Louis Fehrenbacher, MD

For more than a decade, breast cancer experts have wondered whether women with low levels of HER2 might derive some benefit from trastuzumab (Herceptin), based on signals seen in earlier trastuzumab trials. Most notably, in the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, patients found to have “HER2-low” tumors by central testing derived similar benefit as those confirmed to be HER2-positive. The NSABP B-47 trial was designed to evaluate this possibility in a randomized manner. The result was somewhat unexpected. 

In women with tumors that were immunohistochemistry (IHC) 1+ or 2+ and/or negative by fluorescence in situ hybridization (FISH), adding trastuzumab to standard adjuvant chemotherapy did not improve invasive disease–free survival, said Louis Fehrenbacher, MD, Medical Director of Kaiser Permanente Oncology Clinical Trials and an oncologist at the Kaiser Permanente Vallejo Medical Center, California, who reported the study results at the 2017 San Antonio Breast Cancer Symposium.¹

“The primary objective of improving disease-free survival was not met. None of the secondary endpoints were met. No trends of efficacy were seen. There was no difference in outcomes for IHC 1+ or 2+. There is no benefit with trastuzumab therapy in patients with FISH ratios < 2.0 and IHC staining intensity of 1+ or 2+,” Dr. Fehrenbacher announced.

“I think many of us were surprised at this finding,” he commented at a press briefing. “It’s biologically difficult to understand why a tumor with a FISH ratio of 2.1 gets full benefit from trastuzumab, while one with a ratio of 1.9 gets none.”

Breast cancer experts interviewed by The ASCO Post said the question has been answered. “We have many patients who are IHC 1+ or 2+, and we have been wondering whether we should be giving them a year of this expensive drug. Now we can say, stick to the guidelines. Do not offer anti-HER2 therapy in 1+ or 2+ patients,” said Virginia Kaklamani, MD, Professor of Medicine at The University of Texas Health Science Center, San Antonio.

Harold Burstein, MD, PhD, FASCO, Associate Professor of Medicine at Harvard Medical School, added, “People have been so worried about missing the opportunity to give trastuzumab that they have been doing all this extra testing to see if they can find [other suitable clinical circumstances]. I don’t think you need to do that. You need good IHC and good FISH testing, and if that’s negative, you are done.”

Strong Rationale for B-47

Approximately 15% of breast cancers are HER2-positive, but another 45% have low levels of HER2. Although the latter are not considered candidates for adjuvant trastuzumab, some of the early trastuzumab clinical trials found a signal of benefit for the drug in HER2-low tumors. In the NSABP B-31 trial, in which all patients were deemed HER2-positive by local laboratories (FISH ratio > 2.0 or IHC staining intensity of 3+), 9.7% were later determined to be HER2-negative by central testing, ie, negative on FISH or IHC < 3+.² Surprisingly, these patients had responded to trastuzumab, with a relative risk for disease-free survival of 0.34. It raised the possibility that some HER2-negative patients could benefit from anti-HER2 therapy.

“The NSABP designed and conducted NSABP B-47 to test, in a large, rigorous clinical trial, whether this was indeed the case,” Dr. Fehrenbacher said. “Because patients who are IHC 1+ and 2+ and HER2-nonamplified are three times more common than HER2-amplified patients, the potential benefit could be enormous.” 

NSABP B-47 Details

Dr. Fehrenbacher and colleagues enrolled 3,270 patients with early-stage breast cancer that was IHC 1+, IHC 2+, and/or FISH-negative (ratio < 2.0). The patients were randomized 1:1 to receive standard adjuvant chemotherapy with or without a year of trastuzumab. 

After a median follow-up of 46.1 months, 264 patients had a recurrence of their original breast cancer, a diagnosis of a new breast cancer, a diagnosis of new cancer outside the breast, or had died. These events triggered the analysis of the primary endpoint of the trial, invasive disease–free survival. 

“Both arms did very well,” Dr. Fehrenbacher reported. The 5-year invasive disease–free survival rate was 89.6% for the trastuzumab arm and 89.2% for the control arm (hazard ratio [HR] = 0.98, P = .90), and the overall survival rate was 94.8% and 96.2%, respectively (HR = 1.33, P = .14). Similar hazard ratios were observed for a number of other prespecified endpoints, and the findings were consistent across subgroups of HER2 IHC level, extent of lymph node involvement, and hormone receptor status. 

He emphasized that even patients with IHC 2+ staining enjoyed no more benefit than those with IHC 1+ staining. “It’s hard to completely explain these findings,” Dr. Fehrenbacher acknowledged. 

He said the door is still open for additional testing in individual cases of “high suspicion”—ie, clinicians could test other areas of the tumor in conversation with the pathologist. “There’s the possibility of additional testing of equivocal cases, but patients who are IHC 2+ do not benefit from trastuzumab at this point in time,” he concluded. ■

DISCLOSURE: This study was supported by the National Cancer Institute and Genentech. Drs. Fehrenbacher and Burstein reported no conflicts of interest. Dr. Kaklamani is a consultant for Genentech. 

REFERENCES

1. Fehrenbacher L, Cecchini RS, Geyer CE, et al: NSABP B-47 (NRG Oncology): Phase III randomized controlled trial comparing adjuvant chemotherapy with adriamycin and cyclophosphamide followed by weekly paclitaxel, or docetaxel and cyclophosphamide with or without a year of trastuzumab in women with node-positive or high-risk node-negative invasive breast cancer expressing HER2 staining intensity of IHC 1+ or 2+ with negative FISH. 2017 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 6, 2017.

2. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684,2005.