Patients with small HER2-positive breast cancers (tumors ≤3 cm) may no longer need conventional chemotherapy and may require less invasive chemotherapy to achieve good outcomes, according to new research. A single group of 406 patients with stage I lymph node-negative breast cancer received the combination of paclitaxel + trastuzumab after surgery and had a 3-year disease-free survival rate of 98.7%. The results of this study were published in NEJM. Dr. Winer, from the Dana-Farber Cancer Institute in Boston, told Medscape Medical News that the results are very convincing. When treating small tumors ≤3 cm, many doctors recommend trastuzumab + multidrug chemotherapy regimens, which are often toxic. This more damaging regimen is based on randomized clinical trials of larger HER2-positive tumors. The results of this study imply that small tumors can be well treated with only trastuzumab + one chemotherapy agent. It is difficult to envision a more toxic regimen that would work well in practice. Dr. Gralow, from the Fred Hutchinson Cancer Center in Seattle, who was not involved in the study, responded to Dr. Winer’s comment that nothing could have been done better than this, and that shortly after the results were presented at the St. Anthony’s Breast Cancer Forum in 2013, her center began doing real clinical work on this. She added, “We accepted the results of these data and changed our clinical practice as a result, and we did not continue the more aggressive chemotherapy for patients with small tumors.” When asked about the results, Dr. Opyrchal, from Roswell Park Cancer Institute in New York, said, “The disease-free survival results of this study are alarming. But the study was non-randomized, and many of the patients were positive for HR receptors in addition to HER2, and up to 67 percent were either ER or PR receptor positive. These types of breast cancer tend to recur late, and longer follow-up may help reveal the true level of risk for these diseases. The study’s designers also noted this possibility, so the study’s follow-up period was 10 years. The median follow-up time for the most recent results was 4 years. In conclusion, Dr. Opyrchal said the updated data will give oncologists confidence and evidence that lower-intensity therapy will also lead to more favorable clinical outcomes for patients. Patients in this study received once-weekly paclitaxel 80 mg/m2 and trastuzumab 2 mg/kg for 12 weeks, followed by trastuzumab monotherapy for 9 months. Almost all patients were lymph node negative, 1.5% had micro-metastases in their lymph nodes, and the median age was 55 years. Patients treated with resection of the mass required radiotherapy, and adjuvant hormonal therapy at the end of paclitaxel therapy was also recommended for HR-positive patients. There were 12 recurrences in 406 patients, including 2 distant metastases. Only 7 disease-specific events occurred, excluding contralateral HER2-negative breast and non-breast cancers. Serious toxic events were rare, with 14 patients experiencing grade 3 or greater neurotoxicity and 2 patients experiencing grade 3 left ventricular systolic abnormalities, a common side effect of trastuzumab, during the 12 weeks of combination therapy, both of whom recovered after discontinuation of the drug. Thirteen patients experienced asymptomatic decreases in ejection fraction, leading to trastuzumab discontinuation. Two of them failed to return to normal ejection fraction and did not complete trastuzumab therapy. Fatigue, diarrhea and neurological symptoms were common side effects. The investigators acknowledged that some patients, particularly T1a patients, made a joint decision with their physicians to avoid the side effects of the trastuzumab regimen. In other words, the smallest HER2-positive tumors remain controversial for systemic therapy, even if the regimens are less toxic, and Dr. Gralow notes that these findings raise questions about systemic therapy. That is, can all systemic therapy be omitted when treating small tumors? HER2-targeted monotherapy may make sense for these patients, she said (HR therapy is available). There is some evidence that certain subcategories of HER2-positive breast cancer respond only to HER2-targeted therapy. Some patients with HER2-positive but very small tumors may choose to forgo systemic therapy. For small tumors, the benefit of systemic therapy is clearly less than for larger tumors, and the treatment decision to combine trastuzumab with chemotherapy can be influenced by the toxicity of the treatment regimen. However, there is no single standard to follow in this situation. Many physicians recommend treatment with adriamycin + cyclophosphamide + paclitaxel + trastuzumab or docetaxel + carboplatin + trastuzumab. These regimens are associated with greater toxicities and are often used in patients who are more likely to relapse. The purpose of this study was to evaluate the efficacy of a less toxic regimen in patients at low risk of relapse. The study is not a randomized study because patients would not have been recruited into the trial if they were not receiving trastuzumab.