CN109576266B - Marker and kit for predicting sensitivity of HER2 positive metastatic breast cancer patient to trastuzumab - Google Patents
Marker and kit for predicting sensitivity of HER2 positive metastatic breast cancer patient to trastuzumab Download PDFInfo
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Abstract
The invention provides a group of markers for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab, comprising miR-451a, miR-16-5p, miR-17-3p and miR-940, and further provides a kit and a system for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab. The method predicts the treatment effect of trastuzumab by using the change of microRNA amount in serum, and can well predict the sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab by using the system.
Description
Technical Field
The present invention relates to markers, kits and systems for predicting sensitivity to trastuzumab in HER2 positive metastatic breast cancer patients.
Background
HER2 positive breast cancer is a type of breast cancer that is highly malignant, with 20% to 30% of all breast cancer patients being HER2 positive. HER2 is also called as human epidermal growth factor receptor-2, is a protooncogene, expresses HER2 protein on cell membrane, and when EGF is combined with HER-2, causes HER2 to change from monomer into dimer, then triggers autophosphorylation to transmit intracellular information, regulates gene expression, and finally maintains normal cell growth and division. When HER2 is overexpressed, the cells may be abnormally and rapidly grown due to overstimulation, which may ultimately lead to cancer. Trastuzumab is a monoclonal antibody that specifically binds to HER2, specifically binds to HER2, prevents EGF from binding to HER2, and inhibits cancer cell growth. In addition, Trastuzumab can reduce the expression of cancer cell HER2, inhibit the angiogenesis of tumor, induce in vivo immunity including antibody-dependent cell poisoning and complement poisoning, and further cause the death of target cells identified by monoclonal antibodies, thereby playing the role of anti-tumor.
However, nearly 30% of HER2 positive breast cancer patients develop resistance to Trastuzumab during treatment with Trastuzumab and fail to benefit from treatment with a Trastuzumab regimen. There are several reports in the literature that some other treatment options such as Lapatinib, pertuzumab, trastuzumab emtansine (T-DM1) may benefit this segment of patients. Therefore, determining whether a patient is sensitive to Trastuzumab prior to treatment is important in selecting a treatment regimen. Although the literature reports that several markers of HER2 positive tumor cells, such as the activation of PI3K, the activation of ER, the loss of PTEN, the activation of IGFR and the immune cell status, can be used as markers for judging treatment sensitivity, the markers cannot be clinically applied at present.
At present, the diagnosis of HER2 positive breast cancer mainly depends on the pathological characteristics of tumors, such as immunohistochemical staining, FISH and the like, and once HER2 positive is confirmed, a treatment scheme containing Trastuzumab is recommended, at which time the sensitivity of a patient to the treatment with Trastuzumab is unknown, and the treatment effect of Trastuzumab can be confirmed only after a certain period of treatment. For this part of the patients that are resistant to treatment, this means a poor prognosis. Due to the large heterogeneity of tumors, the use of only one of the markers may not reflect the entire tumor or even the entire body of the patient, and may require detection after tumor tissue has been obtained. Therefore, it is desirable to find an accurate evaluation method to determine whether a patient is sensitive to Trastuzumab therapy prior to selecting a treatment regimen.
Disclosure of Invention
The invention aims to provide a group of markers for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab, and also provides a kit and a system for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab.
In order to realize the purpose, the technical scheme is as follows: a group of markers for predicting HER2 positive metastatic breast cancer patients sensitivity to trastuzumab includes miR-451a, miR-16-5p, miR-17-3p and miR-940.
Preferably, the miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
The invention provides a kit for predicting sensitivity of a HER2 positive metastatic breast cancer patient to trastuzumab, which comprises primers for amplifying miR-451a, miR-16-5p, miR-17-3p and miR-940.
Preferably, the miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
Preferably, the kit further comprises reverse transcriptase, a reaction buffer solution of the reverse transcriptase, a random reverse transcription primer, a fluorescent quantitative PCR reaction buffer solution and an external reference.
Preferably, the external parameter is cel-miR-39.
The invention provides application of combined use of miR-451a, miR-16-5p, miR-17-3p and miR-940 in preparation of a kit for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab.
Preferably, the miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
The invention provides a system for predicting sensitivity of a HER2 positive metastatic breast cancer patient to trastuzumab, comprising:
the data input module is used for inputting the expression value of the molecular index of the HER2 positive metastatic breast cancer patient into the model calculation module, the molecular index comprises miR-451a, miR-16-5p, miR-17-3p and miR-940, and the Ct value of the molecular index measured by fluorescence quantitative PCR is calculated according to a formula: Δ Ct ═ CtmicroRNA–CtGinseng radix extractThe external parameter is cel-miR-39, and the obtained delta ct value is an expression value;
a model calculation module comprising a risk score model for calculating a patient risk score result from an expression value of a molecular indicator of a HER2 positive metastatic breast cancer patient and a risk score model comprising a risk score formula of (expression value of 0.611 × miR-940) - (expression value of 0.482 × miR-451 a) - (expression value of 0.525 × miR-16-5 p) - (expression value of 0.719 × miR-17-3 p);
a result output module for determining whether a HER2 positive metastatic breast cancer patient is sensitive to trastuzumab according to the patient risk score result; when the patient risk score result is less than 0.13, the patient is sensitive to trastuzumab; when the patient risk score result is greater than or equal to 0.13 more, the patient is not sensitive to trastuzumab.
Preferably, the miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
The invention has the beneficial effects that: the invention provides a group of markers for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab, and also provides a kit and a system for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab. The invention relates to separation and quantitative analysis of human serum microRNA, provides a technology for predicting trastuzumab treatment effect by using change of microRNA amount in serum, detects the microRNA amount in serum, and has the following advantages:
1. the serum is easy to obtain relative to a tumor tissue sample, and can be collected even in ordinary physical examination;
2. the obtained serum microRNA is representative of the overall level of the microRNA in blood circulation, reflects the overall physiological and pathological conditions of a patient, and has guiding significance in the detection result;
3. the sample processing, microRNA extraction and detection scheme is simple and easy to implement, the time spent is short, and the samples can be processed in a large scale.
The sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab can be well predicted by the system of the invention.
Drawings
FIG. 1 is a picture of differential expression of microRNA in serum of trastuzumab-sensitive and resistant patients detected by a chip in example 1 of the invention;
FIG. 2 is a picture of four microRNA-dependent prediction models dividing a patient into two groups of high risk and low risk in example 2 of the present invention;
FIG. 3 is a clinical factor stratification analysis of 386 patients for predicting risk in example 2 of the present invention.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
Example 1
Of 103 patients with HER2 positive advanced metastatic breast cancer treated with trastuzumab, 61 were sensitive to treatment and 52 were tolerated. In the two groups of patients, the results of detection by the microRNA chip are shown in FIG. 1, and 3 microRNA expressions are up-regulated and 9 microRNA expressions are reduced in the tolerant patients. Wherein the expression of miR-940 is increased, and the expressions of miR-451a, miR-16-5p and miR-17-3p are decreased.
Example 2
First, experiment method
1. HER2 positive metastatic breast cancer patient selection and blood specimen collection
Patient selection criteria: 1) pathologically diagnosed as ductal invasive breast cancer; 2) immunohistochemical HER2 staining 3(+), or in situ hybridization Her2/CEP17ratio ≥ 2.0); 3) the expected survival time is more than or equal to 3, and the physical ability state ECOG score is less than or equal to 2; 4) can be used for blood drawing examination.
Collecting a blood sample: and (3) centrifuging the whole blood immediately after collecting the anticoagulation tube, wherein the centrifugation conditions are as follows: 820g, 4 ℃, 10 min; after centrifugation, the serum was pipetted into a new EP tube for RNA extraction.
2. Adding external ginseng and extracting serum RNA;
the external reference microRNA selects cel-miR-39, and 2.5ul of cel-miR-39(100nM) is added into every 500ul of serum, so that the concentration of the added serum is 0.05nM in each sample. The RNA extraction was carried out using a Kit (Plasma/Serum circulation and expression RNA Purification Mini Kit) from NorgenBiotek, and the RNA was dissolved in 10. mu.l of RNase free water.
3. Reverse transcription of microRNA in serum into cDNA
Reverse transcription kit MicroRNA reverse transcription kit (Mir-X) from Clontech was usedTM miRNA First-Strand Synthesis Kit)
Reverse transcription was performed according to the system of table 1:
TABLE 1 reverse transcription System
Reverse transcription conditions were set as in table 2:
TABLE 2 reverse transcription conditions
After completion of the reverse transcription, 40. mu.L of deionized water was added to make the total volume 50. mu.L.
4. The quantity of 4 microRNAs in serum, the sequence of the microRNAs and the sequence table 3 of the primers are detected by a fluorescent quantitative PCR technology.
TABLE 3 sequences of microRNAs and primer sequences used
The fluorescent quantitative kit adopts SYBR Green master mix (containing universal reverse primer) of TaKaRa company.
The fluorescent quantitative detection was carried out according to the system of Table 4.
TABLE 4 fluorescent quantitative PCR System
The PCR conditions were set as in Table 5.
TABLE 5 PCR conditions
5. And calculating a risk score according to the risk model and obtaining a conclusion.
Calculating the Ct value according to the formula: Δ Ct ═ CtmicroRNA–CtGinseng radix extractAnd obtaining the delta ct value as an expression value. Risk Score (RS) ═ expression value of (0.611 × miR-940) - (expression value of 0.482 × miR-451 a) - (expression value of 0.525 × miR-16-5 p) - (expression value of 0.719 × miR-17-3 p). In the test group, the calculated expression values were correlated with the progression-free survival time of the patients, resulting in a risk score cut-off of 0.13. I.e., the patient is sensitive to Trastuzumab treatment when the patient risk score is < 0.13; when the patient risk score is greater than or equal to 0.13, the patient is not sensitive to Trastuzumab treatment. Sensitivity of Trastuzumab treatment is predicted according to the obtained value, and a treatment scheme is selected.
Second, experimental results
1. According to the values obtained by substituting the expression values of miR-940, miR-451a, miR-16-5p and miR-17-3p in serum into the risk score formula disclosed by the invention, 386 cases of trastuzumab-treated HER2 positive advanced metastatic breast cancer patients are divided into two groups of high risk (the risk score is more than or equal to 0.13) and low risk (the risk score is less than 0.13), and the disease-free survival rate and the overall survival rate of the patients in the high risk group are obviously lower than those in the low risk group (as shown in figure 2).
2. To determine whether confounders had an effect on outcome, the risk model was analyzed hierarchically among six clinically relevant factors (age, Ki67, ECOG score, ER expression status, PR expression status, menstrual status). According to the results obtained by the risk model, analysis is carried out in different clinical factor states, and the risk prediction values obtained by calculating four microRNAs can still well distinguish patients sensitive to Trastuzumab treatment and patients tolerant to Trastuzumab treatment, namely the six clinical factors do not influence the efficacy of the risk prediction model, as shown in figure 3.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A group of markers for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab, wherein the markers are miR-451a, miR-16-5p, miR-17-3p and miR-940.
2. The marker of claim 1, wherein miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
3. A kit for predicting sensitivity of HER2 positive metastatic breast cancer patients to trastuzumab, which is characterized by comprising primers for amplifying miR-451a, miR-16-5p, miR-17-3p and miR-940.
4. The kit of claim 3, wherein the miR-451a, miR-16-5p, miR-17-3p and miR-940 are all from serum.
5. The kit of claim 3, further comprising reverse transcriptase and reaction buffer of reverse transcriptase, random reverse transcription primer, fluorescent quantitative PCR reaction buffer and external reference.
6. The kit of claim 5, wherein the external reference is cel-miR-39.
7. Use of a marker according to claim 1 in the preparation of a kit for predicting sensitivity to trastuzumab in a HER2 positive metastatic breast cancer patient.
8. The use of claim 7, wherein miR-451a, miR-16-5p, miR-17-3p, and miR-940 are all from serum.
9. A system for predicting sensitivity to trastuzumab of a HER2 positive metastatic breast cancer patient, comprising:
the data input module is used for inputting the expression value of the molecular index of the HER2 positive metastatic breast cancer patient into the model calculation module, the molecular index comprises miR-451a, miR-16-5p, miR-17-3p and miR-940, and the Ct value of the molecular index measured by fluorescence quantitative PCR is calculated according to a formula: the method comprises the following steps of (1) obtaining a delta Ct value, wherein the delta Ct value is Ct microRNA-Ct external parameter which is cel-miR-39, and the obtained delta Ct value is an expression value;
a model calculation module comprising a risk score model for calculating a patient risk score result from an expression value of a molecular indicator of a HER2 positive metastatic breast cancer patient and a risk score model comprising a risk score formula of (expression value of 0.611 × miR-940) - (expression value of 0.482 × miR-451 a) - (expression value of 0.525 × miR-16-5 p) - (expression value of 0.719 × miR-17-3 p);
a result output module for determining whether a HER2 positive metastatic breast cancer patient is sensitive to trastuzumab according to the patient risk score result; when the patient risk score result is less than 0.13, the patient is sensitive to trastuzumab; when the patient risk score result is more than or equal to 0.13, the patient is insensitive to trastuzumab.
10. The system of claim 9, wherein miR-451a, miR-16-5p, miR-17-3p, and miR-940 are all from serum.
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| CN101921760A (en) * | 2010-09-08 | 2010-12-22 | 南京医科大学 | Serum/plasma miRNA marker associated with breast cancer and application thereof |
| CN106148538A (en) * | 2016-08-09 | 2016-11-23 | 山东大学 | MicroRNA mark group and the application in preparing evaluating breast cancer chemosensitivity test kit thereof |
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