What is the role of biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in determining prognosis and guiding treatment decisions in breast cancer?

Role of Biomarkers in Breast Cancer Prognostication and Treatment

Biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are essential for determining prognosis and guiding treatment decisions in breast cancer, as they directly impact mortality and quality of life by determining eligibility for targeted therapies. 1

Key Biomarkers and Their Clinical Significance

ER, PR, and HER2 Status

• ER, PR, and HER2 are the only biomarkers with demonstrated clinical validity for guiding treatment decisions in metastatic breast cancer 1
• These biomarkers serve as both prognostic factors (indicating disease outcome) and predictive factors (indicating likelihood of response to specific therapies) 1
• ER and PR status determines eligibility for endocrine therapy, while HER2 status determines eligibility for anti-HER2 targeted therapies (trastuzumab, lapatinib, pertuzumab, T-DM1) 1, 2
• Patients with ER+/HER2- breast cancer generally have a more favorable prognosis with lower locoregional recurrence rates compared to other subtypes 3

Prognostic Implications

• ER+ status, whether in primary or metastatic disease, is associated with prolonged metastasis-free survival compared to ER-negative tumors 4
• Triple-negative breast cancers (ER-/PR-/HER2-) have higher rates of locoregional recurrence and poorer overall survival 3
• PR status provides additional prognostic information, with PR+ tumors generally having better outcomes 3

Testing and Interpretation

Testing Methods

• FDA-approved testing methods for ER, PR, and HER2 include immunohistochemistry (IHC) for protein expression and in situ hybridization (ISH) for gene alterations 1, 5
• Guidelines from ASCO/CAP provide standardized protocols for testing and interpretation 1, 5

Interpretation Challenges

• Test results are typically definitively positive or negative, but equivocal results may require additional testing using alternative methods or different portions of the same specimen 1
• Some results may remain indeterminate or inconsistent with other histopathologic findings, requiring consultation between pathologist and oncologist 1

Receptor Conversion and Retesting

Importance of Retesting in Metastatic Disease

• ER, PR, and HER2 status may change (become discordant) between primary tumor and metastatic sites 1
• Overall discordance rates between primary and metastatic disease: 18.3% for ER, 40.3% for PR, and 13.7% for HER2 4
• Conversion typically occurs as a switch from positive to negative receptor status 4
• Discordance can also occur between different metastatic sites in the same patient 4

Clinical Approach to Discordance

• When discordance occurs between primary and metastatic tissues, the ASCO panel recommends using the receptor status from the metastasis to direct therapy 1
• This recommendation should be applied within the context of the clinical scenario and patient's goals for care 1

Biomarker-Guided Treatment Decisions

Early-Stage Breast Cancer

• In early-stage breast cancer, additional biomarker assays like Oncotype DX, EndoPredict, PAM50, and Breast Cancer Index have demonstrated clinical utility for guiding adjuvant systemic therapy decisions in specific subgroups 1
• For ER+/PR+/HER2- node-negative breast cancer, the 21-gene recurrence score (Oncotype DX) may guide decisions on adjuvant chemotherapy 1

Metastatic Breast Cancer

• For metastatic disease, treatment decisions are primarily guided by ER, PR, and HER2 status 1
• ER+ metastatic disease is typically treated with endocrine therapy 6
• HER2+ disease is treated with HER2-targeted therapies, often in combination with chemotherapy 2

Clinical Pitfalls and Caveats

• Tumor heterogeneity may lead to sampling errors and discordant results 1, 4
• Treatment effects may alter receptor expression over time 4
• Some patients may have equivocal or borderline results requiring additional testing 1
• Failure to retest metastatic sites may lead to suboptimal treatment selection 1, 4
• While multiple biomarker tests are technically possible, only ER, PR, and HER2 have demonstrated clinical validity for treatment decisions outside clinical trials 1

Emerging Biomarkers

• Recent advances include biomarkers at genomic, transcriptomic, and proteomic levels 7, 8
• PD-L1 testing has emerged as important for immunotherapy decisions in triple-negative breast cancer 7
• Other potential biomarkers include mismatch repair deficiency/microsatellite instability, tumor mutational burden, and PIK3CA mutations 7

By understanding and appropriately utilizing these biomarkers, clinicians can develop more personalized treatment approaches that improve survival outcomes and quality of life for breast cancer patients.