Prognostic and predictive role of immune microenvironment in colorectal cancer

Colorectal cancer(CRC)represents a molecularly heterogeneous disease and one of the most frequent causes of cancer-related death worldwide.The traditional classification of CRC is based on pathomorphological and molecular character-istics of tumor cells(mucinous,ring-cell carcinomas,etc.),analysis of mechanisms of carcinogenesis involved(chromosomal instability,microsatellite instability,CpG island methylator phenotype)and mutational statuses of commonly altered genes(KRAS,NRAS,BRAF,APC,etc.),as well as expression signatures(CMS 1-4).It is also suggested that the tumor microenvironment is a key player in tumor progression and metastasis in CRC.According to the latest data,the immune microenvironment can also be predictive of the response to immune checkpoint inhibitors.In this review,we highlight how the immune environment influences CRC prognosis and sensitivity to systemic therapy.

A Th2-score in the tumor microenvironment as a predictive biomarker of response to Bacillus Calmette Guérin in patients with non-muscle invasive bladder carcinoma:A retrospective study

Intravesical Bacillus Calmette Guerin(BCG)is the gold standard therapy for intermediate/high-risk nonmuscle invasive bladder cancer(NMIBC).However,the response rate is~60%,and 50%of non-responders will progress to muscle-invasive disease.BCG induces massive local infiltration of inflammatory cells(Th1)and ultimately cytotoxic tumor elimination.We searched for predictive biomarker of BCG response by analyzing tumor-infiltrating lymphocyte(TIL)polarization in the tumor microenvironment(TME)in pre-treatment biopsies.Pre-treatment biopsies from patients with NMIBC who received adequate intravesical instillation of BCG(n=32)were evaluated retrospectively by immunohistochemistry.TME polarization was assessed by quantifying the T-Bet+(Th1)and GATA-3+(Th2)lymphocyte ratio(G/T),and the density and degranulation of EPX+eosinophils.In addition,PD-1/PD-L1 staining was quantified.The results correlated with BCG response.In most non-responders,Th1/Th2 markers were compared in pre-and post-BCG biopsies.ORR was 65.6%in the study population.BCG responders had a higher G/T ratio and a greater number of degranulated EPX+cells.Variables combined into a Th2-score showed a significant association with higher scores in responders(p=0.027).A Th2-score cut-off value>48.1 allowed discrimination of responders with 91%sensitivity but lower specificity.Relapse-free survival was significantly associated with the Th2-score(p=0.007).In post-BCG biopsies from recurring patients,TILs increased Th2-polarization,probably reflecting BCG failure to induce a pro-inflammatory status and,thus,a lack of response.PD-L1/PD-1 expression was not associated with the response to BCG.Our results support the hypothesis that a preexisting Th2-polarized TME predicts a better response to BCG,assuming a reversion to Th1 polarization and antitumor activity.

BATE curve in assessment of clinical utility of predictive biomarkers

In this paper, for time-to-event data, we propose a new statistical framework for casual inference in evaluating clinical utility of predictive biomarkers and in selecting an optimal treatment for a particular patient. This new casual framework is based on a new concept, called Biomarker Adjusted Treatment Effect （BATE） curve. The BATE curve can be used for assessing clinical utility of a predictive biomarker, for designing a subsequent confirmation trial, and for guiding clinical practice. We then propose semi-p^rametric methods for estimating the BATE curves of biomarkers and establish asymptotic results of the proposed estimators for the BATE curves. We also conduct extensive simulation studies to evaluate finite-sample properties of the proposed estimation methods. Finally, we illustrate the application of the proposed method in a real-world data set.

An integrative approach of digital image analysis and transcriptome profiling to explore potential predictive biomarkers for TGFβblockade therapy

Increasing evidence suggests that the presence and spatial localization and distribution pattern of tumor infiltrating lymphocytes(TILs)is associate with response to immunotherapies.Recent studies have identified TGFβactivity and signaling as a determinant of T cell exclusion in the tumor microenvironment and poor response to PD-1/PD-L1 blockade.Here we coupled the artificial intelligence(AI)-powered digital image analysis and gene expression profiling as an integrative approach to quantify distribution of TILs and characterize the associated TGFβpathway activity.Analysis of T cell spatial distribution in the solid tumor biopsies revealed substantial differences in the distribution patterns.The digital image analysis approach achieves 74%concordance with the pathologist assessment for tumor-immune phenotypes.The transcriptomic profiling suggests that the TIL score was negatively correlated with TGFβpathway activation,together with elevated TGFβsignaling activity observed in excluded and desert tumor phenotypes.The present results demonstrate that the automated digital pathology algorithm for quantitative analysis of CD8 immunohistochemistry image can successfully assign the tumor into one of three infiltration phenotypes:immune desert,immune excluded or immune inflamed.The association between“cold”tumor-immune phenotypes and TGFβsignature further demonstrates their potential as predictive biomarkers to identify appropriate patients that may benefit from TGFβblockade.

Impact of oxaliplatin and trastuzumab combination therapy on tumor markers and T lymphocyte subsets for advanced gastric cancer

BACKGROUND Advanced gastric cancer(AGC)remains a challenging malignancy with poor prognosis.The combination of oxaliplatin and trastuzumab has shown promising results in AGC treatment.This study aimed to investigate the effects of oxaliplatin and trastuzumab combination therapy on serum tumor markers and T lymphocyte subsets in patients with AGC and to explore their potential as predictive biomarkers for treatment response.AIM To investigate the impact of oxaliplatin and trastuzumab combination therapy on serum markers and T cell subsets in patients with AGC.METHODS This prospective study enrolled 60 patients with AGC.All patients received oxaliplatin(130 mg/m^(2),every 3 weeks)and trastuzumab(8 mg/kg loading dose,followed by 6 mg/kg every 3 weeks)for six cycles.Serum carcinoembryonic antigen(CEA),cancer antigen 19-9(CA19-9),and cancer antigen 72-4(CA72-4)were measured before and after treatment.T-lymphocyte subsets,including CD3+,CD4+,CD8+,and CD4+/CD8+ratios,were also evaluated.The clinical response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1.RESULTS After six cycles of treatment,the CEA,CA19-9,and CA72-4 serum levels significantly decreased compared to baseline levels(P<0.001).The percentages of CD3+and CD4+T lymphocytes increased significantly(P<0.05),whereas the percentage of CD8+T lymphocytes decreased(P<0.05).The CD4+/CD8+ratio also significantly increased after treatment(P<0.05).Patients with a higher decrease in serum tumor markers(≥50%reduction)and a higher increase in CD4+/CD8+ratio(≥1.5-fold)showed better clinical response rates(P<0.05).CONCLUSION Oxaliplatin and trastuzumab combination therapy effectively reduced serum tumor marker levels and modulated T lymphocyte subsets in patients with AGC.Combination therapy not only has a direct antitumor effect,but also enhances the immune response in patients with AGC.Serum tumor markers and T lymphocyte subsets may serve as potential predictive biomarkers for treatment response in patients with AGC receiving combination therapy.

Molecular predictive markers in tumors of the gastrointestinal tract

Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors&rsquo; genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis.

Laboratory scoring system to predict hepatic indocyanine green clearance ability during fluorescence imaging-guided laparoscopic hepatectomy

BACKGROUND Indocyanine green(ICG)fluorescence played an important role in tumor localization and margin delineation in hepatobiliary surgery.However,the preoperative regimen of ICG administration was still controversial.Factors associated with tumor fluorescence staining effect were unclear.AIM To investigate the preoperative laboratory indexes corelated with ICG fluorescence staining effect and establish a novel laboratory scoring system to screen specifical patients who need ICG dose adjustment.METHODS To investigate the predictive indicators of ICG fluorescence characteristics in patients undergoing laparoscopic hepatectomy from January 2018 to January 2021 were included.Blood laboratory tests were completed within 1 wk before surgery.All patients received 5 mg ICG injection 24 h before surgery for preliminary tumor imaging.ImageJ software was used to measure the fluorescence intensity values of regions of interest.Correlation analysis was used to identify risk factors.A laboratory risk model was established to identify individuals at high risk for high liver background fluorescence.RESULTS There were 110 patients who were enrolled in this study from January 2019 to January 2021.The mean values of fluorescence intensity of liver background(FI-LB),fluorescence intensity of gallbladder,and fluorescence intensity of target area were 18.87±17.06,54.84±33.29,and 68.56±36.11,respectively.The receiver operating characteristic(ROC)curve showed that FI-LB was a good indicator for liver clearance ability[area under the ROC curve(AUC)=0.984].Correlation analysis found pre-operative aspartate aminotransferase,alanine aminotransferase,gammaglutamyl transpeptidase,adenosine deaminase,and lactate dehydrogenase were positively associated with FI-LB and red blood cell,cholinesterase,and were negatively associated with FI-LB.Total laboratory risk score(TLRS)was calculated according to ROC curve(AUC=0.848,sensitivity=0.773,specificity=0.885).When TLRS was greater than 6.5,the liver clearance ability of ICG was considered as poor.CONCLUSION Preoperative laboratory blood indicators can predict hepatic ICG clearance ability.Surgeons can adjust the dose and timing of ICG preoperatively to achieve better liver fluorescent staining.

Recent advances in immunotherapy for hepatocellular carcinoma

Background:Treatment of hepatocellular carcinoma(HCC)is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions.Conventional systemic chemotherapy has failed in HCC,and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory.Data sources:Literature search was conducted in Pub Med for relevant articles published before January 2021.The search aimed to identify recent developments in immune-based treatment approaches for HCC.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Two immune checkpoint inhibitors(ICIs),nivolumab and pembrolizumab were approved as monotherapies,which has revolutionized HCC treatment.Besides,combination ICIs have also got accelerated FDA approval recently.Immune-based therapies have challenged targeted drugs owing to their safety,tolerability,and survival benefits.In addition to the significant success in ICIs,other immunotherapeutic strategies such as cancer vaccine,chimeric antigen receptor T-cells,natural killer cells,cytokines,and combination therapy,have also shown promising outcomes in clinical trials.Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs.Conclusions:Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years.However,challenges such as low response rate and acquired resistance in previously respondent patients still exist.Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.

Immunohistochemical evaluation of vitamin D receptor(VDR) expression in cutaneous melanoma tissues and four VDR gene polymorphisms

Objective:Vitamin D receptor(VDR)mediates vitamin D activity.We examined whether VDR expression in excised melanoma tissues is associated with VDR gene(VDR)polymorphisms.Methods:We evaluated VDR protein expression(by monoclonal antibody immunostaining),melanoma characteristics,and carriage of VDR-Fok I-rs2228570(C>T),VDR-Bsm I-rs1544410(G>A),VDR-ApaI-rs7975232(T>G),and VDR-TaqI-rs731236(T>C)polymorphisms(by restriction fragment length polymorphism).Absence or presence of restriction site was denoted by a capital or lower letter,respectively:"F"and"f"for Fok I,"B"and"b"for Bsm I,"A"and"a"for ApaI,and "T"and"t"for TaqI endonuclease.Seventy-four Italian cutaneous primary melanomas(52.1±12.7 years old)were studied;51.4% were stage Ⅰ,21.6% stage Ⅱ ,13.5% stage Ⅲ,and 13.5% stage Ⅳ melanomas.VDR expression was categorized as follows:100% positive vs.<100%;over the median 20%(high VDR expression)vs.≤20%(low VDR expression);absence vs.presence of VDR-expressing cells.Results:Stage I melanomas,Breslow thickness of<1.00 mm,level II Clark invasion,Aa heterozygous genotype,and AaTT combined genotype were more frequent in melanomas with high vs.low VDR expression.Combined genotypes BbAA,bbAa,AATt,BbAATt,and bbAaTT were more frequent in 100%vs.<100%VDR-expressing cells.Combined genotype AATT was more frequent in melanomas lacking VDR expression(odds ratio=14.5;P=0.025).VDR expression was not associated with metastasis,ulceration,mitosis>1,regression,tumor-infiltrating lymphocytes,tumoral infiltration of vascular tissues,additional skin and non-skin cancers,and melanoma familiarity.Conclusions:We highlighted that VDR polymorphisms can affect VDR expression in excised melanoma cells.Low VDR expression in AATT carriers is a new finding that merits further study.VDR expression possibly poses implications for vitamin D supplementation against melanoma.VDR expression and VDR genotype may become precise medicinal tools for melanoma in the future.

Immunotherapy in gastric cancer

Gastric cancer is the second most common of cancerrelated deaths worldwide.In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved,survival rates remain poor.Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer,prostate cancer and melanoma.Here,we provide an overview of concepts of modern cancer immunotherapy including the theory,current approaches,remaining hurdles to be overcome,and the future prospect of cancer immunotherapy in the treatment of gastric cancer.Adaptive cell therapies,cancer vaccines,gene therapies,monoclonal antibody therapies have all been used with some initial successes in gastric cancer.However,to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response.Here,we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy.We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment.We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells.Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being.Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright.

Implications of the autophagy core gene variations on brain metastasis risk in non-small cell lung cancer treated with EGFR-TKI

Objective The brain is the main site of failure in cancer patients with epidermal growth factor receptor(EGFR)mutations undergoing treatment.However,identifying patients who may develop brain metastases(BM)is difficult.Autophagy is critical for cancer initiation and progression.We hypothesized that genetic variants in autophagy core genes might contribute to BM risk of non-small cell lung cancer(NSCLC)following treatment with EGFR tyrosine kinase inhibitor(EGFR-TKIs).Methods We systematically examined 16 potentially functional genetic polymorphisms in seven autophagy core genes among 105 TKI-treated NSCLC patients.Kaplan-Meier curves were plotted to assess the cumulative BM probability.Univariate and multivariate Cox proportional hazard regression analyses were utilized to calculate hazard ratios(HRs)and 95%confidence intervals(CIs).We evaluated the potential associations of these genes with subsequent BM development.Results We found that ATG16L1:rs2241880,ATG10:rs10036653,rs3734114,and ATG3:rs7652377 are significantly associated with NSCLC treated with EGFR-TKIs(all P<0.05).BM developed more often in patients with ATG3 rs7652377 CC genotype(33%),ATG10 rs10036653 AA genotype(43%),ATG10:rs3734114 CT/CC genotype(46%),and ATG16L1 rs2241880 AA genotype(37%)compared to patients with AA genotypes at rs7652377(12%),AT/TT genotypes at rs10036653(16%),the TT genotype at rs3734114(13%),or AG/GG genotypes at rs2241880(17%).Conclusion These associations may be critical for understanding the role of autophagy in BM risk.Future prospective studies are needed to determine if prophylactic cranial irradiation(PCI)could offer a survival benefit in this group of patients.

Refractory case of ulcerative colitis with idiopathic thrombocytopenic purpura successfully treated by Janus kinase inhibitor tofacitinib:A case report

BACKGROUND Concomitant ulcerative colitis (UC) and idiopathic thrombocytopenic purpura(ITP) is a rare phenomenon. The management of UC with ITP can be challenging,since a decreased platelet count augments UC.CASE SUMMARY A 24-year-old man with UC and steroid-resistant ITP experienced UC flare.Although continuous infusion of cyclosporine was initiated, UC did not improve.The administration of tofacitinib subsequently led to the induction of remission.The patient has maintained remission of UC and ITP for over one year ontofacitinib treatment. Whole transcriptomic sequencing was performed forinflamed rectal mucosae obtained before and after the initiation of Janus kinase(JAK) inhibitor, suggesting that distinct molecular signatures seemed to beregulated by JAK inhibitors and other conventional therapies including tumornecrosis factor lockers.CONCLUSION Tofacitinib should be considered in refractory cases of UC with ITP.

Potential new applications of immunotherapy for neuroendocrine neoplasms:immune landscape,current status and future perspectives

Neuroendocrine neoplasms(NENs)are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons.After failure of first-line treatment,patients have poor prognosis and limited treatment options.Immune checkpoint inhibitors(ICIs)may be a powerful means of increasing therapeutic efficacy for such patients,but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population.ICIs combined with other immunotherapies,targeted therapies,or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population.In addition,accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis,and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment.In this review,we summarize the immune microenvironment characteristics,advances in immunotherapy,predictive biomarkers of ICI efficacy for NENs,and the effects of common endocrine hormones on the immune system,highlighting possible new application areas for this promising treatment in neglected NENs.

Long survival after immunotherapy plus paclitaxel in advanced intrahepatic cholangiocarcinoma: A case report and review of literature

BACKGROUND Intrahepatic cholangiocarcinoma(iCCA)is the second most common primary hepatic malignancy worldwide.However,currently available systemic therapies are of limited effectiveness,and the median overall survival of patients treated with first-line standard chemotherapy is less than one year.Immune checkpoint inhibitors have been used to treat solid tumors.Clinical studies recently explored the combination of chemotherapy and immunotherapy for CCA.However,the clinical significance of predictive biomarkers for chemo-immunotherapy in CCA remains unclear.It is also worth exploring whether a combination of chemotherapeutic agents can increase the sensitivity of CCA immunotherapy.CASE SUMMARY This study reports a case of advanced iCCA in which clinical complete remission had been achieved using a programmed death 1(PD-1)inhibitor and paclitaxel without known predictive biomarkers,but with BRCA1,KRAS,and NTRK3 mutations after rapid progression to first-line chemotherapy,and has remained in clinical complete remission for more than two years.This case suggests that chemo-immunotherapy is a potential therapeutic option for patients with iCCA and few known predictive biomarkers for immunotherapies as well as synergistic effect of the combination of paclitaxel and PD-1 monoclonal antibody.CONCLUSION The combination of paclitaxel and PD-1 monoclonal antibodyr can be explored in patients with advanced iCCA.

Clinical significance of MDM2 as a tumor biomarker

MDM2 (the product of murine double minute 2 gene) is one of the most important negative regulators of p53,which can binds to p53 and initiates ubiquitin-mediated degradation.Besides,MDM2 also controls the activity of several cell-cycle regulators,e.g.pRB,p21,E2F1,independently of p53.The important role of MDM2 in cell-cycle regulation indicates it to be a point of interest in cancer research.In recent years,studies revealed that MDM2 participated in the genesis and development of human tumors.The expression levels and activity of MDM2 was associated with the invasion,metastasis,prognosis and more practical,chemosensitivity.MDM2 is becoming a novel biomarker in cancer prognosis and chemosensitivity prediction.

Final Results of a Phase II Study of Bevacizumab, Cisplatin and Pemetrexed as First-Line Therapy for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Efficacy and safety data for cisplatin and pemetrexed plus bevacizumabinnon squamousnon non-small cell lung cancer (NSCLC) are still limited. Nevertheless, either bevacizumab plus platinum doublet or pemetrexed plus platinum is approved options for first line therapy. Predictive factors for bevacizumab are needed. KRAS is one of the most common oncogenic drivers in lung cancer. Its prognostic and predictive value in NSCLC is under investigation. Patients and methods: This trial evaluates the addition of bevacizumab 7.5 mg/kg to cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 as first line treatment in stage IV non-squamous NSCLC patients. Maintenance bevacizumab was received as monotherapy until progressive disease, unacceptable toxicityor consent with drawal. The primary objective was progression free survival (PFS). Secondary objectives included overall survival (OS), safety, global objective responses and the determination of KRAS mutation at baseline. Results: From March 2009 to March 2012, 31 patients were enrolled. Mean age was 59.19 (standard deviation (SD) 8.53). From all the patients included in this trial, 67.70% were men. KRAS was wild type in 19 patients (58.06%);in 7 (22.58%) was mutated and was unknown in 6 patients (19.35%). Median PFS for KRAS mutated patients was 4 months, whereas for the KRAS wild type it was 7.9 months (P = 0.0031). Median OS was 4 months for the KRAS population, and 16.1 months for the KRAS wild type (P = 0.0032). Twenty four patients (77.42%) experienced at least a grade 3 - 4 adverse event. The most common grade 3 - 4 toxicity was asthenia. Conclusions: Both PFS and OS were statistically longer for the KRAS wild type patients compared with the KRAS mutated population (P = 0.0031). Median OS was shorter than the reported in previous trials with bevacizumab. Nevertheless, focussing on the OS for KRAS wild type patients, this achieves a result or 16.1 months. Therefore, this would be a consistent data supporting to qualify this parameter as a predictive factor before starting treatment for NSCLC.

Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine

Cancer therapy agents have been used extensively as cytotoxic drugs against tissue or organ of a specific type of cancer. With the better understanding of molecular mcchanislns undcrlying carcinogenesis and cellular events during cancer progression and metastasis, it is now possible to use targeted therapy for these molecular events. Targeted therapy is able to identify cancer patients with dissimilar genetic defects at cellular level for the same cancer type and consequently requires individualized approach for treatment. Cancer therapy begins to shill steadily from the tra- ditional approach of ＂one regimen for all patients＂ to a more individualized approach, through which each patient will be treated specifically according to their specific genetic defects. Personalized medicine accordingly requires identification of indicators or markers that guide in the decision mak- ing of such therapy to the chosen patients for more effective therapy. Cancer biomarkcrs are fre- quently used in clinical practice for diagnosis and prognosis, as well as identification ol responsive patients and prediction of treatment response of cancer patient. The rapid breakthrough and development of microarray and sequencing technologies is probably the main tool for paving the way toward ＂individualized biomarker-driven cancer therapy＂ or ＂personalized medicine＂. In this review, we aim to provide an updated knowledge and overview of the currcnt landscape of cancer biomarkers and their role in personalized medicine, emphasizing the impact of gcnomics Oil the implementation of new potential targeted therapies and development of novel cancer biomarkers in improving the outcome of cancer therapy.

Transcriptomic biomarkers for predicting response to neoadjuvant treatment in oesophageal cancer

Oesophageal cancer is a devastating disease with poor outcomes and is the sixth leading cause of cancer death worldwide.In the setting of resectable disease,there is clear evidence that neoadjuvant chemotherapy and chemoradiotherapy result in improved survival.Disappointingly,only 15%-30%of patients obtain a histopathological response to neoadjuvant therapy,often at the expense of significant toxicity.There are no predictive biomarkers in routine clinical use in this setting and the ability to stratify patients for treatment could dramatically improve outcomes.In this review,we aim to outline current progress in evaluating predictive transcriptomic biomarkers for neoadjuvant therapy in oesophageal cancer and discuss the challenges facing biomarker development in this setting.We place these issues in the wider context of recommendations for biomarker development and reporting.The majority of studies focus on messenger RNA(mRNA)and microRNA(miRNA)biomarkers.These studies report a range of different genes involved in a wide variety of pathways and biological processes,and this is explained to a large extent by the different platforms and analysis methods used.Many studies are also vastly underpowered so are not suitable for identifying a candidate biomarker.Multiple molecular subtypes of oesophageal cancer have been proposed,although little is known about how these relate to clinical outcomes.We anticipate that the accumulating wealth of genomic and transcriptomic data and clinical trial collaborations in the coming years will provide unique opportunities to stratify patients in this poor-prognosis disease and recommend that future biomarker development incorporates well-designed retrospective and prospective analyses.

Biomarkers of resistance to immune checkpoint inhibitors in non-small-cell lung cancer:myth or reality?

Immune checkpoint inhibitors represent a major therapeutic advance in non-small-cell lung cancer with several approved anti-programmed death-1 and anti-programmed death-L1 immunotherapies.A majority of patients however,will not respond to immune checkpoint inhibitors and display primary resistance while a subset of initially responsive patients will present secondary resistance.Thus,there is a crucial need for biomarkers to enable better prediction and diagnosis,and to overcome such resistance.Along with improvement in the understanding of immune escape,new biomarkers are being developed,including large scale proteomic,genomic and transcriptomic approaches in tumor and blood samples.We review the novel biomarkers that have been investigated in non-small-cell lung cancer and discuss how they can rationalize therapeutic strategies.

Resistance to antibody-drug conjugates in breast cancer:mechanisms and solutions

Antibody-drug conjugates(ADCs)are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer.Currently,there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer,one for triple-negative breast cancer,and multiple investigational ADCs in clinical trials.However,drug resistance has been noticed in clinical use,especially in trastuzumab emtansine.Here,the mechanisms of ADC resistance are summarized into four categories:antibodymediated resistance,impaired drug trafficking,disrupted lysosomal function,and payload-related resistance.To overcome or prevent resistance to ADCs,innovative development strategies and combination therapy options are being investigated.Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.