Granulomatosis with polyangiitis induced by the anti-programmed cell death-1 inhibitor tislelizumab:A case report

BACKGROUND Immune checkpoint inhibitors(ICIs)are a new class of antitumor agents.They enhance antitumor effects by blocking inhibitory receptors and related ligands expressed on T cells.ICIs also modulate regular immune cell activity,affecting the immune system and causing immune-related adverse events.The renal system is sometimes affected by these adverse events.Currently,the literature on ICIs-related glomerular injuries is scarce.CASE SUMMARY We present a patient who developed granulomatosis with polyangiitis(GPA)3 weeks after treatment with the anti-programmed cell death-1 inhibitor,tislel-izumab.The patient experienced proteinuria,hematuria,and acute kidney injury without pulmonary hemorrhage and tested positive for anti-neutrophil cyto-plasmic antibody(ANCA)-cytoplasmic type.Renal biopsy confirmed ANCA-associated vasculitis,and GPA was finally diagnosed.The patient received pulse treatment with glucocorticoids and cyclophosphamide,and renal function improved.After self-discontinuation of the drug,the disease recurred,and the original treatment regimen was continued.However,the patient’s renal function continued to deteriorate.CONCLUSION Glucocorticoids plus cyclophosphamide are effective for treating GPA induced by tislelizumab.However,follow-up and patient education are needed.

Efficacy comparison of fruquintinib,regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

BACKGROUND Regorafenib(R)and fruquintinib(F)are the standard third-line regimens for colorectal cancer(CRC)according to the National Comprehensive Cancer Network guidelines,but both have limited efficacy.Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair(MSS/pMMR)CRC.Due to the lack of studies comparing the efficacy between F,R,F plus programmed death-1(PD-1)inhibitor,and R plus PD-1 inhibitors(RP),it is still unclear whether the combination therapy is more effective than monotherapy.AIM To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC(mCRC)patients in clinical practice.METHODS A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital,and 313 MSS/pMMR mCRC patients were finally included.RESULTS A total of 313 eligible patients were divided into F(n=70),R(n=67),F plus PD-1 inhibitor(FP)(n=95)and RP(n=81)groups.The key clinical characteristics were well balanced among the groups.The median progression-free survival(PFS)of the F,R,FP,and RP groups was 3.5 months,3.6 months,4.9 months,and 3.0 months,respectively.The median overall survival(OS)was 14.6 months,15.7 months,16.7 months,and 14.1 months.The FP regimen had an improved disease control rate(DCR)(P=0.044)and 6-month PFS(P=0.014)and exhibited a better trend in PFS(P=0.057)compared with F,and it was also significantly better in PFS than RP(P=0.030).RP did not confer a significant survival benefit;instead,the R group had a trend toward greater benefit with OS(P=0.080)compared with RP.No significant differences were observed between the R and F groups in PFS or OS(P>0.05).CONCLUSION FP is superior to F in achieving 6-month PFS and DCR,while RP is not better than R.FP has an improved PFS and 6-month PFS compared with RP,but F and R had similar clinical efficacy.Therefore,FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

C-reactive protein to albumin ratio predict responses to programmed cell death-1 inhibitors in hepatocellular carcinoma patients

BACKGROUND Over the years,programmed cell death-1(PD-1)inhibitors have been routinely used for hepatocellular carcinoma(HCC)treatment and yielded improved survival outcomes.Nonetheless,significant heterogeneity surrounds the outcomes of most studies.Therefore,it is critical to search for biomarkers that predict the efficacy of PD-1 inhibitors in patients with HCC.AIM To investigate the role of the C-reactive protein to albumin ratio(CAR)in evaluating the efficacy of PD-1 inhibitors for HCC.METHODS The clinical data of 160 patients with HCC treated with PD-1 inhibitors from January 2018 to November 2022 at the First Affiliated Hospital of Guangxi Medical University were retrospectively analyzed.RESULTS The optimal cut-off value for CAR based on progression-free survival(PFS)was determined to be 1.20 using x-tile software.Cox proportional risk model was used to determine the factors affecting prognosis.Eastern Cooperative Oncology Group performance status[hazard ratio(HR)=1.754,95%confidence interval(95%CI)=1.045-2.944,P=0.033],CAR(HR=2.118,95%CI=1.057-4.243,P=0.034)and tumor number(HR=2.932,95%CI=1.246-6.897,P=0.014)were independent prognostic factors for overall survival.CAR(HR=2.730,95%CI=1.502-4.961,P=0.001),tumor number(HR=1.584,95%CI=1.003-2.500,P=0.048)and neutrophil to lymphocyte ratio(HR=1.120,95%CI=1.022-1.228,P=0.015)were independent prognostic factors for PFS.Two nomograms were constructed based on independent prognostic factors.The C-index index and calibration plots confirmed that the nomogram is a reliable risk prediction tool.The ROC curve and decision curve analysis confirmed that the nomogram has a good predictive effect as well as a net clinical benefit.CONCLUSION Overall,we reveal that the CAR is a potential predictor of short-and long-term prognosis in patients with HCC treated with PD-1 inhibitors.If further verified,CAR-based nomogram may increase the number of markers that predict individualized prognosis.

Cytokine release syndrome induced by anti-programmed death-1 treatment in a psoriasis patient:A dark side of immune checkpoint inhibitors

In recent years,cancer immunotherapy has introduced novel treatments,such as monoclonal antibodies,which have facilitated targeted therapies against tumor cells.Programmed death-1(PD-1)is an immune checkpoint expressed in T cells that regulates the immune system’s activity to prevent over-activation and tissue damage caused by inflammation.However,PD-1 is also expressed in tumor cells and functions as an immune evasion mechanism,making it a therapeutic target to enhance the immune response and eliminate tumor cells.Consequently,immune checkpoint inhibitors(ICIs)have emerged as an option for certain tumor types.Nevertheless,blocking immune checkpoints can lead to immune-related adverse events(irAEs),such as psoriasis and cytokine release syndrome(CRS),as exemp-lified in the clinical case presented by Zhou et al involving a patient with adva-nced gastric cancer who received sintilimab,a monoclonal antibody targeting PD-1.Subsequently,the patient experienced exacerbation of psoriasis and CRS.The objective of this editorial article is to elucidate potential immunologic mechanisms that may contribute to the development of CRS and psoriasis in patients receiving ICIs.It is crucial to acknowledge that while ICIs offer superior safety and efficacy compared to conventional therapies,they can also manifest irAEs affecting the skin,gastrointestinal tract,or respiratory system.In severe cases,these irAEs can lead to life-threatening complications such as circulatory shock or multiorgan failure.Consequently,it is recommended that patients receiving ICIs undergo regular monitoring to identify and manage these adverse events effectively.

Programmed cell death-1 inhibitor-related sclerosing cholangitis:A systematic review

BACKGROUND Programmed cell death-1(PD-1)inhibitor has been indicated for many types of malignancies.However,these inhibitors also cause immune-related adverse events.Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%–4.5%of patients treated with PD-1 inhibitors.Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis(SC);however,the associated clinical and pathological features are unclear.AIM To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature.METHODS The review,conducted using electronic databases in PubMed,was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English.We scanned the references of the selected literature to identify any further relevant studies.Six cases previously studied by us,including three that have not yet been published,were included in this review.RESULTS Thirty-one PD-1 inhibitor-related SC cases were evaluated.Median age of patients was 67 years(range,43–89),with a male to female ratio of 21:10.The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer.Agents that caused PD-1 inhibitor-related SC were nivolumab(19 cases),pembrolizumab(10 cases),avelumab(1 case),and durvalumab(1 case).The median number of cycles until PD-1 inhibitor-related SC onset was 5.5(range,1–27).Abdominal pain or discomfort(35.5%,11/31)was the most frequent symptom.Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes,and a normal level of serum immunoglobulin G4.Biliary dilation without obstruction(76.9%,20/26),diffuse hypertrophy of the extrahepatic biliary tract(90.5%,19/21),and multiple strictures of the intrahepatic biliary tract(30.4%,7/23)were noted.In 11/23(47.8%)cases,pathological examination indicated that CD8+T cells were the dominant inflammatory cells in the bile duct or peribiliary tract.Although corticosteroids were mainly used for PD inhibitor-related SC treatment,the response rate was 11.5%(3/26).CONCLUSION Some clinical and pathological features of PD-1 inhibitor-related SC were revealed.To establish diagnostic criteria for PD-1 inhibitor-related SC,more cases need to be evaluated.

Regorafenib combined with programmed cell death-1 inhibitor against refractory colorectal cancer and the platelet-to-lymphocyte ratio’s prediction on effectiveness

BACKGROUND The effectiveness of regorafenib plus programmed cell death-1(PD-1)inhibitor in treating microsatellite stable(MSS)metastatic colorectal cancer(mCRC)remains controversial.AIM To investigate the benefits of regorafenib combined with PD-1 inhibitor in treating MSS mCRC and explore indicators predicting response.METHODS This retrospective study included a total of 30 patients with microsatellite stable metastatic colorectal cancer treated with regorafenib combined with programmed cell death-1 inhibitor at Henan Provincial People’s Hospital between December 2018 and December 2020.During a 4-wk treatment cycle,regorafenib was performed for 3 continuous weeks.PD-1 inhibitor was intravenously injected starting on the first day of the oral intake of regorafenib.We reviewed tumor response,progression-free survival(PFS),overall survival,and treatment-related adverse events(TRAEs)and evaluated association between platelet-tolymphocyte ratio(PLR)and outcomes in this retrospective study.RESULTS Stable disease and progressive disease were found in 18(60.0%)and 12(40.0%)patients,respectively.The disease control rate was 60.0%.The median follow-up time was 12.0 mo,and median PFS was 3.4 mo[95%confidence interval(CI):2.2-4.6 mo].Of the 12 patients with progressive disease,10(83.3%)had liver metastasis before starting the combined treatment.Among the 18 patients with SD,10(55.6%)did not have liver metastases.One patient without liver metastases at baseline was found with a substantially prolonged PFS of 11.2 mo.The liver metastasis,the choice of programmed cell death-1 inhibitor other than nivolumab or pembrolizumab and previous exposure to regorafenib was’t associated with treatment outcome.The median PFS in the low-PLR group was 4.2 mo(95%CI:3.5-4.9 mo),compared with 2.8 mo(95%CI:1.4-4.2 mo)in the high-PLR group(P=0.005).The major TRAEs included hand-foot syndrome(33.3%),hypertension(23.3%),malaise(20.0%),and gastrointestinal reaction(16.7%).The incidence of grade 3 TRAEs was 13.3%(4/30),which comprised abnormal capillary proliferation(n=1),transaminase elevation(n=1),and hand-foot syndrome(n=2).No grade 4 or higher toxicity was observed.CONCLUSION Regorafenib combined with PD-1 inhibitor could lead to a longer PFS in some patients with MSS mCRC.The PLR might be a prediction of the patient response to this therapy.

Advances on biological evaluation methods of programmed cell death protein-1/ligand-1 inhibitors

Immuno-oncology represents a groundbreaking and well-established field within cancer treatment.Among the various immuno-oncology targets,the exploration of programmed cell death-1/ligand-1 for drug discovery has proven to be one of the most successful endeavors.Remarkably,it took nearly 30 years from the initial target identification to the clinical approval of monoclonal antibodies.Providing suitable and reliable bioassays for drug candidate evaluation is of paramount importance throughout the early stages of drug discovery,from lead compound identification to in vivo efficacy testing.This assay review aims to shed light on diverse assays reported in the literature for testing antagonism activity and efficacy of programmed cell death-1/ligand-1 inhibitors.Each of these assays possesses inherent advantages and can be applied in different research scenarios.The insights presented in this summary can serve as a valuable resource for scientists in this field,aiding in the selection of appropriate assays for their specific investigations.

Blood and Histopathological Biomarkers of Immune-related Adverse Effects of Treatment with Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have been a recent major breakthrough in the management of tumors.They have broadened the scope of management in medical oncology,which has been heavily dependent on chemotherapy.Immune checkpoint inhibitors have renewed the hope of many patients for a more effective treatment.However,Immune checkpoint inhibitors are also associated with a variety of adverse effects,most commonly immunerelated adverse events,and these are often different from the known chemotherapy-induced toxicities.Hence,there is a need to identify specific biomarkers which are able to predict or diagnose these immune-related adverse events.

国产程序性细胞死亡蛋白-1抑制药相关心肌炎的文献病例分析

目的:分析国产程序性细胞死亡蛋白-1 (PD-1)抑制药相关心肌炎的临床特点。方法:检索CNKI、WanFang Data、VIP、PubMed和Web of Science等文献数据库,收集国产PD-1抑制药相关心肌炎的病例报道文献,进行描述性统计分析。结果:收集到28篇文献共29个病例,男17例,女12例;年龄33~82(63.34±12.37)岁。22例(75.86%)患者的心肌炎发生在PD-1抑制药用药第1~2周期后;主要临床表现为气促、乏力、心悸、胸闷;11例患者心电图检查发现心脏传导阻滞,11例有ST-T改变。所有患者均接受了糖皮质激素治疗,12例使用了免疫球蛋白。24例(82.76%)患者治疗后症状明显好转,3例死亡。结论:男性及60岁以上患者使用PD-1抑制药发生心肌炎占比较高,发生时间多在用药早期,提示应及时发现潜在风险人群,尽早采取干预措施,确保患者用药安全。

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Type 1 diabetes induced by immune checkpoint inhibitors

With the increasing use of immune checkpoint inhibitors(ICI)including anti-cytotoxic T lymphocyte associated antigen-4(CTLA-4)and anti-programmed cell death-1(PD-1)in cancers,ICI-induced type 1 diabetes has been reported throughout the world.In this review,we aim to summarize the characteristics of this disease and discuss the mechanism of it.As an immune-related adverse event,type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1(PD-L1)in the combination with or without anti-CTLA-4.It usually presented with acute onset,and 62.1%of the reported cases had diabetic ketoacidosis.Only a third of them had positive autoantibodies associated with type 1 diabetes.Susceptible HLA genotypes might be associated.T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology.Insulin was the only effective treatment of ICI-induced type 1 diabetes.In conclusions,ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers.Screening and early recognition is important.Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

Common endocrine system adverse events associated with immune checkpoint inhibitors

Immune checkpoint inhibitors(ICIs),a novel anti-tumor therapeutic modality,are monoclonal antibodies targeting certain immune checkpoints(ICs)that reactivate T cells to achieve anti-tumor immunity by targeting,binding,and blocking ICs.Targeted inhibitory antibodies against the ICs cytotoxic T-lymphocyte antigen and programmed death receptor-1 have demonstrated efficacy and durable anti-tumor activity in patients with cancer.ICs may prevent autoimmune reactions.However,ICIs may disrupt ICs properties and trigger autoimmune-related adverse reactions involving various organ systems including the cardiovascular,pulmonary,gastrointestinal,renal,musculoskeletal,dermal,and endocrine systems.Approximately 10%of patients with damage to target organs such as the thyroid,pituitary,pancreas,and adrenal glands develop endocrine system immune-related adverse events(irAEs)such as thyroid dysfunction,pituitary gland inflammation,diabetes mellitus,and primary adrenal insufficiency.However,the symptoms of immunotherapy-associated endocrine system irAEs may be nonspecific and similar to those of other treatment-related adverse reactions,and failure to recognize them early may lead to death.Timely detection and treatment of immunotherapy-associated endocrine irAEs is essential to improve the efficacy of immunotherapy,prognosis,and the quality of life of patients.This study aimed to review the mechanisms by which ICIs cause endocrine irAEs providing guidance for the development of appropriate management protocols.Here,we discuss(1)the biological mechanisms of ICs in tumorigenesis and progression,focusing on cytotoxic T-lymphocyte antigen and programmed cell death-1/programmed cell death-ligand 1;and(2)the epidemiology,clinical symptoms,diagnosis,and treatment of four immunotherapy-related endocrine complications.

国产程序性死亡受体-1抑制剂致严重免疫相关皮肤不良反应文献分析

目的:分析国产程序性死亡受体-1(PD-1)抑制剂致Stevens-Johnson综合征(SJS)、中毒性表皮坏死松解症(TEN)严重免疫相关皮肤不良反应的规律和特点,为临床合理用药提供参考。方法:检索自建库至2022年12月31日以来中国知网、万方、维普、PubMed、Springer、Elsevier等中外文数据库中关于国产PD-1抑制剂致SJS/TEN的相关病例报告,并进行分析和讨论。结果:共涉及23例患者,其中TEN17例(73.91%),SJS5例(21.74%),SJS/TEN1例(4.35%)。发生TEN的中位时间为首次用药后28.5 d;发生SJS的中位时间为首次用药后90 d。23例患者中19例(82.61%)患者出现黏膜受累情况,23例患者前期均出现不同程度的皮疹。23例患者均采用全身糖皮质激素治疗,14例(60.87%)患者联合使用免疫球蛋白,2例(8.70%)患者联合使用TNF-α抑制剂,1例患者联合使用环孢素(4.35%)。23例患者18例(78.26%)好转或痊愈,3例(13.04%)死亡,1例(4.35%)失明,1例(4.35%)转院治疗。结论:临床使用PD-1抑制剂时应注意皮疹可能是SJS/TEN发生的早期信号,用药晚期也应监测严重皮肤不良反应的发生风险。治疗时应早期足量使用糖皮质激素控制病情,IVIG、环孢素和TNF-α抑制剂也可应用于SJS/TEN的治疗。

Progress in immunotherapy for small cell lung cancer

Small-cell lung cancer(SCLC)is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors.At present,radiotherapy and chemotherapy remain the mainstay of treatment for SCLC.Progress in targeted therapies for SCLC with driver mutations has been slow,and these therapies are still under investigation in preclinical or early-phase clinical trials,and research on antiangiogenic tyrosine kinase inhibitors(e.g.,anlotinib)has achieved some success.Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy.In this article we review the recent advances in immunotherapy for SCLC.

Combination therapy(toripalimab and lenvatinib)-associated toxic epidermal necrolysis in a patient with metastatic liver cancer:A case report

BACKGROUND Both programmed cell death-1(PD-1)inhibitors and lenvatinib,which have a synergistic effect,are promising drugs for tumor treatment.It is generally believed that combination therapy with a PD-1 inhibitor and lenvatinib is safe and effective.However,we report a case of toxic epidermal necrolysis(TEN),a grade 4 toxicity,after this combination therapy.CASE SUMMARY A 39-year-old male presented with erythema,blisters and erosions on the face,neck,trunk and limbs 1 wk after receiving combination therapy with lenvatinib and toripalimab,a PD-1 inhibitor.The skin injury covered more than 70%of the body surface area.He was previously diagnosed with liver cancer with cervical vertebra metastasis.Histologically,prominent necrotic keratinocytes,hyperkeratosis,liquefaction of basal cells and acantholytic bullae were observed in the epidermis.Blood vessels in the dermis were infiltrated by lymphocytes and eosinophils.Direct immunofluorescence staining was negative.Thus,the diagnosis was confirmed to be TEN(associated with combination therapy with toripalimab and lenvatinib).Full-dose and long-term corticosteroids,high-dose intravenous immunoglobulin and targeted antibiotic drugs were administered.The rashes gradually faded;however,as expected,the tumor progressed.Therefore, sorafenib and regorafenib were given in succession, and the patient was still alive at the10-mo follow-up.CONCLUSIONCautious attention should be given to rashes that develop after combination therapy with PD-1inhibitors and lenvatinib. Large-dose and long-course glucocorticoids may be crucial for thetreatment of TEN associated with this combination treatment.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study

Management and treatment of terminal metastatic castration-resistant prostate cancer(mCRPC)remains heavily debated.We sought to investigate the efficacy of programmed cell death 1(PD-1)inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes.We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments.The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA(ctDNA)next-generation sequencing.Statistical analysis showed that 6(24.0%)patients experienced prostate-specific antigen(PSA)response and 11(44.0%)patients experienced PSA reduction.The relationship between ctDNA findings and outcomes was also analyzed.DNA-damage repair(DDR)pathways and homologous recombination repair(HRR)pathway defects indicated a comparatively longer PSA-progressionfree survival(PSA-PFS;2.5 months vs 1.2 months,P=0.027;3.3 months vs 1.2 months,P=0.017;respectively).This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC.PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.

Immunotherapy prototype Mark 3.0 model in primary liver cancer:adding locoregional stereotactic therapy and prognostic factors classification management

Immune checkpoint inhibitors(ICIs)like programmed cell death-1(PD-1)/programmed death-ligand 1(PD-L1)inhibitor have shown considerable efficacy in several important cancers including primary liver cancer(PLC)like hepatocellular carcinoma and cholangiocarcinoma.However,only some patients with PLC will benefit,so combination therapy and biomarker classification detected by next-generation sequencing or immunohistochemistry are very important.Herein,we briefly summarize ICI-based therapies and stratify these evolving therapies for advanced PLC into three stages of immunotherapies Mark(Mk.)1.0,2.0,and 3.0.We illustrated the significance of ICI monotherapy(Mk.1.0),offering combinational approaches with traditional strategies(Mk.2.0)and additional locoregional therapy(Mk.3.0)to achieve longer survival and even meet the“No Evidence of Disease”status.We also highlight the importance of biomarkers and prognostic factors for patients with advanced PLC treated with ICI-based therapies.Multidisci-plinary team management should be investigated and collaborated closely to manage adverse events and sequential therapy suggestions for patients.

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer:opportunities to overcome a difficult problem

Approximately 20%of invasive breast cancers have upregulation/gene amplification of the oncogene human epidermal growth factor receptor-2(HER2/ErbB2).Of these,some also express steroid receptors(the so-called Luminal B subtype),whereas others do not(the HER2 subtype).HER2 abnormal breast cancers are associated with a worse prognosis,chemotherapy resistance,and sensitivity to selected anti-HER2 targeted therapeutics.Transcriptional data from over 3000 invasive breast cancers suggest that this approach is overly simplistic;rather,the upregulation of HER2 expression resulting from gene amplification is a driver event that causes major transcriptional changes involving numerous genes and pathways in breast cancer cells.Most notably,this includes a shift from estrogenic dependence to regulatory controls driven by other nuclear receptors,particularly the androgen receptor.We discuss members of the HER receptor tyrosine kinase family,heterodimer formation,and downstream signaling,with a focus on HER2 associated pathology in breast carcinogenesis.The development and application of anti-HER2 drugs,including selected clinical trials,are discussed.In light of the many excellent reviews in the clinical literature,our emphasis is on recently developed and successful strategies to overcome targeted therapy resistance.These include combining anti-HER2 agents with programmed cell death-1 ligand or cyclin-dependent kinase 4/6 inhibitors,targeting crosstalk between HER2 and other nuclear receptors,lipid/cholesterol synthesis to inhibit receptor tyrosine kinase activation,and metformin,a broadly inhibitory drug.We seek to facilitate a better understanding of new approaches to overcome anti-HER2 drug resistance and encourage exploration of two other therapeutic interventions that may be clinically useful for HER+invasive breast cancer patients.