Large, randomized phase III clinical trials showed that the addition of HER2-targeted therapy to chemotherapy for patients with early-stage, HER2-overexpressing breast cancers substantially decreased the risk of recurrence and improved survival. The chemotherapy given in these trials varied, but it was generally intensive, with many patients receiving anthracyclines (or platinum agents) along with taxanes. These trials included few patients with small, lymph node–negative tumors and virtually none ≤ 1 cm.

While recurrence rates for stage I HER2-overexpressing breast cancer are lower than those associated with higher stages, the overexpression of HER2 is an aggressive enough feature that some combination of systemic therapy is often recommended. Lacking evidence, there has been no standard regimen for small, lymph node–negative, HER2-overexpressing tumors. Optimizing disease-free and overall survival while minimizing short- and long-term toxicity is an important concern for patients with these early-stage but biologically aggressive breast cancers.

APT Trial

The APT (Adjuvant Paclitaxel and Trastuzumab) study was designed to address the need to balance risks and benefits in a group of patients who would likely derive only a small absolute treatment benefit from intensive chemotherapy in combination with trastuzumab (Herceptin) because of their lower risk of recurrence. The study included 406 women with HER2-overexpressing, lymph node–negative tumors that were ≤ 3 cm. All patients received paclitaxel as the only chemotherapy agent plus trastuzumab for 12 weeks, followed by 9 months of trastuzumab given every 3 weeks.

This was a nonrandomized phase II trial, based on the rationale that a prospective trial that randomly assigned patients to trastuzumab or not, or to different types of chemotherapy, would not have been feasible. Concerns that physicians and patients would be unwilling to agree to the randomization, along with the requirement that thousands of patients would be needed to achieve sufficient events for statistical power, would have made it difficult to achieve the necessary accrual goals for an adequately powered, randomized phase III trial.

The results, recently reported by Tolaney and colleagues in The New England Journal of Medicine¹ and reviewed in this issue of The ASCO Post, demonstrated that APT was an effective and well-tolerated regimen. The 3-year rate of survival free from invasive disease was 98.7%.

After 4 years of median follow-up, only two patients had distant breast cancer recurrences, and, interestingly, one of them was determined to be HER2-negative at recurrence (making the point that rebiopsy at metastatic recurrence is critical). Of the remaining events, four were local-regional (ipsilateral breast or axilla), and four were contralateral breast cancers (three were HER2-negative). There were two deaths, none due to breast cancer; one death was due to ovarian cancer, and one was due to stroke.

Toxicity and Limitations

As for toxicity, 2 patients (0.5%) developed symptomatic congestive heart failure (which normalized after discontinuing trastuzumab), and 13 had asymptomatic drops in their cardiac function (11 were able to resume trastuzumab after a brief interruption). Thirteen patients (3.2%) reported at least one episode of grade 3 neuropathy. Seven patients had grade 3 or 4 allergic reactions to the study treatment, and only one of them was able to complete treatment. Few other serious side effects were reported. Adverse events led to withdrawal from the study in 6% of patients.

The APT study has limitations, since it was a single-arm, nonrandomized trial, and about 20% of its patients had tumors < 0.5 cm, which are already associated with a very favorable prognosis. Also, two-thirds of the tumors included in this study were both HER2-overexpressing and estrogen receptor (ER)-positive, and virtually all of these patients also received endocrine therapy as part of their systemic therapy.

Recurrences in ER-positive tumors may occur beyond the current 4 years of follow-up available on the APT trial and will continue to be monitored by the study for 10 years. Nevertheless, paclitaxel plus trastuzumab can be considered a reasonable and fairly well-tolerated approach for the majority of patients with small, lymph node–negative, HER2-overexpressing breast cancer, and more aggressive and toxic chemotherapy regimens can be avoided.

Omitting Chemotherapy

Preclinical as well as clinical data support synergy between chemotherapy and HER2-targeted regimens, but for these lower-risk tumors, an important question remains: Which patients really need chemotherapy at all? The cardiac toxicity and neuropathy in the APT study were low but certainly significant for those experiencing these side effects, and there were allergic reactions presumably to the formulation vehicle, Kolliphor EL (formerly known as Cremophor), in the paclitaxel. These side effects could possibly be avoided in some patients if we could show that chemotherapy offered only a very small improvement in recurrence and survival beyond HER2-directed therapy alone.

For small HER2-overexpressing tumors that are also ER-positive, a regimen of combined HER2- and ER-targeted therapy without chemotherapy is worthy of further study. Even in the HER2-overexpressing/ER-negative subgroup, we have enticing data from preoperative therapy studies showing that pathologic complete responses can be achieved, at least in some tumors, with combination HER2-directed agents and no chemotherapy. Can we define these cancers and omit chemotherapy entirely?

Clinical Context

We’ve made tremendous progress in improving survival for patients with early-stage, HER2-overexpressing breast cancer, at least in developed countries where access to HER2-directed therapy is routinely available. However, the treatment regimens that have so dramatically reduced recurrences and deaths are also associated with real costs for patients and society, including short- and long-term toxicities and financial costs.

It’s time to focus on evaluating regimens that might minimize some of this burden, determining which patients and tumors need more aggressive, toxic, and expensive regimens and which will achieve similar excellent outcomes with less toxicity and cost. Because of our success in dramatically reducing recurrences and deaths in HER2-overexpressing breast cancer—resulting in low event rates for powering clinical trials statistics—asking these questions in a classic, randomized phase III trial design will be prohibitively costly and lengthy.

The APT trial is an important, well-designed phase II study that has convincingly established a less-toxic regimen as standard of care in the small, node-negative HER2-overexpressing population of breast cancer patients. Its design is practical and efficient and can be used as a model for evaluating safer “less therapy” approaches in subsets of breast cancer patients with expected high disease-free and overall survival rates. ■

Disclosure: Dr. Gralow has received research funding from Roche/Genentech.

Reference

1. Tolaney SM, Barry WT, Dang CT, et al: Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 372:134-141, 2015.