Breast cancer is the most common malignant tumor in women, and its morbidity and mortality are both in the first place among female tumors, which poses a serious threat to women's health ^[1]. Faced with such fierce opponents, the diagnosis and comprehensive treatment of breast cancer are also constantly improving. With the deepening of research and advances in diagnosis and treatment methods, breast cancer has been found to be a highly heterogeneous disease, which can be divided into different subtypes of breast cancer on the molecular level, thus providing more accurate and individualized treatment guidance. Molecular typing of breast cancer has thus begun.

I. History of molecular typing of breast cancer

1. Conceptual presentation

In 1999, the concept of tumor molecular typing was first proposed by the National Cancer Institute of the United States. Its purpose is to obtain more and more specific tumor feature information by using comprehensive and comprehensive tumor molecular typing technology, so that the classification of tumors is changed from the traditional morphological classification to a detailed new classification system with molecular features as the classification standard.

2. Initial classification

In 2000, Perou et al. of Stanford University in the United States used microarray technology to analyze the gene expression characteristics of breast cancer specimens and divided them into estrogen receptor (ER) positive and negative groups. The ER positive group was called Luminal type, and the ER negative group included basal type, HER2 positive type and normal breast type ^[2].

3. Simplified detection

In 2006, The Carolina Breast Cancer Study proposed the use of IHC markers instead of gene expression profiles, making it easier for breast cancer molecular typing to be applied to clinical work, and included progesterone receptor (PR) as a typing marker, updating the molecular typing of breast cancer, namely, Luminal A type, Luminal B type, HER2+/ER- type, basal-like /Basal-like and normal breast-like ^[3].

4. Typing optimization

In 2009, based on the original ER, PR and HER2, Cheang et al. added ki-67 as a typing marker and proposed the Ki-67 threshold of 13.25%, which could be better used to distinguish Luminal A type from Luminal B type ^[4].

5. Expert recognition

In 2011, at the 12th St.Gallen International Conference on Breast Cancer, the expert group widely recognized the molecular typing of breast cancer and officially identified Ki-67 as a typing indicator, and the molecular typing of breast cancer was further clarified ^[5].

6. Current classification

In 2013, at the 13th St.Gallen International Breast Cancer Conference, the expert group proposed that the Ki-67 threshold should be adjusted to 20%, and both high Ki-67 and low PR values can be used to distinguish Luminal A from Luminal B (HER2-negative). Hence, the molecular typing of breast cancer was redefined and it is still used today ^[6].

II. Molecular typing of breast cancer

According to the hormone receptor and cellular molecular state of patients, breast cancer is divided into four subtypes: Luminal A type, Luminal B type, HER2 positive type and triple negative type (Basal-like type) ^[7].

Note:

1. ER: Estrogen Receptor. ER detection was positive when ≥1% of tumor cells were positively stained, but 1%–10% belonged to low expression of ER.

2. PR: Progesterone Receptor. PR is positive when ≥1% of the tumor cells are positively stained, and experts recommend that PR 20% be used as the threshold for Luminal A and LUMINAL B.

3. HER2: Human epidermal growth factor receptor. HER2(3+) indicates that HER2 is positive. HER2(2+) needs to be further confirmed by FISH. At present, HER2(1+) and HER2 (2+)/absence of amplification by FISH are defined as low expression of HER2 in most studies.

4. Ki-67: Proliferation index. The judgment value of Ki-67 PI may be different in different pathological experimental centers, and 20%–30% may be used as the cutoff value for judging the high and low Ki-67 PI.

III. Clinical application of molecular typing of breast cancer

Molecular typing provides an important reference for the treatment and prognosis of breast cancer. A large number of studies have shown that patients with breast cancer of different molecular subtypes have different efficacy in chemotherapy, targeted therapy, endocrine therapy, etc. Among them, endocrine treatment is mainly adopted for Luminal A patients, but high-risk patients (such as large tumors or lymph node metastasis) may receive chemotherapy combined with endocrine treatment ^[7–9]. Endocrine therapy and chemotherapy are mostly adopted for patients with Luminal type B (HER2-), and chemotherapy may be more widely used in this subtype; Patients with Luminal type B (HER2+) mainly receive a combination of endocrine therapy, chemotherapy, and anti-HER2 targeted therapy. HER2-positive patients are mainly treated with targeted anti-HER2 therapy combined with chemotherapy ^[7–9]. Patients of triple negative (Basal-like) type are mainly treated with chemotherapy ^[7–9]. In addition, the prognosis of breast cancer patients with different molecular subtypes is also different to a certain extent. The prognosis of patients with Luminal A type, Luminal B type, HER2 positive type and triple negative type (Basal-like type) becomes worse in sequence, and the subtypes with worse prognosis require more active treatment ^[10–12].

The molecular classification of breast cancer has progressively become an indispensable reference for clinicians, guiding the therapeutic strategies and offering personalized treatment options for patients. This innovative approach has unraveled the enigma surrounding the discrepancies between traditional histopathological classification and TNM staging, despite their apparent similarities. Presently, the integration of molecular typing with conventional histopathological methods and TNM staging facilitates a comprehensive evaluation of a patient's condition, paving the way for the formulation of a well-reasoned, individualized treatment regimen that promises to enhance the outcomes for a broader spectrum of patients.

References

[1] CA Cancer J Clin.2024:1-35.

[2] Nature,2000,406(6797):747-752．

[3] Jama,2006,295(21):2492-2502.

[4] JNCI:Journal of the National Cancer Institute,2009,101(10):736-750.

[5] Annals of oncology,2011,22(8):1736-1747.

[6] Annals of oncology,2013,24(9):2206-2223.

[7] CSCO breast cancer diagnosis and treatment guidelines (2024 edition)

[8] Guidelines and specifications for diagnosis and treatment of breast cancer by China Association of Cancer Control (2024 edition)

[9] Breast cancer diagnosis and treatment guidelines (2022 edition)

[10] Human pathology,2006,37(9):1217-1226.

[11] Annals of the Academy of Medicine-Singapore,2011,40(2):90.

[12] Annals of oncology,2009,20(4):628-635.

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