Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel?

The clinical usefulness of assessing the enzymatic activity of CYPD6 in patients taking tamoxifen had been longly debated. In favour of preemptive evaluation of phenotypic profile of patients is the strong pharmacologic rationale, being that the formation of endoxifen, the major and clinically most important metabolite of tamoxifen, is largely dependent on the activity of CYP2D6. This enzyme is highly polymorphic for which the activity is largely depending on genetics, but that can also be inhibited by a number of drugs, i.e. antidepressants, which are frequently used in patients with cancer. Unfortunately, the clinical trials that have been published in the last years are contradicting each other on the association between CYP2D6 and significant clinical endpoints, and for this reason CYP2D6 genotyping is at present not generally recommended. Despite this, the CYP2D6 genotyping test for tamoxifen is available in many laboratories and it may still be an appropriate test to use it in specific cases.

Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy.

OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS: All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS: We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION: Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.