criteria: stage IV pathologically-confirmed lung cancers, presence of a RET rearrangement, KPS >70%, and measurable disease. RET rearrangements were detected by FISH or next-generation sequencing. Cabozantinib was administered in tablet form at 60 mg daily until progression of disease or unacceptable toxicity. The primary objective was to determine the overall response rate (ORR, RECIST v1.1). Secondary objectives included determining progression-free survival (PFS), overall survival (OS), and toxicity. 5 responses in 25 response-evaluable patients were required to meet the primary endpoint (Simon two-stage minimax design: H~0~ 10% vs H~A~ 30% ORR). All patients who received at least one dose of cabozantinib were evaluable for toxicity.
Results:
26 patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The median number of prior chemotherapy lines was 1 (0-5). One patient who discontinued therapy in cycle 1 and did not undergo a response assessment was not response-evaluable as per protocol. The study met its primary endpoint with confirmed partial responses observed in 7 (ORR 28% [95% CI 12-49%]) of 25 response-evaluable patients. The median PFS was 5.5 months (95% CI 3.8-8.4). The median OS was 9.9 months (95% CI 8.1-not reached). Response by RET fusion partner: Unknown (FISH+) 2/6 (33%), KIF5B 3/15 (20%), CLIP1 1/1, TRIM33 1/1, CCDC6 0/1, ERC1 0/1. In 26 patients evaluable for toxicity, the most common all-grade treatment-related adverse events were increased alanine aminotransferase in 25 (96%) patients, increased aspartate aminotransferase in 19 (73%) patients, hypothyroidism in 18 (69%) patients, diarrhea in 16 (62%) patients, and palmar plantar erythrodysesthesia in 15 (58%) patients. Nineteen (73%) patients required dose reduction.
Conclusion:
This study met its primary endpoint. Cabozantinib is an active agent in patients with RET-rearranged lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed therapy.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-029 - Cases Demonstrating Spread Through Air Spaces (STAS) Reflects Invasive Growth and Not an Artifact (ID 6059)
14:30 - 14:30 | Author(s): N. Rekhtman
- Abstract
Background:
STAS is defined as a pattern of tumor cell spread in the lung parenchyma beyond the edge of a lung cancer. It has been postulated that this is an ex vivo artifact due to the force of knife with the premise that STAS is clinically unimportant and it should be ignored like true artifacts.
Methods:
We present three cases providing evidence that STAS is not an artifact and is clinically relevant.
Results:
Case 1: 68F underwent wedge resection of a left upper lobe (LUL) lung adenocarcinoma. During the surgical procedure the surgeon did not cut across the tumor, but sent a separate wedge biopsy as an additional margin. The latter wedge contained an 8 mm focus of adenocarcinoma consisting almost entirely of a STAS pattern with a 1mm area of acinar growth. Case 2: 66M underwent RUL wedge resection in August 2013 for a 1.3 cm lung adenocarcinoma. The resection margin was positive with only STAS in the margin. In the absence of any clinical sign of recurrence or metastases, a completion right upper lobectomy was performed revealing three separate foci of residual adenocarcinoma including 1.5 and 1.0 mm acinar areas and a 0.5 mm focus of STAS with N1 and N2 lymph node metastases. Adjuvant chemotherapy and radiation were given. In 2014, the patient developed multiple bilateral nodules and in November underwent LUL wedge resection that showed three foci of adenocarcinoma with a STAS predominant pattern. In July 2016, the patient remains on chemotherapy with slowly growing bilateral nodules. Case 3: A 77M presented with pneumonia and bilateral ground glass opacities with focal consolidation. A biopsy, originally interpreted as benign, showed diffuse involvement by adenocarcinoma with a STAS predominant pattern. The morphology does not explain the consolidation seen on CT indicating the surgeon did not cut across the main tumor area.
Conclusion:
We present three cases which provide evidence that STAS is not an artifact that should be ignored. In two cases the extensive STAS predominant pattern was not a knife cutting artifact because the main tumor was not cut either by the surgeon or pathologist. In the third case, STAS was the only pattern of tumor identified at a wedge resection margin. If this had been ignored, the residual and metastatic tumor would not have been identified delaying introduction of chemotherapy. These findings support the concept that STAS is a clinically important invasive pattern and not an artifact.
