Clinical Overestimation of HER2 Positivity in Early Estrogen and Progesterone Receptor–Positive Breast Cancer and the Value of Molecular Subtyping Using BluePrint

Abstract

PurposeHuman epidermal growth factor receptor 2 (HER2) positivity is an important prognostic and predictive indicator in breast cancer. HER2 status is determined by immunohistochemistry and fluorescent in situ hybridization (FISH), which are potentially inaccurate techniques as a result of several technical factors, polysomy of chromosome 17, and amplification or overexpression of CEP17 (centromeric probe for chromosome 17) and/or HER2. In South Africa, HER2-positive tumors are excluded from a MammaPrint (MP; Agendia BV, Amsterdam, Netherlands) pretest algorithm. Clinical HER2 status has been reported to correlate poorly with molecular subtype. The aim of this study was to investigate the correlation of clinical HER2 status with BluePrint (BP) molecular subtyping.MethodsClinico-pathologic and genomic information was extracted from a prospectively collected central MP database containing records of 256 estrogen receptor–positive and/or progesterone receptor–positive tumors. Twenty-one tumors considered HER2 positive on immunohistochemistry or FISH were identified for this study.ResultsThe median age of patients was 56 years (range, 34 to 77 years), with a median tumor size of 16 mm (3 to 27 mm). Four (19%) tumors were confirmed HER2-enriched subtype, six (29%) were luminal A, and 11 (52%) were luminal B. The positive predictive values of HER2/CEP17 ratio ≥ 2 and HER2 copy number ≥ 6 were only 29% and 40%, respectively. The differences in means for HER2/CEP17 ratio were significant between BP HER2-enriched versus luminal (P = .0249; 95% CI, 0.12 to 1.21) and MP high-risk versus low-risk tumors (P = .0002; 95% CI, 0.40 to 1.06).ConclusionOf the 21 tumors considered clinically HER2 positive, only four were HER2-enriched subtype with BP, indicating an overestimation of HER2 positivity. FISH testing has a poor positive predictive value.

The cost impact of unselective vs selective MammaPrint testing in early-stage breast cancer in Southern Africa

“…When initially implemented into the South African health system, a pre-screen algorithm was proposed to guide safe and cost-effective use. Initial publications suggested a substantial impact on treatment decision making using MP [ [12] , [13] , [14] ]. In 2016, Pohl et al.…”

“…Of these, 41 entries were excluded due to incomplete data entries. For the purpose of this study, HER2 status was assigned as per the ASCO 2013 Guidelines, which was the classification guideline in effect for most of the records collected in the dataset and in previous publications [ [7] , [12] , [13] , [14] ]. It should be noted that data on treatment decisions and outcomes was not available.…”

“…Since 2006, MP has been available in South Africa and is the only assay with prospectively collected and published data from this region [ 7 , [12] , [13] , [14] ]. While 93% of international breast cancer experts recommend genomic assays [ 15 ], the cost remains prohibitive in South Africa, limiting its use.…”

Reclassification of early stage breast cancer into treatment groups by combining the use of immunohistochemistry and microarray analysis

“…Ongoing validation of emerging genomic technologies against current standards in breast cancer pathology is an important research focus. In South Africa, an increased level of confidence based on growing clinical experience supported the incorporation of MP/BP 19,27 into routine clinical practice. Integration of these results into treatment decision may lead to a change in therapy in one of every two early-stage breast cancer patients treated in South Africa.…”

Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway

“…The fact that approximately 50% of early-stage breast cancer patients at high risk of recurrence could safely forego chemotherapy based on a low-risk MammaPrint profile, confirmed the important role of genomics to stratify breast cancer patients into different treatment groups. The finding that susceptibility to a particular molecular subtype of breast cancer is associated with familial aggregation [ 8 , 12 ] furthermore emphasised the importance of MammaPrint used in conjunction with the 80-gene Blueprint microarray to subdivide tumours into the Luminal A, Luminal B, HER2-enriched and basal-types [ 13 , 14 ].…”