Worse Disease-Free Survival in Never-Smokers with ALK+ Lung Adenocarcinoma

Abstract

Introduction The EML4–anaplastic lymphoma kinase (ALK) translocation is a recognized oncogenic driver in non-small cell lung cancer. We investigated immunohistochemistry (IHC) screening with fluorescence in-situ hybridization (FISH) confirmation for ALK detection and estimated the prevalence of ALK-positivity in our patient cohort of never smokers, together with differences in clinical outcomes and prognostic factors for patients with ALK-positive and ALK-negative tumors. Methods We designed a three-phase study (training, validation, and testing) in 300 never-smokers with lung adenocarcinoma from the observational Mayo Clinic Lung Cancer Cohort. Tumor samples were tested using IHC and FISH, and concordance between the methods was assessed. Clinical outcomes were assessed via 5-year progression or recurrence-free survival from diagnosis. Prognostic factors for ALK-positive tumors and metastases were also investigated. Results ALK-positive patients were significantly (p<0·05) younger and had higher-grade tumors than ALK-negative patients. ALK-positivity was 12.2% by IHC and confirmed at 8.2% of tumors by FISH, with complete concordance between IHC 3+/0 and FISH+/− assessments, respectively. Five-year risk of progression or recurrence was doubled for patients with ALK-positive compared with ALK-negative tumors; ALK-positive tumors also appeared to be associated with a higher risk of brain and liver metastases. Conclusions Our findings suggest that ALK-positivity is associated with a significantly poor outcome in non-smoking-related adenocarcinoma, and that ALK-positive tumors may be associated with an increased risk of brain and liver metastases compared with ALK-negative disease. Consequently, an unmet medical need exists in ALK-positive lung cancer patients, and effective ALK-specific therapies are needed now.

SUV_max and Tumour Location in PET-CT Predict Oncogene Status in Lung Cancer

“…There is limited data on the prognosis of ALK + patients in the absence of ALK TKI treatment. Whereas 1 study suggested similar outcomes [24], another study indicated potentially inferior survival [25], which would support our observation of a potentially more aggressive (metabolically active) disease resulting in an increased SUV max . Our findings of a more aggressive tumour biology of ALK + NSCLC are supported by previous observations: ALK + NSCLC tends to occur in younger patients and those with more advanced disease while this relationship has not been reported for EGFR + NSCLC [26,27].…”

Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology

“…On the other hand, Kim et al were able to demonstrate that patients with ALK-rearranged NSCLC had a significant worse OS outcomes after factoring in age, sex, histology, stage, and performance status [103]. Similarly, Yang et al found that EML4-ALK status is a poor prognostic factor for relapse-free survival after factoring in stage, sex, age, and treatment [104].…”

Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome

“…Point mutations and multiple alk gene copies have been detected in neuroblastomas6 and inversions (eg, EML4-ALK) in a subset of non-small cell lung carcinomas (NSCLCs) 7. alk gene translocations have been associated with the subcellular topography of ALK protein detected by immunohistochemistry8 and can also be assessed with high specificity and sensitivity using fluorescent in situ hybridisation (FISH) 9 10…”