New guidelines for HER2 positivity do not change eligibility criteria for the use of trastuzumab, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium.
Additionally, patients are just as likely to respond to trastuzumab if the original guidelines are used or if the new guidelines are applied retrospectively, according to the results of the oral poster presentation.
“What this tells us is, don't worry too much about the new guidelines,” said session moderator Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at Vall d'Hebron University Hospital in Barcelona.
In 2007, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) recommended new guidelines to define HER2 overexpression by immunohistochemistry (IHC) and or fluorescence in situ hybridization (FISH).
Specifically, as chief investigator Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL, explained, the new guidelines called for uniform intense membrane staining of more than 30% of invasive tumor cells on IHC, and a HER2-to-chromosome 17 centromere (CEP17) ratio of greater than 2.2 on FISH.
The original FDA-approved HER2-positivity criteria used for enrollment in the pivotal North Center Cancer Treatment Group N9831 trial conducted from 2000 to 2005 that helped lead to the approval of trastuzumab used uniform intense membrane staining of more than 10% of invasive tumor cells on IHC and a HER2-to-CEP1 ratio of 2 or more on FISH.
The purpose of the new study was to investigate the impact of the ASCO/ CAP guidelines on patient eligibility and disease-free survival rates, compared with the originally used FDA-approved definitions.
The analysis, she reported, included 2,904 patients enrolled in the N9831 Phase III adjuvant trastuzumab trial. IHC was centrally performed at the Mayo Clinic using the DAKO HercepTest and was re-analyzed to determine the percentage of tumor cells with 0, 1+, 2+, and 3+ staining intensities. Central FISH was performed at the Mayo Clinic using the Vysis kit.
The disease-free survival rates were compared between patients randomized to receive standard chemotherapy either with or without concurrent trastuzumab in the trial within the IHC/FISH subgroups using a Cox proportional hazards regression model stratified by hormone receptor and nodal status.
The results showed that 83 patients (3.7%) would have been classified as having HER2 overexpression on IHC using the FDA-approved guidelines, but not by the ASCO/CAP guidelines.
Using FISH, only 1.4% of patients eligible under the FDA-approved definition would not meet the more restrictive ASCO/CAP guidelines for HER2 positivity, Dr. Perez reported.
Patients also benefited similarly regardless of which set of guidelines were used. When the new ASCO/CAP guidelines for HER2 positivity were applied to the data retrospectively, HER2-positive patients given concurrent trastuzumab plus chemotherapy were 41% less likely to suffer a recurrence, compared with those given trastuzumab alone.
Using the original FDA-approved guidelines, HER2-positive patients given trastuzumab were 40% less likely to have a recurrence than were those given chemotherapy alone.
“Both values were highly statistically significant, with p values less than 0.001,” she said.
“In conclusion, only a very small percentage of patients in the N9831 trial did not meet ASCO/CAP 2007 guidelines when applied retrospectively.
Patients benefit similarly regardless of whether a 10% or 30% cutoff is used [on IHC] and whether a ratio of 2.0 or 2.2 is used [on FISH].”
Original Definition Works
Summing up the poster for the audience, Dr. Baselga said, “The question this study asked is whether the new guidelines change eligibility and disease-free survival for trastuzumab. The take-home message, is that the majority of them do stain [on IHC] at greater than 30%. Only a small number of patients do not meet the new definition. When you look at the two criteria on the graphs, the lines overlap.
“Importantly, the data suggest [that use of] adjuvant trastuzumab may be based on the original definition.”
In response to a question from the audience about the impact of the findings on HER2-normal patients, Dr. Baselga said that while the numbers are very small, patients who are negative on IHC and FISH still respond better when trastuzumab is given than when it is not—“but we need collaborative data, because by themselves, all the studies have too few [HER2-negative] patients.”
The study was funded by the Breast Cancer Research Foundation, Genentech, and the National Institutes of Health.