The long-awaited phase III clinical trial NSABP B-47 showed women with HER2-low invasive breast cancer do not benefit from the addition of trastuzumab to chemotherapy in the adjuvant setting, but questions remain for women who are borderline HER2-low. The results were presented at the 2017 San Antonio Breast Cancer Symposium (Abstract GS1-02).
About a decade ago, the trial NSABP B-31 showed that 174 participants with HER2-low breast cancer (i.e., FISH <2.0 or IHC 1+ of 2+) benefited from adjuvant trastuzumab to a similar extent that the HER2-positive group did (N Engl J Med 2005;353:1673-1684.).
“This was quite bewildering,” said Louis Fehrenbacher, MD, about the NSABP B-31 findings. He presented the findings of the new NSABP-47 trial and is Medical Director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center in California.
Similarly, the N9831 study showed a subpopulation of 103 participants with HER2-low breast cancer benefiting from adjuvant trastuzumab (J Clin Oncol 2010;28:4307-4315).
To validate these previous studies, the prospective clinical trial NSABP B-47 was conducted. A total of 3,270 women were enrolled in the study between 2011 and 2015 and randomized 1:1 to receive chemotherapy plus 1 year of trastuzumab or chemotherapy alone. The chemotherapy regimen for both arms was adriamycin and cyclophosphamide followed by weekly paclitaxel or docetaxel and cyclophosphamide. The chemotherapy regimen prescribed was determined by the investigator. Of the 3,270 patients randomized, only 63 (1.9%) were not followed up. The median follow-up time was 46.1 months.
The study did not meet its primary endpoint of invasive disease-free survival (IDFS). The 5-year IDFS was 89.6 percent for the arm that received trastuzumab and 89.2 percent for the arm that did not. There was no statistically significant difference between the women who received trastuzumab and those who did not (HR=0.98; 95% CI, 0.77-1.26; p=0.90).
“The conclusion was that the primary objective of improving the IDFS was not met. None of the secondary endpoints were met. There were no trends for efficacy seen,” Fehrenbacher said. The forest plot, he said, shows “no hint of efficacy of any of the stratification variables.” Stratification variables included number of positive lymph nodes, IHC score, hormone receptor status, and chemotherapy regimen.
“Severe toxicities were infrequent,” he added. Grade 4 or 5 toxicities were similar between arms; 4.3 percent of women in the chemotherapy plus trastuzumab arm had grade 4 or 5 toxicities compared with 5.0 percent of women in the chemotherapy alone arm. “No new safety signals were seen.”
He concluded, “There's no benefit with trastuzumab therapy in patients with FISH ratios less than 2.0 and IHC staining of 1 and 2+.”
“I'm not sure I totally believe that,” said Adam Brufsky, MD, PhD, regarding the 2.0 cutoff. Brufsky is Professor of Medicine at the University of Pittsburgh School of Medicine and also serves as the Associate Division Chief for the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine's Department of Medicine. “I believe there will be some women under 2.0 who will benefit.”
Fehrenbacher said that the outcome differences between what was found in the two major trials and the NSABP B-47 trial are not “readily explained.”
“It's very difficult to reconcile this with the other results,” Brufsky agreed. He suggested that perhaps the HER2 testing for those women in the other trials wasn't truly negative. “Maybe it was positive, and that's why they had the benefit. I don't know if that's necessarily true. The other possibility is that the prognosis of the women is the B-47 trial was a little bit better.
“Clearly, the major conclusion is that for the vast majority of women who are HER2-negative ER-positive, they are not going to benefit from adjuvant trastuzumab. I would agree with that,” he continued. “It's just those women right on the borderline that I think we need to individualize therapy.
“If a woman comes in with ER-negative breast cancer and has a HER2 ratio of like 1.8, I'm going to think long and hard about giving her adjuvant trastuzumab still, especially if her copy number is around 6,” Brufsky noted. “I don't think this trial answered the question for that particular woman.”
Brufsky thinks it is “unlikely” another trial will be conducted because “it costs a lot of money to do these studies” and conducting a study with enough power would be a challenge.
Christina Bennett is a contributing writer.