In a phase II study reported in The New England Journal of Medicine, Sara M. Tolaney, MD, MPH, of Dana-Farber Cancer Institute, and colleagues found that adjuvant paclitaxel and trastuzumab (Herceptin) was associated with high invasive disease-free survival in women with small, node-negative, HER2-positive breast cancers.¹ Currently, there is no single standard treatment in this setting.

Study Details

In this single-group multicenter study, 406 patients with tumors of up to 3 cm in the longest dimension were enrolled between October 2007 and September 2010 and treated with paclitaxel (80 mg/m² weekly) for 12 weeks and a loading dose of trastuzumab (4 mg/kg) on day 1 followed by 2 mg/kg weekly, for a total of 12 doses. After completion of 12 weeks of trastuzumab treatment, trastuzumab could be continued on a weekly basis, or the regimen could be changed to 6 mg/kg every 3 weeks for 40 weeks to complete 1 year of treatment.

Patients undergoing lumpectomy had to receive partial-breast radiation therapy, performed before the start of study therapy, or whole-breast radiation therapy, started after completion of paclitaxel. Trastuzumab was continued during radiation therapy. Adjuvant hormonal therapy was recommended for women with hormone receptor–positive disease after completion of paclitaxel. The primary endpoint was invasive disease-free survival.

Left-ventricular ejection fraction was assessed in all patients at baseline and at 12 weeks, 6 months, and 1 year after the start of study treatment. Trastuzumab was discontinued in patients developing grade 3 or 4 left-ventricular systolic dysfunction and interrupted in those with a decrease in ejection fraction of 10% to 15%, with the ejection fraction ≥ 1% below the lower limit of the normal range at the particular radiology facility or a decrease of ≥ 16% from baseline.

Patients had a median age of 55 years (range, 24–85 years, 32% < 50 years), 86% were white, and 67% had hormone receptor–positive tumors, including 64% with estrogen receptor–positive and 50% with progesterone receptor–positive disease. The primary tumor size was ≤ 0.1 cm (T1mic) in 2%, > 0.1 to ≤ 0.5 cm (T1a) in 17%, > 0.5 to ≤ 1.0 cm (T1b) in 31%, > 1.0 to ≤ 2.0 cm (T1c) in 42%, and > 2.0 to ≤ 3.0 cm (T2) in 9%. Nodal micrometastases were present in 1.5%. Histologic grades were well, moderately, and poorly differentiated in 11%, 32%, and 56%.

Invasive Disease-Free Survival

The median follow-up was 4.0 years (maximum, 6.2 years). Overall, 88% of patients completed 52 weeks of treatment.

The 3-year invasive disease-free survival rate was 98.7% (95% confidence interval [CI] = 97.6%–99.8%). Recurrence or death occurred in 12 patients (3.0%); no breast cancer–related deaths were observed, and 2 patients died of causes unrelated to breast cancer. Local or regional tumor recurrences consisted of HER2-positive recurrences in the ipsilateral axilla in three patients (0.7%; at 12, 20, and 54 months) and in the ipsilateral breast in one patient (0.2%; at 37 months).

New contralateral breast cancer occurred in four patients, with one (0.2%; at 56 months) having HER2-positive and three (0.7%; at 12, 37, and 59 months) having HER2-negative disease. Distant tumor recurrences consisted of HER2-positive skeletal tissue disease in one patient (0.2%; at 27 months) and HER2-negative soft-tissue disease in one patient (0.2%; at 46 months). The 3-year rate of recurrence-free survival was 99.2% (95% CI = 98.4%–100%).

Toxicities

A total of 24 patients (5.9%) discontinued study therapy due to protocol-specified toxic effects; an additional 6 patients (1.5%) discontinued therapy due to other toxicities. Grade 3 neuropathy occurred in 13 patients (3.2%, 95% CI = 1.7%–5.4%) during 12 weeks of combined therapy; no grade 4 neurotoxic effects were reported. Grade 3 left-ventricular systolic dysfunction (symptomatic congestive heart failure) occurred in two patients (0.5%, 95% CI = 0.1%–1.8%) at 6 and 11 months during therapy, with both recovering after discontinuation of trastuzumab.

Clinically significant asymptomatic declines in ejection fraction led to interruption of trastuzumab in 13 patients (3.2%, 95% CI = 1.7%–5.4%); in two patients, normalization did not occur during treatment interruption, and the patients did not complete the year of treatment. Grade 3 or 4 allergic reactions to study treatment occurred in seven patients (1.7%), with one being unable to complete treatment.

In addition to grade 3 neuropathy, the most common grade 3 or 4 protocol-specified adverse events were neutropenia (3.7% grade 3, 0.5% grade 4), leukopenia (2.5% grade 3), and fatigue (2.2% grade 3). No incidence data were recorded for alopecia, which was expected to occur in the majority of patients.

The investigators concluded: “Among women with predominantly stage I HER2-positive breast cancer, treatment with adjuvant paclitaxel plus trastuzumab was associated with a risk of early recurrence of about 2%; 6% of patients withdrew from the study because of protocol-specified adverse events.”

They noted: “The regimen we used in this study was associated with patient outcomes that were better than expected on the basis of historical data. However, the study does not provide data to support the use of trastuzumab-based chemotherapy in all patients with small HER2-positive tumors, and there will be many patients with T1a disease and some with T1b disease who will decide with their physicians to avoid the toxic effects of a trastuzumab-based regimen.” ■

Disclosure: This study was funded by Genentech. For full disclosures of the study authors, visit www.nejm.org.

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.

Julie R. Gralow, MD, of Washington School of Medicine and Seattle Cancer Care Alliance, offers her perspective on the phase II study discussed above.