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Molecular Pathology of Cancer: The Past, the Present, and the Future

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Mechanisms of Diseases".

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 48131

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Dr. Leonhard Müllauer

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Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria
Interests: molecular pathology; apoptosis; targeted therapy

Special Issue Information

Dear Colleagues,

I would like to invite you to contribute manuscripts for a Special Issue in the Journal of Personalized Medicine covering the past, the present, and the future of molecular pathology in oncology.

Molecular pathology is transforming clinical pathology and contributes to establishing a histopathological diagnosis and disease classification, provides prognostic information, identifies targets for therapy, and reveals mechanisms of resistance to therapy.

This Special Issue on the molecular pathology of cancer aims to provide an overview of different aspects of clinical molecular pathology and encompasses all oncologic and hemato-oncologic diseases. Contributions may address the description of the molecular mechanism of neoplastic diseases in association with their clinical utility, the role of molecular pathology in personalized oncology, laboratory techniques and assays in molecular pathology, bioinformatics, quality control, and potential ethical and legal considerations. Case reports, reviews, and original research articles are welcome.

Assoc. Prof. Leonhard Müllauer
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

personalized oncology
targeted therapy
molecular pathology
medical genetics
oncologic pathology

Published Papers (13 papers)

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Editorial

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3 pages, 185 KiB

Open AccessEditorial

Molecular Pathology of Cancer: The Past, the Present, and the Future

by Leonhard Müllauer

J. Pers. Med. 2021, 11(7), 676; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11070676 - 19 Jul 2021

Cited by 3 | Viewed by 2116

Abstract

Clinical pathology developed from the study of macroscopic organ and tissue changes at autopsies [...] Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

Research

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12 pages, 9643 KiB

Open AccessArticle

Reliability of Tumor Testing Compared to Germline Testing for Detecting BRCA1 and BRCA2 Mutations in Patients with Epithelial Ovarian Cancer

by Christine Bekos, Christoph Grimm, Marlene Kranawetter, Stephan Polterauer, Felicitas Oberndorfer, Yen Tan, Leonhard Müllauer and Christian F. Singer

J. Pers. Med. 2021, 11(7), 593; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11070593 - 24 Jun 2021

Cited by 11 | Viewed by 2143

Abstract

Background: BRCA 1/2 mutation status has become one of the most important parameters for treatment decision in patients with epithelial ovarian cancer (EOC). The aim of this study was to compare tumor DNA with blood DNA sequencing to evaluate the reliability of BRCA tumor testing results. Methods: Patients who were treated for EOC between 2003 and 2019 at the Medical University of Vienna and underwent both germline (gBRCA) and tumor (tBRCA) testing for BRCA mutations were identified. We calculated the concordance rate and further analyzed discordant cases. Results: Out of 140 patients with EOC, gBRCA mutation was found in 47 (33.6%) and tBRCA mutation in 53 (37.9%) patients. Tumor testing identified an additional 9/140 (6.4%) patients with somatic BRCA mutation and negative germline testing. The comparison of germline testing with tumor testing revealed a concordance rate of 93.5% and a negative predictive value of tumor testing of 96.0%. After BRCA variants of uncertain significance were included in the analysis, concordance rate decreased to 90.9%. Conclusion: Tumor testing identified the majority of pathogenic germline BRCA mutations but missed three (2.1%) patients. In contrast, nine (6.4%) patients harboring a somatic BRCA mutation would have been missed by gBRCA testing only. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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20 pages, 2334 KiB

Open AccessArticle

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

by Alicia Baumgartner, Natalia Stepien, Lisa Mayr, Sibylle Madlener, Christian Dorfer, Maria T. Schmook, Tatjana Traub-Weidinger, Daniela Lötsch-Gojo, Dominik Kirchhofer, Dominik Reisinger, Cora Hedrich, Saleha Arshad, Stefan Irschik, Heidrun Boztug, Gernot Engstler, Marie Bernkopf, Fikret Rifatbegovic, Christoph Höller, Irene Slavc, Walter Berger, Leonhard Müllauer, Christine Haberler, Amedeo A. Azizi, Andreas Peyrl and Johannes Gojo Show full author list Hide full author list

J. Pers. Med. 2021, 11(4), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11040292 - 12 Apr 2021

Cited by 14 | Viewed by 3551

Abstract

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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11 pages, 2603 KiB

Open AccessArticle

Risk Reclassification of Patients with Endometrial Cancer Based on Tumor Molecular Profiling: First Real World Data

by Felicitas Oberndorfer, Sarah Moling, Leonie Annika Hagelkruys, Christoph Grimm, Stephan Polterauer, Alina Sturdza, Stefanie Aust, Alexander Reinthaller, Leonhard Müllauer and Richard Schwameis

J. Pers. Med. 2021, 11(1), 48; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11010048 - 15 Jan 2021

Cited by 15 | Viewed by 3362

Abstract

Recently, guidelines for endometrial cancer (EC) were released that guide treatment decisions according to the tumors’ molecular profiles. To date, no real-world data regarding the clinical feasibility of molecular profiling have been released. This retrospective, monocentric study investigated the clinical feasibility of molecular profiling and its potential impact on treatment decisions. Tumor specimens underwent molecular profiling (testing for genetic alterations, (immune-)histological examination of lymphovascular space invasion (LVSI), and L1CAM) as part of the clinical routine and were classified according to the European Society for Medical Oncology (ESMO) classification system and to an integrated molecular risk stratification. Shifts between risk groups and potential treatment alterations are described. A total of 60 cases were included, of which twelve were excluded (20%), and eight of the remaining 48 were not characterized (drop-out rate of 16.7%). Molecular profiling revealed 4, 6, 25, and 5 patients with DNA polymerase-epsilon mutation, microsatellite instability, no specific molecular profile, and TP53 mutation, respectively. Three patients had substantial LVSI, and four patients showed high L1CAM expression. Molecular profiling took a median of 18.5 days. Substantial shifts occurred between the classification systems: four patients were upstaged, and 19 patients were downstaged. Molecular profiling of EC specimens is feasible in a daily routine, and new risk classification systems will change treatment decisions substantially. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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17 pages, 2394 KiB

Open AccessArticle

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

by Lisa Mayr, Armin S. Guntner, Sibylle Madlener, Maria T. Schmook, Andreas Peyrl, Amedeo A. Azizi, Karin Dieckmann, Dominik Reisinger, Natalia M. Stepien, Kathrin Schramm, Anna Laemmerer, David T. W. Jones, Jonas Ecker, Felix Sahm, Till Milde, Kristian W. Pajtler, Mirjam Blattner-Johnson, Miroslav Strbac, Christian Dorfer, Thomas Czech, Dominik Kirchhofer, Lisa Gabler, Walter Berger, Christine Haberler, Leonhard Müllauer, Wolfgang Buchberger, Irene Slavc, Daniela Lötsch-Gojo and Johannes Gojo Show full author list Hide full author list

J. Pers. Med. 2020, 10(4), 290; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040290 - 18 Dec 2020

Cited by 22 | Viewed by 4160

Abstract

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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11 pages, 2463 KiB

Open AccessArticle

Germline Genetic Association between Stromal Interaction Molecule 1 (STIM1) and Clinical Outcomes in Breast Cancer Patients

by Chi-Cheng Huang, Min-Rou Lin, Yu-Chen Yang, Yu-Wen Hsu, Henry Sung-Ching Wong and Wei-Chiao Chang

J. Pers. Med. 2020, 10(4), 287; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040287 - 17 Dec 2020

Cited by 1 | Viewed by 2101

Abstract

Among all cancers in women, breast cancer has the highest incidence. The mortality of breast cancer is highly associated with metastasis. Migration and malignant transformation of cancer cells have been reported to be modulated by store-operated calcium (SOC) channels, which control calcium signaling and cell proliferation pathways. Stromal interaction molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum, triggering the activation of store-operated calcium signaling. However, the clinical relevance of STIM1 in breast cancer is still unclear. Here, we recruited 348 breast cancer patients and conducted a genetic association study to address this question. Four tagging germline single nucleotide variants (SNVs) in STIM1 were selected and RNA sequencing data of 525 breast cancer samples from The Cancer Genome Atlas (TCGA) database were evaluated. The results show that rs2304891 and rs3750996 were correlated with clinical stage of breast cancer. Expression quantitative trait loci (eQTL) analysis indicated that risk G allele of STIM1 contributed to the higher expression of STIM1. In addition, we found an increased risk of rs2304891 G allele and rs3750996 A allele in estrogen receptor (ER) positive and progesterone receptor (PR) positive patients. In conclusion, our results suggest that germline SNV, rs2304891 and rs3750996 as well as STIM1 expression are important biomarkers for the prediction of clinical outcomes in breast cancer patients. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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14 pages, 2581 KiB

Open AccessArticle

A Network-Based Mixed Methods Approach to Analyze Current Perspectives on Personalized Oncological Medicine in Austria

by Ines Viktoria Stelzer, Anna Sierawska, Alena Buyx and Judit Simon

J. Pers. Med. 2020, 10(4), 276; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040276 - 12 Dec 2020

Cited by 3 | Viewed by 2017

Abstract

Personalized medicine (PM) to tailor healthcare (HC) to the individual, is a promising but challenging concept. So far, no study exists investigating stakeholders’ perspectives on PM in oncology in Austria potentially hindering implementation, which was the aim of this study. We performed semi-structured interviews among experts (n = 14) and cancer patients (n = 2) of the Vienna General Hospital and the Medical University of Vienna and analyzed them by a mixed methods network theoretical approach. Study results show a great variety of topics addressed by the interviewees. Clear differences in the topic selection between patients and experts could be observed. Patient-doctor relationship was the most prominent theme among experts, whereas HC systems and public health in PM was more relevant for the patients. Although promising new molecular pathology methods were explicitly mentioned, the experts believed that their practical implementation and the implementation of PM in standard care will take a long time in Austria. A variety of concerns regarding PM were mentioned by the experts, including communication issues and knowledge gaps. Besides important insights into the current situation of PM in Austria, the study has shown that network theory is a powerful tool for analyzing qualitative interview data. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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Review

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14 pages, 1206 KiB

Open AccessFeature PaperReview

Biomarkers for Homologous Recombination Deficiency in Cancer

by Svenja Wagener-Ryczek, Sabine Merkelbach-Bruse and Janna Siemanowski

J. Pers. Med. 2021, 11(7), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11070612 - 28 Jun 2021

Cited by 37 | Viewed by 7339

Abstract

DNA double-strand breaks foster tumorigenesis and cell death. Two distinct mechanisms can be activated by the cell for DNA repair: the accurate mechanism of homologous recombination repair or the error-prone non-homologous end joining. Homologous Recombination Deficiency (HRD) is associated with sensitivity towards PARP inhibitors (PARPi) and its determination is used as a biomarker for therapy decision making. Nevertheless, the biology of HRD is rather complex and the application, as well as the benefit of the different HRD biomarker assays, is controversial. Acquiring knowledge of the underlying molecular mechanisms is the main prerequisite for integration of new biomarker tests. This study presents an overview of the major DNA repair mechanisms and defines the concepts of HRR, HRD and BRCAness. Moreover, currently available biomarker assays are described and discussed with respect to their application for routine clinical diagnostics. Since patient stratification for efficient PARP inhibitor therapy requires determination of the BRCA mutation status and genomic instability, both should be established comprehensively. For this purpose, a broad spectrum of distinct assays to determine such combined HRD scores is already available. Nevertheless, all tests require careful validation using clinical samples to meet the criteria for their establishment in clinical testing. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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15 pages, 463 KiB

Open AccessReview

Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

by Sibylle Madlener and Johannes Gojo

J. Pers. Med. 2020, 10(4), 254; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040254 - 27 Nov 2020

Cited by 10 | Viewed by 2593

Abstract

Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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18 pages, 584 KiB

Open AccessReview

Molecular Profiling of Malignant Pleural Effusions with Next Generation Sequencing (NGS): Evidence that Supports Its Role in Cancer Management

by Georgia Ι. Grigoriadou, Stepan M. Esagian, Han Suk Ryu and Ilias P. Nikas

J. Pers. Med. 2020, 10(4), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040206 - 01 Nov 2020

Cited by 15 | Viewed by 5409

Abstract

Malignant pleural effusions (MPEs) often develop in advanced cancer patients and confer significant morbidity and mortality. In this review, we evaluated whether molecular profiling of MPEs with next generation sequencing (NGS) could have a role in cancer management, focusing on lung cancer. We reviewed and compared the diagnostic performance of pleural fluid liquid biopsy with other types of samples. When applied in MPEs, NGS may have comparable performance with corresponding tissue biopsies, yield higher DNA amount, and detect more genetic aberrations than blood-derived liquid biopsies. NGS in MPEs may also be preferable to plasma liquid biopsy in advanced cancer patients with a MPE and a paucicellular or difficult to obtain tissue/fine-needle aspiration biopsy. Of interest, post-centrifuge supernatant NGS may exhibit superior results compared to cell pellet, cell block or other materials. NGS in MPEs can also guide clinicians in tailoring established therapies and identifying therapy resistance. Evidence is still premature regarding the role of NGS in MPEs from patients with cancers other than lung. We concluded that MPE processing could provide useful prognostic and theranostic information, besides its diagnostic role. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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12 pages, 421 KiB

Open AccessReview

Clonal Hematopoiesis of Indeterminate Potential: A Multidisciplinary Challenge in Personalized Hematology

by Gregor Hoermann, Georg Greiner, Andrea Griesmacher and Peter Valent

J. Pers. Med. 2020, 10(3), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030094 - 20 Aug 2020

Cited by 12 | Viewed by 6244

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that represents a potential pre-phase of hematologic neoplasm. Next-generation sequencing (NGS) is used to detect and monitor clonal hematopoiesis, and the spectrum of mutations substantially overlaps with that of myeloid neoplasms with DNMT3A, TET2, ASXL1, and JAK2 being the most frequently mutated. While, in general, the risk of progression to an overt myeloid neoplasm is only modest, the progression risk increases in patients with unexplained cytopenia or multiple mutations. In addition, CHIP represents a previously unrecognized major risk factor for atherosclerosis and cardiovascular disease (CVD), including coronary heart disease, degenerative aortic valve stenosis, and chronic heart failure; and a causative role of CHIP in the development of CVD has been demonstrated in vitro and in vivo. The management of patients with CHIP is a rapidly emerging topic in personalized medicine, as NGS has become widely available for clinical medicine. It requires a highly multidisciplinary setting, including hematology/oncology, cardiology, (clinical) pathology, and genetics for individualized guidance. Further research is urgently needed to provide robust evidence for future guidelines and recommendations on the management of patients with CHIP in the era of personalized medicine. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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Other

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11 pages, 802 KiB

Open AccessCase Report

A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity

by Mara Fornasarig, Daniela Gasparotto, Luisa Foltran, Michele Campigotto, Sara Lombardi, Elisa Del Savio, Angela Buonadonna, Fabio Puglisi, Sandro Sulfaro, Vincenzo Canzonieri, Renato Cannizzaro and Roberta Maestro

J. Pers. Med. 2020, 10(4), 234; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040234 - 17 Nov 2020

Cited by 13 | Viewed by 2338

Abstract

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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7 pages, 2028 KiB

Open AccessCase Report

Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

by László Urbán, Róbert Dóczi, Barbara Vodicska, Dóra Kormos, László Tóth, István Takács, Edit Várkondi, Dóra Tihanyi, Dóra Lakatos, Anna Dirner, István Vályi-Nagy and István Peták

J. Pers. Med. 2020, 10(3), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10030107 - 28 Aug 2020

Cited by 6 | Viewed by 3547

Abstract

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with continued next-generation regimens upon progression. Results: The tumor showed progression on crizotinib, but long tumor control was achieved following the incremental administration of next-generation ALK inhibitors, despite lack of evident resistance mechanisms. Conclusion: TP53 status should be taken into consideration when selecting ALK-inhibitor treatment for personalized therapies. In TP53-mutant tumors, switching TKI generations may overcome treatment exhaustion even in the absence of ALK-dependent resistance mechanisms. Full article

(This article belongs to the Special Issue Molecular Pathology of Cancer: The Past, the Present, and the Future)

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