Mutational analysis of triple-negative breast cancers within the International Breast Cancer Study Group (IBCSG) Trial 22-00
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We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00.
A matched case–control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence.
Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88–5.92), though this difference was not statistically significant (p = 0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy.
Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.
KeywordsTriple-negative breast cancer Somatic mutation PIK3CA Mass array system Prognosis
We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group (IBCSG) Trial 22-00, which was supported by the IBCSG and participating centers. Support for Trial 22-00 central coordination, data management and statistics was provided by the Swedish Cancer League; The Cancer Council Australia; Australia & New Zealand Breast Cancer Trials Group; the Frontier Science and Technology Research Foundation; the Swiss Group for Clinical Cancer Research; the Swiss Cancer League/Oncosuisse. Funding for this study was provided by Italian Ministry of Health, Ricerca Finalizzata, RF-2009-1536545.
Compliance with ethical standards
Conflicts of interest
The authors declare no conflict of interest related to this study.
- 2.Coates AS, Winer EP, Goldhirsch A et al (2015) Tailoring therapies—improving the management of early breast cancer: St Gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol 26(8):1533–1546. https://doi.org/10.1093/annonc/mdv221 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Dupont WD. (1988) Power calculations for matched case-control studies. Biometrics. 44(4):1157–1168. http://www.ncbi.nlm.nih.gov/pubmed/3233252
- 19.Nowell PC. (1976) The clonal evolution of tumor cell populations. Science. 194(4260):23–28. http://www.ncbi.nlm.nih.gov/pubmed/959840
- 22.Zhu Y, Wang Y, Guan B, et al. (2014) C-kit and PDGFRA gene mutations in triple negative breast cancer. Int J Clin Exp Pathol. 7(7):4280–4285. http://www.ncbi.nlm.nih.gov/pubmed/25120810
- 24.Fouqué A, Jean M, van de Weghe P, Legembre P. (2016) Review of PI3K/mTOR inhibitors entering clinical trials to treat triple negative breast cancers. Recent Pat Anticancer Drug Discov. http://www.ncbi.nlm.nih.gov/pubmed/27194555
- 25.Massihnia D, Galvano A, Fanale D et al (2016) Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway. Oncotarget 5:60712Google Scholar
- 32.André F, Bachelot T, Commo F et al (2014) Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol 15(3):267–274. https://doi.org/10.1016/S1470-2045(13)70611-9 CrossRefPubMedGoogle Scholar
- 34.Cortes J, O’Shaughnessy J, Loesch D et al (2011) Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377(9769):914–923. https://doi.org/10.1016/S0140-6736(11)60070-6 CrossRefPubMedGoogle Scholar