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Trastuzumab fails to improve outcomes for HER-2-low breast cancer
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SAN ANTONIO — Adjuvant trastuzumab did not extend invasive DFS in a cohort of patients with high-risk breast cancer and low levels of HER-2, according to results of the phase 3 NSABP-B-47 trial presented at the San Antonio Breast Cancer Symposium.
Thus, the study failed to meet its primary endpoint.
Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with Kaiser Permanente Vallejo Medical Center of Kaiser Permanente Medical Group, and colleagues defined HER-2 low as immunohistochemistry (IHC) 1+ or 2+ and/or in situ hybridization (ISH) negative.
Fehrenbacher referenced findings from the National Surgical Breast and Bowel Project (NSABP) B-31 trial, presented by Romond and colleagues at the 2005 ASCO Annual Meeting, showing the impact of trastuzumab (Herceptin, Genentech) among HER-2 positive patients.
“It was a great time for oncology,” he said during a press conference, noting that initial study entry criteria that defined HER-2 positive — FISH+ > 2.0 and IHC 3+ — are important to the current analysis.
However, tissue specimens from NSABP-B-31 were later sent to NSABP for additional HER-2 testing. Results showed that 9.7% of the cases were not, in fact, HER-2 IHC 3+, or FISH positive, according to Fehrenbacher.
“They were what we call HER-2 low,” he said.
“Lo and behold, when we the analysis was performed, we looked at the benefit of trastuzumab in the 174 patients considered to be HER-2 low and found that the result was essentially identical,” Fehrenbacher added.
An analysis of those with FISH < 2.0 (HR = 0.54; 95% CI, 0.25-1.17), and those with IHC 0, 1, or 2+ along with FISH < 2.0 (HR = 0.51; 95% CI, 0.21-1.23) showed that the benefit with trastuzumab appeared equal in the HER-2-low group.
“The hypothesis was that only HER-2-amplified patients would benefit from this,” he said. “This was quite bewildering.”
Approximately 45% of patients with breast cancer have HER-2-low tumors, and these patients are not currently treated with trastuzumab.
Given these results, NSABP and NCI initiated a trial to evaluate whether the addition of trastuzumab to chemotherapy would improve invasive DFS among 3,270 women with high-risk breast cancer and HER-2-low tumors, or those HER-2 negative by ISH and with IHC 1+ or 2+ disease.
Chemotherapy regimens — decided per investigator discretion — included 60 mg/m2 doxorubicin and 600 mg/m2 cyclophosphamide for four cycles followed by paclitaxel, or 75 mg/m2 docetaxel plus 600 mg/m2 cyclophosphamide every 3 weeks for six cycles.
The final analysis included 3,207 patients who were followed for a median of 46.1 months.
Results showed that the 5-year EFS was 89.2% among patients not treated with trastuzumab and 89.6% among those receiving the drug, for a comparable overall invasive DFS rate between the two arms (HR = 0.98; 95% CI, 0.77-1.26).
“We could magnify this slide and you still wouldn’t see a difference between those two arms,” Fehrenbacher said. “The event rate was essentially equal.”
He noted, however, that patients “actually did pretty well” for a high-risk cohort.
Stratification by variables including IHC score, number of positive nodes, ER status or intended chemotherapy also failed to impact the results.
“The primary objective of improving invasive DFS was not met,” Fehrenbacher said. He added that secondary endpoints of OS, DFS, breast cancer-free interval, recurrence-free interval and distance recurrence-free interval also were not met, nor were there differences in outcomes for IHC 1 or 2 positivity.
“Severe toxicities were infrequent, and there were no new safety signals seen,” he said.
Fehrenbacher added that the disparity in outcomes for locally tested and centrally tested HER-2 status from the previous adjuvant trial is “not readily explained.”
“There is no benefit with trastuzumab therapy in patients with FISH ratios less than 2.0 and IHC staining of 1+ and 2+,” he concluded. – by Rob Volansky
Reference:
Fehrenbacher L, et al. Abstract GS1-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: Genentech and NCI funded this study. Fehrenbacher reports conducting contracted research for AbbVie, Cascadian, CellDex, Genentech/Roche, Macrogenics and Pfizer. Please see the abstract for a list of all other authors’ relevant financial disclosures.
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Virginia Kaklamani, MD
This is extremely important. We don’t typically choose to present negative slides at this forum, but the reason we chose this presentation is the fact that there are many patients who are IHC 1+ or 2+. We were wondering if we should be giving a pretty expensive drug that has its own toxicities for a whole year.
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