Is Drug Resistance in First-Line Therapy against All Antiretroviral Agents Inevitable?

7079 Background: The treatment of (CML) has undergone major changes in the past decade with the introduction of tyrosine kinase inhibitors (TKI). However the initial enthusiasm is waning with increasing recognition of drug resistance. There is an urgent need to identify the types of receptor mutations which lead to drug resistance and their significance in salvage therapy. Methods: We identified 17 males and 8 female patients with median age 40 yrs (range 9–55 years) with CML who were on imatinib at the time of loss of hematologic response (HR), cytogenetic (CyR), or molecular response (MR) and performed imatinib-resistance mutation analysis. The sequencing was done on ABI machine by direct sequencing method. Results: This group included 22 patients with chronic phase (CP) disease, 2 patients with accelerated phase (AP), and 1 patient with extramedullary blast crisis (BC). Fourteen patients received treatment with agents other than imatinib as the first-line therapy due to either nonavailability of the drug at the time of diagnosis in India, but were started on imatinib when drug became available. The other 11 patients received imatinib as first-line therapy. The best response to imatinib included major CyR in 14 patients which included 3 patients with complete CyR and minor CyR in 6 patients. Lack of HR was noted in 2 patients in whom CyR was not evaluated. Imatinib resistance mutation analysis was prompted by no HR (n = 2); loss of HR after achieving CyR (n = 9); failure to achieve CyR milestones (n = 3); loss of CyR (n = 9); development of extramedullary BC (n = 1). The analysis revealed no mutations-11 patients, M351T-4 patients, G250E-3 patients, F317L-2 patients, M244V- 1 patient, T315I-1 patient, F382L-1 patient, results awaited in 4 patients with 2 patients showing 2 mutations. Conclusions: The majority of patients 11/25 had no detectable mutations while T315I which confers resistance to all TKIs was detected only in 1/25 patients who demonstrated loss of response in our population. The correlation of the other mutations to loss of response and the response to second line TKI needs to be studied in further detail. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. No significant financial relationships to disclose.

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Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15524 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15524-e15524

Author(s):

Hua Cao ◽

Xinyi Liu ◽

Yixin Chen ◽

Pan Yang ◽

Tanxiao Huang ◽

...

Keyword(s):

Colorectal Cancer ◽

Drug Resistance ◽

Cancer Patients ◽

Circulating Tumor Dna ◽

First Line ◽

Tissue Samples ◽

First Line Therapy ◽

Line Therapy ◽

Colorectal Cancer Patients ◽

Tumor Dna

e15524 Background: Colorectal cancer (CRC) is a highly lethal disease worldwide. The majority of patients receiving targeted therapy or chemotherapy develop drug resistance, while its molecular mechanism remains to be elucidated. The plasma circulating tumor DNA (ctDNA) exhibited the potential in identifying gene variations and monitoring drug resistance in CRC treatment. Methods: In this study, we monitored the ctDNA mutational changes in advanced CRC patients underwent first-line therapy with bevacizumab and cetuximab combined with chemotherapy. The mutation spectrum of 43 patients was established by a 605-gene next-generation sequencing (NGS) panel. Results: The baseline measurement shows that genes with the highest mutation frequency were TP53 (74%), APC (58%), KRAS (40%), SYNE1 (33%), LRP1B (23%), TOP1 (23%) and PIK3CA (21%). Mutations in TP53, APC and KRAS were detected in 29 paired plasma and tissue samples with the consistency of 81%, 67% and 42%, respectively. Clinically targetable gene mutations, such as APC, RNF43, SMAD4, BRAD1, KRAS, RAF1, and TP53, were also identified in ctDNA. The overall consistency between ctDNA and tissue samples was 54.6%. Alleviation of mutational burden in BRAF, KRAS, AMER1 and other major driving genes was observed following the first-line therapy. Patients with KRAS and TP53 mutations in tissues appeared to benefit more than the wild-type counterpart. The dynamic change of plasma mutation status was consistent with the tissue tumor burden and was closely correlated with disease progression. Conclusions: ctDNA monitoring is a useful method for molecular genotyping of colorectal cancer patients. Dynamic changes in resistance can be sensitively monitored by gene variation status, which potentially helps to develop treatment strategy.

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