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A.C. Borczuk
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.07 - HHLA2, a New Immune Checkpoint Member of the B7 Family, is Widely Expressed in Human Lung Cancer and Associated with Mutational Status (ID 5184)
11:55 - 12:05 | Author(s): A.C. Borczuk
- Abstract
- Presentation
Background:
Immunotherapy with antibodies against B7/CD28 family members, including PD-1, PD-L1, and CTLA-4 has shifted the treatment paradigm for non-small-cell lung carcinoma (NSCLC) with improved clinical outcome. HHLA2 is a newly discovered member of the family. By regulating T-cell function, HHLA2 could contribute to tumor immune suppression and thus be a novel target for cancer immunotherapy. There is limited information and critical need to characterize its expression profile and clinical significance in NSCLC.
Methods:
We performed immunohistochemistry with an HHLA2-specific antibody (clone 566.1) using tissue microarrays constructed from 679 NSCLC tumor tissues, including 392 cases in the discovery set and 287 cases in the validation cohort. We also studied clinico-pathological characteristics of these patients.
Results:
Overall, HHLA2 was not detected in most of normal lung tissue but expressed in 66% of NSCLC across different subtypes. In particular, EGFR–mutated NSCLC was significantly associated with higher tumor HHLA2 expression in both discovery (EGFR vs. WT: 76% vs. 53%, P=0.01) and validation cohorts (89% vs. 69%, P=0.01). In one of the two cohorts, HHLA2 expression was higher in lung adenocarcinoma as compared to squamous and large cell histology, non-Hispanic White vs. Hispanics, and tumors with high tumor infiltrating lymphocyte (TIL) density. In the multivariate analysis, EGFR mutation status and high TIL intensity were independently associated with HHLA2 expression in lung adenocarcinoma.
Conclusion:
HHLA2 is widely expressed in NSCLC and is associated with EGFR mutation and high TILs in lung adenocarcinoma. It is potentially a novel target for lung cancer immunotherapy.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-056 - Distinct PD-L1 Expression in Different Components of Pulmonary Sarcomatoid Carcinoma and Its Association with MET Mutation (ID 5228)
14:30 - 14:30 | Author(s): A.C. Borczuk
- Abstract
Background:
Pulmonary Sarcomatoid Carcinoma (PSC) is a unique and highly aggressive subtype of non-small cell lung cancer (NSCLC), characterized by a component of sarcoma or sarcoma-like differentiation. It is generally resistant to platinum-based chemotherapy. However, frequent KRAS and the MET exon 14 skipping mutations have been reported in this subtype. Recently, immunotherapy with antibodies against PD-1/PD-L1 has led to clinical benefits in managing NSCLC. Immune biomarker expression of PD-L1 in differential components of PSC and its relationship with other molecular markers has not been defined and thus there is critical need to investigate its expression profile in this deadly disease.
Methods:
We investigated PD-L1 expression by immunohistochemistry (IHC) using tissue microarrays from a cohort of 41 patients with PSC (antibody: PD-L1/CD274 (SP142)). Positive cases were defined as PD-L1 ≥ 1%. The clinical and molecular characterization of these cases was previously reported (PMID: 26215952). Among the 41 cases, 36 had sufficient tumor tissue for PD-L1 assessment, 8 (20%) were identified with MET exon 14 skipping mutation and 6 (15%) were found to have KRAS mutations.
Results:
The PD-L1 expression was positive in 75% (27/36) of cases. Among the positive cases, 78% expressed PD-L1 ≥ 50%, whereas 22% had PD-L1 staining of 1-49%. Interestingly, only 33% (9/27) had PD-L1 expression in both epithelial and sarcomatoid components, whereas the remaining 66% detected PD-L1 in just one component. The PD-L1 expression was statistically different between the two components (P=0.007). Moreover, all 8 patients with MET exon 14 skipping mutation were PD-L1 positive (6 with PD-L1 ≥ 50%), whereas 5 of 6 patients with KRAS mutation expressed PD-L1 (2 with PD-L1 ≥ 50%). The average age at diagnosis was similar between the PD-L1 positive vs. negative groups (71 years). There was a trend of shorter overall survival in patients whose tumors were positive for PD-L1 (671 vs. 985 days).
Conclusion:
In our particular cohort of PSC patients, high PD-L1 (≥ 50%) was expressed in the large majority of cases which favors potential application of immunotherapy in this disease. In addition, it appears that the expression of PD-L1 is different in the epithelial and sarcomatoid components which could affect scoring in practice. Furthermore, the overall positivity of PD-L1 expression in the unique molecular subtype of PSC patients with MET exon 14 skipping mutation indicates potential interplay between the two biomarkers and suggests that exploration of combination MET and immunotherapy in this subtype is warranted.
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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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P3.01-021 - Reproducibility of Comprehensive Histologic Assessment and Refining Histologic Criteria in P Staging of Multiple Tumour Nodules (ID 5365)
14:30 - 14:30 | Author(s): A.C. Borczuk
- Abstract
Background:
Multiple tumor nodules (MTNs) are being encountered, with increasing frequency with the 8[th] TNM staging system recommending classification as separate primary lung cancers (SPLC) or intrapulmonary metastases (IM). Pathological staging requires assessment of morphological features, with criteria of Martini and Melamed supplanted by comprehensive histologic assessment of tumour type, predominant pattern, other histologic patterns and cytologic features. With publication of the 2015 WHO classification of lung tumours, we assessed the reproducibility of comprehensive histologic assessment and also sought to identify the most useful histological features.
Methods:
We conducted an online survey in which pathologists reviewed a sequential cohort of resected multifocal tumours to determine whether they were SPLC, IM, or a combination. Specific histological features for each nodule were entered into the database by the observing pathologist (tumour type, predominant adenocarcinoma pattern, and histological features including presence of lepidic growth, intra-alveolar cell clusters, cell size, mitotic rate, nuclear pleomorphism, nucleolar size and pleomorphism, nuclear inclusions, necrosis pattern, vascular invasion, mucin content, keratinization, clear cell change, cytoplasmic granules¸ lymphocytosis, macrophage response, acute inflammation and emperipolesis). Results were statistically analyzed for concordance with submitting diagnosis (gold standard) and among pathologists. Consistency of each feature was correlated with final determination of SPLC vs. IM status (p staging) by chi square analysis and Fisher exact test.
Results:
Seventeen pathologists evaluated 126 tumors from 48 patients. Kappa score on overall assessment of primary v. metastatic status was 0.60. There was good agreement as measured by Cohen’s Kappa (0.64, p<0.0001) between WHO histological patterns in individual cases with SPLC or IM status but proportions for histology and SPT or IM status were not identical (McNemar's test, p<0.0001) and additional histological features were assessed. There was marked variation in p values among the specific histological features. The strongest correlations (<0.05) between p staging status and histological features were with nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intra-alveolar clusters and necrosis pattern. Correlation between lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization and emperipolesis did not reach a p value of 0.05.
Conclusion:
Comprehensive histologic assessment shows good reproducibility between practicing lung pathologists. In addition to main tumour type and predominant patterns, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate appear to be useful in distinguishing between SPLC and IM.
