PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

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.

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 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.

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.

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.

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.

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.

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.

Comparison of immunohistochemistry with fluorescence in situ hybridization in determining the human epidermal growth factor receptor 2 status of breast cancer specimens： a multicenter study of 3149 Chinese patients

Background Accurate detection of human epidermal growth factor receptor 2 （HER2） expression and gene amplification is crucial for the application of HER2-specific therapy and for evaluating the response of patients with breast cancer.A uniform and standard procedure of immunohistochemistry （IHC） and fluorescence in situ hybridization （FISH） needs to be established for evaluating the HER2 status in breast cancer tissues for the treatment of patients with real HER2-positive tumors.The present multicenter study was aimed to examine the HER2 status in breast cancer specimens from Chinese patients using both IHC and FISH methods.Methods A multicenter study was performed on the HER2 status in 3 149 breast cancer specimens from different ethnic populations and areas in China by IHC and FISH assays.The potential association of HER2 status with demographic and clinical characteristics was analyzed.Results The positive rates for HER2 over-expression and HER2 amplification were 23.3％ and 27.5％ in this study,respectively.The concordance between IHC and FISH was 71.2％ （K=0.494,P ＜0.001）.Furthermore,72.9％ of specimens with IHC 2＋ were negative to FISH.The discordance rates among laboratories were from 5％ to 28％ for IHC and 1％ to 16％ for FISH.HER2 amplification was associated significantly with advanced tumor stage （Ⅲ or Ⅳ,P=0.002）,large tumor size （＞5 cm,P=0.002）,moderate and poor histological grades （P ＜0.0001）,post-menopause （P ＜0.0001）,ER-PR-（P=0.002）,and having ＞4 lymph nodes affected （P ＜0.0001） in this population.The positive rates of HER2 amplification in specimens from Man and Hui Chinese were significantly higher than that in other Chinese populations.There are slightly higher positive rates of HER2 expression and amplification in Chinese patients with breast cancer.Conclusion These findings may provide new insights into understanding the epidemiological features of HER2 expression and amplification,and may be valuable for clinical practice.

Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia - induced cell death

Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-

Epithelial-mesenchymal transition status of circulating tumor cells in breast cancer and its clinical relevance

Objective:Circulating tumor cells(CTCs)play a critical role in cancer metastasis,but their prevalence and significance remain unclear.This study attempted to track the epithelial-mesenchymal transition(EMT)status of CTCs in breast cancer patients and investigate their clinical relevance.Methods:In this study,the established negFACS-IF:E/M platform was applied to isolate rare CTCs and characterize their EMT status in breast cancer.A total of 89 breast cancer patients were recruited,including stage 0–III(n=60)and late stage(n=29)cases.Results:Using the negFACS-IF:E/M platform,it was found that in human epidermal growth factor receptor 2(HER2)+patients,mesenchymal CTCs usually exhibited a high percentage of HER2+cells.Stage IV breast cancer patients had considerably more CTCs than stage 0–III patients.Among stage 0–III breast cancers,the HER2 subtype included a significantly higher percentage of mesenchymal and biphenotypic(epithelial and mesenchymal)CTCs than the luminal A or B subtypes.Among stage IV patients,CTCs were predominantly epithelial in cases with local recurrence and were more mesenchymal in cases with distant metastasis.By applying a support vector machine(SVM)algorithm,the EMT status of CTCs could distinguish between breast cancer cases with metastasis/local recurrence and those without recurrence.Conclusions:The negFACS-IF:E/M platform provides a flexible and generally acceptable method for the highly sensitive and specific detection of CTCs and their EMT traits in breast cancer.This study demonstrated that the EMT status of CTCs had high clinical relevance in breast cancer,especially in predicting the distant metastasis or local recurrence of breast cancer.

Preclinical characterization and validation of a dual-labeled trastuzumab-based imaging agent for diagnosing breast cancer

Objective： The combination of both nuclear and fluorescent reporters provides unique opportunities for noninvasive nuclear imaging with subsequent fluorescence image-guided resection and pathology. Our objective was to synthesize and optimize a dual-labeled trastuzumab-based imaging agent that can be used to validate an optical imaging agent with potential use in identifying tumor metastases in human epidermal growth factor receptor 2 （HER2） positive breast cancer patients. Methods： [111In]-DTPA-trastuzumab-IRDye 800 was synthesized by a three-step procedure. Purity, stability, immunoreactivity, internalization and biodistribution were explored in HER2＋ SKBR-3 cells. Biodistribution of [111In]-DTPA-trastuzumab-IRDye 800 was performed in a SKBR-3 xenograft model. Results： [111In]-DTPA-trastuzumab-IRDye 800 demonstrated high purity by both chemical and fluorometric determinations. Both flow cytometry and the Lindmo assay demonstrated a high binding affinity of [111In]-DTPA-trastuzumab-IRDye 800 to HER2-overexpressing cells. The dual-labeled conjugate was stable in PBS, but not in serum after 24 h at 37 ℃. Larger molecules （〉150 kD） were seen after a 24 h-incubation in human serum. Biodistribution studies revealed tumor-specific accumulation of [111In]-DTPA- trastuzumab-IRDye 800 in SKBR-3 tumors, and tumor uptakes at 24 and 48 h were （12.42±1.72）% and （9.96±1.05） %, respectively, following intravenous administration. The tumor-to-muscle ratio was 9.13±1.68 at 24 h, and increased to 12.79±2.13 at 48 h. Liver and kidney showed marked uptake of the dual-labeled imaging agent. Conclusions： [111In]-DTPA-trastuzumab-IRDye 800 is an effective diagnostic biomarker that can be used to validate dual-labeled, molecularly targeted imaging agents and can allow these agents to be translated into clinical practice for identifying HER2＋ lesions.

Pancreaticoduodenectomy after neoadjuvant chemotherapy for gastric cancer invading the pancreatic head:A case report

BACKGROUND Pancreaticoduodenectomy(PD)for advanced gastric cancer is rarely performed because of the high morbidity and mortality rates and low survival rate.However,neoadjuvant chemotherapy for advanced gastric cancer has improved,and chemotherapy combined with trastuzumab may have a preoperative tumorreducing effect,especially for human epidermal growth factor receptor 2(HER2)-positive cases.CASE SUMMARY We report a case of successful radical resection with PD after neoadjuvant S-1 plus oxaliplatin(SOX)and trastuzumab in a patient(66-year-old male)with advanced gastric cancer invading the pancreatic head.Initial esophagogastroduodenoscopy detected a type 3 advanced lesion located on the lower part of the stomach obstructing the pyloric ring.Computed tomography detected lymph node metastasis and tumor invasion to the pancreatic head without distant metastasis.Pathological findings revealed adenocarcinoma and HER2 positivity(immunohistochemical score of 3+).We performed staging laparoscopy and confirmed no liver metastasis,no dissemination,negative lavage cytological findings,and immobility of the distal side of the stomach due to invasion to the pancreas.Laparoscopic gastrojejunostomy was performed at that time.One course of SOX and three courses of SOX plus trastuzumab were administered.Preoperative computed tomography showed partial response;therefore,PD was performed after neoadjuvant chemotherapy,and pathological radical resection was achieved.CONCLUSION We suggest that radical resection with PD after neoadjuvant chemotherapy plus trastuzumab is an option for locally advanced HER2-positive gastric cancer invading the pancreatic head in the absence of non-curative factors.

HER2 discordance between paired primary gastric cancer and metastasis:a meta-analysis

Background： A number of studies have examined human epidermal growth factor receptor 2 （HER2） status in primary gastric cancer （GC） and associated metastasis, some showed their great concordance in FIER2 expression, but others demonstrated notable discordance. There is still little consensus on HER2 discordance, therefore, a systematic review and meta-analysis was conducted to assess the status on HER2 discordance between primary GC and its paired metastasis. Methods： PubMed, EMBASE, ASCO and The Cochrane Library were searched for studies that explored the concordance between primary tumor and metastasis in patients with GC up to 10 March, 2014. Data of discordance of HER2 between primary GC and corresponding metastasis were extracted from the publications and random-effects models were used to estimate pooled discordance proportions. Results： Eighteen articles including 1,867 patients were included for the meta-analysis in accordance with the selection criteria. Pooled discordance proportions were 7% [95% confidence interval （CI）： 5-10%] for HER2 status. Pooled proportions of tumors shifting from positive to negative and from negative to positive were 17% （95% CI： 7-29%） and 4% （95% CI： 2-6%） respectively. No publication bias was found in the meta-analysis. Conclusions： The discordance of HER2 status is not rare in primary and metastatic GC through our metaanalysis. Prospective studies are needed to testify the clinical significance of the discordance of HER2 status.

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.

HER2-positive adenocarcinoma arising from heterotopic pancreas tissue in the duodenum:A case report

BACKGROUND Adenocarcinoma originating from heterotopic pancreas tissue is a rare disease.Furthermore,to our knowledge,no HER2-positive cases in the duodenum have been reported in the scientific literature nor has the efficacy of trastuzumab treatment for the disease been reported.CASE SUMMARY A 65-year-old woman whose clinical diagnosis was unresectable advanced duodenal cancer with HER2 overexpression responded well to trastuzumab chemotherapy.The main tumor in the duodenum reduced drastically.The patient underwent pancreaticoduodenectomy and lymph node dissection.A small number of cancer cells remained in the submucosal layer of the duodenum and pancreas head.After histological and immunohistochemical examination,the patient was diagnosed with duodenal adenocarcinoma originating from heterotopic pancreas tissue.CONCLUSION Trastuzumab treatment is effective in HER2-positive adenocarcinoma originating from heterotopic pancreas tissue in the duodenum.

Influence of chelator and near-infrared dye labeling on biocharacteristics of dual-labeled trastuzumab-based imaging agents

Objective： To investigate the effect of fluorescent dye labeling on the targeting capabilities of 111 In- （DTPA）.-trastuzumab-（IRDye 800）m. Methods： Trastuzumab-based conjugates were synthesized and conjugated with diethylenetriaminepentaacetic acid （DTPA） at molar ratios of I, 2, 3 and 5 and with a fluorescent dye （IRDye 800CW） at molar ratios of 1, 3 and 5. Immunoreactivity and internalization were assessed on SKBR-3 cells, overexpressing human epidermal growth factor receptor 2. The stability in human serum and phosphate-buffered saline （PBS） was evaluated. The biodistribution of dual-labeled conjugates was compared with that of 111In-（DTPA）2-trastuzumab in a SKBR-3 xenograft model to evaluate the effect of dye-to-protein ratio. Results： All trastuzumab-based conjugates exhibited a high level of chemical and optical purity. Flow cytometry results showed that increasing dye-to-protein ratios were associated with decreased immunoreactivity. Stability studies revealed that the conjugate was stable in PBS, while in human serum, increased degradation and protein precipitation were observed with increasing dye-to-protein ratios. At 4 h, the percentages of internalization of dual-labeled conjugates normalized by dye-to-protein ratio （m） were 24.88%±2.10%, 19.99%±0.59%, and 17.47%±1.26% for ＂m＂ equal to 1, 3, and 5, respectively. A biodistribution study revealed a progressive decrease in tumor uptake with an increase in the dye-to-protein ratios. The liver, spleen and kidney showed a marked uptake with increased dye-to-protein ratios, particularly in the latter. Conclusions： With non-specific-site conjugation of the fluorescent dye with a protein based on imaging agent, the increase in dye-to-protein ratios negatively impacted the immunoreactivity and stability, indicating a reduced tumor uptake.

Accurate Assessment of HER2 Gene Status for Invasive Component of Breast Cancer by Combination of Immunohistochemistry and Chromogenic In Situ Hybridization

Summary： The specimens of ductal carcinoma in situ （DCIS） with early invasion, and specimens col- lected by core needle biopsy （CNB） tend to contain limited amount of invasive component, so it is im- perative to explore a new technique which can assess HER2 gene status accurately for the limited inva- sive cancer component in these specimens. Dual staining technique of combining immunohistochemis- try （IHC） for myoepithelial cells and single or dual probe chromogenic in situ hybridization （CISH） for HER2 gene was performed on routinely processed paraffin sections from 20 cases diagnosed as having DCIS with invasive cancer. Among them, 10 had fluorescence in situ hybridization （FISH）-confirmed amplification of HER2 and 10 had FISH-confirmed non-amplification of HER2. We successfully de- tected HER2 genetic signals and myoepithelial IHC markers （SMM-HC or CK5/6） simultaneously on a single section in all 20 specimens. Myoepithelial markers and HER2 signals detected by dual staining assay were consistent with those by individual technique performed alone. HER2 gene amplification results determined by dual staining assay were 100% consistent with those of FISH. Dual staining tech- nique which allows simultaneous detection of myoepithelial marker protein and cancerous HER2 gene is feasible, and it has potential to be used in clinical practice for effective determination of HER2 ampli- fication in limited invasive component.