Triple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer, that represents 10–20% of all breast carcinomas and characterized by the lack of a specific cell surface marker compared to other breast cancer subtypes. Due to the absence of molecular markers for TNBC his treatment options remains limited, without proven targeted therapies, which emphasize the need for discovering molecular markers that could be targeted for patient treatment, An important number of TNBC cases harbor aberrations in the phosphoinositide 3-kinase (PI3K) pathway, leading to constitutive activation of the downstream signaling pathway. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (~ 30%) observed, along with protein loss of PTEN and AKT activation by phosphorylation (pAkt). Therefore, we propose to analyze clinocopathologic and molecular characteristics of PI3K/AKT/PTEN pathway in Moroccan triple negative breast cancer patients.
We conducted a retrospective study of 39 patients diagnosed with triple negative breast cancer between early 2013 and 2016. In this study, we used the Ion Personal Genome Machine (PGM) and Ion Torrent Ampliseq Cancer panel to sequence hotspot regions from PIK3CA, AKT and PTEN genes to identify genetic mutations in 39 samples of TNBC subtype from Moroccan patients and to correlate the results with clinical-pathologic data.
All patients were female with a median age of 46 years from (34–65). Most patients have had invasive ductal carcinoma (84.6%) and 69.2% of them were grade III SBR. Among the 39, 9 were right sided tumor patients and the remaining 30 were left-sided. Mutational analysis of PIK3CA gene was achieved in all TNBC patients. PIK3CA hotspot mutations were detected in 5/39 of TNBC (13%), in detail, among these 5 TNBC patients, one harbored mutation in exons 9 and four in exon 20.
The PI3KCA gene is highly activated and plays a crucial role in the pathogenesis of TNBC more, therefore, may be a potential therapeutic target to improve outcomes in patients.
Morris GJ, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cancer. 2007;110(4):876–884. https://doi.org/10.1002/cncr.22836. [ PubMed] [ Cross Ref]. CrossRef
Azim HA, Jr, Michiels S, Bedard PL, Singhal SK, Criscitiello C, Ignatiadis M, Haibe-Kains B, Piccart MJ, Sotiriou C, Loi S. Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling. Clin Cancer Res 2012;18:1341–1351. CrossRef
Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;1275–1281(PubMed):26.
Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, et al. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9:R65. [PMC free article] [PubMed].
Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 2015;21:1688–1698. [PMC free article] [PubMed]. CrossRef
Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 2005;4:988–1004. CrossRef
Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7. CrossRef
Wellcome Trust Sanger Institute. Catalogue of somatic mutations in cancer (COSMIC). In: Accessed march 9; 2010. http://www.sanger.ac.uk/genetics/CGP/cosmic/.
Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol CellBiol. 2010;11:329–41. CrossRef
Samuels Y, Wang Z, Bardelli A, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. CrossRef
Comprehensive molecular portraits of human breast tumours Nature 490: 61–70,2012 Cancer Genome Atlas Network Crossref, Medline.
Samuels Y. High frequency of mutations of the PIK3CA gene in human cancers. Science. 2004;304:554. CrossRef
Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM. The oncogenic properties of mutant p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl AcadSci U S A. 2005;102(51):18443–18448. [PMC free article] [PubMed]. CrossRef
Isakoff SJ, Engelman JA, Irie HY, et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65(23):10992–1000 [PubMed]. CrossRef
Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL. Frederick AM, et al.Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486:405–9. CrossRef
Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70. CrossRef
Carpten JD, Faber AL, Horn C, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature. 2007;448:439–44. CrossRef
Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res. 2008;68(15):6084–91. CrossRef
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene. 2008;27:5497–510. CrossRef
Arsenic R, Lehmann A, Budczies J, Koch I, Prinzler J, Kleine-Tebbe A, et al. Analysis of PIK3CA mutations in breast cancer subtypes. ApplImmunohistochemMolMorphol. 2014;50–56(PubMed):22.
Millis SZ, Gatalica Z, Winkler J, Vranic S, Kimbrough J, Reddy S, et al. Predictive biomarker profiling of > 6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications. Clin Breast Cancer. 2015. April 28 pii: S1526–8209(15)00098–1. https://doi.org/10.1016/j.clbc.2015.04.008 [ PubMed]. CrossRef
Gonzalez-Angulo AM, Chen H, Karuturi MS, Chavez-MacGregor M, Tsavachidis S, Meric-Bernstam F, et al. Frequency of mesenchymal-epithelial transition factor gene (MET) and the catalytic subunit of phosphoinositide-3-kinase (PIK3CA) copy number elevation and correlation with outcome in patients with early stage breast cancer. Cancer. 2013; 119(1):7–15. https://doi.org/10.1002/cncr.27608 [ PMC free article][ PubMed]. CrossRef
Yu-Hsiang Chen, Bradley A. Hancock, Jeffrey P. Solzak, et al.Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. NPJ Breast Cancer. 2017;3:24. https://doi.org/10.1038/s41523-017-0028-4. [ Free PMC Article][ PubMed].
Cossu-Rocca P, Orrù S, Muroni MR, Sanges F, Sotgiu G, Ena S, Pira G, Murgia L, Manca A, Uras MG, Sarobba MG, Urru S, De Miglio MR, et al.Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer. PLoS One. 2015 Nov 5;10(11):e0141763. https://doi.org/10.1371/journal.pone.0141763. eCollection 2015. [ Free PMC Article]. CrossRef
Kriegsmann M, Endris V, Wolf T, Pfarr N, Stenzinger A, Loibl S, Denkert C, Schneeweiss A, Budczies J, Sinn P, Weichert W, et al. Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences.Oncotarget. 2014 Oct 30;5(20):9952–65. [ Free PMC Article].
Weisman PS, Ng CK, Brogi E, Eisenberg RE, Won HH, Piscuoglio S, De Filippo MR, Ioris R, Akram M, Norton L, Weigelt B, Berger MF, Reis-Filho JS, Wen HY. Genetic alterations of triple negative breast cancer by targeted next-generation sequencing and correlation with tumor morphology. ModPathol. 2016 May;29(5):476–488. https://doi.org/10.1038/modpathol.2016.39. Epub 2016 Mar 4. https://doi.org/10.1038/modpathol.2016.39.
Hashimoto K, Tsuda H, Koizumi F, Shimizu C, Yonemori K, Ando M, Kodaira M, Yunokawa M, Fujiwara Y, Tamura K. Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer. Ann Oncol. 2014 Oct;25(10):1973–9. https://doi.org/10.1093/annonc/mdu247 Epub 2014 Jul 9. CrossRef
Beg S, Siraj AK, Prabhakaran S, Jehan Z, Ajarim D, Al-Dayel F, Tulbah A, Al-Kuraya KS. Loss of PTEN expression is associated with aggressive behavior and poor prognosis in middle eastern triple-negative breast cancer. Breast Cancer ResTreat. 2015 Jun;151(3):541–53. https://doi.org/10.1007/s10549-015-3430-3 Epub 2015 May 16. CrossRef
Bleeker FE, Felicioni L, Buttitta F, Lamba S, Cardone L, Rodolfo M, Scarpa A, Leenstra S, Frattini M, Barbareschi M, Grammastro MD, Sciarrotta MG, Zanon C, Marchetti A, Bardelli A. AKT1(E17K) in human solid tumours. Oncogene. 2008 Sep 18;27(42):5648–50. https://doi.org/10.1038/onc.2008.170 Epub 2008 May 26. CrossRef
Rudolph M, Anzeneder T, Schulz A, Beckmann G, Byrne AT, Jeffers M, Pena C, Politz O, Köchert K, Vonk R, Reischl J. AKT1 (E17K) mutation profiling in breast cancer: prevalence, concurrent oncogenic alterations, and blood-based detection. BMC Cancer. 2016 Aug 11;16:622. https://doi.org/10.1186/s12885-016-2626-1. CrossRefPubMedPubMedCentral
Sjoblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;268–74(PubMed):314.
Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007; 446:153–8. [ PMC free article] [PubMed].
Gordon V, Banerji S. Molecular pathways: PI3K pathway targets in triple-negative breast cancers. Clin Cancer Res. 2013 Jul 15;19(14):3738–44. https://doi.org/10.1158/1078-0432.CCR-12-0274 Epub 2013 Jun 7. CrossRef
Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005;23:5314–22. CrossRef
- Detection of PIK3/AKT pathway in Moroccan population with triple negative breast cancer
Mohamed El Khasmi
- BioMed Central
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