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MammaPrint risk score distribution in breast cancer patients with BRCA1/2 mutations
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Background: Tumour characteristics such as estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 status are routinely assessed using immunohistochemistry in all newly-diagnosed breast cancer patients. These biomarkers form part of the selection criteria used to determine the appropriateness of transcriptional gene profiling using MammaPrint, a 70-gene assay with level 1A evidence for chemotherapy selection in patients with early-stage breast carcinoma. This MammaPrint pre-screen algorithm does not include screening for pathogenic germline variants underlying differences in tumour pathology, increasingly considered to predict BRCA1/2-related cancer and response to PARP inhibitors that target the DNA repair pathway. Aim: The aim of this study was to determine whether one or more of the eight most common pathogenetic BRCA1/2 variants previously identified in the South African population are predictive of a MammaPrint high risk score. This investigation was prompted by detection of the BRCA2 c.7934delG founder/recurrent mutation in tumour DNA of a female patient diagnosed with bladder cancer four years after receiving a low-risk MammaPrint result. Next generation sequencing of her tumour DNA furthermore revealed genetic variation affecting cytochrome P450 2D6 (CYP2D6) enzyme activity associated with resistance to Tamoxifen, previously used by this patient together with anti-depressants that may inhibit enzyme function. Methods: A database query was performed to identify early-stage breast cancer patients referred for the MammaPrint test followed by CYP2D6 genotyping using the same pathology-supported genetic testing platform. A rapid point-of-care DNA assay was used to screen 50 DNA samples for eight BRCA1/2 founder/recurrent mutations: BRCA1 c.68_69delAG, c.1374delC, c.2641G>T, c.5266dupC and BRCA2 c.5771_5774delTTCA, c.5946delT, c.6448_6449insTA and c.7934delG. Results: The pathogenic BRCA2 c.7934delG variant was confirmed in the germline DNA of the index case with bladder cancer and was the only pathogenic variant detected in 10.2% of the study population (5/49, 1 sample failed). Two breast cancer patients with this pathogenic variant had a low-risk MammaPrint profile (2/25, 8.3%), while three patients with the same BRCA2 variant had a high-risk profile (3/24, 12%) for breast cancer metastasis. None of the other seven BRCA1/2 founder/recurrent mutations were detected in the study cohort. Patients with the BRCA2 c.7934delG founder/recurrent mutation was diagnosed at a significantly younger age than those without this pathogenic variant (p=0.02). Intermediate (36%) and poor metabolizer (2%) status based on CYP2D6*4 genotype was detected in 18 of the 50 patients included in the study. Three of these patients also had the BRCA2 c.7934delG founder/recurrent mutation, one with a low-risk (index case) and two with a high-risk MammaPrint recurrence risk profile. Conclusions: Our findings support use of the MammaPrint pre-screen algorithm to identify a subgroup of early-stage hormone receptor-positive breast cancer patients who may benefit from pharmaco-diagnostic BRCA screening as part of the MammaPrint service. Use of laboratory-based technologies can take several days or weeks from sample collection to report generation, posing a unique opportunity for rapid BRCA1/2 testing during the genomic counselling session. Delivery of a positive test result generated at the point-of-care, or a negative result requiring extended genome sequencing, are important considerations in clinical settings where loss to follow-up or access to gene-based cancer treatment remain a problem.