DNA repair signature is associated with anthracycline response in triple negative breast cancer patients
- 634 Downloads
We hypothesized that a subset of sporadic triple negative (TN) breast cancer patients whose tumors have defective DNA repair similar to BRCA1-associated tumors are more likely to exhibit up-regulation of DNA repair-related genes, anthracycline-sensitivity, and taxane-resistance. We derived a defective DNA repair gene expression signature of 334 genes by applying a previously published BRCA1-associated expression pattern to three datasets of sporadic TN breast cancers. We confirmed a subset of 69 of the most differentially expressed genes by quantitative RT-PCR, using a low density custom array (LDA). Next, we tested the association of this DNA repair microarray signature expression with pathologic response in neoadjuvant anthracycline trials of FEC (n = 50) and AC (n = 16), or taxane-based TET chemotherapy (n = 39). Finally, we collected paraffin-fixed, formalin-embedded biopsies from TN patients who had received neoadjuvant AC (n = 28), and tested the utility of the LDA to discriminate response. Correlation between RNA expression measured by the microarrays and 69-gene LDA was ascertained. This defective DNA repair microarray gene expression pattern was significantly associated with anthracycline response and taxane resistance, with the area under the ordinary receiver operating characteristic curve (AUC) of 0.61 (95% CI = 0.45–0.77), and 0.65 (95% CI = 0.46–0.85), respectively. From the FFPE samples, the 69-gene LDA could discriminate AC responders, with AUC of 0.79 (95% CI = 0.59–0.98). In conclusion, a promising defective DNA repair gene expression signature appears to differentiate TN breast cancers that are sensitive to anthracyclines and resistant to taxane-based chemotherapy, and should be tested in clinical trials with other DNA-damaging agents and PARP-1 inhibitors.
KeywordsBreast cancer DNA repair BRCA1 Gene expression signatures Anthracycline sensitivity
- 2.von Minckwitz G KM, Kümmel S, Fasching P, Eiermann W, Blohmer J-U, Costa SD, Sibylle L, Dietmar V, Untch M (2008) Integrated meta-analysis on 6402 patients with early breast cancer receiving neoadjuvant anthracycline-taxane ± trastuzumab containing chemotherapy. SABCS Abstract 792008Google Scholar
- 9.Delaloge S, Bidard F, El Masmoudi Y, Bressac de Paillerets B, Caron O, Bourgier C, Garbay J, Spielmann M, André F. BRCA1 germ-line mutation: Predictive of sensitivity to anthracyclin alkylating agents regimens but not to taxanes? J Clin Oncol. Abstract 5742008 May 20, 26Google Scholar
- 28.Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):RESEARCH0034Google Scholar
- 40.O’Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, Rocha C, Ossovskaya V, Sherman B, Bradley C (2009) Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol. Abstract 32009; 27Google Scholar