Discrepancies Between Current ASCO-CAP Guidelines on HER2 Amplification Testing and Designations in BCIRG Trials
In an analysis reported in the Journal of Clinical Oncology, Press et al found notable discrepancies between recent ASCO–College of American Pathologists (ASCO-CAP) changes in the recommendations for evaluation of HER2 amplification by fluorescent in situ hybridization (FISH) and FISH scores in the Breast Cancer International Research Group (BCIRG) trials in breast cancer. Long-term clinical follow-up data are now available from these trials.
Study Details
BCIRG-006 was a randomized three-arm study of adjuvant chemotherapy with or without trastuzumab (Herceptin) in patients with HER2-amplified stage I to III breast cancer. BCIRG-005 was a randomized study of concurrent (docetaxel, doxorubicin, and cyclophosphamide) or sequential adjuvant anthracycline-containing chemotherapy in HER2-nonamplified stage II or III breast cancer. BCIRG-007 was a randomized trial of docetaxel and trastuzumab vs docetaxel, carboplatin, and trastuzumab in HER2-amplified metastatic breast cancer. Patients in the three trials were concurrently screened for HER2 status by FISH.
The study re-evaluated the HER2 FISH status of patients from all three studies according to current ASCO-CAP guidelines. These guidelines identify five ISH (in situ hybridization) groups according to HER2 FISH ratio and average HER2 gene copy number per tumor cell as follows: group 1 = ISH-positive, with HER2-to-chromosome 17 centromere ratio ≥ 2.0, average HER2 copies ≥ 4.0; group 2 = ISH-positive, with ratio ≥ 2.0, copies < 4.0; group 3 = ISH-positive, with ratio < 2.0, copies ≥ 6.0; group 4 = ISH-equivocal, with ratio < 2.0, copies ≥ 4.0 and < 6.0; group 5 = ISH-negative, with ratio < 2.0, copies < 4.0.
Discrepancies in HER2 Status
Among 10,468 patients successfully screened for enrollment to the BCIRG trials, 40.8% were in ASCO-CAP ISH group 1, 0.7% were in group 2, 0.5% were in group 3, 4.1% were in group 4, and 53.9% were in group 5. A similar distribution by ISH group was observed among accrued subgroups randomized to BCIRG trials (n = 6,651) and randomly assigned and having HER immunohistochemistry (IHC) assay results available (n = 4,331). Among accrued patients, ISH group 1—but not groups 2, 3, 4, or 5—was strongly correlated with IHC 3+ status (P < .0001). Groups 2, 4, and 5—but not group 3—were strongly correlated with IHC 0/1+ status (all P < .0001).
In patients accrued to BCIRG-005, group 4 did not have significantly worse disease-free or overall survival compared with group 5. In those accrued to BCIRG-006, only group 1 exhibited significant benefit in disease-free survival (hazard ratio [HR] = 0.71, P < .0001) and overall survival (HR = 0.69, P = .0006) with trastuzumab treatment, with no such benefit observed in ISH group 2.
The investigators noted: “Although we find only a small minority of patients (approximately 5%) are affected by the new ASCO-CAP guidelines changes, our findings contradict the designations of these guidelines for groups 2, 3, and 4. Groups 2 and 4, designated ISH positive and ISH equivocal, respectively, by the ASCO-CAP guidelines, seem to be HER2 not amplified on the basis of associations with a lack of protein overexpression (groups 2 and 4), a lack of response to trastuzumab treatment (group 2), and similar prognosis as group 5 for patients (group 4) treated with chemotherapy alone.”
The investigators concluded: “Our findings support the original categorizations of HER2 by FISH status in BCIRG/Translational Research in Oncology trials.
The study was supported by grants from the Breast Cancer Research Foundation, California Breast Cancer Research Program, Tower Cancer Research Foundation, National Cancer Institute, and others.
Michael F. Press, MD, of USC Norris Comprehensive Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
