Breast Cancer Biomarkers

Indications for Testing

Individuals with malignant histology compatible with breast cancer should undergo disease staging, hormone receptor testing, and possible genetic evaluation for prognostic and therapeutic reasons.

Laboratory Testing

Diagnosis and Staging

Diagnosis is established by surgical pathology. Grading and staging are based on histologic features, lymph node involvement, and metastasis. Interpretive guidelines have changed over the years; clinicians are advised to consult the most recent societal statements for recommendations.

Biomarker Testing for Prognosis and Therapy Decisions

Prognostic and therapeutic decisions are made using a combination of tumor features, including ER, PR, and HER2, or ERBB2 status, and, when appropriate, gene expression panels.

Tumor Hormone Receptor Status Testing

ER and PR status should be determined in all patients with invasive breast cancers and breast cancer recurrences.   ER and PR expression are generally associated with improved outcomes when the patient is treated with an antiestrogen therapy.   ER status is used to determine if a patient should or should not receive adjuvant endocrine therapy. PR status appears to be prognostic and independent of ER, and high levels are generally associated with a favorable outcome. 

Human Epidermal Growth Factor Receptor 2 Status

HER2 status should be determined in all patients with invasive breast cancer and first recurrences of breast cancer.  HER2 overexpression confers an unfavorable prognosis in the absence of therapy in patients with pathologically node-positive and node-negative breast cancer.  Immunohistochemistry (IHC) or in situ hybridization (ISH) methods may be used in the initial evaluation; equivocal results by IHC should be resolved by reflex testing using the ISH method on the same specimen or repeating tests if a new specimen is available. Equivocal results by an ISH assay must be confirmed by reflex testing using IHC methodology on the same specimen or by repeating tests if a new specimen is available.  

Multiplexed Gene Expression Assays for Prognosis in Early-Stage, Estrogen Receptor-Positive Breast Cancer

The American Society of Clinical Oncology (ASCO) 2016 recommendations address prognostic biomarker panels that may be helpful in guiding decisions about adjuvant systemic therapy for women with early-stage invasive breast cancer and known ER+/PR+/HER2- status. The results of this testing may help a clinician determine if a patient would benefit from chemotherapy and may also predict the likelihood of breast cancer recurrence.  Oncotype DX, EndoPredict, and Prosigna are three representative multigene tests that are commercially available; specifics about these tests are detailed in the table below.

Familial Risk (Hereditary) Genetic Testing

Up to 10% of all breast cancers are due to specific pathogenic variants (mutations) in single genes passed down in a family.  BRCA1 and BRCA2 are the best characterized and most prevalent breast cancer susceptibility genes, but others (eg, ATM, CDH1, CHEK2, NBN, NFI, PALB2, PTEN, STK11, TP53) are also implicated in conferring an increased susceptibility to breast cancer. 

Major organizations agree that any individual suspected of hereditary cancer risk should be offered genetic counseling. The U.S. Preventive Services Task Force (USPSTF) recommends that women with a family member diagnosed with breast, ovarian, tubal, or peritoneal cancer be screened for a family history that may be associated with an increased chance of having a BRCA1/2 pathogenic variant. Women who screen positive should be offered genetic counseling, and if appropriate, BRCA testing. Routine testing is not recommended in women whose family history is not associated with an increased risk. 

The NCCN recommends that individuals from a family with a known deleterious BRCA1/2 pathogenic variant consider testing. In individuals without a known pathogenic variant, testing should be considered if an individual has a personal history of breast cancer and meets one or more of the following criteria :

• Ashkenazi Jewish ancestry
• Diagnosed at 45 years of age or younger
• Diagnosed with at least two breast cancer primaries, the first at 50 years of age or younger
• Diagnosed at 46-50 years of age with any of the following
  • One or more close blood relatives with breast cancer at any age
  • One or more close blood relatives with high-grade prostate cancer
  • An unknown or limited family history
• Diagnosed with triple-negative breast cancer at 60 years of age or younger
• Diagnosed at any age with one or more close blood relatives with any of the following
  • Breast cancer diagnosed at 50 years of age or younger
  • Ovarian cancer
  • Male breast cancer
  • Metastatic prostate cancer
  • Pancreatic cancer
• Diagnosed at any age with two or more additional diagnoses (in patient and/or close blood relatives) of breast cancer at any age

Additionally, other personal and/or family history meet NCCN BRCA1/2 testing criteria :

• Personal history of
  • Ovarian cancer
  • Male breast cancer
  • Metastatic prostate cancer
  • High-grade prostate cancer at any age with any of the following
    • One or more close blood relatives with ovarian carcinoma, pancreatic cancer, metastatic prostate cancer at any age, or breast cancer diagnosed before 50 years of age
    • Two or more close blood relatives with breast or prostate cancer (any grade) at any age
    • Ashkenazi Jewish ancestry
  • BRCA1/2 pathogenic/likely pathogenic variant detected by tumor profiling of any tumor type in the absence of germline analysis
• Regardless of family history, some individuals with a BRCA-related cancer may benefit from genetic testing related to targeted treatments
• An individual who does not meet any of the above criteria but has at least one first- or second-degree blood relative who does may also benefit from testing (limitations of testing unaffected individuals should be discussed)

Other Testing

Liquid biopsy and circulating tumor DNA (ctDNA) analysis in breast cancer are emerging areas of research interest, but are not currently recommended as part of the standard of care by societal guidelines.

Monitoring

Cancer antigen (CA) 15-3, CA 27.29, and carcinoembryonic antigen (CEA) may be used to monitor metastatic disease in conjunction with diagnostic imaging, history, and physical examination.  Single measurements are uninformative; instead, serial measurements are required, using the same marker sequentially.  Increasing values of these markers are concerning for tumor progression, but may also be seen in the setting of responding disease.

The most recent NCCN guidelines do not include recommendations regarding detection of circulating tumor cells in the management of patients with breast cancer. ASCO recommends that clinicians not use circulating tumor cells to guide decisions about adjuvant systemic therapy. 

Pharmacogenetics

Many pharmacogenes are associated with drug response and optimal dosing. For example, the drug metabolizing enzyme encoded by CYP2D6 is involved in the conversion of tamoxifen, an antiestrogen drug used in the treatment of ER+ breast cancer, to the active metabolite endoxifen. Neither the NCCN nor ASCO recommend CYP2D6 genotyping to determine optimal adjuvant endocrine strategy.   However, gene-based dosing guidelines are available for tamoxifen and many other drugs commonly used in treating patients with breast cancer through the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenomics Working Group. In addition to the gene-based dose guidelines, it is important to be aware of common drug-drug interactions. For example, patients who are prescribed tamoxifen should avoid strong CYP2D6 inhibitors, such as most antidepressant drugs.

Refer to the ARUP Consult Germline Pharmacogenetics topic for more information on pharmacogenetics, and the ARUP Laboratories test directory for access to the complete menu of pharmacogenetic tests available at ARUP.