No Trastuzumab Benefit in HER2-Low Breast Cancer After All

Liam Davenport

December 06, 2017

SAN ANTONIO ― Adding trastuzumab (multiple brands) to standard adjuvant chemotherapy does not improve invasive disease-free survival (IDFS) in early-stage breast cancer patients with low levels of HER2, despite earlier analyses indicating that there might be a benefit, conclude US researchers.

Analyses of previous studies suggested that patients with HER2-low tumors, defined as a level of 1+ or 2+ on immunohistochemistry (IHC) or a fluorescence in situ hybridization (FISH) ratio of <2.0, may have substantial improvements in disease-free survival comparable to those seen in HER2+ tumors.

However, new results conflict with those past analyses. The National Surgical Adjuvant Breast and Bowel Project (NSABP) study of more than 3000 patients reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017 has shown that patients with HER2-low disease do not benefit from 1 year of trastuzumab therapy, regardless of patient stratification.

Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center, California, who presented the research, said that he and his colleagues were "surprised" at the result.

Dr Louis Fehrenbacher

Although he believes that heterogeneity among tumor samples may explain the earlier apparent benefit seen with trastuzumab, he said that "it's hard to imagine that a FISH ratio of 2.1 can still benefit, and a FISH ratio of 1.9 does not benefit, so it's a little biologically difficult to completely understand."

Virginia Kaklamani, MD, codirector of the SABCS and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, reported at a press conference that the results are "extremely important."

She said: "We typically don't choose to present negative slides at this forum, but the reason we chose this presentation is the fact that there are many patients that are ICH 1+ or 2+, and we've been wondering whether or not we should be giving a pretty expensive drug, which also has toxicities."

Previous Studies

Previous landmark studies, such as the NSABP B-31 and N9831 trials, showed that adding 1 year of therapy with trastuzumab to standard adjuvant chemotherapy significantly reduced the risk for recurrence and improved survival in patients with early-stage HER2+ breast cancer, which has been defined as IHC 3+ or FISH ≥2.0.

Dr Fehrenbacher noted, however, that for the NSABP B-31 trial, the initial study entry criteria required that HER2 testing be performed at a local laboratory and that a tissue specimen be sent to the NSABP for later testing.

The subsequent testing showed that 9.7% of submitted tissues did not meet the criteria for being HER2+ and were, in fact, HER2-low.

"Low and behold, when the analysis was performed looking at the benefit of using trastuzumab in these 174 patients considered to be HER2-low, it was found that the result was essentially identical [to the overall result]: the hazard ratio was less than 0.5, the benefit was equal, and statistical testing showed there was no interaction between either FISH or IHC testing," Dr Fehrenbacher said.

"This was quite bewildering, as the hypothesis had been that it would be only the HER2-amplified patients who would benefit," he added.

The samples were then sent to several laboratories, all of which confirmed that they were indeed HER2-low and not amplified.

The potential benefit of trastuzumab in these patients was underlined in an analysis of N9831 outcomes stratified on the basis of HER2 status. That analysis showed a similar, if not significant, improvement in outcomes.

Given that up 45% of breast cancers have low HER2 levels and so any effect of trastuzumab in this population could be of "enormous potential benefit," Dr Fehrenbacher and colleagues set out to explore the issue in the NSABP B-47 study, which has now been presented at the meeting.

New Results From NSABP B-47 Trial

The NSABP B-47 study was conducted in 3207 women with HER2-low breast cancer. The patients were recruited from January 2011 to February 2015 and were randomly allocated to receive standard adjuvant chemotherapy (chosen by participating physicians from two regimens), either with or without the addition of 1 year of therapy with trastuzumab.

Patients were followed for a median of 46.1 months, during which 264 patients either experienced recurrence of the original tumor, were diagnosed with a new breast cancer, were diagnosed with a new cancer outside the breast, or had died.

After 5 years, the rate of IDFS was 89.6% among patients given additional trastuzumab and 89.2% among those treated with standard adjuvant chemotherapy alone, at an overall hazard ratio for IDFS of 0.98 ( P = .90).

Further analysis showed that there was no significant difference in IDFS between the two treatment arms when the patients are stratified by IHC score 1+ or 2+, by the number of positive lymph nodes, by hormone receptor status, and by the chosen chemotherapy regimen.

Dr Fehrenbacher concluded that neither the primary objective of improving IDFS nor any of the secondary endpoints were met, and there were no trends for efficacy. Importantly, there was also no difference in outcomes between IHC 1+ and IHC 2+ tumors.

Although noting that the patients in both arms of the study "did quite well," he said that "the retrospective outcome differences between locally tested HER2+ and HER2-low patients identified in two major trials are not readily explained."

He added: "There is no benefit with trastuzumab therapy in patients with FISH ratios of less than 2.0 and IHC staining intensity of 1+ and 2+."

Asked by Medscape Medical News about the now apparently anomalous findings in the previous trials, Dr Fehrenbacher said: "Certainly one of the explanations for this outcome is that it's a different sample sent to the central laboratory, and tumors, we know, can be very heterogeneous."

Dr Kaklamani agreed with Dr Fehrenbacher's assessment, telling Medscape Medical News that she was "not surprised" by the results of the study and that tumor heterogeneity between the locally and centrally tested samples was the most likely explanation for the benefit with trastuzumab in HER2-low tumors seen previously.

She said: "We see this more and more now that we're doing neoadjuvant chemotherapy and we give anti-HER2 therapy, for example, and then what remains is triple-negative [disease].

"Or, we give regular chemotherapy and then all of a sudden we do HER2 testing and it's positive," she added. "I've had several patients that I had to go back to and give them a year of Herceptin that I wasn't going to give them before, because I killed the part of the tumor that was HER2-, but there was a part that I never knew existed before that was HER2+ that remained."

On the question of whether patients should be tested multiple times to identify HER2+ disease within the tumor, Dr Kaklamani said that "one of the issues is whether the insurance pays for the second test."

She continued: "In many cases, insurance doesn't [pay for the second test], which means that the patient won't, which means that the pathology lab is going to be stuck with a bill, and, as cheap as IHC is (a few hundred dollars), if you add that to all the patients per year, it's a lot of tests that they're not going to get paid for."

Dr Kaklamani emphasized that the earlier data revealed that only 9.7% of patients were incorrectly identified, which means that "we get it right 90% of the time," although she pointed out that "that 9% of is pretty important for the patient."

The study was supported by funds from the National Cancer Institute and Genentech. Dr Fehrenbacher has received contracts for research for Genentech/Roche, CellDez, AbbVie, Macrogenics, Cascadian, and Pfizer, as well as study participation. Other researchers also have disclosed conflicts of interest. Dr Kaklamani has disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS1-01. Presented December 6, 2017.

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