Molecular phenotype of the foci in multifocal invasive breast carcinomas: Intertumoral heterogeneity is related to shorter survival and may influence the choice of therapy

Abstract

BACKGROUND Multiple synchronous, ipsilateral, invasive foci of breast carcinomas are frequent and are associated with a poorer prognosis. Few studies have investigated the prognostic and therapeutic implications of heterogeneity of such foci. METHODS The authors reviewed the tumor type, grade, and size of all invasive foci in a series of 110 multifocal breast carcinomas documented on large‐format slides. Molecular phenotype was determined by immunohistochemistry in tissue microarray blocks using 3 classification systems. The survival of patients who had tumors with microscopic (tumor type and/or grade) heterogeneity and of those who had tumors with phenotypic heterogeneity was compared with the survival of patients who had multifocal homogeneous tumors using Kaplan‐Meier curves. The hazard ratio of dying from breast cancer was also calculated. RESULTS Intertumoral heterogeneity in tumor type and grade was detected in 16 of 110 tumors (14.6%) and in 6 of 110 tumors (5.5%), respectively. The molecular phenotype of invasive tumor foci within the same breast differed in 10% to 12.7% of patients (11‐14 of 110 tumors), depending on the classification system used. Patients who had phenotypically heterogeneous, multifocal cancers had a greater risk of dying from disease (HR=2.879; 95%CI=1.084−7.649; P = .034) and had significantly shorter survival (P = .016). Phenotypic differences were most common in patients who had tumors that were homogeneous in terms of tumor type (11 of 18 tumors) and histology grade (14 of 18 tumors). Phenotyping additional tumor foci had the potential to influence the therapeutic decisions in up to 8 patients. CONCLUSIONS Phenotyping more than 1 invasive focus of multifocal breast carcinomas only if the individual foci deviate microscopically appears to be insufficient, because phenotypic intertumoral heterogeneity may be observed in microscopically identical foci and has potential prognostic and therapeutic consequences. Cancer 2014;120:26–34. © 2013 American Cancer Society.

Systematic review of the impact of breast‐conserving surgery on cancer outcomes of multiple ipsilateral breast cancers

“…Molecular characterization of each cancer focus to distinguish between MC and MF cancers may be important in future classifications8. Intertumoral heterogeneity in MIBC has been reported in 11–27 per cent of patients8 13, 14. Generally, evaluation of the largest cancer using standard immunohistochemical (IHC) biomarkers (oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki‐67) is performed3 9, 15.…”

“…Generally, evaluation of the largest cancer using standard immunohistochemical (IHC) biomarkers (oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki‐67) is performed3 9, 15. However in future, the potential to use extended IHC biomarkers and whole‐genome sequencing may increase the recognition of intertumoral heterogeneity14 16, 17, 18, with prognostic implications19, 20, 21, 22.…”

Review on Practical Approach in Multiple Breast Carcinomas: Does Each Focus Matter?

“…We and other authors have demonstrated that multiple breast carcinomas can differ among foci regarding histology and molecular profile (28,49,53). No studies however analyzing the impact of this heterogeneity on axillary metastases have been performed in multiple breast carcinomas.…”

Original paper Multifocal/multicentric breast carcinomas showing intertumoural heterogeneity: a comparison of histological tumour type and Nottingham histological grade of primary tumour and lymph node metastasis

“…There is a positive correlation between the presence of axillary lymph node metastases and the number of tumour foci [4,5]. In multiple carcinomas, between 3% and 37.5% of cases may have different histological tumour types and/or histological grades (inter-tumour heterogeneity) [3,[6][7][8][9][10]. This is related to shorter survival and may influence the choice of therapy [6].…”

“…In multiple carcinomas, between 3% and 37.5% of cases may have different histological tumour types and/or histological grades (inter-tumour heterogeneity) [3,[6][7][8][9][10]. This is related to shorter survival and may influence the choice of therapy [6]. There are older studies published in English literature concerning the impact of the morphological/ immunohistochemical features of unifocal/multiple tumour foci on the morphological/immunohistochemical features of lymph node metastases [11,12].…”