Abstract P6-07-15: The effect of taxanes in ER+ early breast cancer is likely to be mitigated by chromosomal instability.
Authors: A'Hern RP , Bliss JM , Szallasi Z , Johnston S , Roylance R , Swanton C 
Published: August 2014

Abstract
Background: Mechanisms of tumour sensitivity to microtubule-stabilizing (MTS) agents, such as taxanes, are still a matter of debate. Through an RNA interference screen for regulators of taxane resistance, our group identified a number of genes which initiated taxane resistance and Chromosomal INstability (CIN) (1) when silenced, suggesting that the cellular mechanisms that monitor faithful chromosome segregation may also impact upon taxane sensitivity. Consistent with this hypothesis, we previously reported in a small clinical trial cohort of ovarian cancers that CIN tumours (defined by overexpression of the CIN70 signature) appeared to be relatively resistant to paclitaxel in vivo (2). We have observed that repression of a subset of the CIN70 signature occurs in diploid cancer cells following paclitaxel exposure, contributing to cell death. Conversely, less efficient repression of these CIN70 genes occurs in CIN cells following paclitaxel exposure. Overexpression of the CIN70 signature is associated with poor clinical outcome and chromosomal instability is significantly correlated with high tumour grade in ER positive disease. We hypothesised that in ER+ tumours the effect of taxanes should decrease with tumour grade and relative chromosomal instability (3). We assessed this hypothesis by analysing the differences in the published taxane effect in the EBCTCG Chemotherapy overview (4) according to tumour grade.
Methods: Annual event rate ratios and 95% CIs were calculated from data on over 20,000 early breast cancer patients treated with chemotherapy (4). P-values for trend in taxane effect were calculated across 3 tumour grade categories or for heterogeneity between 2 categories.
Results: The table shows annual event rate ratios (CIs) for grade categories, for taxane-plus-anthracycline-based regimen versus the same, or more (&lt; doubled or ∼doubled) non-taxane cytotoxic chemotherapy. Significantly different taxane effects were observed across categories of tumour grade. For both endpoints taxane benefit increased with lower tumour grade, there was a smaller effect in high grade tumours and no evidence the treatment benefit decreased with follow up time.

Conclusions: These results support the assessment of CIN in ER+ breast cancer to optimize treatment stratification and clinical trial design when using microtubule-stabilizing agents. Significant benefit from adjuvant taxanes appeared to be restricted to the lower risk, low and intermediate grade ER positive cohort. Differences in recurrence and survival in this low risk cohort with the use of taxanes would be detected in a worldwide meta-analysis and could easily be missed in individual trials.
References
1. Swanton C et al. Cancer Cell. 2007;11(6):498–512. 2. Swanton C et al. Proc Natl Acad Sci U S A. 2009;106(21):8671–6. 3. McGranahan N et al. EMBO Rep. 2012. Epub 2012/05/19. 4. Early Breast Cancer Trialists' Collaborative Group (2011). The Lancet, 379 (9814): 432–444, Webappendix.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-15.