SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Adding trastuzumab to the standard regimen for patients with early-stage breast cancer and low levels of HER2 does not improve outcomes, according to new findings presented at the San Antonio Breast Cancer Symposium.

In a randomized trial of more than 3,000 patients, the 5-year invasive disease–free survival (IDFS) was 89.6% for those who received trastuzumab, compared with 89.2% for those who did not (hazard ratio, 0.98 95% confidence interval, 0.77-1.26, P = .90). Even after stratification for HER2 IHC level, extent of lymph node involvement, or hormone receptor status, the findings remained similar.

Patients in both arms did well, explained lead study author Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo (Calif.) Medical Center. “But the primary endpoint of IDFS was not met and none of the secondary endpoints were met. No trends of efficacy were seen.”

Current guidelines classify a breast cancer as HER2 positive if immunohistochemistry testing shows high levels of HER2 protein, defined as IHC 3+, or increased copies of the HER2 gene in situ hybridization. Adding 1 year of treatment with trastuzumab to standard adjuvant chemotherapy has been found to significantly reduce cancer recurrence and to improve survival for patients with early-stage HER2-positive breast cancer.

However, data from some of the early trastuzumab clinical trials suggested that patients with HER2-low breast cancer may benefit from the HER2-targeted treatment as well.

In 2005, the “stunning” results from the NSABP B-31 trial, of trastuzumab used in HER2+ breast cancer, were presented at the annual meeting of the American Society of Clinical Oncology. The study criteria included having a FISH+ test greater than 2.0 or IHC 3+, and testing was initially performed at a local laboratory site. When testing was conducted by the NSABP, submitted tissue samples showed that 9.7% of patients were not HER2 IHC 3+ or FISH+ greater than 2.0.

There were 174 patients defined as HER2 low, and not HER2 +.

“When the analysis was performed looking at the benefit of using trastuzumab in these patients considered low, it was found that the result was essentially identical, the benefit was equal, and statistically there was no interaction between FISH testing of IHC testing,” said Dr. Fehrenbacher. “These results were bewildering as the hypothesis was that only the HER2 amplified patients would benefit.

Because of these results, the NCI [National Cancer Institute] and the NSABP [National Surgical Adjuvant Breast and Bowel Project] initiated another trial, the N9831, which also found the same benefit in patients who were HER2 low.

About 15% of breast cancers are HER2 positive and another 45% have low levels of HER2, but these patients are not currently treated with adjuvant trastuzumab. Therefore, the current study, the NSABP-B-47, was designed and conducted to see if these early results could be validated in a large, prospective, randomized trial.

The study included 3,270 patients with early-stage breast cancer that was either IHC 1+, IHC 2+, and/or ISH negative in the trial. The patients were randomized 1:1 to standard adjuvant chemotherapy with or without a year of trastuzumab.

The standard regimen consisted of either one of the two chemotherapy regimens, per physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2) administered intravenously every 3 weeks for six cycles; the anthracycline regimen is AC followed by weekly paclitaxel (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously either every 3 weeks or every 2 weeks. The same regimen applied to the group that received additional trastuzumab.

The primary endpoint was to determine whether the addition of trastuzumab to chemotherapy improved invasive disease-free survival.

At a median follow-up of 46.1 months, 264 patients had IDFS events. The 5-year estimates for recurrence-free interval, distant recurrence–free interval, and overall survival were not statistically different for patients receiving trastuzumab compared with those not receiving trastuzumab.

There was no difference in outcomes for IHC 1+ (HR for IDFS 0.88, 95% CI, 0.63-1.22) or IHC 2+ (HR for IDFS 1.14 95% CI, 0.79-1.65).

“The retrospective outcome difference between local tested HER2 + and center tested HER2-low patients identified in two major adjuvant trials are not readily explained,” said Dr. Fehrenbacher. “There is no benefit with trastuzumab therapy in patients with a FISH ratio of less than 2 and IHC staining intensity of 1+ or 2+.

SOURCE: Fehrenbacher et al. GS1-02