Pathological Research Of HER2 Expression And Interpretation In Breast Cancer

Part 1 Investigation and analysis of the current status of HER2 detection and interpretation of breast cancer in HebeiProvinceObjective:To understand the current status of HER2 detection and interpretation of breast cancer in Hebei Province after the promulgation of the2019 version of the HER2 interpretation consensus,discover potential problems,and improve the level of detection and interpretation and the reproducibility of results.Methods:1.Using online questionnaires to investigate breast cancer HER2detection and interpretation questions in many hospitals in Hebei Province,pathologists can also ask open questions.By reiterating the content of the guidelines and referring to relevant research documents,specific questions about the detection and interpretation process of HER2 were answered.Analyze the main factors affecting the positive rate of HER2 by multivariate logistic regression.2.Thirty-five pathologists from multiple hospitals performed online interpretation of HER2 in 50 cases of invasive breast cancer,and kappa test analyzed the consistency of the interpretation results.Results:1.Multivariate logistic regression analysis showed that the main factors affecting the positive rate of HER2 were the specimen fixation time(χ~2=36.662,P=0.013),immunohistochemical method(χ~2=26.207,P=0.003)and HER-2 antibody selection(χ~2=32.755,P=0.036).2.The current status of the application of HER2 detection is ideal:96.4%(163/169)of the unit breast cancer patients are routinely tested for HER2 in preoperative and postoperative specimens.Recurrences and metastases occurred during the treatment,and 87%(147/169)of the units were routinely tested for HER2.84.6%(143/169)and 91.1%(154/169)were routinely tested for HER2 for multicentric breast cancer and microinvasive breast cancer.3.The average Kappa value of the consistency analysis of HER2interpretation between each doctor and the other 34 doctors was 0.568,which was poor.The average accuracy rate of all pathologists in interpreting each HER2 case was 0.825.The average correct rate of HER2 interpretation by each doctor was 0.746,and the average Kappa value compared with the gold standard was 0.711.Conclusions:1.Through this questionnaire,we have a clearer understanding of the problems in HER2 detection and interpretation.The sample fixation time,immunohistochemical method and antibody selection have a significant impact on the positive rate of HER2 detection.It is recommended that the specimens be fixed in time,and standardized kits and testing procedures should be used.2.The interpretation consistency between pathologists was poor,and improving the consistency and accuracy of HER2 interpretation in breast cancer is an urgent problem to be solved.Part 2 Research on the consistency and accuracy of AI-assisted in interpretation of HER2 for breast cancerObjective:HER2 protein and gene expression levels in breast cancer are important factors for judging the prognosis of breast cancer patients.Several studies have shown that there is a big difference between pathologists and pathologists when interpreting HER2 under the microscope.In this research,we aim to analyze the accuracy and reliability of artificial intelligence(AI)assisted interpretation of HER2.Methods:We conducted three rounds of research on 50 cases of non-special subtype invasive breast cancer without neoadjuvant treatment,and recruited33 pathologists from 6 hospitals.In the first round of research(RS1),pathologists interpreted 50 HER2 digital pathology images(WSI)through an online system.After a two-week forgetting period,they used the conventional microscope in the second round of study(RS2)to interpret the HER2 sections.After another 2 weeks of forgetting,the pathologist uses AI to assist in the interpretation in the third round of research(RS3).AI is equipped with a HER2scoring algorithm based on cell-level classification and an augmented reality module for conventional microscopes,so that pathologists can obtain AI results in real time.Results:1.Compared with traditional microscopes and online WSI,the consistency and accuracy of AI-assisted interpretation have been significantly improved(P<0.001).2.The confusion matrix of the HER2 score in the three rounds of studies showed that the recall rate of IHC 1+and 2+cases under AI-assisted interpretation was significantly increased(compared with RS1,P<0.05),while the accuracy of the cases of IHC 2+and 3+was significantly improved(compared with RS1 and RS2,P<0.001).AI-assisted improves the accuracy of IHC 3+and 2+scoring,while ensuring the recall rate of fluorescent in situ hybridization(FISH)positive results in IHC 2+.3.The average acceptance rate of AI by all pathologists is 0.90,indicating that pathologists agree with most AI scoring results.Conclusions:The AI-assisted improves the accuracy and consistency of the interpretation of HER2 by pathologists.AI-assisted is a practical tool for pathologists to perform HER2 IHC diagnosis.It combines the advantages of humans and AI,and can be seamlessly integrated with the current clinical workflow.Part 3 Pathological research of HER2 in microinvasive breast cancer and T1a stage breast cancer patientsObjective:To explore the relationship between the expression of HER2and clinicopathological characteristics in patients with microinvasive breast cancer and T1a stage breast cancer and choose patients suitable for HER2targeted therapy.To analyze the consistency of HER2 expression in carcinoma in situ and invasion foci.Methods:A total of 217 cases of breast microinvasive carcinoma and breast cancer stage T1a patients admitted to the hospital from January 2015 to June 2020 in the Fourth Hospital of Hebei Medical University were collected.Interpret the HER2 expression status of the carcinoma in situ and the infiltrated area respectively.The PRECICE 600 automatic digital slice scanner scans HE stained slices.Pathologists use ASAP software to mark the infiltrating foci of breast cancer,and the machine learning model extracts the morphological features in the marked area.Combining pathological features and morphological features to construct a nomogram to predict the HER2expression status of early breast cancer.Chi-square test or Fisher’s exact test compares categorical variables in different groups.The Mann-Whitney U test compares the differences in continuous variables between different groups.Spearman analyzed the clinicopathological characteristics related to HER2expression.The R package draws a nomogram.Mc Nemar’s test analyzes the consistency of HER2 expression in carcinoma in situ and in invasive areas of breast microinvasive carcinoma and breast cancer T1a stage patients.The results were analyzed using SPSS 26.0 statistical software.Results:1.Patients with high nuclear grade,comedy type necrosis,high TILs infiltration and high proliferation index are more likely to have HER2 positive expression(all P<0.001).2.There was no significant difference in the expression of HER2 in microinvasive breast carcinoma and breast cancer stage T1a in carcinoma in situ and invasive area(P=0.25 and P=0.50).The overall agreement rate of HER2 expression of carcinoma in situ and invasive carcinoma area was 97.7%(212/217).3.The feature with the strongest correlation with the HER2 positive rate of early breast cancer is the diameter of the invasion foci(rho=-0.468,P<0.001).When the diameter of the invasion foci>2mm,the positive rate of HER2 decreases significantly(52.6%-16.1%,P<0.001).Conclusions:1.HER2 positive expression of microinvasive breast cancer and T1a breast cancer patients are associated with many unfavorable traditional prognostic factors,indicating that this early breast cancer subtype has an aggressive biological phenotype and may benefit from adjuvant chemotherapy and immunotherapy.2.The consistent rate of HER2 expression in carcinoma in situ and invasive carcinoma area of microinvasive and T1a stage breast cancer is higher.For cases where the invasion foci are small and the HER2 expression status in the invasive cancer area cannot be assessed,the HER2 expression in the carcinoma in situ area can be referred to.3.Compared with T1a stage breast cancer with an invasion foci of 1-2mm in diameter,breast cancer patients with an invasion foci of 2-5 mm in diameter are more malignant,and HER2 targeted therapy is recommended for HER2-positive breast cancer patients with an invasion foci of 2 to 5 mm in diameter.