Immunogenotypic Signatures Predict Pathologic Complete Response (pCR) in HER2 Positive Breast Carcinoma Patients Treated with Neoadjuvant Trastuzumab-Based Therapy
Bryce P Portier, Zhen Wang, Eugen Minca, G Thomas Budd, Chris Lanigan, Larry Morrison, Raymond R Tubbs. Cleveland Clinic, Cleveland, OH; Ventana Medical Systems, Inc., Tucson, AZ
Background: Neoadjuvant breast cancer treatment, primarily used for “downstaging” patients, may achieve a pathologic complete response (pCR), especially non-luminal B HER2 positive cases. Determination of which patients are more or not likely to achieve pCR would allow a more personalized, predictive approach to neoadjuvant management.
Design: Biopsy specimens from 34 patients with invasive ductal carcinoma treated with Trastuzumab-based therapy prior to definitive resection and pathologic staging were evaluated by dual color bright field in situ hybridization (dual ISH) using repeat depleted locus specific probes and reference centromeric probes (CEN). Probe pairs included MET+CEN7, TOP2A+CEN17, PTEN+CEN10, PIK3CA+CEN3; and Ki-67 expression was assessed by immunohistochemistry (IHC). Values of parameters for absolute and relative genomic gain, loss, and collective gain or loss were determined for each locus and CEN for all specimens. A range of cutoffs were applied to each parameter and Receiver Operator Characteristics (ROC) curves were generated. Area Under the Curve (AUC) was calculated as one measure of a parameter's ability to distinguish pCR. Sensitivities, specificities, and X2 probabilities calculated from contingency tables were used to select optimal cutoffs and establish clinical relevance. Combinations of genomic parameters, and combinations of genotype with KI67 IHC results (“immunogenotype”), were also evaluated.
Results: High level of MET/CEN7 gain or loss was predictive of pCR (AUC=0.824, N=25; 100% sensitivity, 69% specificity, p=0.00089 at optimal cutoff), and combined with low PIK3CA/CEN3 gain provided further improvement (AUC 0.937, N=24; 89% sensitivity, 93% specificity, p=0.000056). Combining low PTEN/CEN10 gain or loss with high MET/CEN7 gain and high CEN7 gain also provided improvement (AUC 0.994, N=19; 100% sensitivity, 91% specificity, p=0.000089). The most robust signature for predicting pCR was high MET/CEN7 gain or loss + low PIK3CA/CEN3 gain + high Ki-67 (AUC=1.0, N=24; 100% sensitivity, 100% specificity, p=0.00000096).
Conclusions: Immunogenotypic signatures of moderate complexity generated from dual ISH and IHC predict pCR in HER2 molecular class breast carcinoma patients treated with Trastuzumab-based preoperative therapy. These findings require validation in additional patient cohorts.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 35, Monday Morning