Herceptin (Trastuzumab), the antibody against the HER2/neu protein over-expressed in about 20-30% of breast cancers, has been shown to reduce the risk of recurrence and death from HER2-overexpressing breast cancer in several, large randomized trials and as a result has become a standard part of adjuvant therapy for such patients with early stage breast cancer. However, one group of patients that was excluded from all of the large, randomized trials was patients with node-negative tumors that were 1 cm or smaller. This group of patients is presumed to be at lower risk or recurrence and death than their counterparts with larger or node-positive tumors, and the role of adjuvant Herceptin-based chemotherapy is therefore uncertain and controversial. Does biology (being HER2-positive) trump size? Or does size still matter?
All of the large, randomized adjuvant herceptin trials included some form of chemotherapy (none gave Herceptin alone), which increases the potential risks. Is there a tumor size in which the outlook without adjuvant chemotherapy and Herceptin is so good that the risks of therapy outweigh the potential benefits? These are very important questions and issues to resolve, because the incidence of very small breast cancers has increased in the past two decades, due to the prevalence of mammographic screening programs. This group of patients, however, likely remains too small for randomized trials to be performed. Therefore, we need to rely on other sources of information to make patient care recommendations.
We may be overly optimistic when we assume that the prognosis for these very small tumors is excellent. There is evidence that the prognosis is not as good for small tumors if they are HER2-positive. Investigators at the University of Texas MD Anderson Cancer Center recently reviewed the outcomes of 965 patients with node-negative tumors that were 1cm or smaller. They found that the patients with HER2-positive tumors had a significantly higher risk of recurrence than those who were HER2-negative. Other investigators have obtained similar results.
There is also evidence that node-negative tumors larger than 1 cm benefit from adjuvant Herceptin-based chemotherapy. The benefit from therapy in multiple groups of patients enrolled on one of the large, multinational, randomized adjuvant Herceptin trials, called HERA, was recently evaluated. The investigators were unable to identify any group of patients who did not benefit from receiving herceptin. Importantly, the patients with small (1.1 -2.0 cm), node-negative tumors also benefitted from receiving herceptin.
The folks at Memorial Sloan Kettering Cancer Center also recently reported on the experience of women treated at their institution with node-negative, HER2-positive breast cancers that were less than 2 cm in size. Of the 261 women, 155 received herceptin and 106 did not. There were 99 women whose tumors were 1cm or less, 54 of whom received herceptin and 45 who did not. Among the whole group, there were significantly fewer recurrences among the women who received Herceptin.
Current NCCN guidelines recommend adjuvant chemotherapy plus Herceptin for HER2-positive tumors that are node-positive or are node-negative and more than 1 cm. For node-negative tumors that are 0.6-1.0 cm, the guidelines recommend considering adjuvant chemotherapy and Herceptin. For node-negative tumors that are 5mm or less in size, no adjuvant therapy is recommended, other than consideration of hormonal therapy if the tumor is also ER-positive.
In conclusion, there are unlikely to ever be large, randomized trials evaluating the use of adjuvant Herceptin-based chemotherapy specifically in women with HER2-positive, node-negative tumors that are less than 1 cm. However using data that are presently available, consideration of therapy for these women, particularly those with tumors measuring 0.6 – 1 cm, appears justified. There are currently at least two ongoing trials that include these women. One is a trial at the Dana-Farber Cancer Institute in Boston, MA, looking at the benefit of adjuvant Taxol (paclitaxel) and Herceptin in women with HER2-positive, node-negative tumors measuring less than 3 cm. The other is the BETH trial, which is a multicenter, randomized, phase III trial looking at adjuvant Herceptin plus the anti-angiogenic agent Avastin (bevacizumab), an antibody against vascular endothelial growth factor (VEGF). This trial includes patients with HER2-positive, node-negative tumors measuring less than 2 cm that have at least one of the following high-risk features: ER-negative status, high grade, or young age (less than 35 years of age). Hopefully, women with HER2-positive tumors less than 1 cm will continue to be included in adjuvant trials of HER2-targeted therapy, giving us further data to use to make more informed decisions in the future.