Open Access

Review Article

“OMIC” tumor markers for

breast cancer: A review
Naila Irum Hadi1, Qamar Jamal2
ABSTRACT
Breast cancer is a global health issue, and as the tumor burden increases, we need to come up with newer,
better technologies which are convenient, cheap, rapid, sensitive with a high specificity. Technological
advancements in the field of cancer biomarker has led to the development of techniques such as mass
spectrometric analysis and microarray analysis in which genes, proteins and hundreds and thousands
of metabolites can be identified with the emergence of genomics, proteomics and metabolomics. This
research is focused on finding biomarkers for diagnosis, prognosis, staging, treatment response and targets
for chemotherapy, generating a panel of markers which provide better clinical information compared
to a single marker in the panel. This review briefly summarizes application of genomics and proteomics
followed by key concepts and applications of metabolomics in breast cancer, with the conclusion that an
integration of the three “OMIC” technologies may hold the key to future biomarker discovery.
Sources of Data/Study Selection: The information for this review was collected by searching the Google
Scholar and PubMed database for English articles published in the period from 2002 to 2015. The search terms
included “biomarkers in breast cancer” along with the following search terms: “genomics”, “proteomics”,
“metabolomics”, “breast cancer”, “mass spectrometry”, “molecular markers” and “cancer biomarker”.
We have endeavored to quote only the primary sources. Titles and abstracts of retrieved studies were
assessed first followed by selection and retrieval of selected full text articles.
KEY WORDS: Biomarker, Breast cancer, Genomics, Proteomics, Metabolomics.
Abbreviations:
ASCO – American Society of Clinical Oncology, ER – estrogen receptor, PgR – progesterone receptor, HER2 – human
epidermal growth factor receptor 2,CA – cancer antigen, TAILORx – Trial Assigning Individualized Options for
Treatment (Rx), MINDACT – Microarray InNode Negative Disease may Avoid ChemoTherapy using Mammaprint®, FDA
– Federal Drug Authority, GC-TOF-MS – time of flight, LC/ESI-MS – electrospray ionization, PCho – phosphocholine,
GPCho – glycerophosphocholine, Cdx-2 – caudal type homebox 2, KiSS1 – Kisspeptin 1, KAL1 – Kallman syndrome 1
sequence, NIST – National Institute of Standards and Technology, HMDB – Human metabolome database.
doi: http://dx.doi.org/10.12669/pjms.315.7627
How to cite this:
Hadi NI, Jamal Q. “OMIC” tumor markers for breast cancer: A review. Pak J Med Sci 2015;31(5):1256-1262.
doi: http://dx.doi.org/10.12669/pjms.315.7627
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1. Dr. Naila Irum Hadi, MBBS, MPhil, PhD fellow.

Professor of Pathology,
INTRODUCTION
2. Dr. Qamar Jamal, MBBS, MPhil, PhD.
Professor of Pathology, Breast cancer (BC) is a major health issue in
1, 2: Ziauddin University, Karachi, Pakistan. women Worldwide as well as in Pakistan. Howev-
Correspondence: er marked geographic variation has been noted in
Dr. Naila Irum Hadi, MBBS, MPhil, PhD fellow. the incidence, natural course of the disease as well
Pathology Department, Ziauddin University, as survival statistics. This is reflected in the com-
4/B, Shahrah-e-Ghalib, Block-6, Clifton,
Karachi-75600, Pakistan.
parison between age standardized rates (ASR) and
E-mail: nailahadi@yahoo.com survival rates (SR) of North American women with
* Received for Publication: March 5, 2015
that of Pakistani women i.e. ASR of 99.4 per 100,000
* Revision Received: July 16, 2015
and SR of 80%1 for the former with ASR of 69.1 per
* Revision Accepted: July 25, 2015 100,0002 and SR of less than 40% for the latter.1 The

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 OMIC tumor markers for breast cancer

gravity of the situation further increases when it is study for prediction of breast cancer relapse)9 and
noted that BC in Pakistan affects younger women OncotypeDx (Genome Health, Redwood city,
with an advanced stage at the time of presentation.3 CA, USA) (a 21 gene expression profile by RT-
This puts an enormous burden on the resources PCR).10 These have been approved by FDA and
of a poor country like Pakistan. Mammography are commercially available since 2007 and 2004
for screening, histopathology and blood tests for respectively. Their value in assessing individualized
diagnosis, prognosis and treatment are considered options for treatment in selection of an effective
gold standards for breast cancer.4 According to and appropriate chemotherapeutic agent for breast
2007 recommendations of ASCO for tumor markers cancer patients is being explored in ongoing clinical
ER, PgR and HER2 expression in primary invasive trials: TAILORx11 and MINDACT,12 but their routine
breast cancer should be evaluated for diagnosis clinical use is not yet recommended.13
or recurrence especially as a guide for therapy, Recently researchers are interested in finding out
while increasing levels of CA 27.29 or CA 15-3 may whether other ‘omic’ technologies can also add to
indicate treatment failure.5 This however cannot be the information provided by genomics.14 Elevated
applied to all breast tumors leaving a wide gap in levels of protein in biological fluid in cancer can be
our understanding of this heterogeneous tumor. due to atypical secretion, shedding of membrane-
Hence development of new methods for exploring associated proteins, change in cancer cells polarity,
the molecular pathogenesis of this disease becomes increased expression of proteases15 and single
imperative. Detection of malignancy by a sample nucleotide polymorphism (SNP) of signal peptide,16
blood test for identification of tumor markers etc. HER2 is a cancer biomarker, and classic example
has been explored thoroughly in medical field. of a membrane bound tyrosine kinase, that is shed
These biomarkers are released by the tumor itself into fluids. HER2 protein has an extracellular
or by other tissues as a reaction to the tumor or domain (ECD), a transmembrane domain and a
inflammation occurring in response to tumor. cytoplasmic domain. The ECD of HER2 is cleaved
An ideal tumor marker is easily measured, reliable, by a protease from the receptor protein and can be
and cheap, with a high sensitivity and specificity. detected as a biomarker in serum. Over expression
It should help not only in screening early cancer of HER2 seen in some cases of breast cancer is an
but also recurrence, vary with different stages of indicator of poor prognosis for these patients.5
disease and has prognostic and predictive value.6 Since 2000, HER2 test has been approved by FDA
This review briefly covers the concepts of and is used in the management and follow-up of
genomics and proteomics, followed by an in-depth patients with metastatic breast cancer.
analysis of the evolving field of metabolomics for mRNA transcript does not reflect the function
biomarker discovery in breast cancer. of proteins, hence different proteomic strategies in
1. “Omics” in Breast Cancer: biomarker discovery have emerged as proteins in
In the quest for identification of a suitable biomarker complex mixtures require systemic characterization
for breast cancer, novel and high-yield technologies by mass spectrometry (MS). Limitation of MS
like genomics, proteomics, and metabolomics have for proteomic approaches include improper
received a lot of attention in recent times, prompt- sample collection and storage, inability to
ing the researchers to name this as the era of “Breast identify established serological biomarkers, bias
cancer – OMICS”.7 Studies have shown that malig- in identification of high-abundance molecules
nant transformation of normal breast tissue and within the serum, conflict in reporting of ms peaks
evolution of metastatic clone involves altered gene reported by different research laboratories17,18 and
expression (altered transcription) or altered protein possible artifacts in bioinformatics.19 Hence serum
expression (altered translation).8 This has led to the proteomic analysis and profiling is not currently
development of promising technologies of genom- recommended for clinical use by experts.13
ics, proteomics (respectively) and metabolomics. Enzymes are proteins, and there should be good
Gene expression profiles of certain predictive quantitative relationship between mRNA concen-
and prognostic markers of breast cancer have tration and enzyme function. But on the contrary,
been developed and are available commercially metabolites which are downstream are better indi-
such as molecular technologies for improvement cators of enzyme activity,20 and are more sensitive
in breast cancer diagnosis and treatment with monitors of a change in biological system, repre-
the development of MammaPrint (Agendia, sented by the genome (‘genomics’), transcriptome
Amsterdam, The Netherlands) (a 70 gene microarray (‘transcriptomics’), proteome (‘proteomics’) and

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Naila Irum Hadi et al.

metabolome (‘metabolomics’). At the end of the coupled with gas chromatography (GC-MS) (iden-
spectrum, metabolome represents the phenotypic tification of approximately 1000 metabolites), with
changes and even slight alterations in metabolites liquid chromatography (LC-MS) (identification of
can be detected.21 Hence cancer researchers have re- hundreds of metabolites) or capillary electrophore-
newed interest in the field of metabolomics for the sis (CE-MS).NMR MS identifies a variable number
discovery of specific biomarkers for use as diagnos- of metabolites depending on the nature of samples
tic or prognostic markers.21 i.e. 20 – 40 metabolites in tissue samples and 100
2. Metabolomics: – 200 in urine samples.20,25 GC-MS and LC-MS are
Warburg effect (put forward by Otto Warburg commonly used techniques for cancer samples.21
in 1924)is characterized by an increase in glucose Benefits of NMR include high reproducibil-
uptake by cancer cells converting it into lactate by ity, ability to quantify metabolites in complex mix-
glycolysis in spite of normal oxygen supply, hence tures and metabolite detection in vivo, as well as
also called ‘aerobic glycolysis’ or ‘aerobic fermenta- in biological fluids and tissues without any prior
tion’.22 Cancer cell is also shown to have an altered preparation of the sample. Its main disadvantage
protein metabolism and altered lipid metabolism.23 is its low sensitivity.27 An improvement of NMR
Hence cancer is regarded as a disease with gene spectroscopic procedure is a technique called high
mutation resulting in changes in gene expression to resolution magic angle spinning (HR-MAS) NMR
produce a metabolic phenotype with altered glyco- spectroscopy, which involves spinning of a biopsy
lytic, amino acid, nucleotide and glycerophospho- sample at an angle to the magnetic field, to improve
lipid / lipid metabolism. This results in a cancer cell the spectrum resolution.28 Its advantage include si-
phenotype resulting in cancer cell growth, differen- multaneous in situ assessment of both aqueous and
tiation and survival. lipid soluble metabolites.23 High resolution NMR
Metabolomics technology involves identifica- (HR-NMR) and HR-MAS MRS can be used on bio-
tion of hundreds to thousands of metabolites and fluids and tissues as they do not cause destruction
exploring multiple cellular pathways at the same of samples making it possible to carry out parallel
time. Presence of small molecules in the body flu- analysis.29
ids or tissues contribute to the construction of a Benefits of GC-MS include high sensitivity, quan-
unique ‘fingerprint’, distinguishing between dis- tification of metabolites and ability to identify more
ease and health implying that metabolomics can compounds in comparison to other MS techniques.
distinguish between cancer and normal tissues. So Its main limitation is complex and lengthy steps
metabolomics is emerging as a promising new ‘om- involved in sample preparation and interpretation
ics’ field7 a high throughput technology increasing- of its spectra. Benefits of LC-MS is its use for non-
ly being used for breast cancer research especially volatile compounds, quantification of wide range a
for screening, diagnosis, cancer typing, staging and of metabolites and its complementary nature to GC-
therapeutic intervention.21,24 Advantages of metabo- MS.21
lomics include being cost-effective, high through- CE-MS separates and identifies polar or ionic
put, and being automated with sample analysis compounds in complex mixtures, has high
taking 10 to 30 minutes per sample approximately.23 resolution with no complex and laborious sample
Two terms are frequently used in metabolomics; handling as for GC-MS, and has low sensitivity but
‘metabolic profiling’ and ‘metabolic fingerprint- high variability than that of LC-MS or GC-MS.21
ing’. Metabolic profiling refers to a measure of total 2.2 Diagnosis, Prognosis & Treatment of Breast
number of individual metabolites in a sample while Cancer:
metabolic fingerprinting means measuring a group Heterogeneity of breast cancer (BC) ranges from its
or class of metabolites or quantification of a limited morphology, to prognosis, to metastatic potential
number of metabolites to differentiate between dif- and to treatment response. Studies carried out for
ferent samples.25 In spite of recent advances in the understanding breast cancer pathogenesis are aimed
field of metabolomics its application has been lim- at identification of biomarkers and new targets for
ited by technical problems. effective cancer chemotherapy.30 A GC-TOF MS
2.1 Metabolomic Approaches: based metabolomics study in breast cancer detected
Most popular methods for metabolomics include 368 metabolites that differentiated between cancer
mass spectrometry (MS) and nuclear magnetic res- and normal tissues, a property that can be utilized
onance (NMR) spectroscopy,26 which are comple- for screening of breast cancer. The ratio of cytidine-5-
mentary to each other. Mass spectrometry can be monophosphate / pentadecanoic acid was the most

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 OMIC tumor markers for breast cancer

Fig.1: Schematic representation of “-Omic” platforms in breast cancer biomarker discovery.

Pak J Med Sci 2015 Vol. 31 No. 5 www.pjms.com.pk 1259

Naila Irum Hadi et al.

specific and sensitive discriminator.31 In a research multivariate statistical methods to identify 11 me-
carried out to observe changes in lipid metabolism, tabolites which can predict recurrence with a sensi-
an important feature of cancer, increased levels of tivity of 86% and specificity of 84%. By combining
sn-glycerol-3 phosphate was detected by GC-MS, NMR and LC- MS, four metabolites namely threo-
and increased levels of phospholipids by LC-MS in nine, glutamine, isoleucine and linolenic acid were
breast cancer tissue.32 found to be predictors of response to neoadjuvant
Breast cancer prognosis can be predicted by ana- chemotherapy. Breast cancer patients were placed
lyzing the metabolic profile and comparing with into three groups, i.e. with no response, partial re-
survival rates. Giske degård et al.33 analyzed breast sponse, or complete response. Altered metabolic
cancer tissue by HR-MAS MRS and found high lev- profiles were seen for these four amino acid me-
els of glycine and lactate in a subgroup of ER posi- tabolites which distinguished between the different
tive breast cancer patients with lower survival rates groups.40
and hence poor prognosis. The other subgroup of ER Pharmacometabolomics, a promising and novel
positive patients had better prognosis while these field can predict response to chemotherapeutic
metabolic changes (elevated glycine and lactate) agents. In patients with metastatic breast can-
were not seen in ER negative patients. In another cer treated with paclitaxel and lapatinib, serum
study it was reported that ER positive Luminal type metabolic profile was analyzed before and during
A breast cancer has a variable response to hormone chemotherapy, and was found to have a positive
therapy, dividing this group into responders and correlation with patient survival and time to pro-
non-responders. Metabolomic analysis of luminal gression in HER2 positive patients. Metabolomics
type A identified three groups with the help of ‘a’ also helped in selecting the subset of HER2 positive
and ‘b’ glucose amino acids, myoinositol and lipid breast cancer patients with metastatic disease who
residues. Gene analysis of one of the group of lumi- were responsive to this combination therapy.41
nal A subtype showed its relationship to cell cycle “Omics” in Pakistan: Present and Future:
and DNA repair and most probably represented the Different types and sites of BRCA 1 and 2 gene mu-
non-responders to hormone therapy.34 tations, known risk factors for breast cancer, have
Increased levels of total choline (t-Cho) contain- been studied extensively in Pakistani women with
ing compounds have been detected in breast cancer BC (both sporadic as well as familial cases).42-44
cells forming a basis for many metabolomics analy- Breast cancer research in recent times is focusing
sis carried out in these patients.35-37 For example, in more on gene polymorphisms other than BRCA 1
a study carried out by Mimmi et al.(2011),36 breast and 2 as a possible explanation for racial differences
tissue biopsies from normal subjects, patients with in incidence, clinical presentations and prognosis
fibrocystic disease, benignlesions and breast cancer of breast cancer. Prevalence of TP53 mutations in
were analyzed by LC / ESI-MS for the presence of BRCA1 & 2 negative young Pakistani BC patients (≤
Cho, PCho and GPCho. Results showed raised lev- 30 years) was assessed, uncovering novel mutations
els of choline and its phosphorylated metabolites in which can account for a subset of cancers occurring
subjects with benign and malignant tumors only. in the younger age group.45An association between
Metastasis in breast cancer has also been detected vitamin D receptor Cdx-2 gene polymorphism and
with the help of a distinct metabolic profile in the risk of breast cancer in premenopausal women re-
serum or urine of these patients.35,38 Similarly serum vealed an increased risk of BC in young women
metabolic profile by NMR showed that metastatic with GG genotype,46 while another study reported a
breast cancer can be differentiated from early stage reduced expression of metastasis suppression genes
breast cancer with a prediction accuracy of 72%.35 (KiSS1 and KAL1) in Pakistani BC patients.47 Ab-
Jobard et al.39 carried out serum metabolomics by sence of FANCM c. 5101c &gt: T mutation in triple
HNMR to differentiate between localized early dis- negative and BRCA 1 & 2 negative patients48 and
ease (EBC) and metastatic breast cancer (MBC) with insignificant role of RAD51C, a gene responsible for
respect to diagnosis, prognosis and management of DNA repair and stability of genome, in BRCA 1 & 2
these patients. He constructed a model with 9 dif- negative BC patients49 have also been reported.
ferentiating metabolites which included histidine, Literature search regarding proteomics research
acetoacetate, pyruvate, glycerol, glycoprotein (N- in Pakistan yielded a single article reporting a dis-
acetyl), glutamate, mannose and phenylalanine. tinct proteomic profile distinguishing between
Asiago et al.38 studied recurrence of breast cancer breast cancer, benign breast lesions and healthy
by a combination of analytical (NMR, GC- MS) and controls, serving as diagnostic biomarkers. Sera of

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 OMIC tumor markers for breast cancer

the three groups were analyzed by one-dimension- 10. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al.
al SDS polyacrylamide gel electrophoresis (PAGE) A multigene assay to predict recurrence of tamoxifen-
treated, node-negative breast cancer. N Engl J Med.
and protein identified through LC/MS/MS.50 Simi- 2004;351:2817–2826.
larly in spite of global advances in field of biomark- 11. Coates AS, Colleoni M, Goldhrisch A. Is adjuvant
er discovery for BC by metabolomics, to the best chemotherapy useful for women with luminal A
of our knowledge no work has been carried out in breast cancer? JCO. 2012;30(12):1260-1263. doi:10.1200/
JCO.2011.37.7879
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