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Pharmacokinetics and Pharmacodynamics
PKP-005 Effect of ERB2 ile655val polymorphism on trastuzumab-induced cardiotoxicity in women with HER2-positive breast cancer
  1. C Gómez Peña1,
  2. C García Fernández1,
  3. CL Dávila Fajardo1,
  4. D Blánquez Martínez1,
  5. S Ruiz Fuentes1,
  6. JJ Fernandez Avila2,
  7. MR Cantudo Cuenca3,
  8. S Belda Rustarazo1,
  9. R Damas Fuentes4,
  10. J Cabeza Barrera1
  1. 1Hospital San Cecilio, Farmacia Hospitalaria, Granada, Spain
  2. 2Complejo Hospitalario Torrecardenas, Farmacia Hospitalaria, Almería, Spain
  3. 3Hospital Virgen de Valme, Farmacia Hospitalaria, Sevilla, Spain
  4. 4Hospital Doctor Negrín, Farmacia Hospitalaria, Las Palmas de Gran Canaria, Spain

Abstract

Background HER2 (ERB2, neu) is a proto-oncogene that encodes a transmembrane protein with tyrosine kinase activity. Trastuzumab (Herceptin), a humanised monoclonal antibody that binds to the HER2 extracellular domain, is used to treat HER2-positive breast cancer. Although it is well tolerated, it has a significant adverse effect: cardiotoxicity.

Purpose To evaluate the possible effect of ERB2 gene polymorphism at codon 655 (ATC/isoleucine to GTC/valine) (rs1136201) in cardiac dysfunction related to trastuzumab in women diagnosed with HER2-positive breast cancer.

Materials and methods 54 patients with HER2-positive breast cancer treated with trastuzumab in our hospital were evaluated prospectively from January to December 2012. Trastuzumab was administered as a loading dose of 8 mg/kg followed by 6 mg/kg every three weeks. For all patients, cardiac function (left ventricular ejection fraction, LVEF) was checked at baseline and every 3 months by echocardiogram or MUGA (multigated blood-pool imaging) scan. We considered cardiac toxicity if the LVEF dropped 10 percentage points from baseline and below 50%, as stated in the data sheet. For genotyping we used TaqMan probes and an allelic discrimination technique. Statistical analysis was performed with Statcalc software packages and significance was indicated by a p value lower than 0.05.

Results The mean age of the patients was 51.11 ± 12.16 years. The distribution of genotypes was 55.56% AA, 40.74% AG and 3.7% GG. Of all patients, 12 developed cardiotoxicity during the treatment with trastuzumab: 4 with genotype AA, 8 with AG and none with GG. Significant correlation was not found between genotypes AA (vs. AA/GG) or GG (vs. AA/AG) and cardiac dysfunction. Instead, statistically significant differences were shown when comparing patients with genotype AG and AA/GG with cardiotoxicity (p = 0.046, OR = 4, 95% CI = 1.026–15.599).

Conclusions The results of our study show an association of ERB2 polymorphism Ile655Val with cardiac toxicity associated with trastuzumab. Patients with genotype AG have higher risk of developing cardiac dysfunction related to trastuzumab than those with AA or GG. We need more studies on this polymorphism as well as larger sample sizes to confirm these findings.

No conflict of interest.

https://doi.org/10.1136/ejhpharm-2013-000436.340

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