Research Papers:

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

Annelot G.J. van Rosssum, Marleen Kok, Danielle McCool, Mark Opdam, Nienke C. Miltenburg, Ingrid A.M. Mandjes, Elise van Leeuwen-Stok, Alex L.T. Imholz, Johanneke E.A. Portielje, Monique M.E.M. Bos, Aart van Bochove, Erik van Werkhoven, Marjanka K. Schmidt, Hendrika M. Oosterkamp and Sabine C. Linn _

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Oncotarget. 2017; 8:113531-113542. https://doi.org/10.18632/oncotarget.22697

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Annelot G.J. van Rossum1, Marleen Kok2,3, Danielle McCool1, Mark Opdam1, Nienke C. Miltenburg4, Ingrid A.M. Mandjes5, Elise van Leeuwen-Stok6, Alex L.T. Imholz7, Johanneke E.A. Portielje8, Monique M.E.M. Bos9, Aart van Bochove10, Erik van Werkhoven11, Marjanka K. Schmidt1, Hendrika M. Oosterkamp12,* and Sabine C. Linn1,3,13,*

1Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands

2Division of Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands

3Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands

4Department of Neurology, Medical Center Slotervaart, Amsterdam, The Netherlands

5Data Center, Netherlands Cancer Institute, Amsterdam, The Netherlands

6Dutch Breast Cancer Research Group, BOOG Study Center, Amsterdam, The Netherlands

7Department of Medical Oncology, Deventer Ziekenhuis, Deventer, The Netherlands

8Department of Medical Oncology, HagaZiekenhuis, The Hague, The Netherlands

9Department of Medical Oncology, Reinier de Graaf Groep, Delft, The Netherlands

10Department of Medical Oncology, Zaans Medisch Centrum, Zaandam, The Netherlands

11Biometrics Division, Netherlands Cancer Institute, Amsterdam, The Netherlands

12Department of Medical Oncology, Haaglanden Medisch Centrum, The Hague, The Netherlands

13Department of Pathology, University Medical Center, Utrecht, The Netherlands

*These authors contributed equally to this work

Correspondence to:

Sabine C. Linn, email: [email protected]

Keywords: replication; single nucleotide polymorphisms; association; toxicity; chemotherapy

Received: April 13, 2017     Accepted: October 27, 2017     Published: November 27, 2017


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.

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