2IN - From Molecular Biology to Lazarus Responses

Abstract

ABSTRACT Among the most dramatic incidents in oncology are the Lazarus responses, where moribund patients recover rapidly from the brink of death and return to their normal life. Gastrointestinal stromal tumour (GIST) was the first solid tumour where a tyrosine kinase inhibitor (TKI) proved highly effective, and where subsequently even Lazarus responses could be witnessed. In the 1990's GISTs were considered chemotherapy resistant, and patients survived only for a median of 1.5 years after the detection of metastases. This bleak outcome changed when Seiichi Hirota and his colleagues found activating mutations in KIT in 1998, and imatinib (an inhibitor of KIT) proved effective for GIST in 2001. At present, when also other effective TKIs besides imatinib are available, the median survival time of patients with advanced GIST is approximately 6 years, and up to 30% survive for 10 years or longer after initiation of therapy. Most patients have good quality of life and resume to their normal activities. Secondary mutations in the KIT exons that encode the ATP binding site of the kinase and reduce binding of ATP-mimetic TKIs are the most important cause for treatment failure. The risk of emergence of such mutations is likely the higher the greater the overall tumour mass, and treating patients early when the tumour mass is still small could lead to further survival benefits. Two large randomised trials found adjuvant imatinib to improve recurrence-free survival (RFS) but not overall survival (OS) as compared with placebo or observation, whereas a third trial found 3 years of imatinib to be superior to 1 year of imatinib in terms of both RFS and OS, suggesting that relatively long adjuvant treatment times may be needed for achieving OS benefits. Periodical imaging of the abdomen to detect recurrent disease early is likely beneficial. Research on novel agents with high efficacy will be of key importance, as will studies on concomitant and alternating administration of therapeutic agents, and trials testing longer adjuvant treatments. The transformation of an unresponsive and rapidly fatal disease to a disease where even miraculous Lazarus responses can be seen took place at a rapid pace in GIST. This was achieved by networking between researchers working in different sectors of cancer research. Disclosure: The author has declared no conflicts of interest.