Histopathological biomarkers in breast cancer: Biological classification and personalized treatment

1. An overview of Histopathological biomarkers in breast cancer

Common histopathological biomarkers in breast cancer

The most widely used histopathological biomarkers in breast cancer include [1, 2, 5]:

Estrogen receptor (ER) and progesterone receptor (PR): These are proteins expressed on cancer cells that, upon binding to estrogen and progesterone, promote cancer cell growth.
HER2 (human epidermal growth factor receptor 2): A receptor protein that, when amplified or overexpressed, also promotes cancer cell growth.
Ki-67: A nuclear protein associated with cell proliferation. High Ki-67 expression indicates that cancer cells are dividing rapidly.
PD-L1 (programmed death-ligand 1): A protein located on the surface of cancer cells that can suppress immune system attacks against cancer cells. Identifying PD-L1 expression is important for immunotherapy.
BRCA1/2: Genes involved in DNA repair. Mutations in BRCA1/2 increase the risk of breast cancer and are relevant to selecting targeted therapies, such as PARP inhibitors [1].
PIK3CA: A gene frequently mutated in various cancers, including breast cancer, and associated with cancer cell growth [5].

2. Biological classification of breast cancer based on histopathological biomarkers

Based on the expression of ER, PR, and HER2, breast cancer is classified into major biological subtypes, each with different clinical characteristics and treatment responses [2, 5].

Hormone receptor-positive breast cancer (HR-positive or ER/PR-positive)

This is the most common type of breast cancer, accounting for approximately 70–80% of cases [5].

Characteristics: Cancer cells express ER and/or PR, meaning that their growth is influenced by hormones.
Treatment: These tumors often respond well to endocrine therapy, which may include anti-estrogen drugs such as tamoxifen or aromatase inhibitors.

HER2-positive breast cancer

Characteristics: Cancer cells express excessive amounts of HER2 protein on their surface, leading to faster and more aggressive tumor growth [5].
Treatment: These tumors respond well to HER2-targeted therapies, such as trastuzumab, pertuzumab, or T-DM1 [1].

Triple-negative breast cancer (TNBC)

Characteristics: Cancer cells do not express ER or PR and do not overexpress HER2. This subtype is more aggressive and more difficult to treat because it lacks common molecular targets [5].
Treatment: Chemotherapy is commonly used. Immunotherapy, such as pembrolizumab, may be considered when PD-L1 is expressed [1].

Luminal A and luminal B breast cancer

These are more detailed classifications of HR-positive breast cancer based on gene expression profiling (PAM50) or the Ki-67 index [1, 2].

Luminal A: Typically ER-positive and/or PR-positive, HER2-negative, with a low Ki-67 index. It has a favorable prognosis and generally responds well to endocrine therapy.
Luminal B: Typically ER-positive and/or PR-positive, with HER2 expression that may be negative or positive, and a high Ki-67 index. It has a less favorable prognosis than luminal A and may require adjuvant chemotherapy in addition to endocrine therapy.

3. The role of histopathological biomarkers in prognosis and predicting treatment response

Disease prognosis

Histopathological biomarkers provide important information about the natural course of the disease [3, 5]:

ER/PR-positive: Generally associated with a more favorable prognosis and a good response to endocrine therapy [1, 5].
HER2-positive: Previously associated with a poor prognosis; however, the introduction of HER2-targeted therapies has significantly improved outcomes [1].
High Ki-67: Indicates rapid tumor cell proliferation and is generally associated with a less favorable prognosis and a higher risk of recurrence [1, 5].
Triple-negative breast cancer (TNBC): Tends to have a less favorable prognosis because of its higher risk of early recurrence and metastasis [5].

Prediction of treatment response

These biomarkers help predict the effectiveness of specific treatments [1, 5]:

ER/PR-positive: Predicts the likelihood of responding to endocrine therapy. Patients with strong ER/PR expression generally benefit from drugs such as tamoxifen or aromatase inhibitors [1].
HER2-positive: Predicts a response to anti-HER2 therapy. These drugs can significantly reduce recurrence risk and improve survival rates in patients with HER2-positive breast cancer [1].
PD-L1-positive: Predicts the likelihood of responding to immunotherapy, particularly in metastatic TNBC [1].
BRCA1/2 mutations: Patients with BRCA1/2 mutations may respond well to PARP inhibitors [1].
PIK3CA mutations: May predict a response to PI3K inhibitors [1].

4. Personalized breast cancer treatment based on histopathological biomarkers

Personalized treatment involves tailoring a treatment regimen to the biological characteristics of the tumor and the individual patient’s health status [2].

Endocrine therapy

Candidates: Patients with hormone receptor-positive breast cancer (ER-positive and/or PR-positive).
Principle: Drugs such as tamoxifen, an anti-estrogen agent, or aromatase inhibitors, which reduce estrogen production, are used to block hormonal stimulation of cancer cell growth [1].

Targeted therapy

Candidates: Patients whose tumors have specific molecular targets.
Anti-HER2 therapy: Used for patients with HER2-positive breast cancer. Drugs such as trastuzumab, pertuzumab, trastuzumab emtansine (T-DM1), and trastuzumab deruxtecan (T-DXd) target the HER2 protein to inhibit cancer cell growth [1].
PARP inhibitors: Used for patients with BRCA1/2 mutations. These drugs prevent cancer cells from repairing DNA, leading to cell death [1].
PI3K inhibitors: Used for patients with PIK3CA mutations. These drugs inhibit the PI3K/AKT/mTOR signaling pathway, slowing cancer cell growth [1].

Chemotherapy

Candidates: Commonly used for patients with TNBC, breast cancer with a high risk of recurrence (e.g., a high Ki-67 index), or metastatic breast cancer [1, 5].
Principle: Cytotoxic drugs are used to destroy cancer cells.

Immunotherapy and the role of PD-L1

Candidates: Primarily patients with metastatic TNBC whose tumors express PD-L1 [1].
Principle: Immune checkpoint inhibitors, such as pembrolizumab, help “release the brakes” on the immune system, allowing immune cells to attack tumors more effectively [1].

5. When should you seek medical evaluation and undergo histopathological biomarker testing?

5.1. When is testing necessary?

Histopathological biomarker testing is commonly performed in the following situations [1, 5]:

At the initial diagnosis of breast cancer: This is an essential step in determining the tumor’s biological subtype and guiding initial treatment decisions.
When the disease recurs or metastasizes: Repeat testing may identify changes in the tumor’s biological characteristics, helping physicians adjust treatment accordingly.
To assess recurrence risk: Particularly through multigene assays, such as Oncotype DX, MammaPrint, Prosigna, and EndoPredict, which help estimate recurrence risk and determine whether adjuvant chemotherapy is needed [1].

5.2. Histopathological biomarker testing procedure

The procedure generally includes the following steps:

Step 1 – Biopsy or surgery: A tissue sample is obtained from the tumor.
Step 2 – Tissue processing: The sample is fixed and embedded in paraffin for preservation.
Step 3 – Immunohistochemistry (IHC): A commonly used method for detecting ER, PR, HER2, and Ki-67 in tissue sections [1].
Step 4 – Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR): Used to identify HER2 gene amplification or other genetic alterations, such as BRCA1/2 and PIK3CA mutations, and to assess relevant molecular targets [1].
Step 5 – Next-generation sequencing (NGS): Provides a more comprehensive analysis of genetic alterations, particularly in metastatic breast cancer [1].
Step 6 – Liquid biopsy: Analyzes circulating tumor DNA (ctDNA) in the blood to detect genetic alterations and monitor treatment response. This approach is particularly useful when tissue sampling is not feasible or for ongoing monitoring [1, 4].

6. Frequently asked questions (FAQ)

What is the significance of the Ki-67 histopathological biomarker? Ki-67 is an indicator of the rate of cancer cell proliferation. A high Ki-67 index, often greater than 20%, indicates rapid tumor growth, may suggest the need for more intensive treatment such as chemotherapy, and is generally associated with a less favorable prognosis [1, 5].
Can histopathological biomarker results change over time? Yes. The biological characteristics of a tumor may change over time, particularly after treatment or when the disease recurs or metastasizes. Therefore, repeating biomarker testing on tissue from recurrent or metastatic lesions is important for adjusting the treatment regimen [1].
If my test results are “negative,” do I still need treatment? A negative result for a specific biomarker, such as ER-negative or HER2-negative, does not mean that treatment is unnecessary. It indicates that the tumor lacks that particular characteristic and is unlikely to respond to therapies targeting it. In triple-negative breast cancer (ER-negative, PR-negative, and HER2-negative), chemotherapy remains a primary treatment option, and immunotherapy may be added if PD-L1 is positive [1, 5].
Where can I undergo histopathological biomarker testing? These tests are commonly performed at major hospitals with anatomical pathology and oncology departments, or at specialized laboratories equipped to conduct immunohistochemistry and molecular testing. University Medical Center Ho Chi Minh City is one of the facilities capable of performing these tests.
How much does histopathological biomarker testing cost? Costs vary depending on the type of test (IHC, FISH, NGS, or liquid biopsy), the number of biomarkers analyzed, and the healthcare facility. Patients should consult their physician or contact the hospital’s finance department directly for specific cost information.

7. References

[1] Colomer, R., González-Farré, B., Ballesteros, A. I., Peg, V., Bermejo, B., Pérez-Mies, B., ... & Palacios, J. (2024). Biomarkers in breast cancer 2024: an updated consensus statement by the Spanish Society of Medical Oncology and the Spanish Society of Pathology. Clinical and Translational Oncology, 26(12), 2935-2951. Truy cập: 2025-12-11.
[2] Zhang, C., Li, N., Zhang, P., Jiang, Z., Cheng, Y., Li, H., & Pang, Z. (2024). Advancing precision and personalized breast cancer treatment through multi-omics technologies. American Journal of Cancer Research, 14(12), 5614. Truy cập: 2025-12-11.
[3] Sallauka, R., Horvat, M., Ravnik, M., Rashwan, H., Arioz, U., & Mlakar, I. (2025). Scoping review: (Bio)markers for the prognostication of breast cancer recurrence. BMC Cancer, 25(1), 1-22. Truy cập: 2025-12-11.
[4] Jiang, B., Bao, L., He, S., Chen, X., Jin, Z., & Ye, Y. (2024). Deep learning applications in breast cancer histopathological imaging: diagnosis, treatment, and prognosis. Breast Cancer Research, 26(1), 1-24. Truy cập: 2025-12-11.
[5] Wang, E., Henderson, M., Yalamanchili, P., Cueto, J., Islam, Z., Dharmani, C., & Salas, M. (2024). Potential biomarkers in breast cancer drug development: application of the biomarker qualification evidentiary framework. Biomarkers in Medicine, 18(6), 265-277. Truy cập: 2025-12-11.

8. References

The information above is for reference purposes only and is not intended as medical advice. Please contact your doctor for detailed medical consultation.