Breast cancer laboratory tests

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Laboratory studies play a crucial role in prevention, diagnosis, staging, treatment planning, management, determining prognosis and follow up of patients with breast cancer. Among them are single gene studies (i. e. BRCA1, BRCA2, and HER2), multiple gene panels (i.e. Oncotype DX), tumor markers (Ki67), and metastatic markers such as serum alkaline phosphatase as a marker of bone metastasis. A variety of other blood chemistry tests are also used in the management process of patients with breast cancer, among them are liver function tests (alanine aminotransferase (ALT), aspartate transaminase (AST) , bilirubin, alkaline phosphatase) and markers of kidney function (BUN, creatinine).


  • Receptor tyrosine-protein kinase erbB-2
  • CD340 (cluster of differentiation 340)
  • proto-oncogene Neu
  • Erbb2 (rodent), or ERBB2 (human)
  • HER2 (from human epidermal growth factor receptor 2)
  • HER2/neu [2][3][4]

Signaling pathways

  • Signaling pathways activated by HER2 include:[5]
  • In a nutshell, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

Cancer biopsy

  • HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for trastuzumab therapy.
  • Trastuzumab has been associated with cardiac toxicity.[6]
  • Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision.
  • Immunohistochemistry is used to measure the amount of HER2 protein present in the sample.
  • Examples of this assay include HercepTest, Dako, Glostrup, and Denmark. T
  • he sample is given a score based on the cell membrane staining pattern. Specimens with equivocal IHC results should then be validated using fluorescence in situ hybridisation (FISH).
  • FISH can be used to measure the number of copies of the gene which are present and is thought to be more reliable than IHC.[7]
3D reconstruction of dual color acquistion of Her2/neu and Her 3. A) conventional wide-field fluorescence image of an AG11132 mammary epithelial cells. Her3 is labelled with Alexa488 (green) and Her2/neu with Alexa568 (red). B) magnified image of a small area of A. C) localization microscopy SPDM of the same region of interest as in B. D) and E) show a 3D reconstruction of the protein clusters using the combination of SPDM and SMI microscopy (LIMON technology). Scale bars in D) and E) are 500 nm in each direction. Source:


  • The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation.
  • Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated.
  • Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to trastuzumab therapy.[8]
  • However, its ability to determine eligibility for trastuzumab therapy is less clear.[9]


  • Amplification, also known as the over-expression of the ERBB2 gene, occurs in approximately 15-30% of breast cancers.[1][10]
  • It is strongly associated with increased disease recurrence and a poor prognosis.[11]
  • HER2 is colocalised and most of the time, coamplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and eosophageal tumours.
  • HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[12][13]
  • Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[14]


  • Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression.
  • HER2 is found in a variety of tumours and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2.
  • Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.[15]
  • HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[16]

As a drug target

  • HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin).
  • Trastuzumab is effective only in cancers where HER2 is over-expressed.
  • One year of trastuzumab therapy is recommended for all patients with HER2-positive breast cancer who are also receiving chemotherapy.[17] Twelve months of trastuzumab therapy is optimal. Randomized trials have demonstrated no additional benefit beyond 12 months, whereas 6 months has been shown to be inferior to 12.
  • Trastuzumab is administered intravenously weekly or every 3 weeks.[18]
  • An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[19]
  • Another monoclonal antibody, Pertuzumab, which inhibits dimerisation of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.
  • As of November 2015, there are a number of ongoing and recently completed clinical trials of novel targeted agents for HER2+ metastatic breast cancer, e.g. margetuximab.[20]
  • Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.
  • It has been found that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.[21]
  • Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.
  • The expression of HER2 is regulated by signaling through eostrogen receptors.
  • Normally, estradiol and tamoxifen acting through the eostrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.[22][23]

Multiple gene panels

  • Oncotype DX®:
  • For small hormone receptor-positive tumors that have not spread to more than 3 lymph nodes
  • Also may be used for more advanced tumors
  • Might be used for DCIS (ductal carcinoma in situ or stage 0 breast cancer). as well looks at a set of 21 genes in tumor biopsy samples to get a “recurrence score,” which is a number between 0 and 100.
  • The score reflects the risk of breast cancer coming back (recurring) in the next 10 years and how likely you will benefit from getting chemo after surgery.
  • The lower the score (usually 0-10) the lower the risk of recurrence.
  • Benefit from chemotherapy is in doubt in most women with low scores
  • An intermediate score (usually 11-25): intermediate risk of recurrence.
  • Benefit from chemotherapy is in doubt in most women with intermediate-recurrence scores,
  • Nevertheless chemotherapy is believed to be beneficial for women younger than 50 with a higher intermediate score (16-25)
  • The possible risks and benefits of chemo should be weighted and discussed prior to decision making.
  • A high score (usually 26-100): higher risk of recurrence.Chemotherapy is recommended for women with high scores in order to help lower the chance of cancer *recurrence.
  • OncotypeDx is the only multigene panel with level I of evidence, and hence has been incorporated in the AJCC staging system
  • MammaPrint®:
  • To determine the likelihood of cancer recurrence in a distant part of the body after treatment.
  • May be used in any type of breast cancer with stage 1 or 2 that has spread to no more than 3 lymph nodes.
  • Hormone and HER2 status are also evaluated in this test. Seventy different genes are examined in this test to determine the 10 years cancer recurrence
  • The test results are reported as either “low risk” or “high risk.”
  • Unlike OncotypeDx has not been incorporated in the AJCC staging system yet.



  • The human BRCA1 gene is located on the long (q) arm of chromosome 17 at region 2 band 1, from base pair 41,196,312 to base pair 41,277,500 (Build GRCh37/hg19) (map).[24]
  • BRCA1 orthologs have been identified in most vertebrates for which complete genome data are available [25].

Function and mechanism

  • BRCA1 is part of a complex that repairs double-strand breaks in DNA. Th
  • In the nucleus of many types of normal cells, the BRCA1 protein interacts with RAD51 during repair of DNA double-strand breaks.[26]
  • These breaks can be caused by natural radiation or other exposures, but also occur when chromosomes exchange genetic material (homologous recombination, e.g., "crossing over" during meiosis). TBy influencing DNA damage repair, these three proteins play a role in maintaining the stability of the human genome.
  • BRCA1 is also involved in another type of DNA repair, termed mismatch repair.
  • BRCA1 interacts with the DNA mismatch repair protein MSH2.[27]
  • MSH2, MSH6, PARP and some other proteins involved in single-strand repair are reported to be elevated in BRCA1-deficient mammary tumors.[28]
  • A protein called valosin-containing protein (VCP, also known as p97) plays a role to recruit BRCA1 to the damaged DNA sites.
  • After ionizing radiation, VCP is recruited to DNA lesions and cooperates with the ubiquitin ligase RNF8 to orchestrate assembly of signaling complexes for efficient DSB repair.[29]
  • BRCA1 interacts with VCP.[30]
  • BRCA1 also interacts with c-Myc, and other proteins that are critical to maintain genome stability.[31]
  • BRCA1 directly binds to DNA, with higher affinity for branched DNA structures. This ability to bind to DNA contributes to its ability to inhibit the nuclease activity of the MRN complex as well as the nuclease activity of Mre11 alone.[32]
  • This may explain a role for BRCA1 to promote lower fidelity DNA repair by non-homologous end joining (NHEJ).[33]
  • BRCA1 also colocalizes with γ-H2AX (histone H2AX phosphorylated on serine-139) in DNA double-strand break repair foci, indicating it may play a role in recruiting repair factors.[34][35]
  • This DNA repair function is essential; mice with loss-of-function mutations in both BRCA1 alleles are not viable, and as of 2015 only two adults were known to have loss-of-function mutations in both alleles; both had congenital or developmental issues, and both had cancer. One was presumed to have survived to adulthood because one of the BRCA1 mutations was hypomorphic.[38]
  • Certain variations of the BRCA1 gene lead to an increased risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome.
  • Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer.
  • Females with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast cancer by age 90; increased risk of developing ovarian cancer is about 55% for females with BRCA1 mutations and about 25% for females with BRCA2 mutations.[39]
  • These mutations can be changes in one or a small number of DNA base pairs (the building-blocks of DNA), and can be identified with PCR and DNA sequencing.
  • In some cases, large segments of DNA are rearranged. Those large segments, also called large rearrangements, can be a deletion or a duplication of one or several exons in the gene.
  • Classical methods for mutation detection (sequencing) are unable to reveal these types of mutation.[40]
  • Other methods have been proposed: traditional quantitative PCR,[41] Multiplex Ligation-dependent Probe Amplification (MLPA),[42] and Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF).[43]
  • Newer methods have also been recently proposed: heteroduplex analysis (HDA) by multi-capillary electrophoresis or also dedicated oligonucleotides array based on comparative genomic hybridization (array-CGH).[44]
  • Some results suggest that hypermethylation of the BRCA1 promoter, which has been reported in some cancers, could be considered as an inactivating mechanism for BRCA1 expression.[45]
  • A mutated BRCA1 gene usually makes a protein that does not function properly
  • . Researchers believe that the defective BRCA1 protein is unable to help fix DNA damage leading to mutations in other genes.
  • These mutations can accumulate and may allow cells to grow and divide uncontrollably to form a tumor. Thus, BRCA1 inactivating mutations lead to a predisposition for cancer.
  • In addition to breast cancer, mutations in the BRCA1 gene also increase the risk of ovarian and prostate cancers. Moreover, precancerous lesions (dysplasia) within the Fallopian tube have been linked to BRCA1 gene mutations. Pathogenic mutations anywhere in a model pathway containing BRCA1 and BRCA2 greatly increase risks for a subset of leukemias and lymphomas.[47]
  • Females who have inherited a defective BRCA1 or BRCA2 gene are at a greatly elevated risk to develop breast and ovarian cancer.
  • Their risk of developing breast and/or ovarian cancer is so high, and so specific to those cancers, that many mutation carriers choose to have prophylactic surgery.
  • There has been much conjecture to explain such apparently striking tissue specificity.
  • Major determinants of where BRCA1/2 hereditary cancers occur are related to tissue specificity of the cancer pathogen, the agent that causes chronic inflammation or the carcinogen.
  • The target tissue may have receptors for the pathogen, may become selectively exposed to an inflammatory process or to a carcinogen.
  • An innate genomic deficit in a tumor suppressor gene impairs normal responses and exacerbates the susceptibility to disease in organ targets.
  • This theory also fits data for several tumor suppressors beyond BRCA1 or BRCA2. A major advantage of this model is that it suggests there may be some options in addition to prophylactic surgery.[48]
Low expression of BRCA1 in breast and ovarian cancers
  • BRCA1 expression is reduced or undetectable in the majority of high grade, ductal breast cancers.[49]
  • It has long been noted that loss of BRCA1 activity, either by germ-line mutations or by down-regulation of gene expression, leads to tumor formation in specific target tissues.
  • In particular, decreased BRCA1 expression contributes to both sporadic and inherited breast tumor progression.[50]
  • Reduced expression of BRCA1 is tumorigenic because it plays an important role in the repair of DNA damages, especially double-strand breaks, by the potentially error-free pathway of homologous recombination.[51]
  • Since cells that lack the BRCA1 protein tend to repair DNA damages by alternative more error-prone mechanisms, the reduction or silencing of this protein generates mutations and gross chromosomal rearrangements that can lead to progression to breast cancer.[51]
  • Similarly, BRCA1 expression is low in the majority (55%) of sporadic epithelial ovarian cancers (EOCs) where EOCs are the most common type of ovarian cancer, representing approximately 90% of ovarian cancers.[52]
  • In serous ovarian carcinomas, a sub-category constituting about 2/3 of EOCs, low BRCA1 expression occurs in more than 50% of cases.[53]
  • Bowtell[54] reviewed the literature indicating that deficient homologous recombination repair caused by BRCA1 deficiency is tumorigenic.
  • In particular this deficiency initiates a cascade of molecular events that sculpt the evolution of high-grade serous ovarian cancer and dictate its response to therapy.
  • Especially noted was that BRCA1 deficiency could be the cause of tumorigenesis whether due to BRCA1 mutation or any other event that causes a deficiency of BRCA1 expression.
Mutation of BRCA1 in breast and ovarian cancer
  • Only about 3%–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2.[55] Similarly, BRCA1 mutations are only seen in about 18% of ovarian cancers (13% germline mutations and 5% somatic mutations).[56]
  • Thus, while BRCA1 expression is low in the majority of these cancers, BRCA1 mutation is not a major cause of reduced expression.
BRCA1 promoter hypermethylation in breast and ovarian cancer
  • BRCA1 promoter hypermethylation was present in only 13% of unselected primary breast carcinomas.[57] Similarly, BRCA1 promoter hypermethylation was present in only 5% to 15% of EOC cases.[52]
  • Thus, while BRCA1 expression is low in these cancers, BRCA1 promoter methylation is only a minor cause of reduced expression.
MicroRNA repression of BRCA1 in breast cancers
  • There are a number of specific microRNAs, when overexpressed, that directly reduce expression of specific DNA repair proteins (see MicroRNA section DNA repair and cancer) In the case of breast cancer, microRNA-182 (miR-182) specifically targets BRCA1.[58]
  • Almost all types of breast cancer were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue.[59]
  • In breast cancer cell lines, there is an inverse correlation of BRCA1 protein levels with miR-182 expression.[58]
  • Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182.
  • In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression.
  • These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation.[60]
  • Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
MicroRNA repression of BRCA1 in ovarian cancers
  • Another microRNA known to reduce expression of BRCA1 in ovarian cancer cells is miR-9.[52] Among 58 tumors from patients with stage IIIC or stage IV serous ovarian cancers (HG-SOG), an inverse correlation was found between expressions of miR-9 and BRCA1,[52] so that increased miR-9 may also contribute to reduced expression of BRCA1 in these ovarian cancers.
Population or subgroup BRCA1 mutation(s)[62] Reference(s)
African-Americans 943ins10, M1775R [63]
Afrikaners E881X [64]
Ashkenazi Jewish 185delAG, 188del11, 5382insC [65][66]
Austrians 2795delA, C61G, 5382insC, Q1806stop [67]
Belgians 2804delAA, IVS5+3A>G [68][69]
Dutch Exon 2 deletion, exon 13 deletion, 2804delAA [68][70][71]
Finns 3745delT, IVS11-2A>G [72][73]
French 3600del11, G1710X [74]
French Canadians C4446T [75]
Germans 5382insC, 4184del4 [76][77]
Greeks 5382insC [78]
Hungarians 300T>G, 5382insC, 185delAG [79]
Italians 5083del19 [80]
Japanese L63X, Q934X [81]
Native North Americans 1510insG, 1506A>G [82]
Northern Irish 2800delAA [83]
Norwegians 816delGT, 1135insA, 1675delA, 3347delAG [84][85]
Pakistanis 2080insA, 3889delAG, 4184del4, 4284delAG, IVS14-1A>G [86]
Polish 300T>G, 5382insC, C61G, 4153delA [87][88]
Russians 5382insC, 4153delA [89]
Scottish 2800delAA [83][90]
Spanish R71G [91][92]
Swedish Q563X, 3171ins5, 1201del11, 2594delC [63][93]


  • BRCA2 and BRCA1 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired.
  • They are involved in the repair of chromosomal damage with an important role in the error-free repair of DNA double strand breaks.[94][95]
  • If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer.[96][47]
  • BRCA1 and BRCA2 have been described as "breast cancer susceptibility genes" and "breast cancer susceptibility proteins".
  • The predominant allele has a normal tumor suppressive function whereas high penetrance mutations in these genes cause a loss of tumor suppressive function, which correlates with an increased risk of breast cancer.[97]
  • The BRCA2 gene is located on the long (q) arm of chromosome 13 at position 12.3 (13q12.3).[98] The human reference BRCA 2 gene contains 27 exons, and the cDNA has 10,254 base pairs[99] coding for a protein of 3418 amino acids.[100][101]
  • Certain variations of the BRCA2 gene increase risks for breast cancer as part of a hereditary breast-ovarian cancer syndrome.
  • Researchers have identified hundreds of mutations in the BRCA2 gene, many of which cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs in the gene.
  • As a result of these mutations, the protein product of the BRCA2 gene is abnormal, and does not function properly. Researchers believe that the defective BRCA2 protein is unable to fix DNA damage that occurs throughout the genome.
  • As a result, there is an increase in mutations due to error-prone translesion synthesis past un-repaired DNA damage, and some of these mutations can cause cells to divide in an uncontrolled way and form a tumor.

  • In general, strongly inherited gene mutations (including mutations in BRCA2) account for only 5-10% of breast cancer cases; the specific risk of getting breast or other cancer for anyone carrying a BRCA2 mutation depends on many factors.[102]
  • All germline BRCA2 mutations identified to date have been inherited, suggesting the possibility of a large "founder" effect in which a certain mutation is common to a well-defined population group and can theoretically be traced back to a common ancestor.
  • Given the complexity of mutation screening for BRCA2, these common mutations may simplify the methods required for mutation screening in certain populations
  • . Analysis of mutations that occur with high frequency also permits the study of their clinical expression.[103] A
  • striking example of a founder mutation is found in Iceland, where a single BRCA2 (999del5) mutation accounts for virtually all breast/ovarian cancer families.[104][105]
  • This frame-shift mutation leads to a highly truncated protein product. In a large study examining hundreds of cancer and control individuals, this 999del5 mutation was found in 0.6% of the general population
  • . Of note, while 72% of patients who were found to be carriers had a moderate or strong family history of breast cancer, 28% had little or no family history of the disease.
  • This strongly suggests the presence of modifying genes that affect the phenotypic expression of this mutation, or possibly the interaction of the BRCA2 mutation with environmental factors. Additional examples of founder mutations in BRCA2 are given in the table below.
Population or subgroup BRCA2 mutation(s)[103][62] Reference(s)
Ashkenazi Jewish 6174delT [106]
Dutch 5579insA [71]
Finns 8555T>G, 999del5, IVS23-2A>G [72][73]
French Canadians 8765delAG, 3398delAAAAG [75][107][108]
Hungarians 9326insA [79]
Icelanders 999del5 [104][105]
Italians 8765delAG [109]
Northern Irish 6503delTT [83]
Pakistanis 3337C>T [86]
Scottish 6503delTT [83]
Slovenians IVS16-2A>G [110]
Spanish 3034delAAAC(codon936), 9254del5 [111]
Swedish 4486delG [63]

Commercial BRCA mutation tests

  • The sensitivity of commercial BRCA mutation tests like 23andMe is debated.
  • For example, 23andMe’s testing formula is based on solely three genetic variants, most prevalent among Ashkenazi Jews, while most people carry other mutations of the gene.
  • This will result in false negative results.
  • 23andMe is a commercial BRCA1 screening test, with more than 10 million customers.
  • Even if only a small percentage take the test, that’s thousands who could be misled.
  • As accurately stated by Prof. Mary-Claire King, who discovered the BRCA1, “The F.D.A. should not have permitted this out-of-date approach to be used for medical purposes. Misleading, falsely reassuring results from their incomplete testing can cost women’s lives.”

Blood chemistry

Blood chemistry tests measure certain chemicals in the blood. They show how well certain organs are functioning and can also be used to detect abnormalities. They are used to stage breast cancer. [112]

  • Increased levels could indicate that cancer has spread to the liver.
  • Increased levels could indicate that cancer has spread to the bone.
  • Tumor markers such as Ki67


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