Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

Evaluation of human epidermal growth factor receptor 2 status of breast cancer using preoperative multidetector computed tomography with deep learning and handcrafted radiomics features

Objective:To evaluate the human epidermal growth factor receptor 2(HER2)status in patients with breast cancer using multidetector computed tomography(MDCT)-based handcrafted and deep radiomics features.Methods:This retrospective study enrolled 339 female patients(primary cohort,n=177;validation cohort,n=162)with pathologically confirmed invasive breast cancer.Handcrafted and deep radiomics features were extracted from the MDCT images during the arterial phase.After the feature selection procedures,handcrafted and deep radiomics signatures and the combined model were built using multivariate logistic regression analysis.Performance was assessed by measures of discrimination,calibration,and clinical usefulness in the primary cohort and validated in the validation cohort.Results:The handcrafted radiomics signature had a discriminative ability with a C-index of 0.739[95%confidence interval(95%CI):0.661-0.818]in the primary cohort and 0.695(95%CI:0.609-0.781)in the validation cohort.The deep radiomics signature also had a discriminative ability with a C-index of 0.760(95%CI:0.690-0.831)in the primary cohort and 0.777(95%CI:0.696-0.857)in the validation cohort.The combined model,which incorporated both the handcrafted and deep radiomics signatures,showed good discriminative ability with a C-index of 0.829(95%CI:0.767-0.890)in the primary cohort and 0.809(95%CI:0.740-0.879)in the validation cohort.Conclusions:Handcrafted and deep radiomics features from MDCT images were associated with HER2 status in patients with breast cancer.Thus,these features could provide complementary aid for the radiological evaluation of HER2 status in breast cancer.

Human epidermal growth factor receptor 2 positive rates in invasive lobular breast carcinoma: The Singapore experience

BACKGROUND Invasive lobular carcinomas(ILC)form 5%-10%of breast cancer and rarely show overexpression of human epidermal growth factor receptor 2(HER2).AIM To describe the prevalence and prognostic factors of HER2 positive(HER2+)ILC in an Asian population.METHODS A retrospective review of patients with ILC seen between January 1985 and March 2018 at various SingHealth medical institutions was conducted.Demographic and clinical data were collected from medical records.We examined clinicopathological characteristics and survival in relation to HER2 status.RESULTS A total of 864 patients were included.Prevalence of HER2 positivity was 10.1%(87 patients).Compared with HER2 negative(HER2-)ILC,HER2+ILC was associated with a higher proportion of estrogen receptor negative(24.4%vs 5.9%,P<0.001),progesterone receptor negative(PR-)(40.2%vs 24%,P=0.002)and grade 3 tumours(Grade 3,29.0%vs 10.2%,P<0.001).Overall survival rate was poorer in patients with HER2+compared to HER2-ILC(56.7%vs 72.9%alive at 10 years;hazard ratio 1.87,95%confidence interval:1.21-2.90,P=0.004).Based on multivariate analysis,negative prognostic factors for overall survival included HER2 positivity,PR negativity,older age,Indian ethnicity and higher tumour stage.CONCLUSION Prevalence of HER2+ILC was 10.1%.HER2+ILC was more likely to have poorer prognostic features such as estrogen receptor negative,PR-and higher tumour grade,and have a poorer survival.

Response of human epidermal growth factor receptor 2-positive colorectal cancer to lapatinib monotherapy: A case report

BACKGROUND Human epidermal growth factor receptor 2(HER2)amplification is a molecular driver for a subset of colorectal cancers(CRCs)and one of the major causes of anti-epidermal growth factor receptor(EGFR)treatment failure.Compared to dual anti-HER2 treatments,which have been shown to be effective in HER2-positive metastatic CRC patients,single-agent anti-HER2 therapy is rarely used to treat CRC.CASE SUMMARY Herein,we report a case of RAS/BRAF-wild-type metastatic CRC that was identified as HER2-positive through circulating tumor DNA(ctDNA)testing by next-generation sequencing following the failure of two lines of therapy.Subsequently,the patient was given lapatinib monotherapy that led to a partial response with a progression-free survival of 7.9 mo.Moreover,serial ctDNA detection was used to monitor the efficacy of lapatinib.The aberration of HER2 copy number disappeared when radiographic assessment revealed a partial response.However,a high level of HER2 amplification was detected again at the time of disease progression.Finally,a phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha mutation was identified at the time of tumor progression,which may explain the acquired resistance to lapatinib.CONCLUSION This is the first case report of HER2-positive RAS/BRAF wild-type metastatic CRC patient responding to lapatinib monotherapy.It highlights that ctDNA testing is an effective and feasible approach to evaluate the efficacy of anti-HER2 therapy.

Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann's HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann's HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but low consistency was observed between IHC2+ and FISH(40.00%).The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively(28.57% vs 13.43%,P = 0.0103;37.25% vs 11.64%,P < 0.0001),but were not correlated with gender,age,tumor location or TNM stage,depth of invasion,lymph node metastases and distant metastasis.In poorly-differentiated gastric cancer patients,those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis(26.47% vs 7.14%,P = 0.0021).This association was not present in thosepatients with well-differentiated gastric cancer(28.57% vs 43.33%,P = 0.2832).Within our patient cohort,26 cases were lost to follow-up.The median survival time for the remaining 171 patients was 18 mo.The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively.Overall survival was not significantly different between HER2-positive and negative groups(χ 2 = 0.9157,P = 0.3386),but in patients presenting well-differentiated tumors,the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group(P = 0.0123).In contrast,patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2.Furthermore,the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender,age,tumor location,TNM classification,lymph node metastases and distant metastasis.CONCLUSION:Patients with intestinal type gastric cancer(GC),well-differentiated GC and poorly-differentiated GC without lymph node metastasis,may all represent suitable candidates for targeted therapy using Herceptin.

A CT-based radiomics nomogram for prediction of human epidermal growth factor receptor 2 status in patients with gastric cancer

Objective: To develop and validate a computed tomography(CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2(HER2) status in patients with gastric cancer.Methods: This retrospective study included 134 patients with gastric cancer(HER2-negative: n=87;HER2-positive: n=47) from April 2013 to March 2018, who were then randomly divided into training(n=94) and validation(n=40) cohorts. Radiomics features were obtained from the CT images showing gastric cancer. Least absolute shrinkage and selection operator(LASSO) regression analysis was utilized for building the radiomics signature. A multivariable logistic regression method was applied to develop a prediction model incorporating the radiomics signature and independent clinicopathologic risk predictors, which were then visualized as a radiomics nomogram. The predictive performance of the nomogram was assessed in the training and validation cohorts.Results: The radiomics signature was significantly associated with HER2 status in both training(P<0.001) and validation(P=0.023) cohorts. The prediction model that incorporated the radiomics signature and carcinoembryonic antigen(CEA) level demonstrated good discriminative performance for HER2 status prediction,with an area under the curve(AUC) of 0.799 [95% confidence interval(95% CI): 0.704-0.894] in the training cohort and 0.771(95% CI: 0.607-0.934) in the validation cohort. The calibration curve of the radiomics nomogram also showed good calibration. Decision curve analysis showed that the radiomics nomogram was useful.Conclusions: We built and validated a radiomics nomogram with good performance for HER2 status prediction in gastric cancer. This radiomics nomogram could serve as a non-invasive tool to predict HER2 status and guide clinical treatment.

Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

Aim： To investigate human epidermal growth factor receptor type 2 （HER2） protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods： Immunohistochemistry （IHC） was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate （TURP）. HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2＋ were investigated for HER2 gene amplification status by fluorescent in situ hybridization （FISH）. Results： Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1＋, 2＋ and 3＋ in 49 （47.1%）, 45 （43.3%）, 8 （7.7%） and 2 （1.9%） cases, respectively. There was a significant association between HER2 expression and Gleason score （P = 0.026）. HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2＋ showed HER2 gene amplification. Patients with HER2 scores 〉 2＋ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 （P = 0.004） and 1＋ （P = 0.034）. Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death （P = 0.039）. Conclusion： An HER2 IHC score 〉 2＋ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2)-phosphatidylinositol 3-kinase(PI3K)-vAkt murine thymoma viral oncogene homolog signaling pathway.METHODS:We analyzed 231 formalin-fixed,paraffinembedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment.The patients' age,sex,tumor location,depth of invasion,pathological type,lymph node metastasis,and pathological stage were determined by a review of the medical records.Expression of HER2 was analyzed by immunohistochemistry(IHC) using the HercepTest TM kit.Standard criteria for HER2 positivity(0,1+,2+,and 3+) were used.Tumors that scored 3+ were considered HER2-positive.Expression of phospho Akt(pAkt) was also analyzed by IHC.Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more.PI3K,catalytic,alpha polypeptide(PIK3CA) mutations in exons 1,9 and 20 were analyzed by pyrosequencing.Epstein-Barr virus(EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA(EBER) with an EBER-RNA probe.Microsatellite instability(MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS:HER2 expression levels of 0,1+,2+ and 3+ were found in 167(72%),32(14%),12(5%) and 20(8.7%) samples,respectively.HER2 overexpression(IHC 3+) significantly correlated with intestinal histological type(15/20 vs 98 /205,P = 0.05).PIK3CA mutations were present in 20 cases(8.7%) and significantly correlated with MSI(10/20 vs 9/211,P < 0.01).The mutation frequency was high(21%) in T4 cancers and very low(6%) in T2 cancers.Mutations in exons 1,9 and 20 were detected in 5(2%),9(4%) and 7(3%) cases,respectively.Two new types of PIK3CA mutation,R88Q and R108H,were found in exon1.All PIK3CA mutations were heterozygous missense singlebase substitutions,the most common being H1047R(6/20,30%) in exon20.Eighteen cancers(8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type(13/18 vs 93/198,P = 0.04).There were 7 cases of lymphoepithelioma-like carcinomas(LELC) and 6 of those cases were EBV-positive(percent/EBV:6/18,33%;percent/all LELC:6/7,86%).pAkt expression was positive in 119(53%) cases but showed no correlation with clinicopathological characteristics.pAkt expression was significantly correlated with HER2 overexpression(16/20 vs 103/211,P < 0.01) but not with PIK3CA mutations(12/20 vs 107/211,P = 0.37) or EBV infection(8/18 vs 103/211,P = 0.69).The frequency of pAkt expression was higher in cancers with exon20 mutations(100%) than in those with exon1(40%) or exon9(56%) mutations.One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection.However,no cases showed both PIK3CA mutations and HER2 overexpression.One EBVpositive cancer with PIK3CA mutation(H1047R) was MSI-positive.Three of these 4 cases were positive for pAkt expression.In survival analysis,pAkt expression significantly correlated with a poor prognosis(hazard ratio 1.75;95%CI:1.12-2.80,P = 0.02).CONCLUSION:HER2 expression,PIK3CA mutations and EBV infection in gastric cancer were characterized.pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology

AIM:To assess human epidermal growth factor receptor-2 (HER2)-status in gastric cancer and matched lymph node metastases by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH).METHODS:120 cases of primary gastric carcinomas and 45 matched lymph node metastases from patients with full clinicopathological features were mounted onto multiple-punch and single-punch tissue microarrays,respectively,and examined for HER2 overexpression and gene amplification by IHC and CISH.RESULTS:Twenty-four tumors (20%) expressed HER2 immunohistochemically.An IHC score of ≥ 2+ was observed in 20 tumors (16.6%).HER2 amplification was detected by CISH in 19 tumors (15.8%) and in their matched lymph node metastases.A high concordancerate was found between HER2 positivity (as detected by IHC) and HER2 gene amplification (as detected by CISH),since 19 of the 20 IHC positive cases were amplified (95%).All amplified cases had 2+ or 3+ IHC results.Amplification was associated with intestinal phenotype (P < 0.05).No association with grading,staging or survival was found.CONCLUSION:In gastric cancer,HER2 amplification is the main mechanism for HER2 protein overexpression and is preserved in lymph node metastases.

Role of human epidermal growth factor receptor 2 in gastric cancer:Biological and pharmacological aspects

Amplification of the human epidermal growth factor receptor 2(HER2)gene and overexpression of the HER2protein is found in 15%-20%of patients with gastric and gastroesophageal junction cancer.The degree of HER2 overexpression and amplification varies with the location of the carcinoma,with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach.Further,HER2 overexpression and amplification also seems to be related to the Lauren histological classification,with higher levels found in the intestinal phenotype compared to the diffuse and mixed types.The prognostic properties of HER2 overexpression and amplification are still under debate,but a large number of studies seem to indicate that HER2 is a negative prognostic factor.The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial,where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive5-FU/capecitabine and cisplatin,either alone or in combination with trastuzumab.A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy.Patients with a strong overexpression of the HER2 protein(IHC3+)specifically benefited from the treatment,with a median overall survival of 17.9 mo.As a consequence of the positive results of the ToGA trial,patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2.The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab,ado-trastuzumab emtansine,lapatinib,afatinib,and dacomitinib,which are currently undergoing phaseⅡandⅢclinical testing.Overall,this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.

High levels of serum platelet-derived growth factor-AA and human epidermal growth factor receptor-2 are predictors of colorectal cancer liver metastasis

AIM To develop predictive markers in blood for colorectal cancer liver metastasis.METHODS Twenty colorectal cancer patients were selected and divided into two groups. Group A consisted of 10 patients whose pathological TNM stage was ⅢC(T3-4N2M0), while another 10 patients with synchronous liver metastasis(TNM stage Ⅳ) were recruited for group B. During the surgical procedure, a 10-ml drainage vein(DV) blood sample was obtained from the DV of the tumor-bearing segment prior to the ligation of the DV. At the same time, a 10-ml peripheral vein(PV) blood sample was collected via peripheral venipuncture. The serum levels of 24 molecules that are potentially involved in the mechanism of liver metastasis in both DV blood and PV blood were analyzed by using high-throughput enzyme-linked immunosorbent assay technology.RESULTS Univariate analysis revealed that platelet-derivedgrowth factor AA(PDGFAA) in DV blood(d PDGFAA)(P = 0.001), PDGFAA in PV blood(p PDGFAA)(P = 0.007), and human epidermal growth factor receptor-2 in PV blood(p HER2)(P = 0.001), p MMP7(P = 0.028), pR ANTES(P = 0.013), and pE GF(P = 0.007) were significantly correlated with synchronous liver metastasis. Multivariate analysis identified d PDGFAA(HR = 1.001, P = 0.033) and p HER2(HR = 1.003, P = 0.019) as independent predictive factors for synchronous liver metastasis. Besides, high peripheral HER2 level may also be a risk factor for metachronous liver metastasis, although the difference did not reach statistical significance(P = 0.06). Significant correlations were found between paired DV and PV blood levels for PDGFAA(r = 0.794, P < 0.001), but not for HER2(r = 0.189, P = 0.424).CONCLUSION PDGFAA in tumor drainage and HER2 in PV blood may be useful predictive factors for synchronous liver metastasis of colorectal cancer.

Inetetamab combined with pyrotinib and oral vinorelbine for patients with human epidermal growth factor receptor 2 positive advanced breast cancer:A single-arm phase 2 clinical trial

Background Human epidermal growth factor receptor 2(HER2)-targeted agents have significantly improved the outcomes of patients with HER2-positive breast cancer;however,a large proportion of patients still develop resistance to trastuzumab.In this study,we investigated the efficacy and safety of inetetamab,another anti-HER2 antibody,combined with pyrotinib and oral vinorelbine in patients with HER2-positive advanced breast cancer so as to provide new ideas for the treatment.Methods In this prospective,single-arm,phase 2 trial,patients with HER2-positive advanced breast cancer with disease progression after trastuzumab were recruited.Patients received a combination of inetetamab(loading dose of 8 mg/kg and subsequent doses of 6 mg/kg intravenously once every 3 weeks),pyrotinib(400 mg orally once daily),and vinorelbine(60 mg/m^(2)orally once weekly)until disease progression or intolerable toxicity.The primary endpoint was progression-free survival(PFS).The secondary endpoints included objective response rate(ORR),overall survival(OS),disease control rate(DCR),and safety.Results Between February 13,2022 and December 25,2022,30 patients were screened and enrolled in this study.The median age of the patients at enrollment was 54 years,12 patients(40.0%)had hormone-receptor-positive disease and 23 patients(76.7%)had visceral metastasis.The median PFS was 8.63 months(95%confidence interval[CI]4.15-13.12 months).The median OS was not reached.The ORR was 53.3%(16/30)and the DCR was 96.7%(29/30).The most common Grade III/IV adverse events were leukopenia(n=5,16.7%),neutropenia(n=4,13.3%),and diarrhea(n=3,10%).No treatment-related serious adverse events or deaths occurred.Conclusions The combination regimen of inetetamab,pyrotinib,and oral vinorelbine showed encouraging efficacy and favorable safety in patients with HER2-positive advanced breast cancer and could be considered as an alternative treatment option for the patients.

Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer:Clinical and pathological perspectives

Endometrial cancer is the most common gynecological cancer in developed countries,and its incidence has increased.The majority of patients with endometrial cancer have an early disease and favorable prognosis;however,a significant proportion of endometrial cancer,which mainly comprises high-grade or type II endometrial cancer such as serous,clear cell,and carcinosarcoma,shows advanced/recurrent disease and dismal prognosis.Novel therapeutic development is required for patients with aggressive endometrial cancers.Recent genomic and immunohistochemical analyses revealed human epidermal growth factor receptor 2(HER2)overexpression/gene amplification in 20%-40%of patients with type II endometrial cancer.Historically,HER2 targeted therapy has been developed for various major cancers,including breast and gastric cancer.Notably,recent advances in HER2 targeted therapy for patients with type II endometrial cancer are also expected to change.Simultaneously,an optimized HER2 test for endometrial cancer as companion diagnostics should be established.In this review,we summarize the recent findings on endometrial cancer,current treatment,optimized HER2 testing,key clinical trials on HER2 targeted therapy,and future directions in aggressive endometrial cancer,including serous carcinoma and carcinosarcoma.

Therapeutic options for HER-2 positive breast cancer: Perspectives and future directions

During the last 15 years we have witnessed an unprecedented expansion in the drugs developed to target human epidermal growth factor receptor-2(HER-2) positive breast cancer. Trastuzumab, pertuzumab, adotrastuzumab emtansine and lapatinib are currently food and drug administration(FDA)-approved for the treatment of breast cancer patients with HER-2 overexpressed. However, given the amount of information gathered from years of uninterrupted clinical research, it is essential to have periodic updates that succinctly recapitulate what we have learnt over these last years and help us to apply that information in our daily practice. This review will pursue that objective. We will summarize the most relevant and updated informationrelated to the state of the art management of HER-2 positive breast cancer in all the clinical scenarios including the adjuvant, neoadjuvant and metastatic settings. But we will also critically appraise that literature in order to highlight some key clinical concepts that should not be overlooked. Lastly, this review will also point out some of the most promising strategies that are currently being tested and may soon become available.

Preclinical and clinical applications of specific molecular imaging for HER2-positive breast cancer

Precision medicine and personalized therapy are receiving increased attention, and molecular-subtype classification has become crucial in planning therapeutic schedules in clinical practice for patients with breast cancer. Human epidermal growth factor receptor 2(HER2) is associated with high-grade breast tumors, high rates of lymph-node involvement, high risk of recurrence, and high resistance to general chemotherapy. Analysis of HER2 expression is highly important for doctors to identify patients who can benefit from trastuzumab therapy and monitor the response and efficacy of treatment. In recent years, significant efforts have been devoted to achieving specific and noninvasive HER2-positive breast cancer imaging in vivo. In this work, we reviewed existing literature on HER2 imaging in the past decade and summarized the studies from different points of view, such as imaging modalities and HER2-specific probes. We aimed to improve the understanding on the translational process in molecular imaging for HER2 breast cancer.

Effect of Herceptin combined with paclitaxel neoadjuvant chemotherapy on the proliferation viability of HER-2 positive breast cancer cell

Objective: To study the effect of Herceptin combined with paclitaxel neoadjuvant chemotherapy on the proliferation viability of HER-2 positive breast cancer cell. Methods:The patients who were diagnosed with breast cancer and received neoadjuvant chemotherapy in Ziyang First People's Hospital between February 2015 and October 2017 were selected and randomly divided into the experimental group who received Herceptin combined with docetaxel chemotherapy and the control group who received epirubicin combined with docetaxel chemotherapy. After chemotherapy ended, serum levels of tumor markers were measured;after surgical resection, the breast cancer lesions were collected to measure the mRNA expression of proliferation genes and tumor suppressor genes. Results: The differences in tumor marker levels as well as proliferation gene and tumor suppressor gene expression were statistically significant between the two groups;CA15-3, IGF-1, TSGF and TPS levels in serum as well as CyclinD1, PCNA, Bcl-2, Survivin and VEGF mRNA expression in breast cancer lesions of experimental group were lower than those of control group whereas PTEN, Bax, ARID1A, FasL and Caspase-3 mRNA expression in breast cancer lesions were higher than those of control group. Conclusion: Herceptin combined with paclitaxel neoadjuvant chemotherapy can more effectively inhibit the proliferation activity of HER-2 positive breast cancer cells than epirubicin combined with paclitaxel chemotherapy.

Effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in HER-2-positive breast cancer lesions

Objective: To study the effect of trastuzumab combined with paclitaxel neoadjuvant chemotherapy on the cell proliferation and invasion in human epidermal growth factor receptor-2 (HER-2)-positive breast cancer lesions. Methods: Patients who were diagnosed with HER-2-positive breast cancer in the Central Hospital of Enshi Autonomous Prefecture Hubei Province between April 2015 and January 2017 were selected and randomly divided into two groups, the combined group received trastuzumab combined with paclitaxel chemotherapy, and the control group accepted paclitaxel chemotherapy. The surgically removed breast cancer lesions were collected to determine the expression of cell proliferation genes, cell invasion genes and angiogenesis molecules. Results: USP39, EphA2, NUAK1, Gab2, Raptor, ICAM-1, HIF-1α, VEGF, ANGPLT-2 and ANGPLT-4 mRNA expression in tumor lesion of combined group were significantly lower than those of control group while CCN5, ALEX1, ATG2B, ATG4D, E-cadherin and EBP50 mRNA expression were significantly higher than those of control group. Conclusion: Trastuzumab combined with paclitaxel neoadjuvant chemotherapy can inhibit the cell proliferation and invasion and decrease the angiogenesis in HER-2-positive breast cancer lesions.