Molecular Cytopathology by Bin Yang & Jianyu Rao

Author:Bin Yang & Jianyu Rao
Language: eng
Format: epub
Publisher: Springer International Publishing, Cham

Stability of Hormone Receptor and HER2

The status of hormone receptor and HER2 can be changed during disease progression, or altered by chemotherapy or targeted therapies. Therefore evaluating the stability of these biomarkers in a metastatic breast carcinoma is necessary. In large comparison studies at MD Anderson Cancer Center between primary and paired metastatic breast carcinomas, primary carcinomas were mostly FFPE sections whereas metastatic carcinomas were sampled mostly via FNA, and the biomarker status of metastatic tumors was usually tested in cytology direct smears. For ER testing, a high concordance rate (92.5 %) was observed for ER status in primary breast carcinomas and the paired metastatic breast carcinomas. When evaluating the effects of intervening endocrine therapy and chemotherapy, metastatic site (locoregional vs. distant), intervals between the two ER assays (<5 years vs. ≥5 years), and sample type for the metastatic carcinoma (direct smear vs. cell block vs. CNB), researchers found that these factors did not significantly affect the ER concordance. For HER2 testing, the FISH technique was the sole method used for both primary and paired metastatic breast carcinomas in a study, and a high concordance rate (97 %) was observed for 60 patients with paired primary and metastatic breast carcinoma. It agreed with many other studies, indicating that HER2 status is generally stable during disease progression. Interestingly, several studies including ours showed that if the HER2 status does change, loss of HER2 protein overexpression and/or gene amplification seems to be more common than gain of it. However, the loss of HER2-positive status was seemly unrelated to intervening trastuzumab-based therapy. In addition, discordant ER, PR, and HER2 status between primary and paired metastatic breast carcinomas is associated with poorer clinical outcome compared with those with concordant status. The underlying mechanisms responsible for biomarker discordance could be multifactorial, including biologic evolution, intratumoral heterogeneity, technical (preanalytical and analytical) inconsistency, and inter-laboratory and inter-observer variability.

To standardize hormone receptor and HER2 testing and improve accuracy, reproducibility, and predictive power regarding response to targeted therapies, the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) have published guidelines to unify preanalytic (tissue processing and fixation), analytic (assay validation and standardization), and postanalytic (interpretation and reporting criteria) factors. FFPE tissue obtained via CNB or surgical resection is the typical sample type for primary breast carcinoma, whereas FNA is commonly used to sample metastatic tumors. The processing and fixation conditions for FFPE sections and for FNA smears are quite different. It is not uncommon that, in routine practice, a primary carcinoma is sampled and tested at a local hospital and a metastatic carcinoma from the same patient is biopsied at a tertiary referral hospital. In some patients whose primary carcinoma were diagnosed decades ago when biomarker status may have been tested by an old method (e.g., ligand-binding assay for ER) but the biomarkers for recently developed metastatic carcinoma may be tested using immunostaining. Differences in preanalytic and analytic factors or in testing methods may account for biomarker discordance between primary and metastatic carcinomas.

Similarly, the discordance for HER2 status could be caused by different testing methods used in primary and metastatic carcinoma.

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