genetic difference responsible for herceptin cardiotoxicity MAY have been identified

[Lani]

may help predict those who may suffer cardiac dysfunction



Fcγ-receptor IIa polymorphism and cardiotoxicity in patients with breast cancer treated with adjuvant trastuzumab.


Sub-category:
HER2+

Category:
Breast Cancer - HER2/ER

Meeting:
2011 ASCO Annual Meeting

Abstract No:
565

Citation:
J Clin Oncol 29: 2011 (suppl; abstr 565)


Attend this session at the
ASCO Annual Meeting!
Session: Breast Cancer - HER2/ER

Type: General Poster Session

Time: Monday June 6, 1:00 PM to 5:00 PM

Location: McCormick Place Hall A

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Author(s): N. Cresti, D. Jamieson, M. W. Verrill, M. Pinkilgton, A. V. Boddy; Newcastle University, Northern Institute for Cancer Research, Newcastle upon Tyne, United Kingdom; Freeman Hospital, Northern Centre for Cancer Care, Newcastle upon Tyne, United Kingdom


Abstract Disclosures


Abstract:

Background: Trastuzumab, a humanized monoclonal antibody targeting HER2, is a mainstay of the treatment of advanced and early stage HER2-positive breast cancer patients. It is generally well tolerated but the occurrence of cardiac dysfunction can be a major concern in a proportion of patients. Although a number of clinical parameters have been associated with trastuzumab-related cardiotoxicity, we hypothesized that germline genetic variations may also play a role. In particular we considered four common, coding, non-synonymous single nucleotide polymorphisms (SNPs) in the HER2 gene (Ile655Val and Ala1170Pro) and the Fc gamma receptor genes (FCGR2A His131Arg and FCGR3A Val158Phe). Methods: We evaluated a population of early HER2-positive breast cancer patients treated with three-weekly trastuzumab after adjuvant chemotherapy. Relevant clinical data included baseline clinical characteristics of patients, occurrence of cardiac-related symptoms during trastuzumab therapy, ejection fraction variations and subsequent medical decisions. Germ-line DNA was extracted from peripheral nucleated blood cells and genotyping of the four SNPs was performed using the TaqMan assay. Results: One hundred one patients were recruited in the study. As expected, cardiac risk (age > 60 and/or pre-existing cardiovascular disease) was associated with a higher likelihood of definitive suspension of trastuzumab for cardiotoxicity (log-rank p = 0.018). The FCGR2A 131His homozygous genotype was also associated with the same end-point (log-rank p = 0.006). When these two parameters were combined, we observed no permanent discontinuation of trastuzumab due to cardiotoxicity in patients who had no cardiac risk and were carriers of the FCGR2A 131Arg allele. Interestingly, two patients who experienced severe congestive heart failure were both FCGR2A 131His homozygous. The other SNPs were not associated with cardiac events. Conclusions: The germline FCGR2A His131Arg SNP might contribute to the development of trastuzumab-related cardiotoxicity. If validated in a different population, this finding may impact on trastuzumab prescribing and monitoring of heart function in patients on treatment.