Pub Date : 2021-10-28DOI: 10.1080/23808993.2021.1989303
Annesti F. Elmasri, Hee-soo Hur, Jin Han, James C. Lee
ABSTRACT Background Warfarin dosing varies due to individual genetic and clinical factors. The utility of genotype‐guided warfarin dosing to improve stable warfarin dose is not extensively studied in non-European populations. Research design and methods Retrospective cohort study of patients initiating warfarin receiving genotype (PGx)‐guided or clinically guided dosing. Primary outcomes included dose discordance between estimated dose at discharge and eventual stable dose. Results No significant difference in warfarin dose discordance was observed (PGx: 9.1 ± 8.8 mg/week difference vs. Clinical: 7.9 ± 8.9 mg/week difference; P = 0.446). PGx‐guided dosing did not reduce time to achieve stable dose (1.8 ± 2.5 months vs. 2.1 ± 2.6 months; P = 0.508). Vitamin K intake level did not alter prediction accuracy or time to stable dose (PGx‐predicted: dose difference P = 0.493, time to stable dose P = 0.336; Clinically predicted: dose difference P = 0.145, time to dose INR P = 0.095). Conclusions PGx‐guided warfarin dosing did not improve eventual stable dose discordance or reduce the time to achieve stable dose in this predominantly non‐European cohort. Dietary vitamin K intake level did not impact warfarin dose discordance or time to achieve stable warfarin dose. Additional study is needed to identify populations that best benefit from PGx‐guided warfarin dosing.
{"title":"Genotype-Guided vs Clinically-Guided Stable Warfarin Dose Prediction and Stable Dose Establishment In A Predominantly Non-European Ancestry Population","authors":"Annesti F. Elmasri, Hee-soo Hur, Jin Han, James C. Lee","doi":"10.1080/23808993.2021.1989303","DOIUrl":"https://doi.org/10.1080/23808993.2021.1989303","url":null,"abstract":"ABSTRACT Background Warfarin dosing varies due to individual genetic and clinical factors. The utility of genotype‐guided warfarin dosing to improve stable warfarin dose is not extensively studied in non-European populations. Research design and methods Retrospective cohort study of patients initiating warfarin receiving genotype (PGx)‐guided or clinically guided dosing. Primary outcomes included dose discordance between estimated dose at discharge and eventual stable dose. Results No significant difference in warfarin dose discordance was observed (PGx: 9.1 ± 8.8 mg/week difference vs. Clinical: 7.9 ± 8.9 mg/week difference; P = 0.446). PGx‐guided dosing did not reduce time to achieve stable dose (1.8 ± 2.5 months vs. 2.1 ± 2.6 months; P = 0.508). Vitamin K intake level did not alter prediction accuracy or time to stable dose (PGx‐predicted: dose difference P = 0.493, time to stable dose P = 0.336; Clinically predicted: dose difference P = 0.145, time to dose INR P = 0.095). Conclusions PGx‐guided warfarin dosing did not improve eventual stable dose discordance or reduce the time to achieve stable dose in this predominantly non‐European cohort. Dietary vitamin K intake level did not impact warfarin dose discordance or time to achieve stable warfarin dose. Additional study is needed to identify populations that best benefit from PGx‐guided warfarin dosing.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"375 - 379"},"PeriodicalIF":1.2,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42981298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-20DOI: 10.1080/23808993.2021.1976637
Aikaterini Katsandris, D. Ziogas, M. Kontouri, Stavroula Staikoglou, H. Gogas
ABSTRACT Introduction Breakthrough changes in melanoma management induced by the introduction of BRAF/MEK inhibitors and immune checkpoint inhibitors (ICPIs) have motivated subsequent research to combine these strategies in the frontline approach of BRAFV600-mutant advanced melanoma. Initial preclinical data have shown that targeted agents may have a favorable immune impact on the tumor microenvironment and next, numerous trials tried to identify the optimal combination and sequence of immunotherapy and targeted therapy. Up until last year, when the first immune/targeted regimen including atezolizumab, vemurafenib and cobimetinib, was approved by the FDA. Areas covered Focusing on this first-in-class immune/targeted regimen, we describe here the entire process for its approval, from the bench of preclinical studies to the clinical evaluation of its efficacy and its toxicity profile on treated patients with advanced BRAF-mutant melanoma. All raised concerns about the use of atezolizumab/vemurafenib/cobimetinib triplet are thoroughly discussed. Expert opinion The atezolizumab/vemurafenib/cobimetinib triplet is an effective frontline option for advanced BRAF-mutant melanoma but its generalized implementation remains limited due to toxicity and cost. Results of ongoing trials are expected to identify more clearly the best candidates for such combinations and to update the role of immune/targeted triplets in melanoma treatment.
{"title":"Atezolizumab plus vemurafenib and cobimetinib for the treatment of BRAF V600-mutant advanced melanoma: from an hypothetic triplet to an approved regimen","authors":"Aikaterini Katsandris, D. Ziogas, M. Kontouri, Stavroula Staikoglou, H. Gogas","doi":"10.1080/23808993.2021.1976637","DOIUrl":"https://doi.org/10.1080/23808993.2021.1976637","url":null,"abstract":"ABSTRACT Introduction Breakthrough changes in melanoma management induced by the introduction of BRAF/MEK inhibitors and immune checkpoint inhibitors (ICPIs) have motivated subsequent research to combine these strategies in the frontline approach of BRAFV600-mutant advanced melanoma. Initial preclinical data have shown that targeted agents may have a favorable immune impact on the tumor microenvironment and next, numerous trials tried to identify the optimal combination and sequence of immunotherapy and targeted therapy. Up until last year, when the first immune/targeted regimen including atezolizumab, vemurafenib and cobimetinib, was approved by the FDA. Areas covered Focusing on this first-in-class immune/targeted regimen, we describe here the entire process for its approval, from the bench of preclinical studies to the clinical evaluation of its efficacy and its toxicity profile on treated patients with advanced BRAF-mutant melanoma. All raised concerns about the use of atezolizumab/vemurafenib/cobimetinib triplet are thoroughly discussed. Expert opinion The atezolizumab/vemurafenib/cobimetinib triplet is an effective frontline option for advanced BRAF-mutant melanoma but its generalized implementation remains limited due to toxicity and cost. Results of ongoing trials are expected to identify more clearly the best candidates for such combinations and to update the role of immune/targeted triplets in melanoma treatment.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"349 - 360"},"PeriodicalIF":1.2,"publicationDate":"2021-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49442913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-03DOI: 10.1080/23808993.2021.1964951
H. Saeed, Matthew J. Thoendel, R. Razonable
ABSTRACT Introduction Cytomegalovirus (CMV) is an opportunistic infection that affects immunocompromised solid organ transplant patients. Defining the imbalance between host and virus factors that predispose to its occurrence can assist in individualizing the approach to CMV prevention and treatment. Areas covered In this narrative review article, we provide an up to date overview of host, pathogen, and transplant-related factors that determine the risk and outcome of CMV infection in solid organ transplant recipients. We review the role of CMV-specific cell-mediated and humoral immune status, degree of lymphopenia, degree of viremia, and the dose and type of immunosuppressive regimen in defining the risk and determining the outcome of CMV. We propose that knowledge of these factors should be taken into account in optimizing the management strategies and individualize our approach to CMV prevention and treatment in the posttransplant setting. Expert opinion The management of CMV in transplant recipients is not a one-size-fits-all strategy. We highlight the spectrum of CMV risk and outcomes in solid organ transplant recipients based on host, virus, and transplant-related factors. We provide examples on how to incorporate these factors in the implementation of optimized antiviral prophylaxis, preemptive treatment of asymptomatic infection and management of susceptible, refractory, and resistant CMV disease.
{"title":"Individualized management of cytomegalovirus in solid organ transplant recipients","authors":"H. Saeed, Matthew J. Thoendel, R. Razonable","doi":"10.1080/23808993.2021.1964951","DOIUrl":"https://doi.org/10.1080/23808993.2021.1964951","url":null,"abstract":"ABSTRACT Introduction Cytomegalovirus (CMV) is an opportunistic infection that affects immunocompromised solid organ transplant patients. Defining the imbalance between host and virus factors that predispose to its occurrence can assist in individualizing the approach to CMV prevention and treatment. Areas covered In this narrative review article, we provide an up to date overview of host, pathogen, and transplant-related factors that determine the risk and outcome of CMV infection in solid organ transplant recipients. We review the role of CMV-specific cell-mediated and humoral immune status, degree of lymphopenia, degree of viremia, and the dose and type of immunosuppressive regimen in defining the risk and determining the outcome of CMV. We propose that knowledge of these factors should be taken into account in optimizing the management strategies and individualize our approach to CMV prevention and treatment in the posttransplant setting. Expert opinion The management of CMV in transplant recipients is not a one-size-fits-all strategy. We highlight the spectrum of CMV risk and outcomes in solid organ transplant recipients based on host, virus, and transplant-related factors. We provide examples on how to incorporate these factors in the implementation of optimized antiviral prophylaxis, preemptive treatment of asymptomatic infection and management of susceptible, refractory, and resistant CMV disease.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"333 - 344"},"PeriodicalIF":1.2,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44354255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-03DOI: 10.1080/23808993.2021.1967142
E. Namoglu, M. Hughes, S. Nasta
ABSTRACT Introduction Non-Hodgkin lymphoma is a disease spectrum of multiple subtypes with many potential targets. Given the heterogeneity and evolving landscape for targeted therapy, incorporation of therapeutics in this disease state is complex and dependent upon multiple factors. Areas covered Agents reviewed for either on- or off-label use include: monoclonal antibodies, antibody-drug conjugates, immunotherapy, cellular therapy, and bi-specific antibodies. In the current review, we discuss the most recently identified targets of interest and corresponding therapies. The authors aim to provide insight on where therapies may be incorporated for clinical utility in B cell non-Hodgkin lymphoma as well as future directions for new targets and combinations of these approaches. Expert opinion A multimodality approach to non-Hodgkin lymphoma will now be needed for early identification of potential targets and will be critical for treatment decisions. As each agent is defined in the relapsed refractory setting, the sequencing and combination of these agents will be critical, particularly with overlapping toxicities. The adoption in practice will depend not only on efficacy but ease of administration, limiting side effects and cost.
{"title":"Targeted immunotherapies to consider for B Cell non-hodgkin lymphoma","authors":"E. Namoglu, M. Hughes, S. Nasta","doi":"10.1080/23808993.2021.1967142","DOIUrl":"https://doi.org/10.1080/23808993.2021.1967142","url":null,"abstract":"ABSTRACT Introduction Non-Hodgkin lymphoma is a disease spectrum of multiple subtypes with many potential targets. Given the heterogeneity and evolving landscape for targeted therapy, incorporation of therapeutics in this disease state is complex and dependent upon multiple factors. Areas covered Agents reviewed for either on- or off-label use include: monoclonal antibodies, antibody-drug conjugates, immunotherapy, cellular therapy, and bi-specific antibodies. In the current review, we discuss the most recently identified targets of interest and corresponding therapies. The authors aim to provide insight on where therapies may be incorporated for clinical utility in B cell non-Hodgkin lymphoma as well as future directions for new targets and combinations of these approaches. Expert opinion A multimodality approach to non-Hodgkin lymphoma will now be needed for early identification of potential targets and will be critical for treatment decisions. As each agent is defined in the relapsed refractory setting, the sequencing and combination of these agents will be critical, particularly with overlapping toxicities. The adoption in practice will depend not only on efficacy but ease of administration, limiting side effects and cost.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"317 - 332"},"PeriodicalIF":1.2,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46060593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-03DOI: 10.1080/23808993.2021.1964952
J. Krajewska, A. Kukulska, M. Oczko-Wojciechowska, B. Jarzab
ABSTRACT Introduction The discovery of a pivotal role of tyrosine kinases in the pathogenesis of medullary thyroid carcinoma (MTC) opened up new options in the systemic treatment of advanced disease. During the last decade, two multikinase inhibitors (MKIs) – vandetanib and cabozantinib and, more recently, two potent, selective RET inhibitors selpercatinib and pralsetinib gained regulatory approval. Areas covered The data on efficacy and safety of vandetanib, cabozantinib, selpercatinib, and pralsetinib in MTC published during the recent 10 years. Expert opinion The perspectives of systemic MTC treatment have substantially changed since 2010. However, to date, the question of which drug should be chosen as the first line remains open. There are no recommendations on what to use as the second or other treatment lines. The impact of tumor burden, progression slope, and the presence of MTC symptoms on treatment-decision making is not unequivocally defined. Another important problem is the treatment duration. EBM (evidence-based medicine) study, resolving these issues, is our task for the nearest future. The treatment tolerability and its impact on the quality of life, particularly regarding nonselective MKIs, is also an essential problem.
{"title":"Recent advances in precision medicine for the treatment of medullary thyroid cancer","authors":"J. Krajewska, A. Kukulska, M. Oczko-Wojciechowska, B. Jarzab","doi":"10.1080/23808993.2021.1964952","DOIUrl":"https://doi.org/10.1080/23808993.2021.1964952","url":null,"abstract":"ABSTRACT Introduction The discovery of a pivotal role of tyrosine kinases in the pathogenesis of medullary thyroid carcinoma (MTC) opened up new options in the systemic treatment of advanced disease. During the last decade, two multikinase inhibitors (MKIs) – vandetanib and cabozantinib and, more recently, two potent, selective RET inhibitors selpercatinib and pralsetinib gained regulatory approval. Areas covered The data on efficacy and safety of vandetanib, cabozantinib, selpercatinib, and pralsetinib in MTC published during the recent 10 years. Expert opinion The perspectives of systemic MTC treatment have substantially changed since 2010. However, to date, the question of which drug should be chosen as the first line remains open. There are no recommendations on what to use as the second or other treatment lines. The impact of tumor burden, progression slope, and the presence of MTC symptoms on treatment-decision making is not unequivocally defined. Another important problem is the treatment duration. EBM (evidence-based medicine) study, resolving these issues, is our task for the nearest future. The treatment tolerability and its impact on the quality of life, particularly regarding nonselective MKIs, is also an essential problem.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"307 - 315"},"PeriodicalIF":1.2,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42647580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-09-03DOI: 10.1080/23808993.2021.1970526
W. Tangjittipokin, Nutsakol Borrisut, Patcharapong Rujirawan
ABSTRACT Introduction Diabetes mellitus is a serious metabolic disorder that is associated with high morbidity and mortality, and that affects people worldwide – especially in Asia. Genetics plays an important role in disease development, prevention, and therapeutic approach. Precision medicine in diabetes requires a profound understanding of both genetics and the plethora of mechanisms of diabetes. Areas covered This review comprehensively describes and discusses the recent advances in genetics-based prediction, diagnosis, prevention, and treatment of diabetes, and the potential impact of these advances on precision medicine, especially in the Asian population. We analyzed the available literature from the PubMed Central® (PMC) archive. Expert opinion Advanced genetic knowledge can lead to the precise diagnosis, improved risk prediction, diabetes prevention, and genetics-based diabetes treatment. Increased understanding, availability, and affordability of genetics-based strategies will improve the quality of life of those with and those at risk for developing diabetes.
{"title":"Prediction, diagnosis, prevention and treatment: genetic-led care of patients with diabetes","authors":"W. Tangjittipokin, Nutsakol Borrisut, Patcharapong Rujirawan","doi":"10.1080/23808993.2021.1970526","DOIUrl":"https://doi.org/10.1080/23808993.2021.1970526","url":null,"abstract":"ABSTRACT Introduction Diabetes mellitus is a serious metabolic disorder that is associated with high morbidity and mortality, and that affects people worldwide – especially in Asia. Genetics plays an important role in disease development, prevention, and therapeutic approach. Precision medicine in diabetes requires a profound understanding of both genetics and the plethora of mechanisms of diabetes. Areas covered This review comprehensively describes and discusses the recent advances in genetics-based prediction, diagnosis, prevention, and treatment of diabetes, and the potential impact of these advances on precision medicine, especially in the Asian population. We analyzed the available literature from the PubMed Central® (PMC) archive. Expert opinion Advanced genetic knowledge can lead to the precise diagnosis, improved risk prediction, diabetes prevention, and genetics-based diabetes treatment. Increased understanding, availability, and affordability of genetics-based strategies will improve the quality of life of those with and those at risk for developing diabetes.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"361 - 374"},"PeriodicalIF":1.2,"publicationDate":"2021-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45211627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-19DOI: 10.1080/23808993.2021.1954907
E. De Carlo, B. Stanzione, A. Del Conte, A. Revelant, A. Bearz
ABSTRACT Introduction Anaplastic lymphoma kinase (ALK) gene rearrangements and resulting fusion proteins occur in 3%-7% of patients with non-small-cell lung cancer (NSCLC), conferring sensitivity to treatment with ALK Tyrosine-Kinase Inhibitors. After the first-generation ALK inhibitor crizotinib, newer generation ALK inhibitors have been developed and showed greater potency and brain penetration in both crizotinib-naïve and crizotinib-refractory advanced NSCLC patients. Areas covered Brigatinib is a potent and highly selective second generation ALK inhibitor. Brigatinib is approved by Food and Drug Administration and European Medicines Agency for ALK-positive advanced NSCLC patients previously treated with crizotinib and more recently as first-line treatment in naïve patients. In the current review we present an up-to-date overview of the current and evolving clinical data regarding the biology of the disease, the emerging clinical decision-making and the targeted therapy options in advanced NSCLC harboring ALK translocation, especially focusing on the activity of brigatinib. Expert opinion Brigatinib shows a deep systemic and intracranial efficacy in both naïve and refractory metastatic ALK-positive NSCLC patients in the clinical studies, which marked its clinical development. Given its efficacy and tolerability brigatinib could be an excellent therapeutic option for the treatment of advanced ALK-positive NSCLC patients.
{"title":"Brigatinib as a treatment of ALK-positive non-small cell lung cancer","authors":"E. De Carlo, B. Stanzione, A. Del Conte, A. Revelant, A. Bearz","doi":"10.1080/23808993.2021.1954907","DOIUrl":"https://doi.org/10.1080/23808993.2021.1954907","url":null,"abstract":"ABSTRACT Introduction Anaplastic lymphoma kinase (ALK) gene rearrangements and resulting fusion proteins occur in 3%-7% of patients with non-small-cell lung cancer (NSCLC), conferring sensitivity to treatment with ALK Tyrosine-Kinase Inhibitors. After the first-generation ALK inhibitor crizotinib, newer generation ALK inhibitors have been developed and showed greater potency and brain penetration in both crizotinib-naïve and crizotinib-refractory advanced NSCLC patients. Areas covered Brigatinib is a potent and highly selective second generation ALK inhibitor. Brigatinib is approved by Food and Drug Administration and European Medicines Agency for ALK-positive advanced NSCLC patients previously treated with crizotinib and more recently as first-line treatment in naïve patients. In the current review we present an up-to-date overview of the current and evolving clinical data regarding the biology of the disease, the emerging clinical decision-making and the targeted therapy options in advanced NSCLC harboring ALK translocation, especially focusing on the activity of brigatinib. Expert opinion Brigatinib shows a deep systemic and intracranial efficacy in both naïve and refractory metastatic ALK-positive NSCLC patients in the clinical studies, which marked its clinical development. Given its efficacy and tolerability brigatinib could be an excellent therapeutic option for the treatment of advanced ALK-positive NSCLC patients.","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"299 - 305"},"PeriodicalIF":1.2,"publicationDate":"2021-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1954907","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44886454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-06-30DOI: 10.1080/23808993.2021.1946391
A. Rizzo, A. Ricci, G. Gadaleta-Caldarola
Immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors by producing unprecedented algorithm shifts in a relatively short period of time [1]. However, immune checkpoint inhibitors (ICIs) have been suggested to be effective in approximately onethird of all cancer patients, with the antitumor activity of immunotherapy varying among different malignancies [2]. Thus, the identification of potential responders has recently become one of the key challenges in medical oncology, since there is an urgent need to develop reliable biomarkers that could guide clinicians in patient selection [3,4]. In fact, several predictors of response to ICIs have been tested and evaluated, three of whom have been approved by the United States Food and Drug Administration (FDA): programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability/defective mismatch repair (MSI/dMMR) [5]. Notably enough, all these predictors present notable differences in terms of methodology and specificity as well as strengths and weaknesses. Other potentially useful elements as predictors and/or for prognostic stratification are under evaluation, including tumorinfiltrating lymphocytes (TILs) [6]. Two years after the landmark approval of PD-L1 as predictive biomarker in non-small cell lung cancer (NSCLC), pembrolizumab was approved by the FDA for the treatment of patients with MSI-high (MSI-H)/dMMR advanced solid tumors in 2017 [7]. In particular, this approval was based on the results observed in MSI-H/dMMR malignancies across five clinical trials [7]. In fact, in these studies, the PD-1 inhibitor pembrolizumab reported an overall response rate (ORR) and a complete response (CR) rate of 39.6% and 7%, respectively, in MSI-H/dMMR solid tumors; in addition, the 78% of responders presented duration of response of 6 months or longer. Notably enough, the approval of MSI-H had some historical significance, being the first ‘orphan’ approval of a biomarker, regardless of histology and tumor type. From a molecular point of view, dMMR malignancies accumulate mutations across the genome, leading to the formation of neoantigens as well as the activation of antitumor responses [8]. Mismatch errors are particularly frequent in short tandem repeats, and thus, mutations are more commonly observed in microsatellite regions, a condition termed as MSI. Three different testing methods are available for detecting MSI-H/dMMR status: polymerase chain reaction (PCR) and next-generation sequencing (NGS) for MSI-H while dMMR is commonly determined through immunohistochemistry (IHC) [9]. Two PCR panels are more frequently used in clinical practice to determine MSI-H, the first of which is known as the Bathesda panel, including two mononucleotide (BAT-25 and BAT-26) and three dinucleotide (D5S346, D2S123, and D17S250) repeats [10]. Of note, both cancer and paired normal tissue are necessary for the evaluation of MSI-H using this panel. Conversel
{"title":"MSI-H/dMMR and cancer immunotherapy: current state and future implications","authors":"A. Rizzo, A. Ricci, G. Gadaleta-Caldarola","doi":"10.1080/23808993.2021.1946391","DOIUrl":"https://doi.org/10.1080/23808993.2021.1946391","url":null,"abstract":"Immunotherapy has revolutionized the treatment landscape of several hematological and solid tumors by producing unprecedented algorithm shifts in a relatively short period of time [1]. However, immune checkpoint inhibitors (ICIs) have been suggested to be effective in approximately onethird of all cancer patients, with the antitumor activity of immunotherapy varying among different malignancies [2]. Thus, the identification of potential responders has recently become one of the key challenges in medical oncology, since there is an urgent need to develop reliable biomarkers that could guide clinicians in patient selection [3,4]. In fact, several predictors of response to ICIs have been tested and evaluated, three of whom have been approved by the United States Food and Drug Administration (FDA): programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), and microsatellite instability/defective mismatch repair (MSI/dMMR) [5]. Notably enough, all these predictors present notable differences in terms of methodology and specificity as well as strengths and weaknesses. Other potentially useful elements as predictors and/or for prognostic stratification are under evaluation, including tumorinfiltrating lymphocytes (TILs) [6]. Two years after the landmark approval of PD-L1 as predictive biomarker in non-small cell lung cancer (NSCLC), pembrolizumab was approved by the FDA for the treatment of patients with MSI-high (MSI-H)/dMMR advanced solid tumors in 2017 [7]. In particular, this approval was based on the results observed in MSI-H/dMMR malignancies across five clinical trials [7]. In fact, in these studies, the PD-1 inhibitor pembrolizumab reported an overall response rate (ORR) and a complete response (CR) rate of 39.6% and 7%, respectively, in MSI-H/dMMR solid tumors; in addition, the 78% of responders presented duration of response of 6 months or longer. Notably enough, the approval of MSI-H had some historical significance, being the first ‘orphan’ approval of a biomarker, regardless of histology and tumor type. From a molecular point of view, dMMR malignancies accumulate mutations across the genome, leading to the formation of neoantigens as well as the activation of antitumor responses [8]. Mismatch errors are particularly frequent in short tandem repeats, and thus, mutations are more commonly observed in microsatellite regions, a condition termed as MSI. Three different testing methods are available for detecting MSI-H/dMMR status: polymerase chain reaction (PCR) and next-generation sequencing (NGS) for MSI-H while dMMR is commonly determined through immunohistochemistry (IHC) [9]. Two PCR panels are more frequently used in clinical practice to determine MSI-H, the first of which is known as the Bathesda panel, including two mononucleotide (BAT-25 and BAT-26) and three dinucleotide (D5S346, D2S123, and D17S250) repeats [10]. Of note, both cancer and paired normal tissue are necessary for the evaluation of MSI-H using this panel. Conversel","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":"6 1","pages":"345 - 347"},"PeriodicalIF":1.2,"publicationDate":"2021-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/23808993.2021.1946391","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49328026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-05-31DOI: 10.1080/23808993.2021.1917989
L. Metrock, M. Lobbous, B. Korf
ABSTRACT Introduction: Plexiform neurofibromas (PNs) are present in up to half of patients with neurofibromatosis type 1 (NF1). PNs consist of a proliferation of abnormal cells in the nerve sheath and can lead to significant comorbidities. Most PNs are diagnosed in early childhood when the most rapid growth rate generally occurs. Historically there has been a paucity of effective treatment options for patients with PNs, with surgery being the standard of care. As knowledge has increased regarding the NF1 gene and the function of its protein product neurofibromin, therapies targeting the Ras signaling pathway have been tested, first in preclinical models and subsequently in clinical trials. Areas covered: This review focuses on selumetinib (KOSELUGOTM; AZD6244, ARRY-142,886) and the management of PNs. A literature search was undertaken using PubMed with keywords ‘neurofibromatosis,’ ‘plexiform neurofibromas,’ ‘selumetinib,’ and ‘MEK inhibitor.’ Expert opinion: Selumetinib is the first FDA approved drug for the treatment of PNs. Prior to its development, options for patients with PNs causing morbidity were limited. Surgical intervention can be difficult, debilitating, and often futile. With the efficacy seen in the phase 1 and 2 trials for patients with NF1-associated PNs, the outlook has become one of the hope and excitement.
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Pub Date : 2021-05-13DOI: 10.1080/23808993.2021.1924055
E. Capobianco, Marcus John Beasley
Based on the patient’s characteristics, precision medicine (PM) aims to optimize the time of administration of the most appropriate medicine with the minimum risk of toxicity. This is a multidimensional problem due to the varied disease course and therapeutic responses of patients. General factors, such as genetics, epigenetics, environment, ethnicity, adherence, lifestyle, and diet, determine these outcomes. In clinical trials, some drugs may be not beneficial or even harmful for a given ethnic or co-morbid group. Partial response is also observed outside trials, as the most commonly used drugs show high efficacy in relatively few patients. Therefore, what we call ‘imprecise medicine’ is the first challenge of PM due to the assumption underlying clinical practice that disease treatment and prevention strategies developed at the population level are expected to be accurate when applied at the individual level. The complexity that drives the variations in patient profiles depends on the heterogeneity of information obtained from large volumes of genetic, serological, biochemical, and diagnostic imaging data. These represent dimensions that need harmonization and integration with lifestyle and environmental factors. The second challenge is with assessing the benefits of the data dimensions, such as diagnostic improvements, earlier interventions, increased drug efficiency, and better-targeted treatments. To accommodate the heterogeneity of the etiologies, clinical symptoms, and treatment responses of patients in clinical practice, a revised clinical approach is recommended [1]. The first step is the development of a machine learning (ML)-assisted risk assessment model (see, for instance [2],) followed by the identification of the robust multimodal data-driven prognostic indicators (see, for instance [3],). These two efforts require new strategies for integrating heterogeneous information from different structured and unstructured data sources (electronic health records (EHRs), administrative databases, bioimaging archives, self-quantified measurements, etc.). Big Data has introduced a new paradigm for population-based studies that comes with challenges. For instance, the validity of such studies is based on the diagnostic accuracy used for all cases. A critical problem is the variability of the methods used to perform validations. Currently, there are challenges with validating most disease classification algorithms, and this complicates the assessment of their potential for population studies. Model validation facilitates safer interpretability of the correlations between diverse data types revealed by the models. Data-centric perspectives of complex diseases facilitate their definition as heterogeneous processes that have multifaceted causes, courses of evolution, treatments, and patient’s disease trajectories from the observed responses to treatment (see [4–6], among many other examples). These trajectories differ with each patient and, therefore
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