Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib

Jingjing Li; Bin Zhang; Yu Zhang; Feng Xu; Zhenfa Zhang; Lin Shao; Chunhe Yan; Paola Ulivi; Marc G Denis; Petros Christopoulos; Vincent Thomas de Montpréville; Eric H Bernicker; Anthonie J van der Wekken; Changli Wang; Dongsheng Yue

doi:10.21037/tlcr-21-160

Concomitant mutation status of ALK-rearranged non-small cell lung cancers and its prognostic impact on patients treated with crizotinib

Transl Lung Cancer Res. 2021 Mar;10(3):1525-1535. doi: 10.21037/tlcr-21-160.

Authors

Affiliations

¹ Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin, China.
² Burning Rock Biotech, Beijing, China.
³ Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
⁴ Department of Biochemistry and INSERM U1232, Nantes University Hospital, Nantes Cedex, France.
⁵ Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases at the Heidelberg University Hospital, Heidelberg, Germany.
⁶ Translational Lung Research Center Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany.
⁷ Service d'Anatomie Pathologique, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
⁸ Houston Methodist Hospital, Cancer Center, Houston, TX, USA.
⁹ University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.

Abstract

Background: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement characterizes a subgroup of patients who show sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, the prognoses of these patients are heterogeneous. A better understanding of the genomic alterations occurring in these tumors could explain the prognostic heterogeneity observed in these patients.

Methods: We retrospectively analyzed 96 patients with NSCLC with ALK detected by immunohistochemical staining (VENTANA anti-ALK(D5F3) Rabbit Monoclonal Primary Antibody). Cancer tissues were subjected to next-generation sequencing using a panel of 520 cancer-related genes. The genomic landscape, distribution of ALK fusion variants, and clinicopathological characteristics of the patients were evaluated. The correlations of genomic alterations with clinical outcomes were also assessed.

Results: Among the 96 patients with immunohistochemically identified ALK fusions, 80 (83%) were confirmed by next-generation sequencing. TP53 mutation was the most commonly co-occurring mutation with ALK rearrangement. Concomitant driver mutations [2 Kirsten rat sarcoma viral oncogene homolog (KRAS) G12, 1 epidermal growth factor receptor (EGFR) 19del, and 1 MET exon 14 skipping] were also observed in 4 adenocarcinomas. Echinoderm microtubule associated protein-like 4 (EML4)-ALK fusions were identified in 95% of ALK-rearranged patients, with 16.2% of them also harboring additional non-EML4-ALK fusions. Nineteen non-EML4 translocation partners were also discovered, including 10 novel ones. Survival analyses revealed that patients concurrently harboring PIK3R2 alterations showed a trend toward shorter progression-free survival (6 vs. 13 months, P=0.064) and significantly shorter overall survival (11 vs. 32 months, P=0.004) than did PIK3R2-wild-type patients. Patients with concomitant alterations in PI3K the signaling pathway also had a shorter median overall survival than those without such alterations (23 vs. 32 months, P=0.014), whereas progression-free survival did not differ significantly.

Conclusions: The spectrum of ALK-fusion variants and the landscape of concomitant genomic alterations were delineated in 96 NSCLC patients. Our study also demonstrated the prognostic value of concomitant alterations in crizotinib-treated patients, which could facilitate improved stratification of ALK-rearranged NSCLC patients in the selection of candidates who could optimally benefit from therapy.

Keywords: ALK fusion; Anaplastic lymphoma kinase rearrangement (ALK rearrangement); concomitant mutation; crizotinib; next-generation sequencing (NGS); non-small cell lung cancer (NSCLC).