In addition to the specific classification name of the tumor, the size of the tumor, the clean resection of each margin, the site and number of lymph node metastases and the presence of infiltration in the vascular lymphatic vessels and other tissues, there are some important immunological indicators that can indicate prognosis in the postoperative pathology of breast cancer, and the analysis of these indicators can guide the treatment and estimate the prognosis.
Estrogen receptor, positive indicates a better prognosis than negative patients, the more plus signs the better.
PR: progesterone receptors, positive suggesting a better prognosis than negative patients.
ER and PR are present in normal breast epithelial cells. when cells become cancerous, ER and PR appear partially and completely absent. If ER and/or PR are still retained, the growth and proliferation of the breast cancer cells are still regulated by endocrine control, which is called hormone-dependent breast cancer; if ER and/or PR are absent, the growth and proliferation of the breast cancer cells are no longer regulated by endocrine control, which is called non-hormone-dependent breast cancer.
If both are positive, the prognosis is best. If one is positive and one is negative, estrogen positivity is better than progesterone positivity. The prognosis is not good for both negatives. Positive cases can be treated with postoperative or preoperative endocrine therapy.
Her-2 (CerbB-2): human epidermal growth factor receptor 2, a proto-oncogene. Its overexpression, i.e. the presence of a plus sign, indicates that the patient has a poor prognosis. It also suggests that patients are prone to axillary lymph node metastasis and possible deficiency of both of these hormone receptors. Its expression is positively correlated with breast cancer grade, lymph node metastasis and clinical stage, and the higher the expression rate, the worse the prognosis may be. However, those with more than two plus signs in Fish test have the possibility of biologically targeted therapy. That is, with trastuzumab (Herceptin).
All three of the above are negative patients, which are now medically known as “triple negative” breast cancer, with a relatively poor prognosis and lack of drug treatment.
E-Cadherin: E-calcified adhesion protein is one of the transmembrane protein isoforms in the calcium adhesion protein family of molecules, which is concentrated in the adherens junctions and plays an important role in maintaining the integrity, polarity, morphology and organization of epithelial cells. Its high expression indicates a good prognosis.
Ki-67index: It is a proliferative antigen that responds to cell proliferation. Its expression is associated with breast cancer development and progression, and is a poor prognostic factor. The higher the value, the worse the prognosis.
P53: It is a tumor suppressor gene and its mutation indicates poor prognosis; breast cancer cells with high P53 mutation rate have high proliferation activity, poor differentiation, high malignancy, aggressiveness and high lymph node metastasis rate.
CK5/6: It is a cytokeratin, and its expression rate increases with higher histological grade and tumor stage, and the overall positive prognosis is poor.
EGFR: Epidermal growth factor receptor, the higher the histological grade and tumor stage, the higher the expression rate, and the overall positive indicates poor clinical prognosis.
VEGF: Vascular endothelial growth factor, high expression indicates poor prognosis.
TOP-II: DNA topoisomerase II, high expression indicates higher tumor proliferation and malignancy.
PCNA: proliferating cell nuclear antigen, positive prognosis is poor.
P170: a multidrug resistance gene whose overexpression is detrimental to treatment.
nm23: nm23, also known as an anti-metastatic oncogene, is an oncogene whose product is a protein consisting of 152 amino acids with high homology to the amino acid sequence of nucleoside diphosphate kinase (NDPK). There are 2 isoforms of human nm23 gene: nm23H1 and nm23H2, which have 88% homology. nm23H1 is more closely related to the prognosis of breast cancer.
The nm23 protein has NDPK function, regulates cell motility by affecting microtubule aggregation, and plays a negative regulatory role by affecting G protein signaling, thus inhibiting tumor metastasis. However, its action is not dependent on NDPK activity. Some experimental results suggest that it is the expression level of nm23NDPK rather than NDPK activity that is associated with metastatic potential.
nm23 is an independent prognostic indicator, and its expression is independent of age, tumor size, ER, PR and C-erbB-2, and significantly related to lymph node metastasis status, histological staging, grading and clinical stage. nm23 high expressers have significantly better prognosis than low expressers. breast cancers with reduced nm23 expression are less differentiated, have low ER expression levels, and often have lymph node metastasis and poor prognosis .
During the progression of breast cancer, the expression level of nm23 decreases. By detecting nm23, cases with potential distant metastasis in axillary lymph node positive patients and potentially high metastatic tendency in axillary lymph node negative patients can be screened for appropriate prophylactic treatment, thus improving treatment outcome.
Her-1: similar to the previous Her-2, the positivity is not good.
DNA ploidy: aneuploidy predicts tumorigenesis.
CD44V6: It is a protein with high expression suggesting poor prognosis.
Ck14, Ck17 and CK7: have similar reference standards as the preceding Ck5/6.
Bcl-2: It is an apoptosis-suppressing gene, and its positive expression suggests a high degree of tumor grading and few lymph node metastases.
PS2: PS2 may be more useful than ER assay in predicting response to endocrine therapy, and PS2 expression is the best indicator of response to endocrine therapy in breast cancer.
P63: P63 gene itself is an oncogene, and P63 plays an important role in the occurrence and development of breast cancer; the test can provide the necessary theoretical basis for early diagnosis, timely treatment and prognosis judgment of breast cancer.
Calponin: In the normal, hyperplasia and atypical hyperplasia groups of breast, almost all myoepithelial cells expressed P63, α-SMA and Calponin, while all glandular epithelial cells were negative for the 3 antibodies; it helps to determine infiltrating carcinoma, carcinoma in situ and atypical hyperplasia.
SMA (smooth muscle actin): smooth muscle actin is a reliable marker antibody. It disappears in a gradual process from normal breast tissue, benign lesions to carcinoma in situ, early infiltration and infiltrative carcinoma.
Cyclin D1: High expression of Cyclin D1 may play an important role in the development and progression of human breast cancer. The clinical significance of high expression in breast cancer is that the expression of Cyclin D1 correlates with tumor size, TNM stage and axillary lymph node metastasis.
COX-2 (cyclooxygenase-2): The expression of COX-2 is present in breast cancer tissues.COX-2 may be a practical indicator for clinical evaluation of patient prognosis and identification of patients at high risk of postoperative recurrence.
34βE12: It is a cytokeratin, and its expression correlates with the biological index of tumor malignancy in breast cancer. Negative expression of 34βE12 in breast cancer tissues indicates poor prognosis, which can be used to determine the malignancy degree and prognosis of breast cancer.
P120 membrane: It is abnormally expressed in breast cancer tissues and correlated with E-cadherin expression, which may play an important role in the occurrence and development of breast cancer; P120 membrane is more closely related to the occurrence and development of invasive lobular carcinoma.
Laminin: Laminin mainly exists in the basal lamina structure and is a non-collagenous glycoprotein unique to the basal lamina with a relative molecular mass of 820 kDa, containing 13-15% sugar and three subunits, i.e. heavy chain (α chain, 400 kDa) and two light chains of β1 (215 kDa) and β2 (205 kDa). The structure shows an asymmetric cross shape, consisting of one long arm and three similar short arms. All four arms have rod-shaped segments and spherical end domains.
The short arms of β1 and β2 have two spherical domains, while the short arm of the α chain has three spherical domains, one of which binds to type IV collagen, the second to heparin, and the other to cell surface receptors. It is these independent binding sites that allow LN to act as a bridge molecule that mediates cell binding to the basement membrane. Therefore, the main function of LN is to act as a major structural component of the basement membrane and play a key role in the assembly of the basement membrane, forming a network structure on the cell surface and anchoring the cell to the basement membrane.
LN also has many other roles, such as stimulating cell adhesion and cell motility during cell development, stimulating neuraxis growth in embryos, and promoting regrowth and regeneration after neural injury in adult animals. Like fibronectin, extracellular LN can influence cell growth, migration and differentiation. lN plays a key role in the migration of progenitor germ cells. lN is also a large glycoprotein that, together with type IV collagen, forms the basement membrane and is the earliest component of the extracellular matrix to appear in embryonic development.
The LN molecule consists of a heavy chain (α) and two light chains (β, γ) cross-linked by disulfide bonds, with a cruciform shape and three short arms each consisting of the N-terminal sequences of three peptide chains. Each short arm consists of two spherical regions and two short rod regions, and the long arm also consists of rod and spherical regions (Figure, structural model). there are at least eight sites in the LN molecule that bind to cells. For example, in the long arm near the spherical region. The chain with the IKVAV pentapeptide sequence binds to nerve cells and promotes nerve growth.
The RGD sequence on the mouse LNα1 chain binds to αvβ3 integrins. Seven LN molecules with eight subunits (α1,α2,α3,β1,β2,β3,γ1,γ2) have been identified, and unlike FN, these eight subunits are encoded by eight structural genes. lN is a glycoprotein with high sugar content (15-28%), with about 50 N-linked glycan chains, and is the most complex glycoprotein with the most complex glycan chain structure known to date. Moreover, multiple receptors of LN are recognized and bound to its glycoconjugate structure.
Cyclin D1: High expression of Cyclin D1 may play an important role in the development and progression of human breast cancer. The clinical significance of high expression in breast cancer is that the expression of Cyclin D1 correlates with tumor size, TNM stage and axillary lymph node metastasis.
VEGF: Vascular Endothelial Growth Factor (VEGF) Angiogenesis plays a key role in tumor growth, infiltration and metastasis, which is regulated by a series of promoting and inhibiting factors, one of the most important promoting factors is VEGF secreted by tumor cells during growth, its coding gene is located at 6P21.3 and consists of 8 exons, due to the different shearing forms of mRNA Five different VEGFs are formed, containing 121, 145, 165, 189 and 206 amino acids, respectively, of which VEGF165 is the most important and predominantly expressed in various cells;
VEGF121 and VEGF189 are detected in most of the tissues and cells expressing VEGF, while VEGF145 and VEGF206 are very rare, among which VEGF206 can only be detected in human fetal liver cDNA library. .
VEGF is mainly produced by tumor cells, with a small proportion from the interstitial cells. VEGF is an independent prognostic indicator, independent of age and menopausal status, negatively correlated with ER and PR, and is prone to metastasis and recurrence with poor prognosis;
It is recommended to combine anti-angiogenic therapy for high VEGF expressers, such as using VEGF monoclonal antibodies to block binding to receptors, recombinant VEGF competing with VEGF for receptors, binding VEGF to small molecule toxic substances, using antisense nucleic acid technology to inhibit VEGF expression, etc. VEGF monoclonal antibodies Avastin and Elitecan.
It has been shown that circulating VEGF is a prognostic indicator, that those with high expression are prone to metastatic recurrence, and that this indicator can be used to guide treatment. In this year’s ASCO meeting, Ghosh et al. reported that VEGF expression was significantly higher in breast cancer tissues than in the stroma and correlated with several poor prognostic factors, with high expression suggesting poor prognosis at 20-year survival. The increased expression of survivin suggested a poor prognosis for breast cancer patients.
Traina reported a study of letrozole + VEGF monoclonal antibody bevacizumab in patients with hormone receptor-positive metastatic breast cancer, in which VEGF was measured in tissues to guide treatment and evaluate the correlation with efficacy.
BRCA1: Basal cell-like breast cancers are a group of high-grade breast cancers with poor prognosis, and they typically present with ER, PR and HER-2 negative expression. The incidence is approximately 15-20% of all breast cancer patients and there is a strong association between incidence and BRCA1 gene mutations.
Bcl-2: Apoptosis suppressor genes include Bcl-2, Bcl-x1, Bcl-w, mcl-1, etc.; pro-apoptosis genes include Bcl-xs, Bax, Bad, Bak, Hrk and Bim. These two types of substances bind to each other and inhibit each other, and the relative amount of them often determines whether apoptosis occurs or not. Among the Bcl-2 family, Bcl-2 protein was the first to be identified and isolated, and so far it has been studied more thoroughly. It has been shown that it is located in the mitochondrial membrane, endoplasmic reticulum membrane and nuclear membrane, and has the dual function of ion channel and docking protein, playing a key role in mediating the apoptosis pathway.
Bcl-2 protein prevents the release of cytochrome C from mitochondria by regulating the transport of substances inside and outside the nucleus involving Ca2+ in the endoplasmic reticulum and membrane permeability transition (PT), thus preventing its interaction with Apaf-1 and procaspase-9, and finally inhibiting the apoptotic cascade reaction process triggered by Caspase-9 and Caspase-3. In conclusion, as an anti-apoptotic gene, Bcl-2 can protect cells from apoptosis induced by viruses, oxidants and other stimuli. Current studies suggest that high expression of Bcl-2 gene and its related proteins inhibit apoptosis as an important factor in tumorigenesis and drug resistance phenomenon.
CD44v6: CD44v6 is a transmembrane protein closely related to the invasive and metastatic behavior of cancer cells, mediating not only the adhesion of tumor cells to the extracellular matrix, but also participating in the interactions between tumor cells and between tumor cells and other cells. CD44v6, as a homing receptor for lymphocytes and a major receptor for hyaluronan, is able to connect to the extracellular matrix, bind to cytoskeletal proteins, and It is involved in the formation of cellular pseudopods, causing morphological and swimming changes in cells, and can be directly involved in the invasion and metastasis of tumor cells.
Pokemon: Pokemon is overexpressed in a variety of human tumors. Pokemon acts by specifically inhibiting the transcription of the tumor suppressor gene ARF, and cells lacking Pokemon gene do not respond to oncogenic transformation, thus this gene plays a critical role in tumorigenesis.
CD117: CD117 generally marks gastrointestinal mesenchymal tumors.
S-100: CgA(-), S-100, SyN(-) are neuroendocrine indicators. Negative indicates that it is not a neuroendocrine carcinoma.S-100 protein is an acidic calcium-binding protein with a molecular weight of 21 000, found mainly in the cytosol of astrocytes in various departments of the central nervous system, and is named for its ability to be 100% soluble in saturated ammonium sulfate.
S-100 protein consists of two subunits, α and β, in three different forms: S-100 βββ (S-100 b) is mainly found in neuroglia and Schwann cells, S-100 αα (S-100 a0) is mainly found in glial cells, and S-100 αβ (S-100 a) is mainly found in transverse muscle, heart and kidney. It is generally believed that S-100 protein leaks out of the cytosol into the cerebrospinal fluid (CSF) when CNS cells are injured, and then enters the blood through the damaged blood-brain barrier. Therefore, increased S-100 protein in CSF and blood is a specific and sensitive biochemical marker of CNS injury.
”Triple negative breast cancer” refers to breast cancer patients who are negative for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2). By molecular typing, breast cancers are classified into luminal, HER-2(+) and Basal-like types. basal-like type with molecular expression of ER(-)/PR(-)/HER-2(-) corresponds to triple negative breast cancer and is characterized by high expression of basal epithelial molecular markers (CK5/6 or 17, EGFR) as well as ER or ER-related genes and low expression of HER-2 or HER-2-related genes.
①ER(-)/HER2(-), CK5/6(+) and/or EGFR(+).
There is no universally accepted definition of basal cell-like carcinoma, but there are several definitions of basal cell-like carcinoma gene expression as follows.
(ii) CK5/6(+), caveolin1(+), CAIX(+), p63(+) or CD117+.
③CK5/6(+) and/or CK14(+).
④CK5/14(+).
The 5-year survival rate of this type of breast cancer is less than 15%, mostly seen in young premenopausal patients, with a higher chance of visceral metastasis and brain metastasis, poor histological grading of pathology, mostly grade 3, a higher proportion of cell proliferation, and mostly with p53 mutation, c-kit, p53, EGFR expression mostly positive, basal cell markers CK5/6, CK17 also mostly positive. The tumor is highly aggressive, prone to local recurrence and distant metastasis, and has more similar features to basal cell-like breast cancer and BRCA1 mutation-associated breast cancer.
The prognosis of triple-negative breast cancer has little relationship with tumor size and lymph node status. Recurrence is rapid, with peak recurrence in 1-3 years and peak death in 5 years, with high incidence of brain metastasis and rapid development of distant metastasis leading to death. “Endocrine therapy and targeted trastuzumab therapy are ineffective in triple negative breast cancer, and chemotherapy is the mainstay of treatment. Compared to other types of breast cancer, triple negative breast cancer is more sensitive to chemotherapy and radiotherapy, but its prognosis is still poor if it is treated with standard conventional therapy, with low recurrence-free survival and overall survival.
There are no treatment guidelines for triple-negative breast cancer, and its treatment is generally performed as conventional for poor prognosis breast cancer, with postoperative adjuvant chemotherapy choosing an anthracycline-containing paclitaxel regimen. Neoadjuvant chemotherapy with paclitaxel- and anthracycline-containing regimens is associated with high rates of complete pathological remission. The use of platinum-based agents for neoadjuvant chemotherapy is under investigation.
Metastatic triple-negative breast cancer has progressed rapidly and palliative chemotherapy is being investigated with the following: microtubule stabilizers Paclitaxel, Docetaxel, nab-paclitaxel, ixabepilone; carboplatin/cisplatin; anti-angiogenic Bevacizumab, Sunitinib; EGFR inhibitors Cetuximab, Erlotinib, etc. In new drug studies, ezapyrone has been shown to be more effective than capecitabine alone in combination with capecitabine in advanced anthracycline- and paclitaxel-resistant breast cancer and triple-negative breast cancer.
Endocrine therapy and trastuzumab-targeted therapy are ineffective in “triple negative breast cancer”, but some triple negative breast cancer patients with high expression of EGFR, c-Kit, CK5/6, P-cadherin, and p53 may benefit from targeted therapy for these cancers. The role of cetuximab, a monoclonal antibody to EGFR, and gefitinib and erlotinib, tyrosine kinase inhibitors of EGFR, in the treatment of triple-negative breast cancer is currently being investigated internationally.
In many patients with triple-negative breast cancer with BRCA1 deletion or mutation, the risk of developing breast cancer is as high as 82% for those with BRCA1 deletion and 5% for those with BRCA1 mutation due to the important role of BRCA1 in DNA repair mRNA transcription and cell cycle alignment, and related studies have shown that patients with BRCA1 deletion or mutation have a higher risk of developing breast cancer. Patients with BRCA1 deletion or mutation have been shown to be effective with drugs that disrupt the chemical structure of DNA (e.g., alkylating agents, platinum, mitomycin) and less effective with drugs that act on microtubule protein synthesis (e.g., paclitaxel, vincristine).
Patients with triple-negative breast cancer did not show a higher local recurrence rate after breast-conserving surgery and radiotherapy than patients with non-triple-negative breast cancer, i.e., the local recurrence rate of triple-negative breast cancer after radiotherapy was similar to that of non-triple-negative breast cancer. Triple-negative breast cancer is theoretically effective against DNA toxicity drugs and therefore also against radiotherapy.
ER indicates estrogen. ER(++++) indicates that the disease is hormone-dependent. The higher the estrogen level, the better the effect of treatment with endocrine therapy and the less probability of recurrence and metastasis.
The higher the PR expression (the more plus signs), the lower the recurrence, metastasis and mortality rate. If both ER and PR are positive, the efficiency of endocrine therapy is over 80%. If both ER and PR are positive, the efficiency of endocrine therapy is more than 80%. If ER is positive and PR is negative, the efficiency of endocrine therapy is only about 30%.
C-erbB-2 is an oncogene, the higher the expression of C-erbB-2 (the more plus signs), the worse the prognosis and the more likely to recur and metastasize; C-erbB-2 negative, sensitive to chemotherapy, less recurrence and metastasis, good prognosis.
After chemotherapy is over, please follow the doctor’s orders and carry out endocrine therapy. It should be noted that: when using endocrine drugs, firstly, do not change the drugs easily, and secondly, pay attention to more calcium supplementation.
It is better to have regular review, and it is better to assist Chinese herbal medicine after chemotherapy, the effect will be better.