Abstract P6-07-45: Molecular Morphology Based Genomic Signatures of Moderate Complexity Predict Pathologic Complete Response in HER2 Molecular Breast Carcinoma Class Patients Treated with Trastuzumab-based Preoperative Therapy.
Authors: Tubbs RR , Portier BP , Morrison L , Wang Z , Minca E , Lanigan C , Budd T 
Published: August 2014

Background: Preoperative chemotherapy is an effective approach for “downstaging” some breast cancer patients, some of whom achieve a pathologic complete response (pCR), especially for non-luminal B HER2 positive molecular class (HNL). Determination of which HNL patients are more or not likely to achieve pCR would allow a more personalized, predictive approach to neoadjuvant management.

Methods and Materials: Formalin-fixed 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 dual hapten bright field in situ hybridization (dual ISH) using repeat depleted locus specific probes (designation based on the name of a gene included within the targeted region) and a reference centromeric locus probe (CEN) on the same chromosome. Probe pairs included MET+CEN7, TOP2A+CEN17, PTEN+CEN10, and PIK3CA+CEN3. Only invasive carcinoma tumor cells were scored. In addition to assessing genomic gains and losses by the average number of gene loci or centromeres per cell and the ratio of gene loci to CEN, the percentage of cells with &gt;2 gene or CEN signals (gene locus gain or CEN gain), &lt;2 signals (gene locus loss or CEN loss), gene locus signals &gt; CEN signals (gene locus/CEN gain), and gene locus signals &lt; CEN signals (gene locus/CEN loss) were calculated for each parameter and cut point. The percentage of cells with either gene locus/CEN gain or loss was also evaluated. Sensitivities and specificities for detecting patients with pCR, based on either the high parameter being positive for pCR, and conversely based on the low parameter being positive for pCR, were calculated for each parameter and each cutoff. Receiver Operator Characteristics (ROC) curves were generated as sensitivity versus 1-specificity over all cutoffs tested, and Area Under the Curve (AUC) was calculated as one measure of a parameter's ability to distinguish patients with pCR from patients without pCR, with AUC = 1 being ideal and progressively lower values being less favorable. 2×2 contingency tables were evaluated at each cutoff to provide chi square probabilities as another measure of a parameter's ability to differentiate patients with pCR. Combinations of parameters were also evaluated by ROC and contingency table analyses.

Results: MET/CEN7 gain or loss was predictive of pCR (AUC = 0.824, N=24) achieving 100% sensitivity and 69% specificity at a cutoff of 50% (X2 p &lt; 0.00089). Combining this parameter with PIK3CA/CEN3 gain provided further improvement (AUC 0.937, N=24) with 89% sensitivity and 93% specificity achieved at respective cutoffs of 50 and 55%.

Conclusion: Genomic signatures of moderate complexity generated from dual ISH evaluation of invasive breast carcinoma predict pathologic complete response in HER2 molecular class breast carcinoma patients treated with trastuzumab-based preoperative therapy. These findings require validation in additional patient cohorts.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-45.