Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation

2021 ◽  
pp. 107815522110055
Author(s):  
Clement Chung
Keyword(s):  
Checkpoint Inhibitors ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Tumor Location ◽  
Prognostic Biomarkers ◽  
Her2 Gene ◽  
Braf Mutations ◽  
Therapeutic Implications ◽  
Molecular Alterations

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [ NTRK] fusion genes, and human epidermal growth factor receptor type II [ HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

scholarly journals Expression of Human Epidermal Growth Factor Receptor-2 Status and Programmed Cell Death Protein-1 Ligand Is Associated With Prognosis in Gastric Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Huifang Lv ◽  
Junling Zhang ◽  
Keran Sun ◽  
Caiyun Nie ◽  
Beibei Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Underlying Mechanism ◽  
Tumor Location ◽  
The Cancer Genome Atlas ◽  
Prognostic Indicators ◽  
Her 2

BackgroundPD-L1 and HER-2 are routine biomarkers for gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, immune microenvironment, and clinical features in GC.MethodsBetween January 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). The mRNA and tumor microenvironment of 343 patients with GC from The Cancer Genome Atlas (TCGA) were used to explore the underlying mechanism.ResultsWe retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 (P = 0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P = 0.014, mPFS: 5.3 vs. 11.1 months, P = 0.002, respectively), and the PD-L1 negative and HER-2 negative had the best PFS than other groups (P = 0.0008). In a multivariate model, PD-L1 status, HER-2 status, tumor location, and tumor differentiation remained independent prognostic indicators for PFS (P < 0.05). The results of database further analysis showed that the proportion of PD-L1+/CD8A+ in HER-2 negative patients was higher than that in HER-2 positive patients (37.6 vs 20.3%), while PD-L1−/CD8A− was significantly higher in HER-2 positive patients than HER-2 negative patients (57.8 vs. 28.8%). In addition, it showed that not only CD4+T cells, macrophages, and CD8+T cells, but also the associated inflammatory pathways such as IFN-γ/STAT1 were associated with HER-2.ConclusionHER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients.

scholarly journals Analysis of Predictive Biomarkers in Patients With Lung Adenocarcinoma From Southern Brazil Reveals a Distinct Profile From Other Regions of the Country

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Tiago F. Andreis ◽  
Bruno S. Correa ◽  
Fernanda S. Vianna ◽  
Fernanda De-Paris ◽  
Marina Siebert ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Predictive Biomarkers ◽  
Egfr Mutations ◽  
Southern Brazil ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Histologic Subtype ◽  
Molecular Alterations ◽  
Common Histologic Subtype ◽  
L1 Protein

PURPOSE Adenocarcinoma is the most common histologic subtype of non–small-cell lung cancer, representing 40% of all diagnoses. Several biomarkers are currently used to determine patient eligibility for targeted treatments, including analysis of molecular alterations in EGFR and ALK, as well as programmed death-ligand 1 (PD-L1) protein expression. Epidemiologic data reporting the frequency of these biomarkers in Brazilian patients with lung adenocarcinoma (LUAD) are limited, and existing studies predominantly included patients from the southeast region of the country. MATERIALS AND METHODS The goal of this study was to investigate the frequency of somatic mutations in the EGFR, KRAS, NRAS, and BRAF genes, ALK, and PD-L1 expression in a series of Brazilian patients diagnosed with LUAD predominantly recruited from centers in southern Brazil. Molecular analysis of the EGFR, KRAS, NRAS, and BRAF genes was performed by next-generation sequencing using DNA extracted from tumor tissue. Immunohistochemistry was used to detect ALK and PD-L1 expression. RESULTS Analysis of 619 tumors identified KRAS mutations in 189 (30.2%), EGFR mutations in 120 (19.16%), and BRAF mutations in 19 (3%). Immunohistochemistry demonstrated ALK and PD-L1 expression in 4% and 35.1% of patients, respectively. CONCLUSION To our knowledge, this is the first study investigating the molecular epidemiology of patients with LUAD from southern Brazil and the largest assessing the frequency of multiple predictive biomarkers for this tumor in the country. The study also reveals a distinct mutation profile compared with data originating from other regions of Brazil.

scholarly journals Clinical Data on Immunotherapy in Breast Cancer

Breast Care ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. 450-469
Author(s):  
Julia Caroline Radosa ◽  
Lisa Stotz ◽  
Carolin Müller ◽  
Askin Canguel Kaya ◽  
Erich-Franz Solomayer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
First Line ◽  
Metastatic Setting ◽  
Epidermal Growth

<b><i>Background:</i></b> Breast cancer has traditionally been considered to have a low immunogenic potential compared to other tumor entities. <b><i>Summary:</i></b> The most extensively studied immunotherapeutic agents for breast cancer to date are immune checkpoint inhibitors, with the results of the IMpassion130 trial leading to the approval of atezolizumab plus nab-paclitaxel for first-line treatment of programmed cell death ligand 1-positive, metastatic, triple-negative breast cancer, and studies in earlier stages have yielded promising results. Other immunotherapeutic options being assessed in phases 2 and 3 trials include vaccine-based therapies and treatment with anti-human epidermal growth factor receptor 2 (H-directed immune-linked antibodies) and substances evaluated in early clinical trials as cellular therapies (adoptive cell therapy and chimeric antigen receptor T cells). <b><i>Key Messages:</i></b> Immunotherapy is an emerging modality for the treatment of breast cancer, as evidenced by the plethora of preclinical and clinical concepts and ongoing trials. Early studies established the role of immunotherapeutic agents in the metastatic setting. Ongoing studies will expand our knowledge about the timing of administration, best partners for combination therapy, and predictive biomarkers to guide immunotherapy for breast cancer.

scholarly journals A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

2021 ◽  
Vol 11 ◽  
Author(s):  
Juanni Li ◽  
Kuan Hu ◽  
Jinzhou Huang ◽  
Lei Zhou ◽  
Yuanliang Yan ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor Receptor ◽  
Therapeutic Targets ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Genetic Aberrations ◽  
Therapeutic Implications ◽  
Clinical Associations

Background: Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. Although there have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported.Methods: In this study, we used the large comprehensive datasets available, covering over 10,000 tumor samples across more than 30 cancer types, to analyze FGFR2 abnormal expression, methylation, alteration (mutations/fusions and amplification/deletion), and their clinical associations.Results: Alteration frequency, mutation location distribution, oncogenic effects, and therapeutic implications varied among different cancers. The overall mutation rate of FGFR2 is low in pancancer. CHOL had the highest mutation frequency, and fusion accounted for the major proportion. All these fusion aberrations in CHOL were targetable, and an FDA-approved drug was approved recently. Uterine corpus endometrial carcinoma (UCEC) had the highest number of FGFR2 mutations, and the most frequently mutated positions were S252W and N549K, where the functional impact was oncogenic, but targeted therapy was less effective. Additionally, DNA methylation was associated with FGFR2 expression in several cancers. Moreover, FGFG2 expression and genetic aberrations showed clinical associations with patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets.Conclusions: This study showed the full FGFR2 alteration spectrum and provided a broad molecular perspective of FGFR2 in a comprehensive manner, suggesting some new directions for clinical targeted therapy of cancers.

scholarly journals Current options and future directions of systemic therapy for advanced biliary tract cancer

2021 ◽  
Vol 2 (5) ◽  
Author(s):  
Maria Giuseppina Prete ◽  
Antonella Cammarota ◽  
Antonio D'Alessio ◽  
Valentina Zanuso ◽  
Lorenza Rimassa
Keyword(s):  
Growth Factor ◽  
Biliary Tract ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Biliary Tree ◽  
Driver Mutations ◽  
Anatomical Location ◽  
Braf Mutations ◽  
Future Directions ◽  
Platinum Based Chemotherapy

Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor(FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a “precision medicine” strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.

scholarly journals Recent developments in the treatment of metastatic colorectal cancer

2017 ◽  
Vol 9 (8) ◽  
pp. 551-564 ◽  
Author(s):  
Jonathan M. Loree ◽  
Scott Kopetz
Keyword(s):  
Colorectal Cancer ◽  
Decision Making ◽  
Clinical Decision Making ◽  
Growth Factor Receptor ◽  
Low Frequency ◽  
Clinical Decision ◽  
Tumor Location ◽  
Targeted Agents ◽  
Braf Mutations ◽  
Exon 2

Over the past decade there have been significant advances in the molecular characterization of colorectal cancer (CRC) that are driving treatment decisions. Expanded RAS testing beyond KRAS exon 2 was established as crucial for identifying patients who will respond to anti-epidermal growth factor receptor (EGFR) therapies and low-frequency mutations in RAS/tumor heterogeneity are gaining recognition as potential mechanisms of resistance. Despite this progress, the fact that we do not understand why left-sided but not right-sided tumors have improved outcomes following anti-EGFR therapy highlights our superficial understanding of this disease. Even with few new targeted agents receiving approval in CRC, the incorporation of next-generation sequencing into clinical decision making represents an important step forward. Biomarkers such as BRAF mutations, microsatellite instability, and HER2 amplification represent promising molecular aberrations with therapies in various stages of development, and highlight the importance of companion diagnostics in supporting targeted agents. In this review, we will discuss the importance of incorporating biomarkers into clinical decision making and regimen selection in CRC. We will particularly focus on the recent evidence suggesting an important role for tumor location in selecting first-line therapy, the importance of recent advances in biomarker development and molecular subtyping, as well as recently approved agents (regorafenib and TAS-102) and promising targeted agents that have the potential to change the standard of care.

The host response to immune checkpoint inhibitors: From mechanisms to therapeutic implications.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14584-e14584
Author(s):  
Ella Fremder ◽  
Eyal Jacob ◽  
Irena Khononov ◽  
Eran Issler ◽  
Shani Raveh ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Initial Response ◽  
Cancer Drug ◽  
Therapeutic Implications ◽  
Therapeutic Outcomes ◽  
Clinical Models ◽  
Immune Oncology

e14584 Background: One of the major challenges in clinical immuno-oncology today is predicting which patients will respond to treatment. Although the use of immune checkpoint inhibitors (ICIs) has significantly improved therapeutic outcomes in a subset of patients with advanced malignancies, the majority of patients do not respond to treatment and some even hyper-progress. This response pattern raises questions regarding the possible mechanisms of resistance to ICIs. In the last decade we and others have shown that the host, in response to almost any type of anti-cancer drug, generates pro-tumorigenic and pro-metastatic effects which in turn contribute to tumor relapse and resistance to therapy despite an initial response. However, such host effects have never been investigated using immune-oncology drugs. Methods: We used functional and computational methods on plasma samples from both mouse models and cancer patients to identify the host-mediated tumor promoting molecular pathways that are induced in response to ICI therapy. Results: We found that these pathways are composed of dominant factors that regulate pro-inflammatory, metastatic and proliferation activities and thus contribute to rapid tumor re-growth. In pre-clinical models, we have found that pharmacological blockade of specific dominant factors overcomes the tumor-promoting effects induced by the host in response to ICI therapy. Conclusions: Based on our collective findings, we propose that therapies inhibiting host-mediated pro-tumorigenic effects could be used in combination with ICIs as a strategy to minimize tumor hyper-progression and increase the susceptibility of resistant tumors to ICI therapy. Furthermore, our studies pave the way towards the discovery of new predictive biomarkers for identifying subjects who will benefit from ICI therapy.

scholarly journals The Developing Story of Predictive Biomarkers in Colorectal Cancer

2019 ◽  
Vol 9 (1) ◽  
pp. 12 ◽  
Author(s):  
Stergios Boussios ◽  
Mehmet Ozturk ◽  
Michele Moschetta ◽  
Afroditi Karathanasi ◽  
Nikolaos Zakynthinakis-Kyriakou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Predictive Marker ◽  
Mitogen Activated Protein Kinase ◽  
Disease Stage ◽  
Therapeutic Implications ◽  
Micro Rnas

Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase (MAPK) pathway genes KRAS, NRAS, and BRAF represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.

scholarly journals Colorectal cancer genomic biomarkers in the clinical management of patients with metastatic colorectal carcinoma

2020 ◽  
Vol 1 (1) ◽  
pp. 53-70
Author(s):  
Anna Maria Rachiglio ◽  
Alessandra Sacco ◽  
Laura Forgione ◽  
Claudia Esposito ◽  
Nicoletta Chicchinelli ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Genetic Alterations ◽  
Braf Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Novel Biomarkers ◽  
Epidermal Growth

Colorectal carcinoma (CRC) is an heterogeneous disease in which different genetic alterations play a role in its pathogenesis and progression and offer potential for therapeutic intervention. The research on predictive biomarkers in metastatic CRC (mCRC) mainly focused on the identification of biomarkers of response or resistance to anti-epidermal growth factor receptor monoclonal antibodies. In this respect, international guidelines suggest testing mCRC patients only for KRAS, NRAS and BRAF mutations and for microsatellite instability. However, the use of novel testing methods is raising relevant issue related to these biomarkers, such as the presence of sub-clonal RAS mutations or the clinical interpretation of rare no-V600 BRAF variants. In addition, a number of novel biomarkers is emerging from recent studies including amplification of ERBB2, mutations in ERBB2, MAP2K1 and NF1 and rearrangements of ALK, ROS1, NTRK and RET. Mutations in POLE and the levels of tumor mutation burden also appear as possible biomarkers of response to immunotherapy in CRC. Finally, the consensus molecular subtypes classification of CRC based on gene expression profiling has prognostic and predictive implications. Integration of all these information will be likely necessary in the next future in order to improve precision/personalized medicine in mCRC patients.

scholarly journals PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

Medicines ◽  
2020 ◽  
Vol 7 (9) ◽  
pp. 54
Author(s):  
Angela Dalia Ricci ◽  
Alessandro Rizzo ◽  
Chiara Bonucci ◽  
Nastassja Tober ◽  
Andrea Palloni ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Anticancer Agents ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Comprehensive Overview ◽  
Therapeutic Implications ◽  
Tract Cancer ◽  
Combination Strategies

Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.

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