Abstract:
http://jco.ascopubs.org/cgi/content/...2009.24.1166v1
Supplementary editorial provided by OncologySTAT
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Combination of TOP2A and TIMP-1 is better than other markers to identify epirubicin responsiveness in patients with early breast cancer.
STUDY IN CONTEXT
In patients with early breast cancer, the Danish Breast Cancer Cooperative Group (DBCG) 89D trial showed that chemotherapy with epirubicin plus cyclophosphamide and fluorouracil (CEF) reduced mortality by 21% and the risk of invasive disease-free survival (IDFS) by 16%, in comparison with treatment using methotrexate plus cyclophosphamide and fluorouracil (CMF). Response to anthracyclines appears to be dependent on the status of genes in the primary tumor, especially human epidermal growth factor receptor 2 (HER2), topoisomerase II alpha (TOP2A), and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1). In particular, HER2 positivity, TIMP-1 negativity, and TOP2A abnormality are each associated with increased benefit from anthracyclines. Ejlertsen et al used data from the DBCG 89D trial to compare the strength of HER2, TOP2A, and TIMP-1 as single markers vs that of the combination of HER2 and TIMP-1 (HT) and of TOP2A and TIMP-1 (2T) in identifying responsiveness to CEF and CMF. The results showed that the 2T-responsive profile (TOP2A aberrations and/or TIMP-1 negative) identified patients most likely to benefit from CEF rather than CMF.
DBCG 89D was an open-label, randomized, phase III trial of CEF vs CMF. Eligible patients had hormone-receptor−negative and node-positive breast cancer (or tumor size >5 cm) or were premenopausal and had node-negative tumors (malignancy grade 2 or 3). HER2, estrogen receptor, and TIMP-1 immunoreactivity was measured using tissue microarrays. Fluorescent in situ hybridization was used to assess TOP2A and HER2 copy numbers.
A total of 1224 patients were enrolled in DBCG 89D, of whom 623 were assessable for HER2, TOP2A, and TIMP-1 analyses. The assessable and nonassessable patients differed significantly with respect to menopausal status, tumor size, malignancy grade, and estrogen-receptor (ER) status, but treatment effects in the assessable patients were similar to those in the overall study.
A total of 311 patients (50%) were classified as HT responsive (HER2 positive and/or TIMP-1 negative). On univariate analysis, an HT-responsive profile, compared with HT-nonresponsive status, was associated with similar IDFS (hazard ratio [HR], 1.22; 95% CI, 0.97-1.52; P = .09) and lower overall survival (OS) (HR, 1.33, 95% CI, 1.06-1.67; P = .01). However, on multivariate analysis HT-responsive and HT-nonresponsive status did not differ in IDFS after adjustment for menopausal status, tumor size, number of positive lymph nodes, histologic type and grade, ER and TOP2A status, and treatment.
A total of 269 patients (43%) were classified as 2T responsive. On univariate analysis, 2Tresponsive status was associated with decreased IDFS (HR, 1.26; 95% CI, 1.01-1.58; P = .04) and decreased OS (HR, 1.34; 95% CI, 1.07-1.69; P = .01) compared with 2T-nonresponsive status. However, on multivariate analysis, 2T-responsive and 2T-nonresponsive profiles did not differ significantly in IDFS after adjustment for menopausal status, tumor size, number of positive lymph nodes, histologic type and grade, ER and HER2 status, and treatment.
On multivariate analysis, HER2 status and TIMP-1 were not associated with significant treatment effects on IDFS and OS, wherasTOP2A status and treatment effect were associated with significant differences in IDFS (P = .004) and OS (P = .03). An HT-responsive profile was associated with a marginally significant improvement in IDFS (HR, 0.73; 95% CI, 0.53-1.00; P = .05) and a statistically significant improvement in OS (HR, 0.69; 95% CI, 0.50-0.95; P = .02) in patients treated with CEF vs CMF. This treatment effect became more significant on multivariate analysis. A 2T-responsive profile was associated with significant improvements in IDFS (HR, 0.59; 95% CI, 0.42-0.83; P = .003) and OS (HR, 0.63; 95% CI, 0.45-0.88; P = .007) in patients treated with CEF vs CMF. This treatment effect remained highly significant on multivariate analysis.
In this study, the combination of markers showed greater benefits of CEF vs CMF in patients with HT- or 2T-responsive profiles than in those with HT- or 2T-nonresponsive profiles. In particular, the 2T-responsive profile was most able to identify patients who were likely to benefit from epirubicin-based adjuvant chemotherapy and to separate out those patients who were unlikely to benefit.
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