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Natasha Rekhtman
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ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)
- Event: WCLC 2019
- Type: Educational Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Masayuki Noguchi, Beatriz Bellosillo
- Coordinates: 9/08/2019, 15:15 - 16:45, Toronto (1985)
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ES12.05 - Impact of STAS in Lung Cancer Staging (Now Available) (ID 3222)
15:15 - 16:45 | Author(s): Natasha Rekhtman
- Abstract
- Presentation
Abstract
Spread through air spaces (STAS) is an established histologic marker of poor prognosis found in 15-60% of lung cancers. The association with poor prognosis is supported by data from over 3500 patients from multiple multidisciplinary investigative groups worldwide. This prognostic significance has been demonstrated in all major types of lung cancer including adenocarcinoma,1 squamous cell carcinoma,2 small cell carcinoma,3 large cell neuroendocrine carcinoma,3, atypical carcinoid3 and pleomorphic carcinoma.4, 5
As this large volume of clinical data has accumulated some important issues that have arisen. 1) Importance of processing, 2) Role in Staging? 3) Limited resection vs lobectomy and 4) Frozen section.
Criteria for STAS
The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. In adenocarcinoma it can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 6 In a recent paper we also proposed to require the presence of more than a single STAS cluster.3 The solid nest pattern is characteristic in other lung cancer histologies such as squamous cell carcinoma and neuroendocrine tumors. 3-dimensional studies with serial histologic sectioning and microCT whole block imaging suggest that there may be two mechanisms of spread into the adjacent lung: 1) detachment, migration through air spaces and reattachment with vessel co-option and 2) tumor islands of continuous tumor spread into adjacent air spaces.
An important component of the diagnostic criteria is the distinction from artifacts: 1) mechanically induced tumor floaters that are randomly situated often at the edge of the tissue section or out of the plane of section; 2) jagged edges of tumor cell clusters suggesting fragmentation or edges of a knife cut during specimen processing; 3) isolated tumor clusters at a distance from the tumor rather than spreading in a continuous manner from the tumor edge and 4) linear strips of cells lifted off alveolar walls.
Importance of Processing
To assess for STAS histologic sections need to be taken in such a way to maximize the interface between the tumor and adjacent non-neoplastic lung parenchyma. For example, sections of subpleural tumors that maximize assessment of the visceral pleura or the interface with dense fibrotic scars or post-obstructive organizing are not well suited for assessment of STAS. This applies to both frozen and permanent sections.
Role of STAS in Staging?
Although the prognostic significance of STAS, has led some to suggest it might be included as a factor in staging,7, 8 there is insufficient data at this time to make such a recommendation. Tumor size should continue to be measured according to the gross and/or microscopically recognized edge of lung cancers rather than according to the maximum distance of furthest STAS. Although vascular (V) and lymphatic (L) invasion are recognized in TNM staging, only visceral pleural invasion (VPI) is officially incorporated as a T-factor in the 8th Edition. STAS is regarded as a sign of invasion similar to V, L and VPI, however, more data is needed before introducing this as a T-factor for staging.
Limited resection vs lobectomy
Evidence is accumulating that indicates an increased risk of recurrence and worse survival associated with STAS positive tumors treated by limited resection compared to lobectomy.5, 9
Role of Frozen Sections in Assessing STAS
There is limited data evaluating pathologist’s ability to recognize STAS in frozen section. Eguchi et al found the sensitivity and specificity of frozen section for prediction of STAS were 71% and 92%. respectively and interrater reliability across 5 pathologists was 0.67.9
Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.10 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. These studies suggest if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both studies were retrospective so attention was not always given to including the tumor edge and adjacent lung. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.
REFERENCES
1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.
2. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.
3. Aly RG, et al. Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung. J Thorac Oncol 2019.
4. Yokoyama S, et al. Tumor Spread Through Air Spaces Identifies a Distinct Subgroup With Poor Prognosis in Surgically Resected Lung Pleomorphic Carcinoma. Chest 2018;154:838-47.
5. Liu H, et al. Prognostic Impact of Tumor Spread Through Air Spaces in Non-small Cell Lung Cancers: a Meta-Analysis Including 3564 Patients. Pathol Oncol Res 2019.
6. Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.
7. Uruga H, et al. Will spread through air spaces be a staging parameter in lung cancer? Journal of thoracic disease 2018;10:593-6.
8. Dai C, et al. Tumor Spread through Air Spaces Affects the Recurrence and Overall Survival in Patients with Lung Adenocarcinoma >2 to 3 cm. J Thorac Oncol 2017;12:1052-60.
9. Eguchi T, et al. Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis. J Thorac Oncol 2019;14:87-98.
10. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-39 - Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers (ID 1529)
09:45 - 18:00 | Author(s): Natasha Rekhtman
- Abstract
Background
Targeted therapy for Class I BRAF mutant lung cancers (V600) is well described and there is growing literature on their response to immune checkpoint inhibitors (ICI). In contrast, the molecular characteristics, immunophenotype, and response rates of class II and III BRAF mutations are not well defined.
Method
Patients with BRAF Class I, II, III mutant and variants of unknown significance (VUS) lung cancers detected on NGS (MSK-IMPACT) from 1/2014-1/2018 were identified. PD-L1 by immunohistochemistry (E1L3N) was evaluated. Tumor mutation burden (TMB; mut/Mb) was determined by MSK-IMPACT. Best objective response to ICI was assessed by RECIST v1.1. Time to treatment discontinuation (TTD) and overall survival (OS) were assessed. Statistical analysis was performed with Fisher’s exact and Kaplan-Meier. BRAF V600 lung cancers were used as a comparator and analyzed separately from BRAF non-V600.
Result
6.0% (177/2962) of lung cancers harbored a BRAF-mutation. Median TMB of BRAF non-V600 mutant lung cancers was 10.8 mut/Mb (n=136) overall compared to 4.9 mut/Mb in V600 (n=41; p<0.0001) and 5.9 mut/Mb in BRAF wild-type patients (n=2785; p<0.0001). 69% (127/177) of BRAF-mutant cases were metastatic (29 Class I, 36 Class II, 23 Class III, and 39 VUS). 57% of patients were female, 82% were smokers, and 90% were adenocarcinoma. More smokers were seen in the BRAF V600 group than in the non-V600 group (n = 16 vs 88 respectively, p<0.0001). PD-L1 expression in 49 non-V600 cases with available tissue was 0%, 1-49%, and >50% in 59% (n=29), 31% (n=15), and 10% (n=5) respectively. 7 BRAF V600 cases with PDL1 testing had expression of 0%, 1-49%, and >50% in 2, 3, and 2 cases, respectively. No BRAF V600 cases had concurrent RAS/NF1-alterations compared to 11 non-V600 (p=0.07).
36 patients with BRAF non-V600 mutations received ICI (nivolumab (n=25), pembrolizumab (n=5), atezolizumab (n=2), ipilimumab/nivolumab (n=4); median line of therapy=2) with an ORR of 22% (8/36). 10 BRAF V600 mutant lung cancer patients received ICI (nivolumab (n=5), pembrolizumab (n=2), atezolizumab (n=1), ipilimumab/nivolumab (n=2); median line of therapy=2) with an ORR of 10% (1/10). There was no difference in ORR between non-V600 and V600 patients that received ICI (p=0.66). TTD in BRAF non-V600 was 3.2 months compared to 1.4 months for BRAF V600 mutant lung cancer patients (HR 0.59, p=0.26). Median TMB in patients with BRAF non-V600 mutations that responded vs those who did not was 13.2 and 10.8 mut/Mb respectively (p=0.92). One response to ICI was seen in a BRAF V600 with TMB of 19.3. OS of BRAF non-V600 patients was 1.7 years compared to 2.5 years in V600 (HR 1.25, p=0.38). OS was higher in BRAF non-V600 lung cancer patients who received ICI (2.4 years) compared to those that did not (1.2 years; HR 0.60, p=0.04).
Conclusion
The molecular characteristics and immunophenotype of BRAF non-V600 mutant lung cancers is typified by high TMB and low PD-L1 expression, with reasonably higher response rates and improved OS to later line ICI compared to BRAF V600. Further studies of immunotherapy in this oncogene subset is warranted.
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-06 - Tissue-Based Molecular and Histologic Landscape of Acquired Resistance to Osimertinib in Patients with EGFR-Mutant Lung Cancers (ID 1392)
09:45 - 18:00 | Author(s): Natasha Rekhtman
- Abstract
Background
Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after acquiring EGFR T790M on treatment with another EGFR inhibitor. Other studies of osi resistance have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements.
Method
To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had targeted next-generation sequencing (MSK-IMPACT) performed on tumor tissue obtained before treatment and after developing resistance to osi received as either first-line or later line EGFR-TKI.
Result
From January 2016 to March 2019, we collected paired pre-treatment and resistance specimens from 53 patients (1st line osi: 21. Osi after prior TKI: 32). MOR are summarized in the table. Histologic transformation was identified in 18% of 1st line cases and 17% of all cases. When osi was given as initial treatment, with median follow up of 18 months, early emerging MOR rarely included on-target resistance mechanisms (acquired EGFR G724S in 1/21). Other acquired alterations representing potential resistance mechanisms not listed in the table included CCNE1 and MYC amplifications, and mutations in MTOR A1098S and MET H1094Y.
ConclusionFirst line (n = 21)
Osi after prior TKI
(n = 32)
All
(n = 53)
Squamous transformation
3
3
6
Neuroendocrine transformation
1
2
3
On target mutation (EGFR C797X or other)
1
9
10
Loss of EGFR T790M only
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8
8
Fusions (ALK, RET, BRAF)
0
3
3
Amplifications (HER2, MET, EGFR)
2
3
4
Off target mutations (KRAS, BRAF, HER2)
1
2
3
In this analysis of MOR identified on NGS from tumor tissue, we found a spectrum of resistance mechanisms to osi. By evaluating tissue rather than plasma we provide data on histologic transformation (including squamous cell transformation). Subsequent studies are needed to assess patients with a longer time on initial osi as early progressors may have different MOR, with off-target MOR emerging earlier and on-target resistance mutations later.
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P1.14-50 - A Phase 2 Trial of Cabozantinib in ROS1-Rearranged Lung Adenocarcinoma (Now Available) (ID 2753)
09:45 - 18:00 | Author(s): Natasha Rekhtman
- Abstract
Background
To date, no ROS1 inhibitor is approved for the treatment of ROS1-rearranged lung cancers after progression on crizotinib. Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.
Method
In this single-center, open-label, Simon two-stage, phase 2 study, eligible patients had ROS1-rearranged unresectable/metastatic non-small cell lung cancer, a Karnofsky performance status >70%, and measurable disease. ROS1 fusion was identified by local testing in a CLIA-compliant environment. Cabozantinib was dosed at 60 mg once daily. The primary endpoint was objective response (RECIST v1.1). In the first stage of this trial, 1 response was required to move to the second stage. Secondary endpoints included safety.
Result
Six patients received cabozantinib in the ongoing first stage of this study. All patients had >1 prior ROS1 inhibitor. The median age was 59 years; all were never smokers. The best response to therapy was: 1 partial response (-92%, confirmed), 1 unconfirmed partial response (-31%), and 4 stable disease. All patients had disease regression (-7 % to -92%); no patients had primary progressive disease. The only patient with a confirmed partial response was a patient whose cancer acquired a ROS1D2033N solvent front mutation after crizotinib. None of the other five ROS1 inhibitor pre-treated patients (who did not have a confirmed response) had a known on-target acquired resistance mutation in their cancer. After progression on cabozantinib (9.1 months after therapy initiation), the patient whose cancer harbored the ROS1D2033N mutation acquired a METD1228N kinase domain mutation on paired sequencing of pre-cabozantinib and post-progression tumor. The most common grade 3 treatment-related adverse events were hypertension (50%), and mucositis, palmar-plantar erythrodysesthesia, and hypophosphatemia (each in 17%). Most patients (83%) required a dose reduction.
Conclusion
Cabozantinib can re-establish disease control in ROS1-rearranged lung cancers after progression on a prior ROS1 inhibitor. The first stage of this ongoing trial met its prespecified endpoint for efficacy to move into the second stage. Response was only observed in the setting of a known ROS1 kinase domain resistance mutation.
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P2.09 - Pathology (ID 174)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.09-24 - IASLC Global Survey for Pathologists on PD-L1 Testing for Non-Small Cell Lung Cancer (ID 906)
10:15 - 18:15 | Author(s): Natasha Rekhtman
- Abstract
Background
PD-L1 immunohistochemistry (IHC) is now performed for advanced non-small cell lung cancer (NSCLC) patients to examine their eligibility for pembrolizumab treatment, as well as in Europe for durvalumab therapy after chemoradiation for stage III NSCLC patients. Four PD-L1 clinical trial validated assays (commercial assays) have been FDA/EMA approved or are in vitro diagnostic tests in multiple countries, but high running costs have limited their use; thus, many laboratories utilize laboratory-developed tests (LDTs). Overall, the PD-L1 testing seems to be diversely implemented across different countries as well as across different laboratories.
Method
The Immune biomarker working group of the IASLC international pathology panel conducted an international online survey for pathologists on PD-L1 IHC testing for NSCLC patients from 2/1/2019 to 5/31/2019. The goal of the survey was to assess the current prevalence and practice of the PD-L1 testing and to identify issues to improve the practice globally. The survey included more than 20 questions on pre-analytical, analytical and post-analytical aspects of the PDL1 IHC testing, including the availability/type of PD-L1 IHC assay(s) as well as the attendance at a training course(s) and participation in a quality assurance program(s).
Result
344 pathologists from 310 institutions in 64 countries participated in the survey. Of those, 38% were from Europe (France 13%), 23% from North America (US 17%) and 17% from Asia. 53% practice thoracic pathology and 36%, cytopathology. 11 pathologists from 10 countries do not perform PD-L1 IHC and 7.6% send out to outside facility. Cell blocks are used by 75% of the participants and cytology smear by 9.9% along with biopsies and surgical specimens. Pre-analytical conditions are not recorded in 45% of the institutions. Clone 22C3 is the most frequently used (61.5%) (59% with the commercial assay; 41% with LDT) followed by clone SP263 (45%) (71% with the commercial assay; 29% with LDT). Overall, one or several LDTs are used by 57% of the participants. A half of the participants reported turnaround time as 2 days or less, while 13% reported it as 5 days or more. Importantly, 20% of the participants reported no quality assessment, 15%, no formal training session for PD-L1interpretation and 14%, no standardized reporting system.
Conclusion
There is marked heterogeneity in PD-L1 testing practice across individual laboratories. In addition, the significant minority reported a lack of quality assurance, formal training and/or standardized reporting system that need to be established to improve the PD-L1 testing practice globally.
