ABL Kinase Domain Mutation in Chronic Myeloid Leukemia - Compliance to Imatinib Matters

Background: Imatinib resistance mutation analysis (IRMA) or abl kinase domain mutation analysis is performed in patients with Chronic myeloid leukemia (CML) whenever the response to treatment is inadequate. We have analyzed the reports of IRMA at our centre. Methods: The clinical details of 71 patients with CML on Imatinib, who underwent IRMA testing during the period of January 2017 to March 2019 were collected from the patient records and analyzed. IRMA was performed for failure or warning or progression, anytime during the course of treatment. IRMA was done by either Sanger sequencing (n=45) or next generation sequencing (n=26, Illumina, NGS). The associations between variables were tested using Chi - Square test. Results: Median age at diagnosis of 71 patients was 44 years (Range 18 - 71 years). Males constituted 70% (n=50). At diagnosis, 92% (n=65) of patients were in chronic phase and the remainder were in accelerated phase (n=4) or blast crisis (n=2). Mutations in the abl kinase domain were detected in 26 patients (37%). Next Generation Sequencing (NGS) could identify more mutations (13/26 - 50%) compared to conventional Sanger Sequencing (13/45 - 29%), but the difference was not significant (p=0.07). NGS could identify three or more mutations in 5 patients in contrast to Sanger. All the mutations detected were those previously described except for an insertion of 35bp near the C-Terminal which was identified in 3 patients. E459K translocation was identified in 6 patients. E355G translocation was identified in 4 patients. F359V, M351T, Y253H, G250E, H396R, T315I translocations were identified in 3 patients each. Patients who were not compliant to therapy had increased frequency of mutations (14/26 - 54%) compared to those who were compliant (12/45 - 27%), which was significantly different (p=0.02). Patients who had loss of complete hematological response (CHR) had significantly higher frequency of mutations (14/21- 67%) compared to other reasons for performing the test (p=0.001). Patients who had failure to achieve targets at various time points had a significantly lower frequency of mutations (4/23 - 17%, p=0.02) compared to other reasons for performing the test. Conclusion: Patients who were not compliant for treatment were more likely to have mutations. Loss of CHR showed an increased frequency compared to other reasons. NGS could identify mutations in more number of patients. NGS identified numerically higher mutations in patients. Larger prospective data are needed to confirm these observations. Table Disclosures No relevant conflicts of interest to declare.

Identification of a novel oncogenic mutation of FGFR4 in gastric cancer

Gastric cancer remains one of the leading causes of cancer death worldwide. Despite intensive investigations of treatments over the past three decades, the poor prognosis of patients with unresectable advanced or recurrent gastric cancer has not significantly changed, and improved therapies are required. Here, we report the identification of an oncogenic mutation in FGFR4 in a human gastric tumour that leads to constitutive activation of its product, FGFR4. The G636C-FGFR4 tyrosine kinase domain mutation was found in 1 of 83 primary human gastric tumours. The G636C mutation increased FGFR4 autophosphorylation, and activated FGFR4 downstream signalling molecules and enhanced anchorage-independent cell growth when expressed in NIH/3T3 cells. 3D-structural analysis and modelling of FGFR4 suggest that G636C destabilizes an auto-inhibitory conformation and stabilizes an active conformation, leading to increased kinase activation. Ba/F3 cell lines expressing the G636C-FGFR4 mutant were significantly more sensitive to ASP5878, a selective FGFR inhibitor, than the control. Oral administration of ASP5878 significantly inhibited the growth of tumours in mice engrafted with G636C-FGFR4/3T3 cells. Together, our results demonstrate that mutationally activated FGFR4 acts as an oncoprotein. These findings support the therapeutic targeting of FGFR4 in gastric cancer.