Research Projects

Breast cancer research – Prof Maritha Kotze

Breast cancer research – Prof Maritha Kotze

Prof Maritha Kotze

Prof Maritha Kotze

Project title

Assessment of the impact of hereditary factors on health outcomes in relation to breast cancer risk.

Project Description

Due to the heterogeneous nature of breast cancer novel methods to identify treatable disease subtypes need to be developed. The purpose of this study is to combine different pieces of information into a single estimate of risk or outcome in the form of a treatment program designed to prevent cumulative risk at an early stage of breast cancer. A comprehensive gene-based, pathology supported intervention program involving follow-up studies to document clinical outcome will be implemented based on the following hypothesis: Given the fact that genes determine response to drugs (pharmacogenetics) and certain nutrients (nutrigenetics), cancer prognostication and treatment guided by molecular pathology tests will improve clinical outcome and compliance to cancer treatment and risk reduction strategies, at least in a subgroup of patients with specific requirements due to their genetic make-up.

Non-scientific report

Oncology is leading the way in personalised medicine with a range of single- and multi-gene tests available to identify genetic subgroups of the population that are at increased risk of breast cancer development, recurrence or medication side effects due to the genetic background. Both DNA-based BRCA1 and BRCA2 gene testing and RNA-based transcriptional profiling are offered as a routine service to South African patients who fulfil the criteria for these tests. Highly penetrant mutations mainly in the BRCA1 and BRCA2 tumour suppressor genes are responsible for early-onset familial breast cancer in 5-10% of affected patients. Polymorphic variants in genes coding for drug-metabolising enzymes or those dependant on vitamin co-factors for optimal activity may explain variable clinical expression and differences in treatment response, drug toxicity and/or recurrence risk in patients with the same diagnosis.

More accurate determination of the risk of breast cancer recurrence is now possible with use of multi-gene assays, such as the 70-gene MammaPrint profile, which reflects all known hallmarks of breast cancer biology. A highly versatile microarray platform is used to sub-classify tumour tissue into luminal A, luminal B, human epidermal growth factor receptor-2 (HER2)-positive and basal-like subtypes. This distinction cannot be achieved by standard pathology and confirms the importance of genomics in directing the best treatment strategy for each patient based on the disease pathways identified.

Furthermore, 30 – 40 % of breast cancer patients treated with hormone therapy experience side effects from the treatment or drug failure. Ways and the best means of identifying these subjects at greatest risk remains largely unknown. This study may provided insight into the pathophysiology and risk factors which underlie adverse drug response and provided clinicians who treat breast cancer patients with new tools to identify those at greatest risk of recurrence, thus allowing the most appropriate therapy to be implemented in a timely manner.

Breast cancer genetic testing

Peer-reviewed publications

Conference Presentations

Joint International Conference of the African and Southern African Societies of Human Genetics

Date: 6-9 March 2011, Venue: International Convention Centre, Cape Town, South Africa, Presentation Title: Van der Merwe N, Jamieson G, Geiger D, Kotze MJ. Assessment of clinical utility and implementation of the Tamoxifen Resistance CYP2D6 genotyping assay. Presentation type: Poster.

Biological Psychiatry Congress

Date: 22-25 September 2011, Venue: Protea Hotel, Stellenbosch, South Africa, Presentation: Van der Merwe N, Bouwens CHS, Pienaar FM, van der Merwe L, Yako YY, Geiger DH, Kotze MJ. CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application.  Presentation type: Poster

Biological Psychiatry Congress

Date: 29 August – 01 September 2013, Venue: Wild Coast Sun, Port Edward, South Africa, Presentation: Van der Merwe N, Pienaar R, van Rensburg SJ, Bezuidenhout J, MJ Kotze. Identification of Breast Cancer patients at increased risk of “chemobrain”: case study and review of the literature. Presentation type:Oral.

15th Biennial Congress of the Southern African Society for Human Genetics

Date: 6-9 October 2013, Venue: Maslow Hotel, Sandton, Johannesburg, South Africa, Presentation: N van der Merwe, Bouwens CSH, van der Merwe L, Yako YY, Geiger DH, Kotze MJ. The significance of CYP2D6 pharmacogenetic testing in oestrogen receptor-positive breast cancer patients. Presentation type: Poster

WITS Multi-Disciplinary Oncology Congress

Date: 14-16 February 2014, Venue:Hilton Hotel, Sandton, Johannesburg, South Africa. Presentation: Van der Merwe N, Jamieson G, Geiger D, Kotze MJ.  Clinical significance of MTHFR 677 C>T in breast cancer patients screened for mutations in the BRCA1 and BRCA2 genes. Presentation type: Poster

Metabolism and Cancer Conference

Date: 25-26 September 2014, Venue: Nice, France, Presentation: N van der Merwe, CSH Bouwens, J Harvey, R Pienaar, J Bezuidenhoudt, SJ van Rensburg, MJ Kotze. Clinical significance of MTHFR 677 C>T evaluated in South African breast cancer patients. Presentation type: Poster

14th Gallen International Breast Cancer Conference

Date:18-21 March 2015, Venue: International Centre Vienna, Vienna, Austria, Presentation: N van der Merwe, AV Peeters, SJ van Rensburg, FM Pienaar, J Bezuidenhout, MJ Kotze. Discordance between genome reference sequences applied in breast cancer exome sequencing. Presentation type: Poster

12th International Meeting for Society of Neuroscientists of Africa

Date: 26-30 March 2015, Venue: Durban, South Africa, Presentation: N van der Merwe, SJ van Rensburg, FM Pienaar, J Bezuidenhout, MJ Kotze. Clinical relevance of the MTHFR 677C>T mutation in breast cancer patients at increased risk of depression​. Presentation type: Oral

16th Southern African Society of Human Genetics Biennial Congress

Date: 16-19 August 2015, Venue:KleinKaap Boutique Hotel, Centurion, South Africa, Presentation: N van der Merwe, AV Peeters, FM Pienaar, JM Bezuidenhout, SJ van Rensburg, MJ Kotze. Functional DNA mismatch repair variant missed in exomes of BRCA-negative breast cancer patients using variant calling with the public human genome reference sequence (hg19). Presentation type:Oral

Presentation by Dr KA Grant at the MLS conference, Port Elizabeth, May 2015

Abstract:  Accurate determination of human epidermal growth factor receptor-2 (HER2) status is essential for optimal selection of patients for effective gene targeted therapy. The analytical performance of microarray analysis using TargetPrint for assessment of HER2 status was evaluated in 138 breast tumours, including 41 fresh and 97 formalin-fixed paraffin embedded (FFPE) specimens. Reflex testing using immunohistochemistry/in situ hybridization (IHC/ISH) in four discordant cases confirmed the TargetPrint results, achieving 100% agreement regardless of whether fresh tissue or FFPE specimens were used. One equivocal IHC/ISH case was classified as HER2-positive based on the microarray result. The proven clinical utility in resolving equivocal and borderline cases justifies modification of the testing algorithm under these circumstances, to obtain a definitive positive or negative test result with the use of TargetPrint. Determination of HER2 status across three assay platforms facilitated improved quality assurance and led to a higher level of confidence on which to base treatment decisions.

Journal Publications

Van der Merwe N, Lückhoff HK, Pienaar FM, Bezuidenhoudt J, van der Merwe L, van Rensburg SJ, Kotze MJ. Implementation of a pathology supported genetic testing strategy to facilitate the assessment of common risk factors shared between breast carcinoma and associated comorbidities. Metabolic Brain Disease, submitted 10 July 2015.

Kotze MJ, Lückhoff HK, Peeters AV, Baatjes K, Schoemann M, van der Merwe L, Grant KA, Fisher LR, van der Merwe N, Pretorius J, van Velden DP, Myburgh EJ, Pienaar FM, van Rensburg SJ, Yako YY, September AV, Moremi KE, Cronje FJ, Tiffin N, Bouwens CSH, Bezuidenhout J, Apffelstaedt JP, Hough FS, Erasmus RT, Schneider JW. Genomic medicine and risk prediction across the disease spectrum. Critical Reviews in Clinical Laboratory Sciences 2015, 19: 1-18.

Delport D, Schoeman R, Van der Merwe N, van der Merwe L, Fisher LR, Geiger DH, Kotze, M. Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application. Metabolic Brain Disease 2014; 29: 377-384.

Van der Merwe N, Bouwens CHS, Pienaar FM, van der Merwe L, Yako YY, Geiger DH, Kotze MJ. CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application. Metabolic Brain Disease 2012; 27: 319-326.

 

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