Context .- Evaluation of HER2 gene amplification by fluorescence in situ hybridization (FISH) was changed by recent American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines. Objective . -To determine frequencies and assess patterns of HER2 protein expression for each ASCO-CAP guideline FISH category among 7526 breast cancers accrued to our consultation practice. Design .- We retrospectively reevaluated the HER2 FISH status of breast cancers in our consultation practice according to ASCO-CAP FISH guidelines, and documented HER2 protein levels in each category. Results . -According to new guidelines, 17.7% of our consultation breast cancers were "ISH-positive" with HER2:CEP17 FISH ratios ≥2.0 and average HER2 gene copies per cell ≥4.0 (group 1); 0.4% were "ISH-positive" with ratios ≥2.0 and average copies <4.0 (group 2); 0.6% were "ISH-positive" with ratios <2.0 and average copies ≥6.0 (group 3); 4.6% were "ISH-equivocal" with ratios <2.0 and average copies ≥4.0 and <6.0 (group 4); and 76.7% were "ISH-negative" with ratios <2.0 and average copies <4.0 (group 5). However, only groups 1 (HER2 amplified) and 5 (HER2 not amplified) agreed with our previously reported status, and only these groups demonstrated the expected immunohistochemistry status, overexpression and low expression, respectively. Groups 2 and 4 breast cancers lacked overexpression, whereas group 3 was not significantly associated with either increased or decreased HER2 expression. Conclusions .- Although the status of approximately 95% of our cases (groups 1 and 5) is not affected by the new guidelines, those of the other 5% (groups 2-4) conflict with previous HER2 gene amplification status and with HER2 status by immunohistochemistry.

The use of human epidermal growth factor receptor type 2 (HER2) gene amplification and overexpression as a molecular predictive marker has become critically important for proper selection of breast cancer patients for treatment with targeted therapeutic agents such as trastuzumab, lapatinib, pertuzumab, and T-DM1. A high level of sensitivity and specificity of molecular tests for this alteration is desirable. The American Society of Clinical Oncology and College of American Pathology have jointly established consensus guidelines to standardize characterization of this alteration in breast cancers. This chapter provides a brief overview of pre-analytic and analytical processing of breast specimens as well as subsequent molecular evaluation for HER2 status.

Two parameters in high-frequency ultrasound (20-80 MHz) have been found to be sensitive to a range of pathologies in resected margins from breast conservation surgery: The number of peaks (the peak density) in the waveform spectrum and the slope of the Fourier transform of the waveform spectrum. Previous studies have indicated that peak density and slope may correlate to microscopic heterogeneity in tissue structure, which is modified by atypical and malignant processes. To test this hypothesis, through-transmission and pulse-echo measurements were acquired from gelatin-based phantoms containing polyethylene microspheres and nylon fibers (2.5-10% volume concentration). Multipole methods were also used to model through-transmission measurements of tumor progression in lobular carcinoma in situ. The simulated breast tissue contained 1000-2000 nucleated cells with random lobular cavities. The peak densities of the heterogeneous phantoms were significantly greater than those of the homogeneous control samples, whereas the slopes were less. Similarly, the models produced spectra with peak densities that increased with malignant cell proliferation. The results are consistent with breast tissue data, and provide a physical mechanism for the use of peak density and slope in the imaging of breast tissues with atypical and malignant pathologies. This work was supported by Utah Valley University.

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A critical issue in breast conservation surgery (lumpectomy) for breast cancer treatment is ensuring the tissue surrounding the excised tumor, the margins, are cancer-free. In collaboration with the Huntsman Cancer Institute at the University of Utah, researchers from Utah Valley University are using high-frequency (HF) ultrasound to test the pathology of lumpectomy surgical margins. This preclinical study is a blind study which will involve 80 patients, approximately 320 specimens, and use traditional pathology as the “gold standard” for measuring the accuracy of the HF ultrasound method. Ultrasonic waveforms of margins were acquired at the Huntsman Cancer Hospital in pitch-catch and pulse-echo modes using 50-MHz transducers with 6.35 mm-diameter active elements. The data were analyzed to obtain ultrasonic parameters such as ultrasonic wavespeed, attenuation, and spectral peak density (the number of peaks and valleys in a HF ultrasonic spectral band). Preliminary results indicate variations in peak density between margin specimens and individual locations on specimens that are indicative of malignant and atypical breast pathologies. The objective of this paper is to search for trends in the data acquired to date to provide an assessment of reliability, stability, and robustness of the study.