Cancers

Editorial

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6 pages, 211 KiB

Open AccessEditorial

Precision Medicine in Solid Tumors: How Far We Traveled So Far?

by Nandini Dey and Pradip De

Cancers 2022, 14(13), 3202; https://doi.org/10.3390/cancers14133202 - 30 Jun 2022

Cited by 3 | Viewed by 1484

Abstract

The future of disease management in solid tumors will rely heavily on how effectively we understand precision medicine and how successfully we can deliver personalized medicine [...] Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

Research

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29 pages, 4323 KiB

Open AccessArticle

A Laboratory-Friendly CTC Identification: Comparable Double-Immunocytochemistry with Triple-Immunofluorescence

by Raed Sulaiman, Pradip De, Jennifer C. Aske, Xiaoqian Lin, Adam Dale, Ethan Vaselaar, Nischal Koirala, Cheryl Ageton, Kris Gaster, Joshua Plorde, Benjamin Solomon, Bradley Thaemert, Paul Meyer, Luis Rojas Espaillat, David Starks and Nandini Dey

Cancers 2022, 14(12), 2871; https://doi.org/10.3390/cancers14122871 - 10 Jun 2022

Cited by 9 | Viewed by 2539

Abstract

The source of circulating tumor cells (CTC) in the peripheral blood of patients with solid tumors are from primary cancer, metastatic sites, and a disseminated tumor cell pool. As 90% of cancer-related deaths are caused by metastatic progression and/or resistance-associated treatment failure, the [...] Read more.

The source of circulating tumor cells (CTC) in the peripheral blood of patients with solid tumors are from primary cancer, metastatic sites, and a disseminated tumor cell pool. As 90% of cancer-related deaths are caused by metastatic progression and/or resistance-associated treatment failure, the above fact justifies the undeniable predictive and prognostic value of identifying CTC in the bloodstream at stages of the disease progression and resistance to treatment. Yet enumeration of CTC remains far from a standard routine procedure either for post-surgery follow-ups or ongoing adjuvant therapy. The most compelling explanation for this paradox is the absence of a convenient, laboratory-friendly, and cost-effective method to determine CTC. We presented a specific and sensitive laboratory-friendly parallel double-detection format method for the simultaneous isolation and identification of CTC from peripheral blood of 91 consented and enrolled patients with various malignant solid tumors of the lung, endometrium, ovary, esophagus, prostate, and liver. Using a pressure-guided method, we used the size-based isolation to capture CTC on a commercially available microfilter. CTC identification was carried out by two expression marker-based independent staining methods, double-immunocytochemistry parallel to standard triple-immunofluorescence. The choice of markers included specific markers for epithelial cells, EpCAM and CK8,18,19, and exclusion markers for WBC, CD45. We tested the method’s specificity based on the validation of the staining method, which included positive and negative spiked samples, blood from the healthy age-matched donor, healthy age-matched leucopaks, and blood from metastatic patients. Our user-friendly cost-effective CTC detection technique may facilitate the regular use of CTC detection even in community-based cancer centers for prognosis, before and after surgery. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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19 pages, 12366 KiB

Open AccessArticle

Relationship between Tumor Mutational Burden, PD-L1, Patient Characteristics, and Response to Immune Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma

by Kimberly M. Burcher, Jeffrey W. Lantz, Elena Gavrila, Arianne Abreu, Jack T. Burcher, Andrew T. Faucheux, Amy Xie, Clayton Jackson, Alexander H. Song, Ryan T. Hughes, Thomas Lycan, Jr., Paul M. Bunch, Cristina M. Furdui, Umit Topaloglu, Ralph B. D’Agostino, Jr., Wei Zhang and Mercedes Porosnicu

Cancers 2021, 13(22), 5733; https://doi.org/10.3390/cancers13225733 - 16 Nov 2021

Cited by 20 | Viewed by 3093

Abstract

Failure to predict response to immunotherapy (IO) limited its benefit in the treatment of head and neck squamous cell cancer (HNSCC) to 20% of patients or less. Biomarkers including tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) were evaluated as predictors of [...] Read more.

Failure to predict response to immunotherapy (IO) limited its benefit in the treatment of head and neck squamous cell cancer (HNSCC) to 20% of patients or less. Biomarkers including tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) were evaluated as predictors of response to IO, but the results are inconsistent and with a lack of standardization of their methods. In this retrospective study, TMB and PD-L1 were measured by commercially available methodologies and were correlated to demographics, outcome, and response to PD-1 inhibitors. No correlation was found between TMB and PD-L1 levels. High TMB was associated with smoking and laryngeal primaries. PD-L1 was significantly higher in African Americans, patients with earlier stage tumors, nonsmokers, and nonethanol drinkers. Patients with high TMB fared better in univariate and multivariate survival analysis. No correlation was found between PD-L1 expression and prognosis. There was a statistically significant association between PFS and response to IO and TMB. There was no association between response to ICI and PD-L1 in this study, possibly affected by variations in the reporting method. Further studies are needed to characterize the biomarkers for IO in HNSCC, and this study supports further research into the advancement of TMB in prospective studies. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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19 pages, 1493 KiB

Open AccessArticle

Regulations, Open Data and Healthcare Innovation: A Case of MSK-IMPACT and Its Implications for Better Cancer Care

by Takaharu Jibiki, Hayato Nishimura, Shintaro Sengoku and Kota Kodama

Cancers 2021, 13(14), 3448; https://doi.org/10.3390/cancers13143448 - 9 Jul 2021

Cited by 2 | Viewed by 4438

Abstract

This study investigated a case of Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a tumor profiling test approved by the U.S. Food and Drug Administration (FDA) in 2017, to examine what factors would contribute to healthcare innovation. First, we set [...] Read more.

This study investigated a case of Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT), a tumor profiling test approved by the U.S. Food and Drug Administration (FDA) in 2017, to examine what factors would contribute to healthcare innovation. First, we set the following three parameters to observe cases: (i) the FDA regulatory reforms, (ii) early application of new technologies, such as next-generation sequencing (NGS), to both research and clinical settings, and (iii) accumulation of open data. Then, we performed a comparative analysis of MSK-IMPACT with FoundationOne CDx and Oncomine Dx Target Test, both of which were FDA-approved tumor profiling tests launched in 2017. As a result, we found that MSK-IMPACT secures neutrality as a non-profit organization, achieves the active incorporation of basic research results, and performs superiorly in clinical operations, such as patient enrollment. On the contrary, we confirmed that FoundationOne CDx was the most prominent case in terms of the number of new drugs and expanded indications approved in which the FDA’s expedited approval programs were considerably utilized. Consequently, to uncover the full potential of MSK-IMPACT, it is suggested that more intersectoral collaborative activities between various healthcare stakeholders, in particular, pharmaceutical companies, for driving clinical development must be carried out based on an organizational framework that facilitates collaboration. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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19 pages, 1972 KiB

Open AccessArticle

Prevalence of DNA Repair Gene Mutations in Blood and Tumor Tissue and Impact on Prognosis and Treatment in HNSCC

by Kimberly M. Burcher, Andrew T. Faucheux, Jeffrey W. Lantz, Harper L. Wilson, Arianne Abreu, Kiarash Salafian, Manisha J. Patel, Alexander H. Song, Robin M. Petro, Thomas Lycan, Jr., Cristina M. Furdui, Umit Topaloglu, Ralph B. D’Agostino, Wei Zhang and Mercedes Porosnicu

Cancers 2021, 13(13), 3118; https://doi.org/10.3390/cancers13133118 - 22 Jun 2021

Cited by 16 | Viewed by 2803

Abstract

PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA [...] Read more.

PARP inhibitors are currently approved for a limited number of cancers and targetable mutations in DNA damage repair (DDR) genes. In this single-institution retrospective study, the profiles of 170 patients with head and neck squamous cell cancer (HNSCC) and available tumor tissue DNA (tDNA) and circulating tumor DNA (ctDNA) results were analyzed for mutations in a set of 18 DDR genes as well as in gene subsets defined by technical and clinical significance. Mutations were correlated with demographic and outcome data. The addition of ctDNA to the standard tDNA analysis contributed to identification of a significantly increased incidence of patients with mutations in one or more genes in each of the study subsets of DDR genes in groups of patients older than 60 years, patients with laryngeal primaries, patients with advanced stage at diagnosis and patients previously treated with chemotherapy and/or radiotherapy. Patients with DDR gene mutations were found to be significantly less likely to have primary tumors within the in oropharynx or HPV-positive disease. Patients with ctDNA mutations in all subsets of DDR genes analyzed had significantly worse overall survival in univariate and adjusted multivariate analysis. This study underscores the utility of ctDNA analysis, alone, and in combination with tDNA, for defining the prevalence and the role of DDR gene mutations in HNSCC. Furthermore, this study fosters research promoting the utilization of PARP inhibitors in HNSCC precision oncology treatments. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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11 pages, 1697 KiB

Open AccessArticle

Clinical Guideline-Guided Outcome Consistency for Surgically Resected Stage III Non-Small Cell Lung Cancer: A Retrospective Study

by Hiroaki Kuroda, Yusuke Sugita, Katsuhiro Masago, Yusuke Takahashi, Takeo Nakada, Eiichi Sasaki, Noriaki Sakakura, Rui Yamaguchi, Hirokazu Matsushita and Toyoaki Hida

Cancers 2021, 13(11), 2531; https://doi.org/10.3390/cancers13112531 - 21 May 2021

Cited by 1 | Viewed by 2423

Abstract

Clinical guidelines can help reduce the use of inappropriate therapeutics due to localism and individual clinician perspectives. Nevertheless, despite the intention of clinical guidelines to achieve survival benefit or desirable outcomes, they cannot ensure a robust outcome. This retrospective study aimed to investigate [...] Read more.

Clinical guidelines can help reduce the use of inappropriate therapeutics due to localism and individual clinician perspectives. Nevertheless, despite the intention of clinical guidelines to achieve survival benefit or desirable outcomes, they cannot ensure a robust outcome. This retrospective study aimed to investigate whether guideline-consistency, including adjuvant treatments after surgical resection (ATSR) and guideline-matched first-line treatment for recurrence (GMT-R), according to the genomic profiles and immune status, could influence overall survival (OS). From 2006 to 2017, the clinical data of 308 patients with stage III non-small cell lung cancer (NSCLC) after surgical resection were evaluated. ATSR and GMT-R were allowed in 164 (53.2%) and 129 (62.3%) patients cases after surgical pulmonary resection, among which 207 (67.2%) recurrences were identified. The 5-year OS in guideline-consistent cases was significantly better than that in guideline-inconsistent cases (p < 0.01). Subgroup analyses further showed that the 5-year OS after propensity adjustment was significantly better in guideline-consistent than in guideline-inconsistent cases (p < 0.01), but not in either ATSR or GMT-R (p = 0.24). These data suggest that the guideline-consistent alternatives, which comprise ATSR or GMT-R, can contribute to survival benefits in pathological stage III NSCLC. However, only either ATSR or GMT-R has a potential survival benefit in these patients. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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13 pages, 1257 KiB

Open AccessArticle

Clinical Utility of Next-Generation Sequencing-Based Panel Testing under the Universal Health-Care System in Japan: A Retrospective Analysis at a Single University Hospital

by Chiaki Inagaki, Daichi Maeda, Kazue Hatake, Yuki Sato, Kae Hashimoto, Daisuke Sakai, Shinichi Yachida, Norio Nonomura and Taroh Satoh

Cancers 2021, 13(5), 1121; https://doi.org/10.3390/cancers13051121 - 5 Mar 2021

Cited by 17 | Viewed by 4200

Abstract

Next-generation sequencing (NGS) assay is part of routine care in Japan owing to its reimbursement by Japan’s universal health-care system; however, reimbursement is limited to patients who finished standard treatment. We retrospectively investigated 221 patients who underwent Foundation One CDX (F1CDx) at our [...] Read more.

Next-generation sequencing (NGS) assay is part of routine care in Japan owing to its reimbursement by Japan’s universal health-care system; however, reimbursement is limited to patients who finished standard treatment. We retrospectively investigated 221 patients who underwent Foundation One CDX (F1CDx) at our hospital. Every F1CDx result was assessed at the molecular tumor board (MTB) for treatment recommendation. Based on patients’ preferences, presumed germline findings were also assessed at the MTB and disclosed at the clinic. In total, 204 patients underwent F1CDx and 195 patients completed the analysis; however, 13.8% of them could not receive the report due to disease progression. Among 168 patients who received the results, 41.6% had at least one actionable alteration, and 3.6% received genomically matched treatment. Presumed germline findings were nominated in 24 patients, and 16.7% of them contacted a geneticist counselor. The NGS assay should be performed earlier in the clinical course to maximize the clinical benefit. Broader reimbursement for the NGS assay would enhance the delivery of precision oncology to patients. Access to clinical trials affects the number of patients who benefit from NGS. Additionally, the disclosure of presumed germline findings is feasible in clinical practice. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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12 pages, 3116 KiB

Open AccessArticle

Primary Driver Mutations in GTF2I Specific to the Development of Thymomas

by Rumi Higuchi, Taichiro Goto, Yosuke Hirotsu, Yujiro Yokoyama, Takahiro Nakagomi, Sotaro Otake, Kenji Amemiya, Toshio Oyama, Hitoshi Mochizuki and Masao Omata

Cancers 2020, 12(8), 2032; https://doi.org/10.3390/cancers12082032 - 24 Jul 2020

Cited by 19 | Viewed by 2983

Abstract

Thymomas are rare mediastinal tumors that are difficult to treat and pose a major public health concern. Identifying mutations in target genes is vital for the development of novel therapeutic strategies. Type A thymomas possess a missense mutation in GTF2I (chromosome 7 c.74146970T>A) [...] Read more.

Thymomas are rare mediastinal tumors that are difficult to treat and pose a major public health concern. Identifying mutations in target genes is vital for the development of novel therapeutic strategies. Type A thymomas possess a missense mutation in GTF2I (chromosome 7 c.74146970T>A) with high frequency. However, the molecular pathways underlying the tumorigenesis of other thymomas remain to be elucidated. We aimed to detect this missense mutation in GTF2I in other thymoma subtypes (types B). This study involved 22 patients who underwent surgery for thymomas between January 2014 and August 2019. We isolated tumor cells from formalin-fixed paraffin-embedded tissues from the primary lesions using laser-capture microdissection. Subsequently, we performed targeted sequencing to detect mutant GTF2I coupled with molecular barcoding. We used PyClone analysis to determine the fraction of tumor cells harboring mutant GTF2I. We detected the missense mutation (chromosome 7 c.74146970T>A) in GTF2I in 14 thymomas among the 22 samples (64%). This mutation was harbored in many type B thymomas as well as type A and AB thymomas. The allele fraction for the tumors containing the mutations was variable, primarily owing to the coexistence of normal lymphocytes in the tumors, especially in type B thymomas. PyClone analysis revealed a high cellular prevalence of mutant GTF2I in tumor cells. Mutant GTF2I was not detected in other carcinomas (lung, gastric, colorectal, or hepatocellular carcinoma) or lymphomas. In conclusion, the majority of thymomas harbor mutations in GTF2I that can be potentially used as a novel therapeutic target in patients with thymomas. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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17 pages, 1355 KiB

Open AccessArticle

Whole Exome Sequencing of Multi-Regional Biopsies from Metastatic Lesions to Evaluate Actionable Truncal Mutations Using a Single-Pass Percutaneous Technique

by Valerie Heong, Darwin Tay, Shane Ee Goh, Bernard Wee, Tuan Zea Tan, Ross Soo, Brendan Pang, Diana Lim, Anil Gopinathan, Samuel Ow, Cheng Ean Chee, Boon Cher Goh, Soo Chin Lee, Wei Peng Yong, Andrea Wong, Mohamed Feroz Mohd Omar, Richie Soong and David SP Tan

Cancers 2020, 12(6), 1599; https://doi.org/10.3390/cancers12061599 - 17 Jun 2020

Cited by 2 | Viewed by 2868

Abstract

We investigate the feasibility of obtaining multiple spatially-separated biopsies from a single lesion to explore intratumor heterogeneity and identify actionable truncal mutations using whole exome sequencing (WES). A single-pass radiologically-guided percutaneous technique was used to obtain four spatially-separated biopsies from a single metastatic [...] Read more.

We investigate the feasibility of obtaining multiple spatially-separated biopsies from a single lesion to explore intratumor heterogeneity and identify actionable truncal mutations using whole exome sequencing (WES). A single-pass radiologically-guided percutaneous technique was used to obtain four spatially-separated biopsies from a single metastatic lesion. WES was performed to identify putative truncal variants (PTVs), defined as a non-synonymous somatic (NSS) variant present in all four spatially separated biopsies. Actionable truncal mutations—filtered using the FoundationOne panel—were defined as clinically relevant PTVs. Mutational landscapes of each biopsy and their association with patient outcomes were assessed. WES on 50 biopsied samples from 13 patients across six cancer types were analyzed. Actionable truncal mutations were identified in 9/13 patients; 31.1 ± 5.12 more unique NSS variants were detected with every additional multi- region tumor biopsy (MRTB) analyzed. The number of PTVs dropped by 16.1 ± 17.9 with every additional MRTB, with the decrease most pronounced (36.8 ± 19.7) when two MRTB were analyzed compared to one. MRTB most reliably predicted PTV compared to in silico analysis of allele frequencies and cancer cell fraction based on one biopsy sample. Three patients treated with actionable truncal mutation-directed therapy derived clinical benefit. Multi-regional sampling for genomics analysis is feasible and informative to help prioritize precision-therapy strategies. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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11 pages, 556 KiB

Open AccessArticle

Impact and Diagnostic Gaps of Comprehensive Genomic Profiling in Real-World Clinical Practice

by Aditi P. Singh, Elaine Shum, Lakshmi Rajdev, Haiying Cheng, Sanjay Goel, Roman Perez-Soler and Balazs Halmos

Cancers 2020, 12(5), 1156; https://doi.org/10.3390/cancers12051156 - 4 May 2020

Cited by 23 | Viewed by 4231

Abstract

Purpose: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. [...] Read more.

Purpose: next-generation sequencing based comprehensive genomic profiling (CGP) is becoming common practice. Although numerous studies have shown its feasibility to identify actionable genomic alterations in most patients, its clinical impact as part of routine management across all cancers in the community remains unknown. Methods: we conducted a retrospective study of all patients that underwent CGP as part of routine cancer management from January 2013 to June 2017 at an academic community-based NCI-designated cancer center. CGP was done in addition to established first tier reflex molecular testing as per national guidelines (e.g., EGFR/ALK for non-small cell lung cancer (NSCLC) and extended-RAS for colorectal cancer). Results: 349 tests were sent for CGP from 333 patients and 95% had at least one actionable genomic alteration reported. According to the reported results, 23.2% had a Food and Drug Administration (FDA) approved therapy available, 61.3% had an off-label therapy available and 77.9% were potentially eligible for a clinical trial. Treatment recommendations were also reviewed within the OncoKB database and 47% of them were not clinically validated therapies. The CGP results led to treatment change in only 35 patients (10%), most commonly in NSCLC. Nineteen of these patients (54% of those treated and 5% of total) had documented clinical benefit with targeted therapy. Conclusion: we demonstrate that routine use of CGP in the community across all cancer types detects potentially actionable genomic alterations in a majority of patients, however has modest clinical impact enriched in the NSCLC subset. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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19 pages, 1613 KiB

Open AccessArticle

A Novel Comprehensive Clinical Stratification Model to Refine Prognosis of Glioblastoma Patients Undergoing Surgical Resection

by Tamara Ius, Fabrizio Pignotti, Giuseppe Maria Della Pepa, Giuseppe La Rocca, Teresa Somma, Miriam Isola, Claudio Battistella, Simona Gaudino, Maurizio Polano, Michele Dal Bo, Daniele Bagatto, Enrico Pegolo, Silvia Chiesa, Mauro Arcicasa, Alessandro Olivi, Miran Skrap and Giovanni Sabatino

Cancers 2020, 12(2), 386; https://doi.org/10.3390/cancers12020386 - 7 Feb 2020

Cited by 15 | Viewed by 3352

Abstract

Despite recent discoveries in genetics and molecular fields, glioblastoma (GBM) prognosis still remains unfavorable with less than 10% of patients alive 5 years after diagnosis. Numerous studies have focused on the research of biological biomarkers to stratify GBM patients. We addressed this issue [...] Read more.

Despite recent discoveries in genetics and molecular fields, glioblastoma (GBM) prognosis still remains unfavorable with less than 10% of patients alive 5 years after diagnosis. Numerous studies have focused on the research of biological biomarkers to stratify GBM patients. We addressed this issue in our study by using clinical/molecular and image data, which is generally available to Neurosurgical Departments in order to create a prognostic score that can be useful to stratify GBM patients undergoing surgical resection. By using the random forest approach [CART analysis (classification and regression tree)] on Survival time data of 465 cases, we developed a new prediction score resulting in 10 groups based on extent of resection (EOR), age, tumor volumetric features, intraoperative protocols and tumor molecular classes. The resulting tree was trimmed according to similarities in the relative hazard ratios amongst groups, giving rise to a 5-group classification tree. These 5 groups were different in terms of overall survival (OS) (p < 0.000). The score performance in predicting death was defined by a Harrell’s c-index of 0.79 (95% confidence interval [0.76–0.81]). The proposed score could be useful in a clinical setting to refine the prognosis of GBM patients after surgery and prior to postoperative treatment. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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14 pages, 996 KiB

Open AccessArticle

Assessment of Tumor Mutational Burden in Pediatric Tumors by Real-Life Whole-Exome Sequencing and In Silico Simulation of Targeted Gene Panels: How the Choice of Method Could Affect the Clinical Decision?

by Hana Noskova, Michal Kyr, Karol Pal, Tomas Merta, Peter Mudry, Kristyna Polaskova, Tina Catela Ivkovic, Sona Adamcova, Tekla Hornakova, Marta Jezova, Leos Kren, Jaroslav Sterba and Ondrej Slaby

Cancers 2020, 12(1), 230; https://doi.org/10.3390/cancers12010230 - 17 Jan 2020

Cited by 11 | Viewed by 5193

Abstract

Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various [...] Read more.

Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various settings of bioinformatic pipelines. In pediatric oncology, no study has been published describing this variability so far. Methods: In our study, we performed whole exome sequencing (WES, both germline and somatic) and calculated TMB in 106 patients with high-risk/recurrent pediatric solid tumors of 28 distinct cancer types. Subsequently, we used WES data for TMB calculation using an in silico approach simulating two The Food and Drug Administration (FDA)-approved/authorized comprehensive genomic panels for cancer. Results: We describe a strong correlation between WES-based and panel-based TMBs; however, we show that this high correlation is significantly affected by inclusion of only a few hypermutated cases. In the series of nine cases, we determined TMB in two sequentially collected tumor tissue specimens and observed an increase in TMB along with tumor progression. Furthermore, we evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment. We confirmed that this technological variability could significantly affect ICI indication in pediatric cancer patients; however, this significance decreases with the increasing cut-off values. Conclusions: For the first time in pediatric oncology, we assessed the reliability of TMB estimation across multiple pediatric cancer types using real-life WES and in silico analysis of two major targeted gene panels and confirmed a significant technological variability to be introduced by different laboratory techniques and various settings of bioinformatic pipelines. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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Review

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31 pages, 1624 KiB

Open AccessReview

Bête Noire of Chemotherapy and Targeted Therapy: CAF-Mediated Resistance

by Pradip De, Jennifer Aske, Raed Sulaiman and Nandini Dey

Cancers 2022, 14(6), 1519; https://doi.org/10.3390/cancers14061519 - 16 Mar 2022

Cited by 15 | Viewed by 3698

Abstract

In tumor cells’ struggle for survival following therapy, they resist treatment. Resistance to therapy is the outcome of well-planned, highly efficient adaptive strategies initiated and utilized by these transformed tumor cells. Cancer cells undergo several reprogramming events towards adapting this opportunistic behavior, leading [...] Read more.

In tumor cells’ struggle for survival following therapy, they resist treatment. Resistance to therapy is the outcome of well-planned, highly efficient adaptive strategies initiated and utilized by these transformed tumor cells. Cancer cells undergo several reprogramming events towards adapting this opportunistic behavior, leading them to gain specific survival advantages. The strategy involves changes within the transformed tumors cells as well as in their neighboring non-transformed extra-tumoral support system, the tumor microenvironment (TME). Cancer-Associated Fibroblasts (CAFs) are one of the components of the TME that is used by tumor cells to achieve resistance to therapy. CAFs are diverse in origin and are the most abundant non-transformed element of the microenvironment in solid tumors. Cells of an established tumor initially play a direct role in the establishment of the CAF population for its own microenvironment. Like their origin, CAFs are also diverse in their functions in catering to the pro-tumor microenvironment. Once instituted, CAFs interact in unison with both tumor cells and all other components of the TME towards the progression of the disease and the worst outcome. One of the many functions of CAFs in influencing the outcome of the disease is their participation in the development of resistance to treatment. CAFs resist therapy in solid tumors. A tumor–CAF relationship is initiated by tumor cells to exploit host stroma in favor of tumor progression. CAFs in concert with tumor cells and other components of the TME are abettors of resistance to treatment. Thus, this liaison between CAFs and tumor cells is a bête noire of therapy. Here, we portray a comprehensive picture of the modes and functions of CAFs in conjunction with their role in orchestrating the development of resistance to different chemotherapies and targeted therapies in solid tumors. We investigate the various functions of CAFs in various solid tumors in light of their dialogue with tumor cells and the two components of the TME, the immune component, and the vascular component. Acknowledgment of the irrefutable role of CAFs in the development of treatment resistance will impact our future strategies and ability to design improved therapies inclusive of CAFs. Finally, we discuss the future implications of this understanding from a therapeutic standpoint and in light of currently ongoing and completed CAF-based NIH clinical trials. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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21 pages, 594 KiB

Open AccessReview

Precision Medicine and Triple-Negative Breast Cancer: Current Landscape and Future Directions

by Fokhrul Hossain, Samarpan Majumder, Justin David and Lucio Miele

Cancers 2021, 13(15), 3739; https://doi.org/10.3390/cancers13153739 - 26 Jul 2021

Cited by 28 | Viewed by 5992

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer associated with a high recurrence and metastasis rate that affects African-American women disproportionately. The recent approval of targeted therapies for small subgroups of TNBC patients by the US ‘Food and Drug Administration’ is a promising development. The advancement of next-generation sequencing, particularly somatic exome panels, has raised hopes for more individualized treatment plans. However, the use of precision medicine for TNBC is a work in progress. This review will discuss the potential benefits and challenges of precision medicine for TNBC. A recent clinical trial designed to target TNBC patients based on their subtype-specific classification shows promise. Yet, tumor heterogeneity and sub-clonal evolution in primary and metastatic TNBC remain a challenge for oncologists to design adaptive precision medicine-based treatment plans. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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Other

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11 pages, 269 KiB

Open AccessOpinion

Using Electronic Medical Records to Identify Potentially Eligible Study Subjects for Lung Cancer Screening with Biomarkers

by Lamorna Brown, Utkarsh Agrawal and Frank Sullivan

Cancers 2021, 13(21), 5449; https://doi.org/10.3390/cancers13215449 - 29 Oct 2021

Cited by 5 | Viewed by 2343

Abstract

Lung cancer screening trials using low-dose computed tomography (LDCT) show reduced late-stage diagnosis and mortality rates. These trials have identified high-risk groups that would benefit from screening. However, these sub-populations can be difficult to access and retain in trials. Implementation of national screening [...] Read more.

Lung cancer screening trials using low-dose computed tomography (LDCT) show reduced late-stage diagnosis and mortality rates. These trials have identified high-risk groups that would benefit from screening. However, these sub-populations can be difficult to access and retain in trials. Implementation of national screening programmes further suggests that there is poor uptake in eligible populations. A new approach to participant selection may be more effective. Electronic medical records (EMRs) are a viable alternative to population-based or health registries, as they contain detailed clinical and demographic information. Trials have identified that e-screening using EMRs has improved trial retention and eligible subject identification. As such, this paper argues for greater use of EMRs in trial recruitment and screening programmes. Moreover, this opinion paper explores the current issues in and approaches to lung cancer screening, whether records can be used to identify eligible subjects for screening and the challenges that researchers face when using EMR data. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

15 pages, 1276 KiB

Open AccessBrief Report

A Highly Sensitive Next-Generation Sequencing-Based Genotyping Platform for EGFR Mutations in Plasma from Non-Small Cell Lung Cancer Patients

by Jung-Young Shin, Jeong-Oh Kim, Mi-Ran Lee, Seo Ree Kim, Kyongmin Sarah Beck and Jin Hyoung Kang

Cancers 2020, 12(12), 3579; https://doi.org/10.3390/cancers12123579 - 30 Nov 2020

Cited by 1 | Viewed by 2168

Abstract

Sel-Cap^TM, a digital enrichment next-generation sequencing (NGS)-based cancer panel, was assessed for detection of epidermal growth factor receptor (EGFR) gene mutations in plasma for non-small cell lung cancer (NSCLC), and for application in monitoring EGFR resistance mutation T790M in [...] Read more.

Sel-Cap^TM, a digital enrichment next-generation sequencing (NGS)-based cancer panel, was assessed for detection of epidermal growth factor receptor (EGFR) gene mutations in plasma for non-small cell lung cancer (NSCLC), and for application in monitoring EGFR resistance mutation T790M in plasma following first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment. Using Sel-Cap, we genotyped plasma samples collected from 185 patients for mutations Ex19del, L858R, and T790M, and compared results to those of PNAclamp^TM tumor biopsy (reference method, a peptide nucleic acid-mediated polymerase chain reaction clamping) and two other NGS liquid biopsies. Over two-thirds of activating mutations (Ex19del and L858R), previously confirmed by PNAclamp, were detected by Sel-Cap, which is 4–5 times more sensitive than NGS liquid biopsy. Sel-Cap showed particularly high sensitivity for T790M (88%) and for early-stage plasma samples. The relationship between initial T790M detection in plasma and progression-free survival (PFS) following first-line EGFR-TKIs was evaluated in 34 patients. Patients with T790M detected at treatment initiation (±3 months) had significantly shorter PFS than patients where T790M was first detected >3 months post treatment initiation (median PFS: 5.9 vs. 26.5 months; p < 0.0001). However, time from T790M detection to disease progression was not significantly different between the two groups (median around 5 months). In conclusion, Sel-Cap is a highly sensitive platform for EGFR mutations in plasma, and the timing of the first appearance of T790M in plasma, determined via highly sensitive liquid biopsies, may be useful for prediction of disease progression of NSCLC, around 5 months in advance. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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Evaluation of Two EGFR Mutation Tests on Tumor and Plasma from Patients with Non-Small Cell Lung Cancer

by Jeong-Oh Kim, Jung-Young Shin, Seo Ree Kim, Kab Soo Shin, Joori Kim, Min-Young Kim, Mi-Ran Lee, Yonggoo Kim, Myungshin Kim, Sook Hee Hong and Jin Hyoung Kang

Cancers 2020, 12(4), 785; https://doi.org/10.3390/cancers12040785 - 26 Mar 2020

Cited by 6 | Viewed by 3635

Abstract

Epidermal growth factor receptor (EGFR) mutation testing is essential for individualized treatment using tyrosine kinase inhibitors. We evaluated two EGFR mutation tests, cobas v2 and PANAMutyper, for detection of EGFR activating mutations Ex19del, L858R, and T790M in tumor tissue and plasma [...] Read more.

Epidermal growth factor receptor (EGFR) mutation testing is essential for individualized treatment using tyrosine kinase inhibitors. We evaluated two EGFR mutation tests, cobas v2 and PANAMutyper, for detection of EGFR activating mutations Ex19del, L858R, and T790M in tumor tissue and plasma from 244 non-small cell lung cancer (NSCLC) patients. The Kappa coefficient (95% CI) between the tests was 0.82 (0.74–0.92) in tumor samples (suggesting almost perfect agreement) and 0.69 (0.54–0.84) in plasma (suggesting substantial agreement). In plasma samples, both tests showed low to moderate sensitivity depending on disease stage but high diagnostic precision (86%–100%) in all disease stages (sensitivity: percentage of mutations in tumors that are also detected in plasma; precision: percentage of mutations in plasma which are also detected in tumors). Among the 244 patients, those previously diagnosed as T790M carriers who received osimertinib treatment showed dramatically better clinical outcomes than T790M carriers without osimertinib treatment. Taken together, our study supports interchangeable use of cobas v2 and PANAMutyper in tumor and plasma EGFR testing. Both tests have high diagnostic precision in plasma but are particularly valuable in late-stage disease. Our clinical data in T790M carriers strongly support the clinical benefits of osimertinib treatment guided by both EGFR mutation tests. Full article

(This article belongs to the Special Issue Precision Medicine in Solid Tumors)

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