Currently, breast cancer has become a common tumor threatening women’s physical and mental health, and its high heterogeneity at the molecular level is receiving increasing attention. The molecular typing of breast cancer has been used by more and more clinicians as a reference indicator to guide the treatment of breast cancer. How to better combine the traditional clinical pathological indicators with the molecular typing of breast cancer will be of great significance for the individualized adjuvant treatment of breast cancer patients.
1.Breast cancer molecular typing
The concept of molecular tumor staging was first proposed by the National Cancer Institute in 1999, which is a new tumor classification system based on molecular characteristics using molecular analysis techniques. and negative groups.
The ER-positive group was called the luminal epithelial breast cancer (Luminal type); the ER-negative group was divided into three types: humanepidermalgrowthfactorreceptor-2 (HER2) overexpression type, basal cell-like type, and normal breast-like type. Subsequently, several scholars have further confirmed and enriched the theory of molecular typing of breast cancer through numerous studies, and very great progress has been made.
Carey et al. demonstrated that the use of immunohistochemistry can be a general alternative to gene expression profiling, and the method is simple, easy to perform, and accepted by more hospitals, so the results of immunohistochemistry are now commonly used in clinical practice. The molecular typing of breast cancer is now commonly used in clinical practice.
Although the results of molecular typing based on immunohistochemistry and those based on gene microarray technology are not entirely consistent, the former basically reflects the clinical characteristics of each molecular subtype with a sensitivity of 76% and specificity of 100%. recognition.
Cheang et al. used four immunohistochemical results of ER, progesteronereceptor (PR), HER2, and Ki-67 index to approximate the molecular typing of breast cancer and classified them into: LuminalA, LuminalB, HER2 overexpressing, Basal-like, and other specific types. LuminalA refers to tumors that are ER and/or PR positive and HER2 negative with Ki-67 index <0, 14; LuminalB is further divided into HER2 negative and HER2 positive.
LuminalB type (HER2 negative) refers to tumor ER and/or PR positive, and HER2 negative, Ki-67 index ≥0, 14; LuminalB type (HER2 positive) refers to ER and/or PR positive, and HER2 overexpression; HER2 overexpression type refers to tumor HER2 overexpression, and ER and PR negative; Basal cell-like type ( Basal-like) is characterized by negative expression of ER, PR, and HER2 with positive expression of CK5/6 and/or HER1.
Because triple-negative breast cancer (TNBC) and basal-like type mostly overlap, most experts in clinical work believe that breast cancer can be similarly classified into four types based on the results of immunohistochemical detection of ER, PR, HER2 and Ki-67 as a close substitute, including LuminalA, LuminalB, HER2-positive and triple-negative breast cancer. Carey et al. reported that 51,4% of each molecular typing was LuminalA, 15,5% was LuminalB, 6,7% was HER2-positive and 20,2% was triple negative breast cancer.
The 2011 St. Gallen meeting also gave detailed guidance on the treatment of each type of breast cancer in terms of endocrine therapy, chemotherapy, and targeted therapy, etc. The 2013 St. Gallen Consensus further defined the molecular typing of breast cancer and classified LuminalA types (ER-positive, PR-negative, Ki-67 <0, 14) as LuminalB types. And there is a rational return in the application of cytotoxic drugs, further emphasizing the importance of chemotherapy (Table 1).
The national and international emphasis on molecular typing of breast cancer implies that with the advancement of medicine and the progress of molecular biology, medical research has entered the era of molecular level, and breast cancers with different molecular typing have different disease processes, treatment modalities and response to treatment as well as prognosis, ;
These differences suggest that the traditional histological classification of breast cancer can no longer meet the current needs of breast cancer research and treatment, and a better integration of molecular typing and histological classification of breast cancer is necessary for clinicians to develop effective individualized treatment plans for breast cancer patients.
2.Treatment of different molecular types of breast cancer
1LuminalA type
This type is the most common molecular subtype of breast cancer, accounting for 44.5% to 69.0% of breast cancers. In addition to high expression of ER and PR, it also expresses hormone receptor and adenoepithelial type cytokeratin as well as expresses transcription factor FOXA1, etc. The expression of FOXA1 gene is related to prognosis, and those with high expression have better prognosis. LuminalA type belongs to tumor subtypes sensitive to endocrine therapy.
ER positive, the efficiency of endocrine therapy is 50% to 60%, and the ER level is positively correlated with the sensitivity of endocrine therapy, because HER2 level is negative and not suitable for molecular targeted therapy. If both ER and PR are positive, the effective rate can be as high as 80%. This type of breast cancer has the best prognosis, is mostly early-stage breast cancer, has a low risk of recurrence, and is not sensitive to chemotherapy.
Currently, the National Comprehensive Cancer Network (NCCN) guidelines state that ER or PR positive cells ≥1% are considered ER or PR positive and have indications for endocrine therapy; and recommend that patients with ER positive invasive breast cancer should be considered for adjuvant endocrine therapy regardless of age, lymph node status or whether adjuvant chemotherapy is administered. Tamoxifen was once the gold standard of premenopausal endocrine therapy for patients with ER-positive breast cancer, and 5 years of tamoxifen therapy was the standard of care.
However, the long-term follow-up results of the ATAC and TEAM trials have shaken the status of tamoxifen as the gold standard, and all three studies have shown that aromatase inhibitors are superior to tamoxifen in the treatment of postmenopausal women. This does not mean, however, that there is an advantage to using aromatase inhibitors in premenopausal patients.
The 2013 edition of the NCCN guidelines states that endocrine therapy remains the treatment of choice for endocrine-sensitive breast cancer unless life-threatening acute disease or very severe symptoms are present. As LuminalA breast cancer is not sensitive to chemotherapy, endocrine therapy with a change of regimen is still preferred after tumor recurrence. In principle, endocrine therapy is still the main treatment for patients without organ metastases in the first-line relief treatment, and if the disease progresses rapidly with visceral metastases, systemic chemotherapy can be preferred and endocrine therapy is performed for maintenance after disease control.
In practice, it is often found that some early-stage LuminalA patients have recurrence and metastasis despite regular endocrine therapy, indicating that there may be therapeutic defects in this group of patients, and if adjuvant chemotherapy is administered to all patients, a significant proportion of patients will have the problem of over-chemotherapy.
Therefore, the 2013 St, Gallen expert consensus has a rational return from focusing on endocrine therapy, and patients with LuminalA breast cancer who have high risk factors such as high RS (recurrence index) assessed by 21 genes, high recurrence status assessed by 70 genes, histological grade 3, lymph node metastasis >4, presence of choroidal carcinoma emboli, and age <35 years (50/50 expert support against) can be Consider standardized adjuvant chemotherapy after surgery and endocrine therapy after chemotherapy.
The 2013 edition of the NCCN guidelines further standardized adjuvant chemotherapy for this subtype. In the adjuvant treatment regimen for hormone receptor-positive, HER2-negative breast cancer, chemotherapy and endocrine therapy are required for those with axillary lymph node metastasis; only endocrine therapy is required for those without axillary lymph node metastasis and tumor diameter ≤0,5 cm, and 21-gene testing is performed for those with tumor diameter >0,5 cm to analyze the recurrence Risk score.
Those with risk score <18 are at low risk of recurrence and only need endocrine therapy; those with risk score 18-30 are at moderate risk of recurrence and need endocrine therapy and/or chemotherapy, and there is no conclusion whether they can benefit from chemotherapy; those with risk score >30 are at high risk of recurrence and need chemotherapy and endocrine therapy, and patients can benefit from adjuvant chemotherapy.
Endocrine therapy and/or chemotherapy may be considered for those who have not undergone 21-gene testing analysis. Therefore, it is necessary to individualize the treatment of patients with Luminal A according to their genetic and biological characteristics in order to avoid overtreatment.
LuminalB type
This type is divided into two subtypes. LuminalB type (HER2-positive) is also endocrine-therapy sensitive, but because of the presence of HER2 amplification in this type, it responds less well to tamoxifen than LuminalA type, whereas it is 88% more effective to aromatase inhibitor drugs.
Therefore, aromatase inhibitors should be preferred for postmenopausal patients with LuminalB, and premenopausal patients should be treated with aromatase inhibitors on top of sex hormone-releasing hormone analogs, along with targeted therapy for HER2 to obtain the best results. For patients with LuminalB type (HER2 negative), because of the rapid cell proliferation rate, it is recommended that most patients should choose whether or not to take chemotherapy based on endocrine therapy at their discretion.
Clinically, neoadjuvant chemotherapy is often given to patients with advanced tumor stage, who need to achieve surgical conditions through downstaging, and for patients with breast-conserving requirements in order to achieve breast-conserving conditions. Studies have confirmed that patients who achieve pathological complete remission (pCR) after neoadjuvant chemotherapy will have a significantly improved prognosis. Therefore, achieving pCR with neoadjuvant chemotherapy is one of the goals pursued by many mammologists.
Due to the poor responsiveness of patients with Luminal type to chemotherapy, their overall pCR rate with neoadjuvant chemotherapy is not high, ranging from 6% to 12%, but due to the differences in proliferation characteristics between LuminalB breast cancer and LuminalA breast cancer, some studies have suggested that LuminalB type may achieve better outcomes with neoadjuvant chemotherapy than LuminalA type.
Zhou Bo et al [13] reported that after combined neoadjuvant chemotherapy with paclitaxel and anthracycline, the pCR rate was 10, 3% for LuminalA and 25% for LuminalB, and the effect after neoadjuvant chemotherapy was significantly better for LuminalB than LuminalA.
Carey et al. compared neoadjuvant chemotherapy for four subtypes of breast cancer: LuminalA, LuminalB, HER2-positive and triple-negative, and also suggested that the sensitivity of chemotherapy for LuminalB was better than that for LuminalA, and the combination of anti-HER2-targeted therapy with neoadjuvant chemotherapy for HER2-positive breast cancer in LuminalB could further The difference in efficacy between HER2-positive and HER2-positive patients was not statistically significant.
3. Prognosis of different molecular types
The clinical characteristics and prognosis of breast cancer with different molecular typing are different. Foreign literature reports that LuminalA breast cancer is the most common molecular subtype, usually early-stage breast cancer with low risk of recurrence, sensitive to endocrine therapy, insensitive to chemotherapy, and has a better prognosis; LuminalB type is mostly seen in elderly breast cancer patients, sensitive to endocrine therapy (including selective estrogen receptor modulators and aromatase inhibitors), but its sensitivity to chemotherapy is variable, and There is no clear clinical staging;
HER2-positive breast cancer is mostly advanced, with a tendency of axillary lymph node metastasis, high malignancy, sensitivity to chemotherapy, and poor prognosis; triple-negative breast cancer is commonly found in advanced, young and premenopausal female patients, with characteristics of sensitivity to chemotherapy and easy recurrence and metastasis.
One report suggested that after a median follow-up of 70 months for 720 breast cancers, the difference in local recurrence rate between LuminalA and LuminalB types was not statistically significant, and the risk of local recurrence was higher for HER2-positive and triple-negative breast cancers than for LuminalA and LuminalB types, with a 5-year local recurrence rate of 0,8% for LuminalA (95% CI 0,3%~ 2,2%), LuminalB type 1,5% (95% CI 0,2%-10%), HER2-positive type 8,4% (95% CI 2,2%-30,0%), and triple-negative breast cancer 7,1% (95% CI 3,0%-16,0%).
Compared with LuminalA, HER2-positive type and LuminalB tended to have more multiple foci and axillary lymph node metastasis, but the rate of distant metastasis was significantly higher in triple-negative breast cancer (42, 9%) than in LuminalA (37, 1%), HER2-positive type (11, 4%) and LuminalB (8, 6%), and triple-negative breast cancer was a predictor of distant metastasis as an independent prognostic factor.
Carey et al. reported that HER2-positive and triple-negative breast cancers had the worst prognosis and LuminalA had the best prognosis among 496 patients with breast cancer with a follow-up period of 8, 1 to 11, 2 years. The survival rates of breast cancers with different molecular typing were significantly different: Luminal A was the longest, followed by Luminal B, and triple-negative breast cancer was the shortest.
In conclusion, breast cancer is not a disease caused by a single factor, and the age of onset, clinical features, malignancy and prognosis vary among molecular subtypes. The prognosis of lymph node positive patients is worse than that of lymph node negative patients, and the prognosis of patients with Luminal A, Luminal B, HER2-positive and triple negative breast cancers is worse in that order.
Individualized treatment plans should be developed according to the molecular typing of breast cancer patients to maximize the safety and efficacy of treatment and avoid harm to patients due to over- or under-treatment.