Browsing by Author "Grant, Kathleen A."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    MammaPrint Pre-screen Algorithm (MPA) reduces chemotherapy in patients with early-stage breast cancer
    (Health & Medical Publishing Group, 2013-07-03) Grant, Kathleen A.; Apffelstaedt, Justus P.; Wright, Colleen A.; Myburgh, Ettienne; Pienaar, Rika; De Klerk, Manie; Kotze, Maritha J.
    Background. Clinical and pathological parameters may overestimate the need for chemotherapy in patients with early-stage breast cancer. More accurate determination of the risk of distant recurrence is now possible with use of genetic tests, such as the 70-gene MammaPrint profile. Objectives. A health technology assessment performed by a medical insurer in 2009 introduced a set of test eligibility criteria – the MammaPrint Pre-screen Algorithm (MPA) – applied in this study to determine the clinical usefulness of a pathology-supported genetic testing strategy, aimed at the reduction of healthcare costs. Methods. An implementation study was designed to take advantage of the fact that the 70-gene profile excludes analysis of hormone receptor and human epidermal growth factor receptor 2 (HER2) status, which form part of the MPA based partly on immunohistochemistry routinely performed in all breast cancer patients. The study population consisted of 104 South African women with early-stage breast carcinoma referred for MammaPrint. For the MammaPrint test, RNA was extracted from 60 fresh tumours (in 58 patients) and 46 formalin-fixed, paraffin-embedded (FFPE) tissue samples. Results. When applying the MPA for selection of patients eligible for MammaPrint testing, 95 of the 104 patients qualified. In this subgroup 62% (59/95) were classified as low risk. Similar distribution patterns for risk classification were obtained for RNA extracted from fresh tumours v. FFPE tissue samples. Conclusions. The 70-gene profile classifies approximately 40% of early-stage breast cancer patients as low-risk compared with 15% using conventional criteria. In comparison, more than 60% were shown to be low risk with use of the MPA validated in this study as an appropriate strategy to prevent chemotherapy overtreatment in patients with early-stage breast cancer.
  • Thumbnail Image
    Item
    Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics
    (Frontiers Media S.A, 2021-09) Mampunye, Lwando; Van der Merwe, Nerina C.; Grant, Kathleen A.; Peeters, Armand V.; Torrorey-Sawe, Rispah; French, David J.; Moremi, Kelebogile E.; Kidd, Martin; Van Eeden, Petrus C.; Pienaar, Fredrieka M.; Kotze, Maritha J.
    Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.
  • Thumbnail Image
    Item
    Reclassification of early stage breast cancer into treatment groups by combining the use of immunohistochemistry and microarray analysis
    (Academy of Science of South Africa, 2019) Grant, Kathleen A.; Myburgh, Ettienne J.; Murray, Elizabeth; Pienaar, Fredrieka M.; Kidd, Martin; Wright, Colleen A.; Kotze, Maritha J.
    ENGLISH ABSTRACT: Immunohistochemistry (IHC) is routinely used to approximate breast cancer intrinsic subtypes, which were initially discovered by microarray analysis. However, IHC assessment of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status, is a poor surrogate of molecular subtype. Therefore, MammaPrint/BluePrint (MP/BP) microarray gene expression profiling is increasingly used to stratify breast cancer patients into different treatment groups. In this study, ER/PR status, as reported by standard IHC and single-gene mRNA analysis using TargetPrint, was compared with molecular subtyping to evaluate the combined use of MP/BP in South African breast cancer patients. Pathological information of 74 ER/PR positive, HER2 negative tumours from 73 patients who underwent microarray testing, were extracted from a central breast cancer genomics database. The IHC level was standardised by multiplying the intensity score (0–3) by the reported proportion of positively stained nuclei, giving a score of 0–300. Comparison between mRNA levels and IHC determination of ER/PR status demonstrated a significant correlation (p<0.001) for both receptors (ER: 0.34 and PR: 0.54). Concordance was shown in 61 (82%) cases and discordance in 13 (18%) of the 74 tumours tested. Further stratification by MP/BP identified 49 (66.2%) Luminal A, 21 (28.4%) Luminal B and 4 (5.4%) Basal-like tumours. Neither IHC nor TargetPrint could substitute BP subtyping, which measures the functional integrity of ER and can identify patients with false-positive tumours who are resistant to hormone therapy. These findings support the implementation of a pathology-supported genetic testing approach combining IHC and microarray gene profiling for definitive prognostic and predictive treatment decision-making in patients with early stage breast cancer.