Anthracyclines: The First Generation of Cytotoxic Targeted Agents? A Possible Dream
Authors: Angelo Di Leo, Erica Moretti
Journal: Journal of Clinical Oncology (2008)

In this issue of Journal of Clinical Oncology, Bartlett et al report the results of a retrospective study evaluating human epidermal growth factor receptor (HER) family membrane receptors and topoisomerase II(TOP2A) as markers predicting sensitivity to anthracycline-based therapy in early breast cancer patients. In the original phase III clinical trial, patients were randomly allocated to one of two study arms, either an all intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) regimen administered every 3 weeks or a sequential regimen consisting of full-dose, singleagent epirubicin followed by the same type of CMF regimen. Treatment duration was 24 weeks in both study arms. Archival primary tumor samples were collected and made available for a centralized biomarker analysis in 322 of 374 patients who participated in the clinical trial. Protein expression was evaluated by immunohistochemistry. HER2 and TOP2A gene aberrations were investigated by fluorescent in situ hybridization. The study has, in our opinion, two interesting features. It investigates, for the first time to our knowledge, the interaction between the HER family membrane receptors and anthracycline activity in the context of a randomized trial for early-stage breast cancer patients. Furthermore, this is the first study (of five) suggesting that TOP2A gene amplification is not a helpful marker in predicting sensitivity to anthracyclines. Interestingly enough, the authors report that, in contradiction with the a priori study hypothesis, patients with normal HER1, HER2, and HER3 levels derive the largest benefit from the anthracyclinebased therapy. Conversely and surprisingly, no superiority for anthracyclines over CMF is seen in the cohort of patients who have tumors with overexpression of at least one of the three HER family membrane receptors. On the basis of previously reported literature, the cohort of patients with HER1 to HER3 normal tumors is expected to be characterized by a high level of expression of hormone receptors (estrogen and progesterone receptors) and low proliferation rates. Why should an anthracycline-based therapy be more active than CMF in this specific subgroup of patients with endocrine-sensitive tumors? A possible explanation is that, in this cohort of patients, the level of ovarian suppression achieved with a full-dose, anthracycline-based regimen is expected to be more pronounced than with all intravenous CMF administered every 3 weeks. Supporting this explanation is the fact that almost 55% of the study population had a preor perimenopausal status. The present article and the clinical trial report do not provide details on the percentage of preand perimenopausal women with endocrine-sensitive tumors who actually received adjuvant tamoxifen for 5 years sequentially after adjuvant chemotherapy. The clinical trial report specifies that adjuvant hormonal treatment was not restricted and that 46% of those patients who were candidates for adjuvant tamoxifen were to receive this treatment concomitantly with chemotherapy. Accordingly, we speculate that a relevant proportion of the HER1 to HER3 normal population was preor perimenopausal, had endocrine-sensitive tumors, and did not receive adjuvant tamoxifen for 5 years sequentially after chemotherapy. Under these conditions, a full-dose, anthracycline-based therapy might produce a clinical benefit over a nonintensive CMF regimen that is independent of a cytotoxic mechanism and that is mediated by endocrine effects (ie, interference with ovarian function). Arguing against this hypothesis is the fact that rates of chemotherapy-related amenorrhea reported in the clinical trial report are 73% and 74% for the anthracycline-based and CMF regimens, respectively. It is meaningful to emphasize that rates of chemotherapy-related amenorrhea can vary over time and that differences in amenorrhea rates between two treatment groups can emerge and become clinically relevant several months after the end of adjuvant chemotherapy. Unfortunately, the limited study sample size (146 patients with HER1 to HER3 normal tumors) makes any reliable conclusion impossible in subgroup analysis according to hormone receptors and menopausal status. Hence, the conclusion that the suggested superiority of anthracyclines over CMF in the cohort of HER1 to HER3 normal tumors is mediated by endocrine effects has to remain hypothetical. Differently from the HER1 to HER3 normal cohort, the group of tumors carrying overexpression of at least one of the three markers is biologically heterogeneous, potentially represented by HER2-positive, triple-negative, and moderately hormone-sensitive tumors. Accordingly, it is difficult to formulate any hypothesis to explain the observed results in this specific cohort (ie, lack of superiority of anthracyclines over CMF). It is relevant to emphasize that, in the cohort of HER1to HER3-positive tumors, the hazard ratio for the comparison of anthracyclines with CMF has a wide 95% CI. This makes the results unstable and, at the same time, highlights two different problems encountered in the vast majority of studies looking at molecular predictive markers—lack of adequate statistical power and biologic heterogeneity of the study population. As alluded to earlier, this is the first time that a retrospective analysis from a randomized trial suggests that TOP2A gene amplification JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 31 NOVEMBER 1 2008