What is the role of immunohistochemical stains, such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), in detecting and guiding treatment for breast cancer in patients with a history suggestive of increased breast cancer risk, like atypical ductal hyperplasia (ADH) and family history of breast cancer?

Immunohistochemical Stains in Breast Cancer Detection and Treatment Guidance

Immunohistochemical stains are mandatory biomarkers that determine treatment selection and prognosis in breast cancer, with estrogen receptor (ER), progesterone receptor (PR), and HER2 being the three essential markers that must be assessed in all invasive breast cancer cases. 1, 2

Core Mandatory Markers

Estrogen and Progesterone Receptors (ER/PR)

• ER and PR determination is mandatory in all samples of invasive ductal carcinoma, preferably by immunohistochemistry, and must be reported as positive if ≥1% of tumor cells show nuclear staining of any intensity. 1, 2
• The percentage of cells with nuclear staining and the average intensity (strong, moderate, or weak) must be reported in the pathology report. 2
• ER/PR status represents the most relevant predictive factor for treatment choice, specifically determining eligibility for endocrine therapy (tamoxifen or aromatase inhibitors). 1
• Patients with cancers showing 1%-100% ER immunohistochemistry staining are considered ER-positive and eligible for endocrine therapies, though the ER-low-positive (1%-10%) subgroup is heterogeneous with biologic behavior often similar to ER-negative cancers, requiring individualized consideration of risks versus benefits. 1

Human Epidermal Growth Factor Receptor 2 (HER2)

• HER2 determination must be performed simultaneously with ER/PR in all cases of newly diagnosed invasive carcinoma for treatment planning. 1, 2
• HER2 can be evaluated by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), with the method requiring ≥95% concordance with another validated method. 2
• When IHC results are ambiguous (2+), FISH or CISH must be performed to determine HER2 gene amplification. 1, 2
• HER2-positive status (3+ by IHC or gene amplification by FISH) determines eligibility for HER2-targeted therapies such as trastuzumab. 3

Clinical Application in High-Risk Patients

For Patients with Atypical Ductal Hyperplasia (ADH) and Family History

• In women with ADH and family history presenting with suspicious findings, core needle biopsy should be obtained before any surgical procedure to establish diagnosis. 1
• If invasive carcinoma is diagnosed, the complete immunohistochemical profile (ER, PR, HER2) must be performed on the biopsy specimen to guide neoadjuvant or adjuvant treatment decisions. 1, 2
• For occult primary breast cancer presenting as adenocarcinoma with positive axillary nodes in women, elevated ER/PR levels provide strong evidence for breast cancer diagnosis. 1

Treatment Stratification Based on IHC Results

HR-Positive, HER2-Negative Disease

• Patients with ER-positive and/or PR-positive, HER2-negative tumors receive adjuvant endocrine therapy to reduce recurrence risk. 1
• Those deemed at high risk for distant recurrence despite adjuvant endocrine therapy receive adjuvant chemotherapy in addition to endocrine therapy. 1

HR-Positive, HER2-Positive Disease

• These patients require both HER2-targeted therapy (trastuzumab) and endocrine therapy following chemotherapy. 1, 3

Triple-Negative Disease (ER-Negative, PR-Negative, HER2-Negative)

• Tumors with staining of ER <1% and PR <1% and HER2-negative results are defined as triple-negative breast cancer (TNBC). 1
• These patients are not candidates for endocrine therapy or HER2-targeted therapy and rely on chemotherapy as primary systemic treatment. 1

Critical Technical Considerations

Quality Control Requirements

• Internal and external controls must react appropriately before reporting patient results; if controls fail, results should not be reported and the assay must be repeated. 2
• The tissue should be oriented adequately for the pathologist with sutures or other markers, and relevant clinical history including laterality and quadrant must be provided. 2
• Large panels of immunohistochemical markers should be avoided, focusing on the essential ER, PR, and HER2 markers. 1

Important Clinical Caveats

Receptor Status Instability

• Hormone receptor and HER2 status can change throughout tumor progression in 32.4% (ER), 40.7% (PR), and 14.5% (HER2) of patients between primary tumor and relapse. 4
• Marker investigations at relapse may potentially improve patient management, particularly when considering second-line therapies. 4

Interinstitutional Concordance

• While interinstitutional concordance for ER, PR, and HER2 interpretation is excellent (κ = 0.93,0.90,0.93 respectively), approximately 0.8% of patients receive potential benefit from pathology review at another institution. 5
• This justifies inclusion of immunohistochemistry slides for review when patients transfer care or seek second opinions before completing hormonal and/or chemotherapy. 5

ER-Low Positive Tumors (1%-10% Staining)

• This subgroup represents a new reporting category with heterogeneous biologic behavior often similar to ER-negative cancers. 1
• More limited data exist on endocrine therapy benefit in this group, requiring careful consideration of both endocrine therapy and chemotherapy options. 1