An Update on Breast Cancer Biomarkers

MOJ Immunology

Abstract Review Article

Breast cancer is the most common cancer that affects millions of people Volume 5 Issue 2 - 2017 worldwide. Delayed diagnosis of these cancers has increased the morbidity and mortality. However, the vast research on cancer biomarkers during recent years provide a powerful and dynamic approach to understand the wide spectrum of cancers with applications in prognosis, diagnosis, screening, randomized clinical 1Centre for Applied Molecular Biology, University of the trials, and observational and analytic epidemiology. Cancer biomarkers have Punjab, Pakistan tremendously increased the efficacy of treatment and efficacy of detection. We 2Lahore College for Women University, Pakistan have comprehensively summarized various biomarkers of breast cancer and 3Lahore Garrison University, Defence Campus Lahore, Pakistan highlighted recent research. Braira Wahid, Centre for Applied Keywords: *Corresponding author: Baig, University of the Punjab, Lahore, Pakistan, Tel: +92-42- Biomarkers; Breast cancer; VEGF; Diagnosis Molecular Biology, 87-West Canal Bank Road Thokar Niaz

5293141; Fax: +92-42-5293149; Email: Received: | Published: Abbreviations: 2017 February 01, 2017 February 16, BC: Breast Cancer; EGFR: Epidermal Growth AA: AbirateroneFactor Receptor; Acetate VEGF: Vascular Endothelial Growth Factor; NSE: Neuron-Specific Enolase; MBC: Metastatic Breast Cancer; Introduction mutations have been detected in the hotspot regions of exon 9 and 20 of the PIK3CA in single circulating tumor cells of patients Breast cancer is the leading cause of death worldwide. In suffering from HER2-negative metastatic breast cancer [8]. 2013, Centre for Disease Prevention and Control documented that 230,815 women were diagnosed with breast cancer in United Based on candidate gene approach, large number of breast- States of which 40,860 women were died [1]. Delayed diagnosis cancer related methylation biomarkers have been discovered or limitations of mammography lead to poor prognosis of breast related gene such as APC [10], RASSF1A [11], and SOX17 [12]. for diagnosis of breast cancer gives false positive results, only Cohort-study[9]. As such, revealed regions identifiedthat methylated lie in CST6 the promoters differentiated of cancerbreast observedcancer. Screen-film in aged women, mammography and is less sensitive (SFM) in that women is being with dense used cancer samples from control samples. The study was based on breast tissue. There is dire need to overcome these limitations to two separate cohorts of breast-cancer patients including two improve the detection of breast cancer. Development of resistance separate cohorts of breast cancer patients, with methylation to chemotherapeutics is another factor contributing towards increased mortality. It is crucial to develop novel biomarkers individualsfound in 49/123 showed patients methylation (39.8%) [13]. in oneAnother cohort, retrospective and 14/73 patient’s treatment choice and drug resistance development [2]. study,patients based (19.2%) on 30 in healthy other cohort, controls while and none 36 early of the stage 37 healthybreast Thiswith reviewpotential article to confirm focuses diagnosis promising and biomarkers prognosis andfor diagnosis,to predict included CST6 for breast cancer. cancer patients showed that use of 8-gene biomarker panel (that prognosis, and prediction of which therapies will be efficacious ) provided highest sensitivity and specificity by Circulating DNA controlcorrectly samples identifying was also90% observed of cancer in negative this study samples [10]. and 91.7% of cancer samples. Significant level of CST6 methylation in the Circulating DNA is ideal and non-invasive biomarker isolated Likewise, another study evaluated the ability of circulating DNA to identify the tumors in 640 patients with diverse cancer amount of free DNA circulate in both diseased and healthy types. The results exhibited the presence of circulating DNA in humanfrom body serum fluids or plasma especially however, human an serum increased and plasma/serum plasma. Small concentration of DNA is observed in cancer patients because of gastroesophageal, hepatocellular, breast, ovarian, pancreatic, higher cellular turnover in cancer cells [3-5]. >75% patients with advanced head and neck cancers, melanoma, brain, and thyroid cancers. In patients with localized tumors, colorectal, and bladder and in <50% of primary prostate, renal, mutations such as TP53/ PIK3CA and PI3Kgene mutations in circulatingNext generation DNA has sequencingsuccessfully ofdemonstrated somatic tumor that tracking specific of patients with pancreatic cancer, breast adenocarcinoma, gastroesophagealcirculating DNA wascancer, detected and colorectal in 48%, cancer, 50%, respectively 57%, and [14]. 73% accurate and feasible tool for monitoring disease and therapy Another prospective study included 52 women of which 30 had tumor-specific circulating free DNA may provide valuable, in breast cancer patients [6,7]. Genomic aberration specifically genomic alterations in tumor samples that were patient specific

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in this study circulating tumor DNA was found suitable for [26]. All these adjuvant therapies exhibited the association of PgR monitoringand tumor tumor specific. cells Of [15]. three blood-born biomarkers assessed expressionPgR status hadlevel not and varied prognosis the efficacy of endocrine of letrozole therapy. over Evaluation tamoxifen of degree of correlation between immunohistochemical and immunocytochemical determination of PR and ER in breast cancer showed that both PR and ER were negative in nine cases but concentrationBaseline serum observed levels in cancer of circulating patients cell-free than in healthy DNA (ALU247, controls [16].ALU115) It has can been predict recently disease been reported prognosis that serum because cell-free of higher DNA support the use of ER and PR in prognosis of breast cancer [30]. CREBBP, SMAD4, AKAP9, PIK3CA, and TP53 positive in four cancer (PR in 1 and ER in 3). All these evidences act as biomarkers breast cancer patients receiving tamoxifen [17]. Androgen receptor (cfDNA) mutations in Estrogen receptor The androgen receptor is well-studied in context of male physiology because of its proven clinical target in prostate cancer. Expression of estrogen receptor acts as biomarker of breast Basal cytokeratins and androgen receptors provide powerful cancer, because it provides the index for sensitivity to endocrine prognostic information in triple-negative breast cancer [31]. treatment. Estrogen expression increased with age in breast Several studies show that association of breast cancer survival with AR status depends upon ER expression thus causing cancer patients [18]. Likewise, ER (estrogen receptor) level in ameliorated survival in ER+ tumors. The expression level of AR was inTDLU-PT postmenopausal (terminal women duct lobular [19]. A units-recent proximal study has to demonstrated tumor) and found to be considerably higher in endocrine responsive tumors. thatTDLU-DT neo-tanshinlactone (terminal duct lobulardecreased units-distal steady state to tumor) expression was higher level of ESR1 mRNA in ER+ breast cancer cells. Analysis of ER mRNA importance of AR for prognosis and survival outcome. The results levels and protein levels of target genes of transcription factor Multivariate analysis of disease free survival demonstrated the chemo-endocrine therapy and endocrine therapy thus, suggesting theof the prediction study exhibited of systematic that 90% treatments of ER-positive [32]. patientsWhereas, received in ER ERespecially negative GREB1, and PR CCND1,positive TFF1,breast BRCA1,cancer is ESR2,not a reproducible ABCA3, and negative and triple negative breast cancer subset no prognosis subtype.SERPINB9 The further expression confirms of the progesterone aforementioned receptor finding is [20].not or poor prognosis impact of ER and AR negative tumor patients associated with prognosis of estrogen receptor negative breast was observed compared to ER-positive tumor patients. AR was cancer [21]. K303R ER mutation has been associated with breast found to be more frequently expressed than ER and PR in another cancer and benign breast hyperplasia [22]. An abiraterone acetate study that recruited 980 Chinese patients with invasive breast carcinoma. However, the expression of AR was closely associated progesterone and decrease serum androgen and estrogen levels. with PR and ER with higher level observed in ER+ subtypes than Dual(AA) expression pharmacodynamic of ER and effect AR havein circulating been found tumor to cells increase and in ER- subtypes. It was related to more favorable pathological features such as marker of proliferation in breast cancer, lower Ki-67 expression and small tumor size [33]. isnewly being obtained investigated formalin-fixed as imaging paraffin-embedded biomarker to predict tissues tumor may Another retrospective study based on 287 females diagnosed aggressivenesspredict AA sensitivity in patients [23]. with Tumor estrogen-receptor-positive apparent diffusion coefficient breast therefore, it ER may serve as predictor of response to endocrine with TNBC (triple negative breast cancer) showed that AR were cancer [24]. ER-α is expressed in about 70% of breast cancers breast cancers. AR positivity was associated with longer overall survivalpresent and at rate disease of 25.8% free survival in TNBC whereas, lower thanpoor prognosis in ER-positive was [25]. therapy and confirm resistance to certain endocrine therapies noticed in AR-negative patients [34]. In the prospective GeparTrio Progesterone receptor (PgR) phase-III trial, tissue microarray of 673 core biopsies from primary breast cancer patients were treated with neoadjuvant The expression of progesterone receptor depends upon cyclophosphamide/ doxorubicin/ docetaxel chemotherapy followed by immunohistochemistry to predict the effect of AR cases express progesterone receptor but not estrogen receptor. on pathological response and its role as prognostic marker Suchestrogen reanalysis receptor. of theLess ER than status 1% of of such tumors tumors in all is breast necessary cancer to eliminate false ER negativity [26]. Absence of PR expression response and triple negative breast cancer [35]. The response of acts as powerful and independent biomarker for prognosis in specifically in patients not attaining pathological complete ER-positive breast cancer patients receiving endocrine therapy to ER ratio which makes them a promising biomarker of breast [27]. Initial studies suggested poor prognosis in ER-positive/ cancerbreast cancer[36]. to traditional endocrine therapy is influenced by AR PgR-negative breast compared to PgR-positive tumors [28]. ATAC Human epidermal growth factor receptor-2 (HER2) demonstrated that patients with PgR negative breast cancer (Arimidex, Tamoxifen, Alone or in Combination) trialist group compared with PgR-positive patients [29]. These results were The HER2 (ERBB2) oncogene encodes a transmembrane patients gain more benefit from anastrozole than tamoxifen of breast cancers makes it an effective therapeutic treatment targettyrosine and kinase biomarker receptor. for breast Over-expression cancer and is of a HER2validated in 10−25% adverse 1856 ER expressing patients. The BIG 1-98 trial revealed that not confirmed in centrally analyzed material from PgR and/or

Citation: 10.15406/moji.2017.05.00150

prognostic factor with a mean relative risk for overall survival of survival, and distant disease-free survival. Tumor size, grade, and 2.74 [37,38]. Accumulating evidence suggest an extraordinary therapy in HER2-positive breast because of poor prognosis observed in HER2-positive breast cancer than HER2-negative metastatic sites are also influenced by VEGF levels. Despite of breast cancer [39]. therapy, disease progresses in the patients with high VEGF levels. Significantly lower progression free survival is noticed in patients A recent study investigated the predictive value of CTC [51].with highAll this VEGF data level suggest compared its promising to those role with as lower biomarker. levels [50]. In triple negative breast cancer patients bevacizumab targets VEGF Epidermal growth factor receptor (EGFR) (Circulating Tumor Cell) HER2 expression and prognostic resultssignificance provided of CTC valuable enumeration predictive for andefficient prognostic anti-HER2 information therapy in HER2-positive metastatic breast cancer (MBC) patients. The Overexpression of EGFR in all types of breast cancers Researchers found direct tumour-promoting interactions of uPAR to optimize therapies in HER-2 positive MBC patients [40]. outcomes,(specifically and in triple-negativelarge tumor size. breast Several cancer therapies and inflammatory including breast cancer) is associated with poor differentiation, poor clinical in triple negative breast cancer cells thus, suggesting the role of uPARwith uPAas biomarker and the insulin-like and therapeutic growth target factor [41]. receptor Novel interacting1 (IGF1R) apatinib, cetuximab, gefitinib have been shown to target EGFR. partners of uPAR i.e, Cyr61 and YB-1 may also act as therapeutic hereditary breast Mutations in EGFR genes cause the overexpression of EGFR. A targets because of their reported elevation in the malignancy of study reported EGFR mutation in 11 of 24 triple-negative breast cancer [42]. It has been reported that BC expression level or gene mutation status may act as predictive carcinomas and 7 of 48 sporadic breast carcinomas [52]. EGFR cause brain metastasis but there is no biomarker yet available biomarker [53]. Phosphorylation of EGFR may act as biomarker of serum S100ß protein are elevated in brain damages induced by such as lung cancer and triple negative breast cancer [54,55]. A that predicts brain metastasis. Neuron-specific enolase (NSE) and recentresponse study to time-staggered revealed that inhibition immunoexpression in EGFR driven of tumorbiomarkers types brain metastasis. Matrix metalloproteinase 9 (MMP-9), NSE, and breast cancer patients [56]. Likewise, recent study revealed like CK5/6 and EGFR predict the survival of triple negative BCHER2 patients have a [43]. particular In vivo, tropism CDK4/6 for inhibitors central nervous have found system to (CNS)delay that combined measurement of three non-intuitive proteins recurrencethese three of biomarkers tumor in transgenic are correlated model of with HER-2 BM positive in metastatic breast cancer because CDK4/6 inhibitors sensitize patient-derived targeting their constituents and cellular dependence on PI3K vs. EGFR, ERBB3, and CDKN1B determines responsiveness to drugs xenograft tumors to HER2-targeted therapies [44]. MicroRNAs (miRNAs) MAPKOther signaling genetic pathwaysbiomarkers [57]. mircroRNAs act as tumor suppressor genes or oncogenes because dysregulation of miRNAs plays an important role in the the use of different genes as biomarkers of response to therapy Over the last few years, retrospective and clinical data suggests initiation and progression of different human cancers, including as well as diagnosis. Level of CA15-3 and CEA in serum predict prognosis in breast cancer. A study showed an elevation in that predict therapeutic outcomes miR-30c, miR-339-5p, miR- 187,breast prognostic cancer (BC). biomarkers Several differentmiR-148a, miRNAs miR-33a act, andas biomarkers diagnostic respectively [58]. Alabama Breast Cancer Project has investigated serum levels of CA15-3A and CEA in 60 (13.9%) and 47 (10.9%), biomarkers miR-9, miR-10b, and miR-17-5p. All these miRNAs play diverse role in controlling metastasis, invasion, proliferation, expression in breast cancer [59]. Preclinical studies have also the independent prognostic significance of p53 and c-erbB-2 miR-155 breast cancer patients therefore, it can be used as predictive confirmed the chemosensitive nature of BRCA-1 mutations in ,apoptosis, miR-210 [45,46]. genomic instability, and resting death. Other important marker of response to different types of chemotherapy agents miRNAs of breast cancer that circulate in body fluids are [60]. The microarray data analysis of 1809 patients to assess Vascular endothelial growth factor (VEGF) effect of 22,277 genes on breast cancer prognosis revealed the stimuli such as growth factors, nitric oxide, hypoxia, HER-2, TK,high Cox-2, prognostic heat powershock ofprotein TOP2A, 90, TOP2B, MKI67,Ki67, and CCND3, CCND2,are The gene expression of VEGF is controlled by several different PARP, TOP-2A importantCDKN1A, CCNE2, biomarkers and TK2 of triple [61]. negative Mammalian breast target cancer of rapamycin,[62]. neovascularization in the tumor by elevating expression of XIAP, survivin,tumor suppressor and Bcl2 genes,that are and anti-apoptotic oncogenes [47]. proteins VEGF [48]. regulates The Emerging biomarkers of future ductal carcinoma in citu therefore, it can be used to predict the Epigenetic changes especially DNA methylation has shown prognosisexpression of of breast VEGF cancer is increased [49]. in invasive breast cancer and promise as biomarker of prognosis and diagnosis [63,64]. breast cancer to devise predictive “signatures” in the setting of level and larger tumour size, grade III tumours, and negative neoadjuvantOligonucleotide chemotherapy microarrays setting and cDNA [65]. are being applied to study Recent studies confirmed the correlation between VEGF and poor survival is observed. In triple negative breast cancer The activity of PI3K/PTEN pathway in ER-negative and basal- hormone status. Level of VEGF decreases with chemotherapy like breast cancer supports the future clinical evaluation of higher level of VEGF is related to original survival, disease free

Citation: 10.15406/moji.2017.05.00150

5. of breast like breast cancer [66]. in the circulation as a potential cancer biomarker. Anticancer res combining PI3K with EGFR pathway inhibitors for the treatment Kohler C, Barekati Z, Radpour R, Zhong XY (2011) Cell-free DNA mRNA expression and aromatase inhibitor therapy. A recent 6. 31(8): 2623-2628. studyIn included breast cancer, 9 patients PIK3CA who developed genotype metastatsis, is influenced 15 by patients LRG1 Nakauchi, Kagara N, Shimazu K, Shimomura A, Naoi Y, et al. (2016) with favourable outcome, and 24 patients with invasive ductal Detection of TP53/PIK3CA Mutations in Cell-Free. Plasma DNA breast cancer were kept under observation for 5 years. Set of From Metastatic Breast Cancer Patients Using Next Generation 7. Sequencing. Clin Breast Cancer 16(5): 418-423 analysis of plasma cell-free DNA for breast cancer early detection Li, Z, Guo X, Tang L, Peng L, Chen M, et al. (2016) Methylation 58 differentially expressed genes (p ≤ 0.01) between the two was generated by using tumor samples from all patients. RT-qPCR 13111-13119. groups were identifiedGTSE1, B3GNT7, in global PPM1D, gene expression TNKS2, and profiles PHB were that using bisulfite next-generation sequencing. Tumor Biol 37(10): 8. confirmed that Gasch C, Oldopp T, Mauermann O, Gorges TM, Andreas A, et al. mRNAupregulated expression in patients and considerable with poor outcomes.BAD protein Oligoarray expression data in tumor cells of patients suffering from HER2-negative metastatic (2016) Frequent detection of PIK3CA mutations. in single circulating metastaticrevealed reduced cases and BCL2-associated 1276 BC tissue agonist samples of respectively. cell death (BAD)These 9. breast cancer. 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Citation: 10.15406/moji.2017.05.00150

Wahid B, Wahid K, Wahid SB (2017) An Update on Breast Cancer Biomarkers. MOJ Immunol 5(2): 00150. DOI: