Complete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib

doi:10.1016/j.lungcan.2013.02.018

Lung Cancer

Volume 81, Issue 1, July 2013, Pages 142-143

https://doi.org/10.1016/j.lungcan.2013.02.018 Get rights and content

Abstract

A 55-year-old Caucasian woman with lung adenocarcinoma stage IV presented with repeated relapse after treatment with cytotoxic chemotherapy (carboplatin, gemcitabine, docetaxel, pemetrexed) and targeted agents (erlotinib, cetuximab, sunitinib). Comprehensive molecular diagnostics (EGFR-, ALK-, RAS-, BRAF-, PIK3CA-, HER2- and DDR2-aberrations) were performed and failed initially to detect any driver mutation. While the patient suffered from rapid deterioration of her general condition, in particular from progressive dyspnea due to lung metastases, we implemented screening for RET- and ROS1 translocations into our molecular diagnostic program based on recent reports of these new molecular subgroups in lung adenocarcinoma. On retesting the patient's tumor sample was found to harbor a ROS1-translocation. The patient was subsequently treated with crizotinib and experienced a pronounced clinical improvement corresponding to a complete metabolic response in ¹⁸F-FDG-PET and a good and confirmed partial response in CT (RECIST 1.1). Our case exemplifies the need for rapid implementation of newly discovered rare genetic lung cancer subtypes in routine molecular diagnostics.

Introduction

Deregulation of the receptor tyrosine kinase ROS1 by gene fusion, overexpression or mutation leads to activation of downstream signaling pathways among them the PI3K/AKT – and the RAS/RAF/MAPK pathways [1]. Recently, ROS1 gene fusions were detected in about 1% of lung adenocarcinomas [2]. Since a high homology exists between the kinase domains of ROS1 and ALK, ALK inhibitors were tested and shown to be inhibitory in ROS1 positive cell lines and tumors. Recent reported results of a phase I trial for treatment of ROS1 positive lung cancer patients with the ALK-inhibitor crizotinib in the US suggests high clinical efficacy [3].

Section snippets

Case report

In January 2008 stage IV lung adenocarcinoma (cT4, cNx, M1a; EGFR-wild-type) was diagnosed in a 55-year-old Caucasian female never-smoker. The patient was treated within a clinical trial with 2 cycles of gemcitabine/cetuximab followed by 2 cycles of docetaxel/cetuximab and cetuximab maintenance. In January 2009 ¹⁸F-FDG-PET/CT revealed new lesions in the left upper and both lower lobes. Second line treatment with 6 cycles of carboplatin/gemcitabine resulted in tumor control until April 2010,

Conclusion

Here we report to our knowledge the first European lung cancer patient with ROS1 rearrangement and excellent response to crizotinib. Our patient exemplifies not only the high efficacy of crizotinib in this new genetically defined lung cancer subtype, but also the necessity of rapid implementation of comprehensive molecular diagnostics including newly discovered rare genetic lung cancer subtypes like ROS1 and RET rearrangements in order to deliver new personalized treatment approaches to all

Conflict of interest statement

Jürgen Wolf Consultant/Advisory role: Pfizer.

Lucia Nogova Other Remuneration: Pfizer.

Acknowledgment

We thank the patient for assenting to this publication. Supported by the state of North Rhine-Westfalia (NRW), Germany and the EUROPEAN UNION, European Regional Development Fund, grant no. FKZ:005-111-0027.

References (3)

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The multifaceted roles of the receptor tyrosine kinase ROS in development and cancer
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ROS1 rearrangement was pivotally identified as a potential target for ROS1 kinase inhibition on the basis of preclinical evidences in cell lines [11,65]. Before evidence from clinical studies was available, single reports [3,66] and case series [67] had testified the impressive efficacy of crizotinib administration in ROS1-positive lung cancers. The clinical results of crizotinib in patients harboring ROS1 rearrangement across clinical trials is reported in Table 2.
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¹: MB and MG share equal first authorship.

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Early reportComplete metabolic response in a patient with repeatedly relapsed non-small cell lung cancer harboring ROS1 gene rearrangement after treatment with crizotinib