Independent replication of polymorphisms predicting toxicity in breast cancer patients randomized between dose-dense and docetaxel-containing adjuvant chemotherapy

// Annelot G.J. van Rossum 1 , Marleen Kok 2, 3 , Danielle McCool 1 , Mark Opdam 1 , Nienke C. Miltenburg 4 , Ingrid A.M. Mandjes 5 , Elise van Leeuwen-Stok 6 , Alex L.T. Imholz 7 , Johanneke E.A. Portielje 8 , Monique M.E.M. Bos 9 , Aart van Bochove 10 , Erik van Werkhoven 11 , Marjanka K. Schmidt 1 , Hendrika M. Oosterkamp 12, * and Sabine C. Linn 1, 3, 13, * 1 Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands 2 Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands 3 Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands 4 Department of Neurology, Medical Center Slotervaart, Amsterdam, The Netherlands 5 Data Center, Netherlands Cancer Institute, Amsterdam, The Netherlands 6 Dutch Breast Cancer Research Group, BOOG Study Center, Amsterdam, The Netherlands 7 Department of Medical Oncology, Deventer Ziekenhuis, Deventer, The Netherlands 8 Department of Medical Oncology, HagaZiekenhuis, The Hague, The Netherlands 9 Department of Medical Oncology, Reinier de Graaf Groep, Delft, The Netherlands 10 Department of Medical Oncology, Zaans Medisch Centrum, Zaandam, The Netherlands 11 Biometrics Division, Netherlands Cancer Institute, Amsterdam, The Netherlands 12 Department of Medical Oncology, Haaglanden Medisch Centrum, The Hague, The Netherlands 13 Department of Pathology, University Medical Center, Utrecht, The Netherlands * These authors contributed equally to this work Correspondence to: Sabine C. Linn, email: s.linn@nki.nl Keywords: replication; single nucleotide polymorphisms; association; toxicity; chemotherapy Received: April 13, 2017      Accepted: October 27, 2017      Published: November 27, 2017 ABSTRACT Introduction: Although pharmacogenomics has evolved substantially, a predictive test for chemotherapy toxicity is still lacking. We compared the toxicity of adjuvant dose-dense doxorubicin-cyclophosphamide (ddAC) and docetaxel-doxorubicin-cyclophosphamide (TAC) in a randomized multicenter phase III trial and replicated previously reported associations between genotypes and toxicity. Results: 646 patients (97%) were evaluable for toxicity (grade 2 and higher). Whereas AN was more frequent after ddAC ( P < 0.001), TAC treated patients more often had PNP ( P < 0.001). We could replicate 2 previously reported associations: TECTA (rs1829; OR 4.18, 95% CI 1.84-9.51, P = 0.001) with PNP, and GSTP1 (rs1138272; OR 2.04, 95% CI 1.13-3.68, P = 0.018) with PNP. Materials and methods: Patients with pT1-3, pN0-3 breast cancer were randomized between six cycles A60C600 every 2 weeks or T75A50C500 every 3 weeks. Associations of 13 previously reported single nucleotide polymorphisms (SNPs) with the most frequent toxicities: anemia (AN), febrile neutropenia (FN) and peripheral neuropathy (PNP) were analyzed using logistic regression models. Conclusions: In this independent replication, we could replicate an association between 2 out of 13 SNPs and chemotherapy toxicities. These results warrant further validation in order to enable tailored treatment for breast cancer patients.