Intrinsic subtype and response to paclitaxel in CALGB 9344 tissue microarrays
Large number of luminal A cancers and small group with ER-/HER2-/nonbasal tumors failed to get a significant benefit from addition of the taxane to the adjuvant AC chemotherapy
Cancer and Leukemia Group B (CALGB 9344) trial enrolled 3121 women with node positive early breast cancer, and demonstrated that adding paclitaxel to adjuvant doxorubicin-cyclophosphamide (AC) in patients receiving standard local and hormonal therapies was associated with a 5% absolute improvement in disease-free survival. This finding had established taxane-based chemotherapy regimens in routine practice for women at high risk of relapse but among the 42% of patients with complete ER and HER2 information, no benefit was found in the ER+/HER2- subset. Dr Torsten O Nielsen of the University of British Columbia in Vancouver led a group that used a high-throughput tissue microarray, to determine more complete and detailed subclassification into intrinsic biological subtypes, and an immunohistochemical panel for a more detailed look at which patients benefit.
Using an intergroup-approved protocol, tissue microarrays were constructed from 2039 of the 3121 trial subjects, whose outcomes were representative of the trial as a whole. Immunohistochemistry for ER, HER2, Ki67, cytokeratin 5/6 and EGFR was performed and interpreted by prespecified published methods, allowing categorization of each case into intrinsic subtypes. Cox proportional hazards modeling was used to determine significant prognosis of intrinsic subtype or paclitaxel treatment on relapse free survival. Correlation with outcome was performed independently by the CALGB Statistical Center.
Cases were assigned as follows: 790 luminal A, 340 luminal B, 221 HER2-enriched, 444 core basal, and 93 ER-/HER2-/nonbasal. Tissue microarray results showed substantial agreement with previous whole section HER2 and clinical ER data. Intrinsic subtype was prognostically significant in multivariate analysis (p<0.001). There was no significant interaction of Ki67 with paclitaxel among ER+/HER2- patients. Core basal status predicted benefit from paclitaxel in multivariate analysis (p=0.033); benefit in ER-/HER2-/nonbasal cases was not significant. Results are presented at the American Society of Clinical Oncology Breast Cancer Symposium held in San Francisco from 8 to 10 October 2009.
However, investigators concluded that intrinsic biological subtype by immunohistochemistry is independent prognostic, and predicts benefit in HER2 positive and core basal subtypes when adding paclitaxel to adjuvant AC chemotherapy. Although these results were from a retrospective, unplanned analysis, the size and quality of the study were convincing and would likely have an immediate impact on treatment recommendations. This is important step toward more targeted chemotherapy and may permit tailoring adjuvant paclitaxel treatment in early breast cancer. Future work will assess qPCR-based biological subtyping.
The study was funded by The Hope Foundation, the Breast Cancer Research Foundation, and a grant from the National Institutes of Health.
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