Among responsive wt patients, 5 showed a partial response with a median duration of 10 months (range 7C12 months) while the others had stable disease as a best response with a median response duration of 9

jamha January 5, 2023 0 Comments

Among responsive wt patients, 5 showed a partial response with a median duration of 10 months (range 7C12 months) while the others had stable disease as a best response with a median response duration of 9.5 months (range 6C14 months). Table 3 Clinical-pathological characteristics and type of response in mutated responder patients. sensitivity Del 1976MNoPDCSD (6)L858R *77FNoADCSD (10) mutation. with TKI sensitivity. wt, mutated NSCLC. Moreover, the EURTAC study [2] led to the approval of erlotinib (TARCEVA Genentech, Inc., South San Francisco, CA, USA and OSI Pharmaceuticals, Inc., Melville, NY, USA) in the same patient setting. In unselected populations, erlotinib has shown activity in about 10% of patients in terms of response rate and progression-free survival (PFS) [3,4,5]. For this reason, it has already been approved for the treatment of locally advanced or metastatic NSCLC after the failure of at least one prior chemotherapy regimen, regardless of status. However, recent work by Garassino and colleagues [6] showed that, in a second-line setting, chemotherapy is more effective than erlotinib in terms of response rate and progression-free survival (PFS) in wild type (wt) NSCLC patients. Two recent meta-analyses focusing on the role of TKIs in wt Kobe2602 patients confirmed the superiority of chemotherapy over TKIs in terms of PFS but not of overall survival (OS) [7,8]. However, in each of the studies reviewed there was a subgroup of wt patients who obtained a clinical benefit from TKI treatment, suggesting that factors other than mutation may lead to TKI sensitivity in a small number of patients. Other biological mechanisms may, in fact, be responsible for TKI sensitivity in wild type NSCLC patients, such as expression or phosphorylation, amplification, pathway [9]. Moreover, highly sensitive methods for the evaluation of status can lead to the identification of activating mutations not highlighted by other conventional methodologies, justifying the response to TKIs [10]. In the present study we characterized NSCLC wt patients responding to erlotinib to identify potential biological markers of sensitivity and resistance to TKIs on the basis of their clinical features. 2. Results In accordance with selection criteria, we identified 34 responsive patients among those treated with erlotinib in our institutions between January 2007 and June 2013. Median age was 69 years (range 44C88). Nineteen patients were male and 15 female. Twenty-five patients had adenocarcinoma (ADC), 6 had squamous cell carcinoma (SCC) and 3 had poorly differentiated carcinoma. Ten patients were current smokers, 8 former smokers and 8 non-smokers; smoking status was unknown Kobe2602 for 8 patients. An equal number of nonresponder patients, with similar characteristics for age, gender, smoking status and histotype, were analyzed. Patient characteristics are described in Table 1. Table 1 Patient characteristics. (level Kobe2602 of sensitivity)2 (3%)2 (6%)-(resistance)2 (3%)-2 (6%) L858R mutation; One of these individuals also experienced a G245C mutation. Among responders, the analysis performed by MassARRAY? System identified 2 individuals with sensitizing mutations, one exon 19 deletion and one point mutation in exon 21 (L858R), previously missed by Pyrosequencing. The patient with the L858R mutation showed a concomitant mutation in (N375S). No sensitizing mutations were seen in non-responders, but 2 showed exon 20 mutations (P753S and L747S). Mutation of gene was observed in 5 responders (15%) and in 5 non-responders (15%). In the former group, 2 individuals experienced G12C mutation of (40%), one G12V (20%), one G12D (20%) and one G13D (20%). Among non-responders, 4 experienced G12C mutations (80%) and one G12V mutations (20%). All mutated tumors were adenocarcinoma (ADC). Mutation of (R248Q) was recognized in one responder with ADC, and in 5 non-responders (G245C, R273L, R249S, Y220C, R158C), 2 of these inside a squamous cell carcinoma (SCC), 2 in ADC and one in large cell carcinoma. A higher mutation rate (15%) was observed in the nonresponder individuals as compared to responders (3%), (= 0.09). All mutated non-responsive patients were smokers, whereas the mutated responsive patient had by no means been a smoker. Mutation R2328W of the gene was present in one responsive SCC patient and in 3 non-responders (1 SCC and 2 ADC). Mutation S566Y of was found in one responsive and one non-responsive patient, both with ADC. In the non-responder group, one patient with ADC showed an E17K mutation in the gene. In the responsive group, 9 mutations (26%) were found in genes concerning proliferation pathways: (2 ADC with exon 9 E545K, and a poorly differentiated carcinoma with H1047R), (V600E.Paola Ulivi, Elisa Chiadini and Laura Capelli performed the biological determinations. has shown activity in on the subject of 10% of individuals in terms of response rate and progression-free survival (PFS) [3,4,5]. For this reason, it has already been approved for the treatment of locally advanced or metastatic NSCLC after the failure of at least one prior chemotherapy routine, regardless of status. However, recent work by Garassino and colleagues [6] showed that, inside a second-line establishing, chemotherapy is more effective than erlotinib in terms of response rate and progression-free survival (PFS) in crazy type (wt) NSCLC individuals. Two recent meta-analyses focusing on the part of TKIs in wt individuals confirmed the superiority of chemotherapy over TKIs in terms of PFS but not of overall survival (OS) [7,8]. However, in each of the studies reviewed there was a subgroup of wt individuals who acquired a clinical benefit from TKI treatment, suggesting that factors other than mutation may lead to TKI level of sensitivity in a small number of patients. Other biological mechanisms may, in fact, be responsible for TKI level of sensitivity in crazy type NSCLC individuals, such as manifestation or phosphorylation, amplification, pathway [9]. Moreover, highly sensitive methods for the evaluation of status can lead to the recognition of activating mutations not highlighted by other conventional methodologies, justifying the response to TKIs [10]. In the present study we characterized NSCLC wt individuals responding to erlotinib to identify potential biological markers of level of sensitivity and resistance to TKIs on the basis of their medical features. JAM2 2. Results In accordance with selection criteria, we recognized 34 responsive individuals among those treated with erlotinib in our organizations between January 2007 and June 2013. Median age was 69 years (range 44C88). Nineteen individuals were male and 15 female. Twenty-five patients experienced adenocarcinoma (ADC), 6 experienced squamous cell carcinoma (SCC) and 3 experienced poorly differentiated carcinoma. Ten individuals were current smokers, 8 former Kobe2602 smokers and 8 non-smokers; smoking status was unfamiliar for 8 individuals. An equal quantity of nonresponder individuals, with similar characteristics for age, gender, smoking status and histotype, were analyzed. Patient characteristics are explained in Table 1. Table 1 Patient characteristics. (level of sensitivity)2 (3%)2 (6%)-(resistance)2 (3%)-2 (6%) L858R mutation; One of these individuals also experienced a G245C mutation. Among responders, the analysis performed by MassARRAY? System identified 2 individuals with sensitizing mutations, one exon 19 deletion and one point mutation in exon 21 (L858R), previously missed by Pyrosequencing. The patient with the L858R mutation showed a concomitant mutation in (N375S). No sensitizing mutations were seen in non-responders, but 2 showed exon 20 mutations (P753S and L747S). Mutation of gene was observed in 5 responders (15%) and in 5 non-responders (15%). In the former group, 2 individuals experienced G12C mutation of (40%), one G12V (20%), one G12D (20%) and one G13D (20%). Among non-responders, 4 experienced G12C mutations (80%) and one G12V mutations (20%). All mutated tumors were adenocarcinoma (ADC). Mutation of (R248Q) was recognized in one responder with ADC, and in 5 non-responders (G245C, R273L, R249S, Y220C, R158C), 2 of these inside a squamous cell carcinoma (SCC), 2 in ADC and one in large cell carcinoma. A higher mutation rate (15%) was observed in the nonresponder individuals as compared to responders (3%), (= 0.09). All mutated non-responsive patients were smokers, whereas the mutated responsive patient had by no means been a smoker. Mutation R2328W of Kobe2602 the gene was present in one responsive SCC patient and in 3 non-responders (1 SCC and 2 ADC). Mutation S566Y of was found in one responsive and one non-responsive.