Breast cancer global tumor biomarkers: a quality assurance study of intratumoral heterogeneity.

Biomarker analysis of invasive breast carcinoma is useful for prognosis, as surrogate for molecular subtypes of breast cancer, and prediction of response to adjuvant and neoadjuvant systemic therapies. Breast cancer intratumoral heterogeneity is incompletely studied. Comprehensive biomarker analysis of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 labeling index was performed on each tissue block of 100 entirely submitted breast tumors in 99 patients. Invasive carcinoma and in situ carcinoma was scored using semiquantitative histologic score (H-score) for ER and PR, HER2 expression from 0 to 3+, and percentage positive cells for Ki67. Core biopsy results were compared with surgical excision results, invasive carcinoma was compared with in situ carcinoma, and interblock tumoral heterogeneity was assessed using measures of dispersion (coefficient of variation and quartile coefficient of dispersion). Overall concordance between core biopsy and surgical excision was 99% for ER and 95% for PR. Mean histologic score of ER was significantly lower in invasive carcinoma between core biopsy and surgical excision (p = 0.000796). Intratumoral heterogeneity was higher for PR than for ER (mean coefficient of variation for ER 0.08 stdv 0.13 vs. PR 0.26 stdv 0.41). Ki67 labeling index was significantly higher in invasive carcinoma as compared with associated ductal carcinoma in situ on surgical resection specimen (p ≤ 0.0001). Ki67 hotspots were identified in 47% of cases. Of 52 HER2 negative cases on core biopsy, 10 were scored as equivocal on surgical resection. None (0/10) were amplified by Her-2/neu fluorescence in situ hybridization. Overall, biomarkers on core biopsy showed concordance with the surgical excision specimen in the vast majority of cases. Biomarker expression of in situ closely approximates associated invasive carcinoma. Intratumoral heterogeneity of PR is greater than ER. Biomarker expression on diagnostic core biopsy or single tumor block is representative of breast carcinoma as a whole in most cases and is appropriate for clinical decision-making.