A targeted expression panel for classification, gene fusion detection and PD-L1 measurements – Can molecular profiling replace immunohistochemistry in non-small cell lung cancer?

The histological classification of non-small-cell lung cancer (NSCLC) and identification of possible therapeutic targets are important for disease management. However, as biopsies are often small, with a limited amount of tumor cells, it can be challenging to obtain enough tissue for the needed number of diagnostic immunohistochemical stains and molecular analyses. In this study, we combined a small custom designed targeted expression panel with a commercial fusion transcript assay by which we were able to perform both a histological classification (transcribing the expression of the genes encoding TTF1, Napsin A, CK5/6, and the truncated P63 isoform ΔNp63 (p40) into either adenocarcinoma or squamous cell carcinoma) and an identification of fusion genes involving ALK, RET, and ROS1. The expression panel also included the PD-L1 encoding gene, CD274, in order to evaluate the PD-L1 mRNA potential for identification of patients who will benefit from immune checkpoint inhibitor treatment. We evaluated the panel using 42 NSCLC patient samples. The molecular profiling agreed with the original immunohistochemistry (IHC)-based classification in 93% of the cases. For ten of the patients, being fusion gene positive, the fusion transcripts were detected in 100%. The molecular assessment of PD-L1 also showed agreement with the original assessment made by IHC. In conclusion, this study presents a small, targeted expression panel with the potential to perform both a molecularly based histological classification and a fusion gene identification in NSCLC patients as well as identifying PD-L1 status from a very limited amount of starting material. READ ARTICLE

Experimental and Molecular Pathology DOI:10.1016/j.yexmp.2022.104749

Authors: Anita Tranberg Simonsen, Amalie Utke, Johanne Lade-Keller, Lasse Westphal Thomsen, Torben Steiniche, Magnus Stougaard

Case StudyKirk SmithApril 1, 2022RNA expression, NSCLC, NGS, Gene fusion, PD-L1

Genetic alteration and PD-L1 expression profiles of Chinese patients with lung squamous cell carcinoma

Backgrounds: Despite the achievements made in treating lung cancer during the past decades, lung cancer still leads in cancer incidence and mortality worldwide. Compared to lung adenocarcinoma, the gene mutation profiles of Chinese lung squamous cell carcinoma (SQCC) have not been well established yet... Conclusion: Our study identified unique genomic profiles of Chinese SQCC patients and provided novel insights into the detection of additional actionable genes and ctDNA in further genotyping. Genetic testing on expanded panel merits further study to comprehensive understanding the therapeutic value of targetable alterations in Chinses SQCC patients. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2022.153761

Authors: Ying Chen, Wencui Kong, Zongyang Yu, Zhongquan Zhao

New Insights into the Clinical Implications of Yes-Associated Protein in Lung Cancer: Roles in Drug Resistance, Tumor Immunity, Autophagy, and Organoid Development

Innovative advancements in lung cancer treatment have developed over the past decade with the advent of targeted and immune therapies. Yes-associated protein (YAP), an effector of the Hippo pathway, promotes the resistance of these targeted drugs and modulates tumor immunity in lung cancer. YAP is involved in autophagy in lung cancer and plays a prominent role in forming the tubular structure in lung organoids and alveolar differentiation. In this review, we discuss the central roles of YAP in lung cancer and present YAP as a novel target for treating resistance to targeted therapies and immunotherapies in lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13123069

Authors: Yoo G, Park D, Kim Y and Chung C.

Review Paper, group5Kirk SmithJune 17, 2021YAP, TAZ, Hippo pathway, lung cancer, drug resistance, EGFR-TKI, PD-L1, autophagy, organoid

Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma

We present a case study of a 32-year-old female patient with ALK-rearrangement-positive LCNEC, who had multiple distant metastases including mediastinal lymph-node, bilateral breasts, multiple bones, liver and brain. Multiple biopsy samples obtained from primary lung and three metastatic tumors were analyzed by fluorescent multiplex immunohistochemistry. Tissue localizations of tumor-infiltrating lymphocytes in the tumor nest and surrounding stroma were evaluated. T cell and B cell infiltrations were decreased with distance from primary lung lesion. Although each tumor displayed a unique TIME, all tumors exhibited concomitant regression after treatment with an ALK-inhibitor. This study provides the first evidence of the coexistence of distinct TIME within a single individual with ALK-rearrangement-positive LCNEC. The present study contributes to our understanding of heterogeneous TIMEs between primary and metastatic lesions and provides new insights into the complex interplay between host-immunity and cancer cells in primary and metastatic lesions. READ ARTICLE

International Journal of Molecular Science DOI: 10.3390/ijms21249705

Authors: Tashiro T, Imamura K, Tomita Y, Tamanoi D, Takaki A, Sugahara K, Sato R, Saruwatari K, Sakata S, Inaba M, Ushijima S, Hirata N, Sakagami T

Impressive clinical response to anti-PD-1 therapy in epithelioid mesothelioma with high clonal PD-L1 expression and EML4-ALK rearrangement

Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.02.006

Authors: Giuseppe Bronte, Angelo Delmonte, Marco Angelo Burgio, Alberto Verlicchi, Maurizio Puccetti, Sara Bravaccini, Paola Cravero, Maria MaddalenaTumedei, Danila Diano, Giulio Rossi, Paola Ulivi, Giovanni Martinelli, Lucio Crinòa

Case StudyKirk SmithApril 1, 2020Mesothelioma, PD-L1, Immunotherapy, Immune checkpoint inhibitors, EML4-ALK

Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma

Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients’ survival...... READ ARTICLE

Virchows Archiv DOI:10.1007/s00428-019-02528-6

Authors: Elisa Schmoeckel, Sophie Hofmann, Daniel Fromberger, Miriam Rottmann, Beate Luthardt, Alexander Burges, Udo Jeschke, Thomas Kirchner, Sigurd F. Lax, Doris Mayr

Tobacco smoking and cessation and PD-L1 inhibitors in non-small cell lung cancer (NSCLC): a review of the literature

Background: Programmed death ligand 1 (PD-L1) targeting immunotherapies, as pembrolizumab and nivolumab, have significantly improved outcome in patients with non-small cell lung cancer (NSCLC). Tobacco smoking is the number one risk factor for lung cancer and is linked to 80%–90% of these cancers. Smoking during cancer therapy may influence on radiotherapy and chemotherapy outcome. We aimed to review the knowledge in immunotherapy... Conclusions: Tobacco smoking patients with NSCLC generally have a higher PD-L1 tumour proportion score and experience a better ORR of immunotherapy than no smokers. There is little evidence on the effect of smoking during immunotherapy, but one study (KEYNOTE-024) may indicate survival gains of smoking cessation. READ ARTICLE

ESMO Open DOI:10.1136/esmoopen-2018-000406

Authors: Jan Norum, Carsten Nieder

Review PaperKirk SmithJuly 1, 2018Lung cancer, PD-L1, immunotherapy, tobacco, smoking, cessation