Abstract
‘Trastuzumab in combination with standard chemotherapy has been shown to prolong the survival of women with human epidermal growth factor receptor 2-positive advanced breast cancer, and now represents the optimal standard treatment in the setting of metastatic disease.’
Trastuzumab (Herceptin®) is a therapeutic monoclonal antibody (mAb) targeting the human epidermal growth factor receptor type 2 (HER2), a cell-surface tyrosine kinase receptor overexpressed in 25–30% of breast cancers [1].
Trastuzumab in combination with standard chemotherapy has been shown to prolong the survival of women with HER2-positive advanced breast cancer and now represents the optimal standard treatment in the setting of metastatic disease [2]. This activity in the metastatic setting and the demonstrated association of HER2 overexpression with poor prognosis represented the rationale for adjuvant clinical trials examining its potential role in early breast cancer. Four randomized trials of adjuvant trastuzumab have included more than 13,500 early breast cancer patients who were overexpressing HER2, node-positive, or high-risk node-negative, worldwide [3]. In the National Surgical Adjuvant Breast and bowel Project (NSABP) B-31, sponsored by the US National Cancer Institute, a total of 2700 patients were randomized to receive doxorubicin and cyclophosphamide (AC) followed by 3-weekly paclitaxel alone or in combination with trastuzumab weekly, for a total of 52 weeks. The primary end point was overall survival. The North Central Cancer Treatment Group (NCCTG) N9831 trial included 3300 patients randomized to receive one of three treatment arms: AC for four cycles followed by weekly paclitaxel for 12 cycles; AC followed by weekly paclitaxel for 12 cycles followed by trastuzumab weekly for 1 year; or the same chemotherapy schedule but with trastuzumab administered early in combination with paclitaxel. The primary end points were disease-free survival and cardiac tolerability The National Cancer Institute decided to pool the NSABP B-31 and NCCTG N9831 trials in order to increase the power of treatment comparisons. The HERceptin Adjuvant (HERA) trial investigated the role of trastuzumab independently from previous neoadjuvant chemotherapeutic regimens in 5082 patients. In this three-arm design, trastuzumab was administered every 3 weeks for 1 or 2 years and compared with an observation arm. The primary end point was disease-free survival. The Breast Cancer International Research Group (BCIRG) trial included three arms comparing AC for four cycles followed by docetaxel every 3 weeks for four cycles, AC for four cycles followed by docetaxel every 3 weeks for four cycles with concomitant administration of weekly trastuzumab and then trastuzumab alone every 3 weeks for 1 year, or carboplatin and docetaxel every 3 weeks for six cycles concomitant with weekly trastuzumab followed by trastuzumab alone every 3 weeks for 1 year. The interim results of the first three of these trials were presented at the 2005 American Society for Clinical Oncology (ASCO) meeting. The interim analysis of the BCIRG trial will be presented at the San Antonio (TX, USA) 2005 meeting. The interim analyses of the HERA results [4], the pooled results from the North American trials [5] and the BCIRG trial demonstrated a major disease-free survival advantage with trastuzumab in the adjuvant treatment of women with HER2-positive early breast cancer.
Overall survival is also enhanced in the US trials, while a favorable trend emerged in the HERA trial (hazard ratio [HR]: 0.78; p-value not significant), which has the shortest median follow-up (1 year instead of 2). In conclusion, we can underline the following results from the interim analysis of the four randomized trials: all of these trials demonstrated a major disease-free survival advantage with trastuzumab in the adjuvant treatment setting; concurrent trastuzumab with paclitaxel given after AC provides a clear survival advantage; the survival effects of other adjuvant trastuzumab regimens await adequate follow-up; and the risk:benefit ratio of adjuvant trastuzumab warrants its routine use in the adjuvant therapy of HER2-positive early breast cancer patients.
Severe congestive heart failure represented a potential serious adverse effect of trastuzumab in all four trials. The risk appeared to be higher in the US trials (2.9–4.1% of cardiac heart failures) and in the BCIRG trial (1.7%), which initiated trastuzumab sooner than in HERA (0.5%), where trastuzumab was administered after completion of adjuvant chemotherapy and radiotherapy. However, long-term follow-up is essential in order to better quantify this risk in all four studies.
On the basis of these results, the standard therapy of patients with HER2-positive breast cancer in the adjuvant setting must change today. Although the results presented in these reports are impressive, there are important differences between the trials that deserve stressing and that may raise many new questions. For example, what is the optimal schedule for therapy with trastuzumab: should it be given simultaneously with or sequentially after chemotherapy? This is an open question and we will have the answer only after presentation of the final results of the adjuvant trials. The interim analyses of the pooled US trials and the BCIRG trial seem to demonstrate that concurrent trastuzumab with taxanes given after AC provides a clear survival advantage. The survival effects of other adjuvant trastuzumab regimens (e.g., the HERA trial) await adequate follow-up. The optimal duration of trastuzumab therapy is another question. The final results of the HERA trial (1 vs 2 years) will answer this important question. There are several critical points that deserve a specific study regarding cardiac toxicity, the most important adverse event related to trastuzumab therapy. What is the nature and reversibility of cardiac dysfunction? There is only very preliminary information regarding a potential symptomatic control of heart failure in the majority of patients. What will be the long-term effects of congestive heart failure in the surviving population? These data are currently completely lacking in the literature. The BCIRG trial will answer the question of whether including a group that does not receive anthracyclines will decrease the incidence of heart toxicity without decreasing the survival advantage of a trastuzumab-based adjuvant therapy.
Another important issue to be addressed is if all patients, node-negative in addition to node-positive patients, whose tumors overexpress HER2/neu are to be offered adjuvant trastuzumab. The question is relevant as HER2/neu has been shown to be an independent prognostic factor in node-negative breast cancer, but the increase in risk is modest [6]. So, what is the benefit deriving from trastuzumab adjuvant therapy in node-negative patients? Is the benefit greater than the cardiotoxicity risk related to immunotherapy? The answer to this issue is quite difficult, as the NSABP B-31 trial included only node-positive patients, the NCCTG included mostly node-positive patients, with only 10% node-negative patients, and the HERA trial included approximately 30% node-negative patients. The HERA trial reported the analyses of disease-free survival according to subgroup and demonstrated that there was no evidence of substantial heterogeneity in the relative treatment effect among node-relative status subgroups [4]. The definitive answer to this issue will be possible when we have the final and long-term survival results of all trials in which node-negative patients have been included.
What about the use of trastuzumab-based therapies in the neoadjuvant setting? The literature clearly demonstrated a statistically significant correlation between incidence of pathological complete responses (pCR) and outcome of patients [7]. A recent small, randomized trial from the MD Anderson Cancer Center (TX, USA) combined anthracycline/taxane-based neoadjuvant chemotherapy with trastuzumab in HER2/neu-positive patients and demonstrated a pCR rate of 65% with the trastuzumab-based regimen [8]. These results suggest that the correlation between pCR and outcome should extend to regimens containing trastuzumab in combination with chemotherapy. The indication of trastuzumab-based chemotherapy in the neoadjuvant setting as standard care deserves prospective, randomized trials.
What is to be done in the case of trastuzumab-based therapy resistance? The development of new targeted molecular therapies against multiple members of the HER family may have a greater impact on inhibiting cell proliferation and angiogenesis and may overcome the resistance to trastuzumab. Finding the optimal way to introduce and associate these new agents into the adjuvant treatment of HER2-overexpressing breast cancer patients will be the aim of preclinical studies and clinical trials in the coming years.
Is it actually possible to use molecular factors to predict the subset of patients who will respond to and benefit from trastuzumab-based adjuvant chemotherapy? The use of microarray technology as a tool to study the molecular heterogeneity of breast cancer and to improve treatment tailoring is increasing exponentially, but no routine clinical application has been indicated. For this purpose, the European Organisation for the Research and Treatment of Cancer (EORTC) has proposed the TRANSlating molecular knowledge into early breast cancer management: building on the Breast International Group (TRANSBIG) multinational project. This project is the first large, prospective trial to investigate the role of the gene expression signature with the aim of improving chemotherapy decision-making for early breast cancer [9]. Patients with a good gene signature had a greater than 90% survival rate at 12 years, as opposed to those with a poor signature (either node-negative or -positive), who had an approximately 50% survival rate at 12 years [9]. This ‘genetic score’ could be of great help in choosing who to treat and who not to treat. Further understanding of genomic signature heterogeneity is mandatory for the development of individualized therapy in breast cancer. For this reason, new approaches deriving from genomic and proteomic knowledge are needed for trial design, patient selection and choice of end points (including surrogate markers). There is an urgent need to change the traditional clinical development and use new molecular knowledge and translational research in the design of clinical trials.
‘On the basis of these results, our adjuvant care of patients with HER2-positive breast cancer is changing today. Patients with lymph node-positive, HER2-positive breast cancer should be treated with trastuzumab-based adjuvant systemic therapy’
On the basis of these results, our adjuvant care of patients with HER2-positive breast cancer is changing today. Patients with lymph node-positive, HER2-positive breast cancer should be treated with trastuzumab-based adjuvant systemic therapy, and also if there are some medical conditions in which the antibody could be contraindicated. In patients with pre-existing high-risk medical conditions, the trastuzumab sequential approach could be the preferred challenge. For HER2-positive breast cancer patients with negative lymph nodes, the selection of optimal therapy is difficult. It is clearly reported that most HER2-positive tumors (also node-negative tumors) have several adverse prognostic factors and, at the same time, the HERA trial supports the beneficial effect of trastuzumab in this patient setting. For all these reasons, a trastuzumab-based adjuvant therapy should be considered in high-risk, node-negative, HER2-positive breast cancer patients. Finally, preclinical and early clinical studies suggest that combining HER-2 targeted with other molecular therapies may be a potentially interesting approach for the future.