China
Africa
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Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Despite the impressive response rates, the majority of patients stop responding to the initial EGFR TKI within approximately 10–12 months [19, 24–26]. The most common mechanisms of development of resistance to EGFR TKIs include development of resistance mutations in the EGFR gene; T790M is the most common resistance mutation accounting for almost half of the patients who develop resistance [27]. Other mechanisms include MET amplification (5%), EGFR overexpression (5%), small cell transformation (8%) and PIK3CA mutations (5%).
EML4-ALK Fusion Gene and Therapy with ALK-Targeted Agents in Non-Small Cell Lung Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Francisco E. Vera-Badillo, Janet E. Dancey
Several mechanisms of resistance to crizotinib have been described, with the most common being the development of a secondary mutations within the ALK tyrosine kinase domain. The most common resistance mutation is the gatekeeper L1196M mutation, followed by the G1269A mutation. The G1202R mutation is very important, as it confers high-level resistance to crizotinib and other next-generation EML4-ALK inhibitors. Amplification of the EML4-ALK fusion gene may cause resistance to ALK-TKIs and this event may arise de novo or emerge after initiation of crizotinib therapy. Lastly, but not less important, is the activation of alternative or bypass signaling pathways. These include abnormalities in EGFR, KIT, and insulin-like growth factor 1 receptor (IGFR1R) pathways [51, 52].
Amodiaquine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
In an area of Malawi where chloroquine sensitivity has returned, the combination of amodiaquine with SP was superior to SP alone or SP with artesunate (Bell et al., 2008). The combination of SP and amodiaquine selected for an increase in the prevalence of the pfmdrl 86Y amodiaquine resistance mutation, but did not affect the improved clinical response rates (Bell et al., 2008; see section 2b, Emerging resistance and cross-resistance). This resistance mutation remains a concern; follow-up studies after the introduction of combination amodiaquine and SP into national protocols showed that resistance rates increased relatively rapidly (Marfurt et al., 2007). Because of the concern of selection for resistance, SP and amodiaquine were compared with dihydroartemisinin and piperaquine for seasonal malaria prophylaxis in Burkina Faso. Although these regimens had equivalent protective efficacy, there was a higher frequency of resistance mutations found in the SP- and amodiaquine-treated children (Zongo et al., 2015).
Azole resistance in Aspergillus species: promising therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Shirisha Pasula, Pranatharthi H. Chandrasekar
Passive surveillance in the United States from 2011 to 2013 did not find any isolates with TR34/L98H mutation, in 1026 samples [26]. The resistance mutation was first reported in 2016 among 26 of 200 isolates [27]. Passive surveillance that followed during 2015–2017 noted 20 of 1356 isolates showing azole resistance [28]. The linkage of environmental fungicide exposure as the possibility for azole resistance in the United States has been described [29,30]. Low level resistance is reported from other countries. ARTEMIS global surveillance program showed 5.8% of azole resistance from China [31]. Resistance frequency in Taiwan, Pakistan, Japan, and India were 7.9%, 6.6%, 11.2%, 1.5–2%, respectively [32]. The recent study from Brazil showed 2/199 isolates with azole resistance [24,28]. No isolates with azole resistance were identified from one hospital in South Korea [33].
Fusion proteins in lung cancer: addressing diagnostic problems for deciding therapy
Published in Expert Review of Anticancer Therapy, 2021
Federica Zito Marino, Greta Alì, Francesco Facchinetti, Luisella Righi, Gabriella Fontanini, Giulio Rossi, Renato Franco
Resistance mutations mainly occur in ALK exons 22, 23 and 25 and their frequency depends on the specific TKI. The ALK mutations p.L1196M and p.G1269A are the most frequently described after the first generation of TKI treatment, while p.G1202R is predominant after the second generation of TKI. ALK TKIs have a distinct efficacy on different alterations, therefore their characterization is crucial to establish the most appropriate treatment. For example, lorlatinib, a third generation inhibitor, is the only one able to bypass the resistance mutation p.G1202R. On November 2018, the FDA granted accelerated approval to lorlatinib for ALK-positive metastatic NSCLC patients developing disease progression on crizotinib treatment and at least on another ALK inhibitor or in case of disease progression on alectinib or ceritinib treatment as the first ALK inhibitor therapy for metastatic disease [36].
Lessons learned from routine, targeted assessment of liquid biopsies for EGFR T790M resistance mutation in patients with EGFR mutant lung cancers
Published in Acta Oncologica, 2019
Sebastian Mondaca, Michael Offin, Laetitia Borsu, Mackenzie Myers, Sowmya Josyula, Alex Makhnin, Ronglai Shen, Gregory J. Riely, Charles M. Rudin, Marc Ladanyi, Helena A. Yu, Bob T. Li, Maria E. Arcila
At a technical level, our study highlights important challenges and limitations one should consider when implementing cfDNA testing in routine clinical practice. Although platforms like dPCR and BEAMing have been well established among the existing technologies providing the highest sensitivity levels with limits of detection as low as 0.1–0.01% (1 in 1000 to 1 in 10,000), the ultimate sensitivity that can be attained by any assay is dependent on the quantity of cfDNA recovered from the sample. For NGS assays interrogating multiple genomic targets, the sensitivity can also be highly variable from target to target, often not reaching beyond 1%. In our clinical cohort, the total cfDNA recovered varied widely from patient to patient and 31% samples had total yields that limited the sensitivity of detection in the range of 1 to 0.1%. While this can be circumvented by cfDNA extraction from multiple tubes, there are also technical limitations in the handling of samples with very low cfDNA content. In these cases, additional steps for sample concentration are required, adding to the total turnaround time and often affecting the performance of the assays downstream. Importantly, in the setting of resistance, while the detection of the sensitizing EGFR mutation is often facilitated by the common co-occurrence of EGFR amplification, the detection of the resistance mutation can be compromised by their subclonal nature.