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Wendy Cooper
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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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ES12.03 - Tumor Heterogeneity (Now Available) (ID 3220)
15:15 - 16:45 | Presenting Author(s): Wendy Cooper
- Abstract
- Presentation
Abstract
While intertumoral heterogeneity is well recognised in many solid tumours including NSCLC, intratumoral heterogeneity has only recently gained attention. Heterogeneity of tumor morphology, protein expression, gene expression, epigenetic or genetic alterations has the potential to impact optimal biopsy strategies, diagnostic assessment, treatment decisions and clinical outcome.
Sequencing of NSCLC from multiple sites of disease shows frequent evidence of intratumoral heterogeneity in terms of genetic mutations, translocations and copy number alterations, although not to the same extent as seen in other tumor types, such as clear cell renal cell carcinoma. NSCLC studies have demonstrated a common pattern of intratumoral heterogeneity with main clonal driver mutations and branched evolutionary acquired mutations. Of clinical relevance, mutations in known lung cancer driver oncogenes (such as EGFR, BRAF and MET) are generally present in all tumor regions in keeping with early evolutionary events. This finding is consistent with the high response rates to tyrosine kinase inhibitors that target these genetic alterations, across multiple sites of disease.
Later subclonal driver mutations are found commonly in NSCLC and include alterations in genes such as PIK3CA and NF1. Metastatic sites can exhibit mutational profiles closely related to specific spatial regions of the primary tumor demonstrating that subclones can determine the course of systemic disease resulting in subclonal diversification. Clonal evolution is driven by multiple factors including selective pressure from targeted therapies and adaptive mechanisms due to interaction with immune cells and the microenvironment. Treatment resistance can occur due to acquisition and/or selection of clones and contributes to temporal heterogeneity. The hierarchy of genetic alterations can be used to trace clonal intratumoral heterogeneity although adequate sequencing depth is required to accurately assess for subclonal mutations.
Reassuringly, sequencing of a single region of a tumor should be sufficient to identify known targetable driver mutations as they generally occur early in the evolutionary course of the disease. The exact clinical significance of various subclonal mutations is less well understood. Intratumoral heterogeneity can potentially lead to sampling errors when single sites of disease are sampled for mutational events that may only exist in another metastatic site. For this reason, testing for genetic markers of treatment resistance may be more appropriately performed on circulating tumour DNA as the ctDNA may derive from multiple metastatic deposits, although lower sensitivity limits the effectiveness of this approach. Liquid biopsy approaches also have the advantage of providing a contemporaneous sample, more likely to reflect impact of most recent therapy.
Further investigation of spatial and temporal tumoral heterogeneity by comprehensive deep sequencing of multiple spatially discrete sites of disease at different time points may assist in understanding the complexity of intratumoral heterogeneity and could potentially impact optimal biopsy and treatment strategies, particularly when assessing for drug resistance.
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-26 - Prevalence of PD-L1 Expression Rates in Different NSCLC Specimens (ID 2125)
09:45 - 18:00 | Presenting Author(s): Wendy Cooper
- Abstract
Background
Programmed death-ligand 1 (PD-L1) expression on tumor cells by immunohistochemistry (IHC) is a predictor of response to immune checkpoint inhibitors used to treat advanced non-small cell lung cancer (NSCLC). High PD-L1 expression (≥50% of tumor cells) is required for patients to receive first line pembrolizumab monotherapy. Assessing expected PD-L1 expression rates in real-world specimens is an important factor in ensuring patients are accessing the most effective treatments available. The aim of this retrospective assessment was to review the local prevalence of PD-L1 expression in NSCLC and compare different specimen types.
Method
We retrospectively reviewed cases of NSCLC stained with PD-L1 IHC Ventana SP263 assay between January 2017 and March 2019. PD-L1 expression was assessed as a tumor proportion score (TPS) of 0-<1%, 1-49% or ≥50% positive membrane staining within tumor cells. Results were compared with specimen type and mutation status.
Result
PD-L1 expression was assessed in 264 cases of NSCLC during the 51 month period. The median patient age was 70 years, 64.4% were >65 years old and 60.9% were male.
Histologically, 79.9% were adenocarcinoma, 10.6% squamous cell carcinoma and 9.5% NSCLC-NOS. Overall 29.5% of NSCLC showed high PD-L1 expression (≥50%), 43.9% low (1-49%), and 26.5% no expression (<1%). In known EGFR/ALK negative cases (n=176), high, low and negative PD-L1 was seen in 34.7%, 43.2% and 22.1% respectively.
Histology samples accounted for 80.7% of cases and 19.3% were cytology. Lung resections accounted for 27.7% with other specimen types (small biopsies, cytology and metastatic resections) accounting for 72.3%. 61.0% were primary tumors and 39.0% were from metastases.
A PD-L1 TPS of ≥50% was seen in 29.1% of histology and 31.4% of cytology specimens, with no statistically significant difference (p=0.55). Amongst lung resections, high PD-L1 expression was observed in 19.2% of cases compared to 33.5% in other specimen types (p<0.01). In primary tumors, high PD-L1 expression was seen in 27.3% compared to 33.0% in metastases (p=0.51)
Of the cases that had mutation results available, only 8.8% of NSCLC haboring EGFR mutations expressed high PD-L1 expression (≥50%) compared to 44.1% of tumors with KRAS mutations (p<0.01).
Conclusion
Our overall prevalence of PD-L1 expression in cases of NSCLC is in keeping with rates demonstrated in a large clinical trial investigating the efficacy of pembrolizumab as first line treatment in NSCLC. The same rates of high PD-L1 in cytology and histology specimens suggest cytological specimens are valid for assessment.
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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): Wendy Cooper
- 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.
