Editor's Note:
Approximately 15% to 20% of all newly diagnosed invasive breast cancers are found to have gene amplification or receptor overexpression of the human epidermal growth factor receptor (HER)-2. This subset of breast tumors, defined by HER-2 positivity, is characterized by unique biological and clinical features. Trastuzumab, a humanized monoclonal antibody that targets the HER-2 gene product, has a well-established role in the treatment of women with metastatic breast cancer. Given the success of trastuzumab in metastatic disease, several large, randomized trials were initiated to evaluate the role of trastuzumab in early-stage breast cancer.
Since the release of data from the adjuvant trastuzumab trials – the combined NSABP B-31/NCCTG 9831 and HERA trials at the American Society of Clinical Oncology (ASCO) meeting in May 2005 and BCIRG 006 at the San Antonio Breast Cancer Symposium in December 2005 – the management algorithm for patients with HER-2-positive breast cancer has evolved.[1-3] All 3 analyses demonstrated robust improvements in disease-free survival from the addition of either concurrent or sequential trastuzumab to standard cytotoxic chemotherapy. Since May 2005, adjuvant trastuzumab has become an accepted and standard component of adjuvant management for patients with HER-2-positive breast cancer. Many questions remain, however, and these are being addressed by ongoing clinical trials.
At ASCO 2006, several abstracts provided new information on the adjuvant treatment of women with HER-2-positive disease. On behalf of Medscape, Erica L. Mayer, MD, an Instructor in Medicine at Harvard Medical School and a Member of the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, Massachusetts, discussed updates from the 2006 meeting with Eric P. Winer, MD, Associate Professor of Medicine at Harvard Medical School and the Director of the Breast Oncology Center at Dana-Farber Cancer Institute. Dr. Winer is a leader in the field of breast medical oncology. He is also Co-Chairman of the Cancer and Leukemia Group B (CALGB) breast cancer committee.
Medscape: In the past 12 months, we've seen clinicians become comfortable with the administration of adjuvant trastuzumab. What do you think is the appropriate duration of adjuvant treatment with trastuzumab? Do you think that we should be giving more or less treatment than the current 1-year, which was described in the adjuvant studies?
Dr. Winer: I don't think that we should be giving either more or less. On the basis of what we know from the 4 large, randomized trials, all of which have shown benefits for trastuzumab with a 1-year duration of therapy, I think that outside of a clinical trial, we should continue giving 1 year of adjuvant trastuzumab therapy. The recently published FinHER study[4] did demonstrate benefits with a much shorter duration of therapy. However, this was a small study and without further confirmatory data; I would not offer that approach.
Medscape: Although the criteria for use of adjuvant trastuzumab in high-risk HER-2-positive diseases are well defined, many clinicians struggle with whether to give trastuzumab to lower risk patients, such as those with small hormone receptor-positive tumors who may not require cytotoxic chemotherapy. What has been your approach to such patients, and how can we develop "softer and safer regimens," as described by Dr. Martine Piccart at ASCO 2006?
Dr. Winer: This is a difficult issue, and I think that it's one with which many clinicians have struggled. It's unclear what to do for patients who have relatively low-risk disease, such as subcentimeter node-negative tumors with either positive or negative hormone receptors, or hormone receptor-positive node-negative tumors of 2 cm or less. The NSABP, Intergroup, and HERA trials did not include any patients with tumors less than 1 cm, and the Intergroup trial only included patients with estrogen receptor-positive, node-negative tumors if they were greater than 2 cm. The NSABP study included node-positive patients only. The concern with regard to trastuzumab treatment is that rare, but serious side effects, such as cardiotoxicity, can be associated with it. Generally speaking, I have been cautious about giving trastuzumab to this low-risk group, and I think that it requires an in-depth discussion with the patient. I won't say that I absolutely haven't done it, but by no means do I believe that it's the standard of care at the moment. These are the clinical settings for which we need data on kinder and gentler regimens, such trastuzumab monotherapy, trastuzumab in combination with hormonal therapy, or trastuzumab in combination with single-agent non-anthracycline-based therapy, such as single-agent paclitaxel. There is, of course, the non-anthracycline-containing regimen evaluated in BCIRG 006.[3] Although the docetaxel, carboplatin, trastuzumab (TCH) regimen represents an alternative to anthracycline-containing regimens, TCH is also associated with fairly significant toxicity and is not a regimen that I would tend to suggest for a low-risk patient population.
Medscape: There continues to be debate in regard to the superiority of either concurrent chemotherapy and trastuzumab, as in NSABP B31 and Arm C of N9831, or sequential treatment, as in HERA and Arm B of N9831. Which method do you think is preferable, and will data emerge to clarify this debate?
Dr. Winer: I don't think that we have a final answer to this question at the moment, and it may depend on the setting in which trastuzumab is given and the specific type of chemotherapy with which it is given. I don't think that there's any question that the use of sequential trastuzumab was beneficial within the context of the HERA study, and the benefits seen in HERA in terms of risk reduction were equivalent to those seen in the other trials. Data from N9831 suggested that concurrent paclitaxel with trastuzumab is superior to sequential treatment. It's important to note that the comparison was somewhat underpowered, and the difference between concurrent and sequential therapy did not meet prespecified criteria for early stopping or reporting. It is possible that this is a chemotherapy-specific effect, and when giving adjuvant doxorubicin, cyclophosphamide, and paclitaxel, trastuzumab must be given concurrently to achieve substantial added benefit. I think that we're just going to have to continue to follow these studies and see what leads they provide us in the years ahead. At present, however, if one is going to give a taxane, it is prudent to administer it concurrently with trastuzumab.
Medscape: Can trastuzumab be given safely in the preoperative setting, and what are acceptable approaches to preoperative management of HER-2-positive breast cancer?
Dr. Winer: Trastuzumab can safely be given in the preoperative setting, and there have been multiple single-arm, phase 2 trials and 1 small, randomized trial demonstrating the safety and efficacy of preoperative trastuzumab.[5-7] In my own view, outside of a clinical trial, the only compelling reason to give preoperative trastuzumab is if a woman has a relatively large tumor and desires conversion from mastectomy to breast-conserving surgery, or for locally advanced HER-2-positive disease. In these settings, I would use one of the regimens that have demonstrated benefit in the adjuvant setting, or perhaps one of the preoperative regimens that has been described in the context of phase 2 clinical trials.
Medscape: What is the best method to determine HER-2 positivity? Do you think that all tumor samples should undergo FISH [Fluorescence In Situ Hybridization] testing?
Dr. Winer: This has been a hotly debated subject that is part of a bigger question: How can we improve our testing not only for HER-2, but also for estrogen and progesterone receptors? Clearly, when many of our most important treatment decisions are based on these tests, it's absolutely critical that the tests be as accurate as possible. For a patient with less than a 3+ result by IHC [immunohistochemistry], FISH should be performed before one considers giving trastuzumab. I personally don't believe that a FISH test is mandatory in patients with 3+ IHC scores from a reputable laboratory. FISH should be performed, however, if the clinician has any reason to question the result of the IHC test. Ultimately, not everyone trusts the lab that they use, and if you don't trust your lab, then you either need to find a different lab or rely on FISH, which tends to be performed in a central lab.
Medscape: Several abstracts at ASCO 2006 reported on the cardiotoxicity of adjuvant trastuzumab, including data from NSABP B31 demonstrating that approximately 1 in 5 women are unable to complete 1 year of adjuvant trastuzumab due to cardiotoxicity.[8] Can we predict who will experience cardiotoxicity? What about the safety of trastuzumab given with dose-dense chemotherapy?
Dr. Winer: Cardiotoxicity is the most concerning adverse effect with trastuzumab therapy, and can limit the patient's ability to complete a full year of trastuzumab. At this point, we have a hard time forecasting which patients will experience cardiotoxicity, and there is debate about the validity of clinical predictors. In the NSABP analysis, older patients and those with a borderline ejection fraction (EF) at baseline were more likely to develop cardiotoxicity. The age relationship has been observed in other studies as well, although the data concerning baseline EF are somewhat more mixed. It's worth pointing out that given the fairly stringent eligibility criteria for NSABP B31, few women with borderline heart function were enrolled. In daily practice, however, we may consider these women for treatment, which could lead to an even greater incidence of cardiotoxicity. In terms of dose-dense therapy, our colleagues at Memorial Sloan-Kettering Cancer Center, New York, NY, reported on a study[9] in which they looked at the use of dose-dense doxorubicin and cyclophosphamide followed by concurrent paclitaxel and trastuzumab. In that phase 2 trial of approximately 70 patients, the regimen appears to be a safe approach; however, this is still a relatively limited experience compared with the wealth of safety information from the larger trials.
Medscape: You've mentioned the use of non-anthracycline-containing adjuvant regimens. Do you think that concurrent use of trastuzumab and anthracycline chemotherapy is a regimen that deserves further exploration?
Dr. Winer: I think that it deserves further exploration. Buzdar and colleagues[7] from MD Anderson Cancer Center, Houston, Texas, evaluated preoperative paclitaxel followed by 5-FU [5-fluorouracil], epirubicin, and cyclophosphamide (FEC) chemotherapy with or without concurrent trastuzumab in both a randomized and a single-arm extension protocol. A very high pathologic complete response rate (60%) was reported in the combination therapy arm. The favorable response rate may be due to several factors, including patient selection, preoperative anthracycline administration, or the prolonged duration of therapy (6 months), but it also may be related to the concurrent exposure to both anthracycline and trastuzumab. I think that this finding needs to be explored further within the context of clinical trials, which are currently under way. It is not a regimen that I would routinely use outside of a clinical trial until we have more safety data.
Medscape: Provocative data were presented at both the San Antonio Breast Cancer Symposium 2005 and ASCO 2006 in regard to identifying patient subgroups – such as those with c-Myc amplification – for whom trastuzumab may be particularly beneficial. What can we learn from these markers, and can we expect this information to guide our clinical practice?
Dr. Winer: What we've learned from these analyses is that when we start looking at what is thought to be a relatively uniform group of patients with HER-2-positive disease, it turns out that there is more heterogeneity than we initially thought. Subgroup analysis from NSABP B-31 suggests that trastuzumab may be a particularly crucial drug in patients with coamplification of c-Myc and HER-2.[10] Although trastuzumab was found to be beneficial in women with c-Myc nonamplified tumors, those with coamplified tumors had very poor prognoses if they did not receive trastuzumab. However, in contrast, when trastuzumab was given, these patients had the best prognoses among all women on the trial. If these findings are confirmed, we may want to consider different approaches in clinical trials for c-Myc amplified vs and nonamplified tumors.
Medscape: Since the release of the adjuvant trastuzumab data in 2005, thousands of women have received this agent with chemotherapy. Unfortunately, some may experience recurrent disease. Do you think that recurrent breast cancer after adjuvant trastuzumab therapy is trastuzumab-resistant, or is there a role for further trastuzumab?
Dr. Winer: I suspect that one approach will not fit all patients in this setting; the decision to administer further treatment will depend on the specific tumor type and the time lag until recurrence. For a woman who has received adjuvant trastuzumab and then develops recurrent disease 3 years later, I would tend to think that there is a role for further trastuzumab: It would be one of the first treatments that I would consider. On the other hand, in a woman who develops progressive cancer very shortly after stopping adjuvant trastuzumab, I would be concerned that her disease is less likely to respond to trastuzumab. I personally don't have a definition for trastuzumab resistance, and I suspect that there are many different ways for a tumor to become trastuzumab-resistant. Since trastuzumab first became commercially available, the big unanswered question is whether there is any benefit to continuing it once a tumor begins to progress on therapy. Despite the fact that we have been dealing with this problem for the past 8 years, we don't have an answer yet.
Medscape: Exciting data were presented with regard to the role of lapatinib in the treatment of patients with advanced HER-2-positive disease.[11,12] What are your thoughts about lapatinib in the adjuvant setting?
Dr. Winer: Given the data suggesting activity of lapatinib in the treatment of metastatic HER-2-positive breast cancer, it is quite possible that lapatinib will have activity in the adjuvant setting as well, either given sequentially with trastuzumab, in place of trastuzumab, or in combination with trastuzumab. It's possible that lapatinib may be approved by the FDA [US Food and Drug Administration] and become commercially available in the next year or so; however, at this time, lapatinib has no role in the adjuvant setting outside of a clinical trial. Trials evaluating the role of lapatinib in the adjuvant setting should open within the next year in both North America and Europe.
Medscape: We have recently seen advancements in the treatment of HER-2-positive brain metastases.[13] Are there any new methods at this time to detect or prevent the development of brain metastases for women with early-stage HER-2-positive disease?
Dr. Winer: I think that it's important to recognize that brain metastases affect a very small proportion of patients who have early-stage HER-2-positive breast cancer, and although it was one of the frequent sites of recurrence in the adjuvant trials, the vast majority of women with early-stage HER-2-positive disease are not going to develop brain metastases. It is unclear whether early detection of brain metastases is clinically important. There is reason to believe that finding brain metastases when a patient has a lower burden of disease would lead to a better response to treatment, but the long-term impact of early detection on a woman's quality of life and survival is unknown. I would not recommend that women with early-stage breast cancer have any routine brain imaging after the completion of adjuvant therapy, and I know of no way to prevent brain metastases in the adjuvant setting at this time.
Medscape: A phase 1 trial[14] has reported activity with a combination of trastuzumab and bevacizumab. Bevacizumab is an active agent in the metastatic setting. Do you think that this combination has potential in the adjuvant setting?
Dr. Winer: There is good reason to believe that concurrent trastuzumab and bevacizumab could be an effective combination for several reasons, including preliminary results from the small phase 1 study, and encouraging preclinical data showing that VEGF [vascular endothelial growth factor] is upregulated in a substantial proportion of patients with HER-2-positive disease. On the basis of these data, concurrent trastuzumab and bevacizumab is potentially a very interesting regimen and will be investigated in the adjuvant setting by the NSABP. Until we have the results of that trial, however, it is not a regimen that should be used in general practice.
Medscape: Just a few years ago, HER-2-positive breast cancer carried a poor prognosis, but now has become a much more treatable disease. What future advances do you see for treatment of women with HER-2-positive breast cancer?
Dr. Winer: Over the next several years, we're going to see very substantial advances in the treatment of HER-2-positive breast cancer. We've already seen great progress with the use of trastuzumab in both the metastatic and adjuvant settings, and this year, with the development of lapatinib as an agent with activity in the metastatic setting after progression on trastuzumab. I anticipate that over the next 5-10 years we're going to gain a much finer understanding of mechanisms of resistance to trastuzumab and will identify new molecular targets to consider as we develop clinical trials. In the years ahead, recurrence rates after a diagnosis of early-stage HER-2-positive disease will fall dramatically. At the same time, we will continue to extend the lives of those women living with HER-2-positive metastatic disease.
