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Long-term follow-up in a large phase II trial of early HER2-positive breast cancer showed high rates of disease control and survival with a longstanding standard regimen.

Treatment with adjuvant paclitaxel and trastuzumab (Herceptin) led to a 7-year disease-free survival (DFS) of 93% and overall survival (OS) of 95%. Additionally, 97.5% of the 410 patients remained relapse-free for at least 7 years, according to Sara M. Tolaney, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

An exploratory analysis identified one variant associated with an increased risk of paclitaxel-induced peripheral neuropathy, they reported in the .

The findings showed little change since the 4 years ago and were consistent with long-term follow-up data from large pivotal trials that showed "dramatic and sustained benefit" with the addition of trastuzumab to standard chemotherapy for early HER2-positive breast cancer.

"The updated data are suggesting that the low event rate initially seen with shorter follow-up has held up with longer follow-up," Tolaney told 名媛直播. "I think it was particularly relevant in this trial because the majority of patients had hormone-receptor positive, HER2-positive disease, where we know these patients can experience later recurrences than those patients who have hormone receptor-negative disease."

"I think it was important to show that the low event rate holds with longer follow-up. I think this regimen was adopted to see whether a fairly standard regimen could be used for patients with stage I HER2-positive tumors after the initial presentation. These findings helped confirm that it's a reasonable approach for stage I patients," she added.

The findings came from the prospective, multicenter Adjuvant Paclitaxel and Trastuzumab (APT) trial. When trial enrollment began in 2007, retrospective data suggested that patients with small node-negative HER2-positive tumors had recurrence rates as high as 30%. Randomized trials of adjuvant trastuzumab included few patients with stage I disease, providing a rationale for the APT study, the first trial that specifically addressed appropriate treatment for patients with small, node-negative HER2-positive breast cancer, the authors noted.

A single-arm design was adopted because of investigators' belief that a randomized trial would not be feasible, given data suggesting increased risk of recurrence for the patient population. Additionally, no standard treatment existed at the time for patients with small node-negative, HER2-positive breast cancer, Tolaney and colleagues continued.

Eligible patients had pathologically confirmed HER2-positive tumors, primary tumor size ≤3 cm, and no lymph-node involvement. Approximately 2 years into enrollment (n=188), investigators amended the protocol to include patients with a single micrometastatic node. Patient accrual ended in September 2010. The trial had a primary endpoint of DFS.

The patients had a median age of 55, and 67% had hormone receptor (HR)-positive disease. Half the patients had tumors ≤1 cm, and 9% had tumors 2-3 cm. The mean tumor size was 1.1 cm.

The first report from the APT trial, after a median follow-up of 4 years, showed a 3-year invasive DFS of 98.7%. The updated analysis occurred after a median follow-up of 6.5 years, during which time 23 DFS events occurred: five locoregional recurrences, four distant recurrences, six new contralateral breast cancers, and eight deaths without disease recurrence. The 7-year DFS of 93.3% included 94.6% in patients with HR-positive tumors and 90.7% in the HR-negative subgroup. Key secondary outcomes at 7 years included:

• Relapse-free interval: 97.5%
• Breast cancer-specific survival: 98.6%
• OS: 95%

Using tumor specimens, investigators determined risk of recurrence scores for 264 patients. They characterized nine (3.4%) samples as low risk, 56 (21.2%) as intermediate risk, and 199 (75.4%) as high risk.

The exploratory analysis of taxane-induced peripheral neuropathy (TIPN) included genetic data for 230 patients. Overall, 24 patients developed grade ≥2 TIPN; no grade 4 neurotoxicity occurred in the subgroup or in the overall study population. Evaluation of 50 single nucleotide polymorphisms showed that one (rs3012437) was associated with an increased risk of grade ≥2 TIPN.

As part of ongoing drug development, clinical trials are evaluating potentially less toxic therapies for patients with lower-risk disease, said Tolaney. Results of a trial comparing T-DM1 (Kadcyla) with the paclitaxel-trastuzumab regimen will likely be reported before the end of 2019.

"Trastuzumab has remained a staple in our approach to patients with HER2-positive disease," she said "Having said that, I think we're learning there might be more potent anti-HER2 therapies that are emerging, particularly antibody-drug conjugates, that might be able to provide highly effective therapy and potentially replace chemotherapy and trastuzumab."

"I'm hoping that the field continues to evolve, because I think the goal is to provide the right amount of therapy to the right patient. We'd like to avoid overtreating patients, particularly with these lower-risk tumors," she stated.

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