NEW YORK (Reuters Health) – Although trastuzumab is directed against the HER2 protein, patients with HER2-negative breast cancer may also benefit from adjuvant trastuzumab therapy, researchers report.

They say this provides “justification for testing trastuzumab in HER2-negative patients,” in their report in the Journal of the National Cancer Institute online November 21.

Dr. Soonmyung Paik, with the National Surgical Adjuvant Breast and Bowel Project (NSABP) Operations and Biostatistical Centers in Pittsburgh, Pennsylvania and colleagues point out that current guidelines recommend trastuzumab only for HER2-positive patients.

However, the NSABP trial B-31 indicated that trastuzumab is not effective for some HER2-positive patients while some HER2-negative patients may benefit.

To investigate further, the team undertook an analysis of genes expressed in archived tumor blocks from the B-31 trial, in relation to the benefit from adjuvant trastuzumab in terms of disease-free survival.

Results from a discovery cohort of 588 tumor samples showed that, after probing for 462 genes, differing expression levels of 8 genes related to HER2 or ER (estrogen receptor) predicted the degree of response to trastuzumab.

 

A prediction model based on expression levels of those 8 genes identified three degrees of benefit from trastuzumab in a confirmation cohort of 991 tumor samples: Group 1, no benefit with a hazard ratio for relapse of 1.58; Group 2, moderate benefit (HR, 0.60); and Group3, large benefit (HR, 0.28).

The authors note that the 8-gene prediction model was developed without knowing results of HER2 testing performed in the trial. When those test results were overlaid on the three subsets of benefit, 10% of HER2-positive patients belonged to Group 1, i.e., deriving no benefit from trastuzumab. These patients expressed intermediate levels of the ERBB2 gene related to HER2 and high levels of ESR1 related to ER.

On the other hand, almost all HER2-negative patients fell into the moderate-benefit group. “Because HER2-negative patients belong to Group 2,” Dr. Paik and colleagues conclude, “approximately 40% reduction in recurrences is expected from the addition of trastuzumab to adjuvant chemotherapy with minor side effects.”

They add, “This hypothesis is currently being tested through a randomized clinical trial (NSABP protocol B-47).”

In a related editorial, Dr. Ian E. Krop and Dr. Harold J. Burstein, with the Dana-Farber Cancer Institute in Boston, Massachusetts, say the results are “counterintuitive but important.”

That is, the data indicate that cancers with low HER2 and moderate ER expression benefit from trastuzumab, while those with intermediate HER2 and very high ER expression do not. “If this finding is validated,” they comment, “it points to a very complex relationship between HER2, ER, and trastuzumab sensitivity.”

SOURCE: Predicting Degree of Benefit From Adjuvant Trastuzumab in NSABP Trial B-31

SOURCE: Trastuzumab: Qui Bono?

J Natl Cancer Inst 2013