Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: A systematic review

Abstract

Copyright and moral rights to this thesis/research project are retained by the author and/or other copyright owners. The work is supplied on the understanding that any use for commercial gain is strictly forbidden. A copy may be downloaded for personal, non-commercial, research or study without prior permission and without charge. Any use of the thesis/research project for private study or research must be properly acknowledged with reference to the work's full bibliographic details.This thesis/research project may not be reproduced in any format or medium, or extensive quotations taken from it, or its content changed in any way, without first obtaining permission in writing from the copyright holder(s).If you believe that any material held in the repository infringes copyright law, please contact the Repository Team at Middlesex University via the following email address:The item will be removed from the repository while any claim is being investigated. Methods: A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFRTKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated.Results: Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150 mg/day erlotinib and 250 mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients.Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for ...

EGFR–TKI is effective regardless of treatment timing in pulmonary adenocarcinoma with EGFR mutation

“…Although the RR was not different according to the treatment timing in this study, some studies have shown that the RR to gefitinib in chemotherapy-naive patients was higher than that in patients with prior chemotherapy [22,23]. However, no general cross-resistance has been demonstrated and EGFR-TKIs are suitable for the treatment of patients with NSCLC who have been treated with platinum-based therapy, particularly those with EGFR mutation-positive tumors [24]. Several studies, including our data, showed no statistical difference between chemotherapy-naive patients and patients who had received prior chemotherapy in terms of PFS or time to progression [10,22].…”

MicroRNA‐133b inhibits the growth of non‐small‐cell lung cancer by targeting the epidermal growth factor receptor

“…EGFR-TKIs have limited but valuable activity in previously treated NSCLC patients. EGFR mutation (exons [18][19][20][21], increased EGFR copy number or increased expression of EGFR/phosphorylated EGFR (pEGFR) leads to significantly improved response rates to EGFR-TKIs in patients with pretreated NSCLC [2]. These biomarkers are not mutually exclusive, and the expression of EGFR may predict EGFR gene status (including copy number and mutation) to some extent [3].…”

Lentivirus-Mediated RNAi Silencing Targeting ERCC1 Reverses Cisplatin Resistance in Cisplatin-Resistant Ovarian Carcinoma Cell Line

“…Compared with low levels of ERCC1, high ERCC1 levels were associated with shorter survival and poor prognosis in patients with nonsmall-cell carcinoma, which was not related to clinical therapy (Milovic-Kovacevic et al, 2011;Murphy and Stordal, 2011;Rubatt et al, 2012). High expression level of ERCC1 is one of the predictive indicators for poor effects of platinum-based chemotherapy (Li et al, 2014).…”