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Abstract
Genomic instability could be a beneficial predictor for anthracycline or taxane chemotherapy. We interrogated 188 DNA repair genes in the METABRIC cohort (n = 1980) to identify genes that influence overall survival (OS). We then evaluated the clinicopathological significance of ERCC1 in early stage breast cancer (BC) (mRNA expression (n = 4640) and protein level, n = 1650 (test set), and n = 252 (validation)) and in locally advanced BC (LABC) (mRNA expression, test set (n = 2340) and validation (TOP clinical trial cohort, n = 120); and protein level (n = 120)). In the multivariate model, ERCC1 was independently associated with OS in the METABRIC cohort. In ER+ tumours, low ERCC1 transcript or protein level was associated with increased distant relapse risk (DRR). In ER−tumours, low ERCC1 transcript or protein level was linked to decreased DRR, especially in patients who received anthracycline chemotherapy. In LABC patients who received neoadjuvant anthracycline, low ERCC1 transcript was associated with higher pCR (pathological complete response) and decreased DRR. However, in patients with ER−tumours who received additional neoadjuvant taxane, high ERCC1 transcript was associated with a higher pCR and decreased DRR. High ERCC1 transcript was also linked to decreased DRR in ER+ LABC that received additional neoadjuvant taxane. ERCC1 based stratification is an attractive strategy for breast cancers.
Highlights
Anthracycline and taxane based adjuvant and neoadjuvant chemotherapies are standard approaches in the management of early stage or locally advanced breast cancers to reduce distant recurrence and improve survival [1,2,3]
A large body of clinical evidence confirms that high grade breast cancer (BC) is associated with chromosomal instability
ERCC1 is non-catalytic but partners with XPF endonuclease to form the ERCC1–XPF heterodimer which processes abnormal DNA repair intermediates generated during NER, double strand breaks (DSB) repair and Interstrand Cross Link (ICL) repair [29]
Summary
Anthracycline and taxane based adjuvant and neoadjuvant chemotherapies are standard approaches in the management of early stage or locally advanced breast cancers to reduce distant recurrence and improve survival [1,2,3]. In early breast cancer patients, duplication of chromosome 17 centromere enumeration probe (Ch17CEP), a CIN marker, was previously shown to be a strong predictor of benefit from anthracycline adjuvant chemotherapy in a prospective clinical trial [8]. In a meta-analyses by the early breast cancer trialists collaborative group (EBCTCG), benefit from taxanes (paclitaxel, docetaxel) based chemotherapy was most evident in chromosomally stable low grade breast cancers [9,10]. CIN has been shown previously to predict paclitaxel resistance in ovarian cancer patients [11]
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