Abstract
Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer. We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455). Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours. Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.
Highlights
Findings from several retrospective analyses of randomised trials have suggested that anthracyclinecontaining adjuvant therapy might be beneficial to only those patients with breast cancer who have HER2 gene amplification or protein overexpression,[1,2,3,4] but this effect cannot be explained by any biological rationale
We report the final results with data from 3452 patients to assess the predictive value of HER2 and 3102 patients to assess the predictive value of TOP2A
We recorded no significant difference in the treatment effect of anthracyclines or CMF between molecular subgroups, but individuals with HER2-amplified tumours seemed to respond better to anthracyclines and those with highly hormone-sensitive tumours seemed to respond better to CMF
Summary
Findings from several retrospective analyses of randomised trials have suggested that anthracyclinecontaining adjuvant therapy might be beneficial to only those patients with breast cancer who have HER2 gene amplification or protein overexpression,[1,2,3,4] but this effect cannot be explained by any biological rationale. One of the intracellular targets of anthracycline is the topoisomerase IIα protein—the gene for which, TOP2A, is on chromosome 17q12-q21.5 Other retrospective analyses have suggested that anthracycline-containing adjuvant therapy might be most effective in patients whose tumours carry amplified TOP2A.6–8. This association was not seen in a study reported in 2008.9 Two studies suggested that TOP2A gene deletion might confer increased sensitivity to anthracyclines,[10,11] as with HER2, this effect cannot be explained by any biological rationale.[5]. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer
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