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Personalized Medicine: Recent Progress in Cancer Therapy

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 82649

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Special Issue Editors

Prof. Dr. Marieke H.J. van den Beuken-van Everdingen

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Guest Editor

Centre of Expertise for Palliative Care, Maastricht University Medical Centre, Maastricht, The Netherlands
Interests: palliative care; cancer pain; opioids; NMDA; symptoms in cancer

Dr. Ann Hoeben

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Division of Medical Oncology, GROW—School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
Interests: neuro-oncology; palliative care; personolised medicine

Prof. Dr. Elbert A.J. Joosten

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Department of Anesthesiology and Pain Management, Maastricht University Medical Center+, Maastricht, The Netherlands
Interests: neuropathic pain; NMDA; opioids; cancer pain; spinal cord; nociception; mechanism of action; pharmacology of pain

Special Issue Information

Dear Colleagues,

Personalized medicine (PM) or precision medicine in oncology is an emerging approach for tumor treatment and prevention, which takes into account inter- and intra-tumoral variability in genes, tumor (immune) environment, and lifestyle and morbidities of each person diagnosed with cancer. PM has the potential to tailor therapy towards the oncogenic drivers of the tumor and modulate the tumor immune environment, not only attempting to optimize tumor response, but also taking into account therapy-induced toxicities for each specific patient. In this way, optimized tumor response is combined with the preservation of organ function and quality of life, ensuring better patient care.

Biomarker development is a rapidly evolving field in PM and makes it possible to not only predict prognosis, but also to predict treatment response. Predictive biomarker models are not only defined by serum markers, but also by different imaging modalities (CT, MR, nuclear imaging modalities), creating multimodal (non-invasive) predictive platforms identifying the molecular fingerprint of the tumor.

Finetuning of predictive models will enable the construction of tumor-tailored treatment plans and improve prognostic models, which will facilitate shared decision-making, allowing for a patient-tailored treatment plan.

By enabling each patient to receive earlier diagnoses, risk assessments, and optimal treatments, PM holds promise for improving health care while also lowering costs.

This Special Issue will highlight recent advances in personalized medicine in treating cancer and its accompanying symptoms.

Prof. Dr. Marieke H.J. van den Beuken-van Everdingen
Dr. Ann Hoeben
Prof. Dr. Elbert A.J. Joosten
Guest Editors

Manuscript Submission Information

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Keywords

personalized medicine
genetics
epigenetics
immunotherapy

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Published Papers (11 papers)

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Editorial

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3 pages, 180 KiB

Open AccessEditorial

Personalized Medicine: Recent Progress in Cancer Therapy

by Ann Hoeben, Elbert A. J. Joosten and Marieke H. J. van den Beuken-van Everdingen

Cancers 2021, 13(2), 242; https://doi.org/10.3390/cancers13020242 - 11 Jan 2021

Cited by 76 | Viewed by 6152

Abstract

Personalized medicine (PM) or precision medicine in oncology is an emerging approach for tumor treatment and prevention that takes into account inter- and intra-tumor variability in genes, tumor (immune) environment, and lifestyle and morbidities of each person diagnosed with cancer [...] Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

Research

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12 pages, 1415 KiB

Open AccessArticle

Multi-Gene Prognostic Signatures and Prediction of Pathological Complete Response to Neoadjuvant Chemotherapy in ER-Positive, HER2-Negative Breast Cancer Patients

by Claudia Mazo, Stephen Barron, Catherine Mooney and William M. Gallagher

Cancers 2020, 12(5), 1133; https://doi.org/10.3390/cancers12051133 - 1 May 2020

Cited by 16 | Viewed by 3762

Abstract

Determining which patients with early-stage breast cancer should receive chemotherapy is an important clinical issue. Chemotherapy has several adverse side effects, impacting on quality of life, along with significant economic consequences. There are a number of multi-gene prognostic signatures for breast cancer recurrence but there is less evidence that these prognostic signatures are predictive of therapy benefit. Biomarkers that can predict patient response to chemotherapy can help avoid ineffective over-treatment. The aim of this work was to assess if the OncoMasTR prognostic signature can predict pathological complete response (pCR) to neoadjuvant chemotherapy, and to compare its predictive value with other prognostic signatures: EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes. Gene expression datasets from ER-positive, HER2-negative breast cancer patients that had pre-treatment biopsies, received neoadjuvant chemotherapy and an assessment of pCR were obtained from the Gene Expression Omnibus repository. A total of 813 patients with 66 pCR events were included in the analysis. OncoMasTR, EndoPredict, Oncotype DX and Tumor Infiltrating Leukocytes numeric risk scores were approximated by applying the gene coefficients to the corresponding mean probe expression values. OncoMasTR, EndoPredict and Oncotype DX prognostic scores were moderately well correlated according to the Pearson’s correlation coefficient. Association with pCR was estimated using logistic regression. The odds ratio for a 1 standard deviation increase in risk score, adjusted for cohort, were similar in magnitude for all four signatures. Additionally, the four signatures were significant predictors of pCR. OncoMasTR added significant predictive value to Tumor Infiltrating Leukocytes signatures as determined by bivariable and trivariable analysis. In this in silico analysis, OncoMasTR, EndoPredict, Oncotype DX, and Tumor Infiltrating Leukocytes were significantly predictive of pCR to neoadjuvant chemotherapy in ER-positive and HER2-negative breast cancer patients. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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14 pages, 1109 KiB

Open AccessArticle

Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-cell Lymphoma

by Sara Alonso-Álvarez, Miguel Alcoceba, María García-Álvarez, Oscar Blanco, Marta Rodríguez, Mónica Baile, Juan Carlos Caballero, Julio Dávila, María Belén Vidriales, Carmen Esteban, Piedad Arias, Luis G. Díaz, Pilar Tamayo, María Dolores Caballero, Norma C. Gutiérrez, Marcos González and Alejandro Martín

Cancers 2020, 12(2), 474; https://doi.org/10.3390/cancers12020474 - 18 Feb 2020

Cited by 16 | Viewed by 3592

Abstract

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans’ algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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19 pages, 958 KiB

Open AccessFeature PaperArticle

A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia

by Fatih M. Uckun, Christopher R. Cogle, Tara L. Lin, Sanjive Qazi, Vuong N. Trieu, Gary Schiller and Justin M. Watts

Cancers 2020, 12(1), 74; https://doi.org/10.3390/cancers12010074 - 26 Dec 2019

Cited by 28 | Viewed by 4715

Abstract

Combretastatin A1 (OXi4503) is a dual-function drug with vascular disrupting and cytotoxic properties that has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML) and in a prior Phase 1A clinical study for relapsed/refractory (R/R) AML. The purpose of the present multicenter Phase 1B study was to define the maximum tolerated dose (MTD) and safety profile of OXi4503 and cytarabine (ARA-C) administered in combination (OXA). At four centers, 29 patients with R/R AML or myelodysplastic syndrome (MDS) were treated with OXA. The most common grade 3/4 treatment-emergent adverse events (AEs) were febrile neutropenia (28%), hypertension (17%), thrombocytopenia (17%), and anemia (14%). There were no treatment-emergent grade 5 AEs. Drug-related serious adverse events (SAEs) developed in 4/29 patients (14%) and included febrile neutropenia (N = 2), pneumonia/acute respiratory failure (N = 1), and hypotension (N = 1). 9.76 mg/m² was defined as the MTD of OXi4503 when administered in combination with 1 g/m² ARA-C. In 26 evaluable AML patients, there were 2 complete remissions (CR), 2 complete remissions with incomplete count recovery (CRi) and one partial response (PR), for an overall response rate (ORR) of 19%. The median overall survival (OS) time for the four patients who achieved a CR/CRi was 528 days (95% CI: 434–NA), which was significantly longer than the median OS time of 113 days (95% CI: 77–172) for the remaining 22 patients who did not achieve a CR/CRi (Log Rank Chi Square = 11.8, p-value = 0.0006). The safety and early evidence of efficacy of the OXA regimen in R/R AML patients warrant further investigation in a Phase 2 clinical study. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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21 pages, 3057 KiB

Open AccessFeature PaperArticle

Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFβ2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up

by Fatih M. Uckun, Sanjive Qazi, Larn Hwang and Vuong N. Trieu

Cancers 2019, 11(12), 1892; https://doi.org/10.3390/cancers11121892 - 28 Nov 2019

Cited by 29 | Viewed by 5077

Abstract

Background. OT101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of transforming growth factor beta 2 (TGFβ2). Here, we report our post-hoc analysis of the single-agent activity of OT101 in adult patients with recurrent and/or refractory (R/R) high-grade gliomas. Methods. In a Phase 2 clinical trial (ClinicalTrials.gov, NCT00431561), OT101 was administered to 89 R/R high-grade glioma (HGG) (anaplastic astrocytoma/AA: 27; glioblastoma multiforme/GBM: 62) patients with an intratumoral catheter using a convection enhanced delivery (CED) system. Seventy-seven patients (efficacy population; GBM: 51; AA: 26) received at least the intended minimum number of four OT101 treatment cycles. Response determinations were based on central review of magnetic resonance imaging (MRI) scans according to the McDonald criteria. Standard statistical methods were applied for the analysis of data. Findings. Nineteen patients had a complete response (CR) or partial response (PR) following a slow but robust size reduction of their target lesions (median time for 90% reduction of the baseline tumor volume = 11.7 months, range: 4.9–57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (median = 1.4: range: 0.4–4.5) logs. In addition, seven patients had a stable disease (SD) lasting ≥6 months. For the combined group of 26 AA/GBM patients with favorable responses, the median progression-free survival (PFS) of 1109 days and overall survival (OS) of 1280 days were significantly better than the median PFS (p < 0.00001) and OS (p < 0.00001) of the non-responders among the 89 patients or the 77-patient efficacy population. Conclusion. Intratumorally administered OT101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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Review

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18 pages, 706 KiB

Open AccessReview

Genetics and Opioids: Towards More Appropriate Prescription in Cancer Pain

by Dario Bugada, Luca F. Lorini, Roberto Fumagalli and Massimo Allegri

Cancers 2020, 12(7), 1951; https://doi.org/10.3390/cancers12071951 - 18 Jul 2020

Cited by 25 | Viewed by 6789

Abstract

Opioids are extensively used in patients with cancer pain; despite their efficacy, several patients can experience ineffective analgesia and/or side effects. Pharmacogenetics is a new approach to drug prescription based on the “personalized-medicine” concept, i.e., the ability of tailoring treatments to each individual’s genetic/genomic profile. Pharmacogenetics aims to identify specific genetic variants that influence pharmacokinetics and pharmacodynamics of drugs, better determining their effectiveness/safety profile. Opioid response is a complex scenario, but some gene variants have shown a correlation with pain sensitivity, as well as with opioid metabolism and clinical efficacy/adverse events. Although questions remain unanswered, some of these gene variants may already be used to identify specific patients’ phenotypes that are more prone to experience better clinical response (i.e., better analgesia and/or less adverse events). Once adopted, this approach to opioid prescription may improve a patient’s outcome. This review summarizes the available data on genetic variants and opioid response: we will focus on basic pharmacogenetic and its impact in the clinical scenario discussing how they may lead to more appropriate opioid prescription in cancer patients. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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21 pages, 357 KiB

Open AccessReview

Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives

by Miriam Grazia Ferrara, Vincenzo Di Noia, Ettore D’Argento, Emanuele Vita, Paola Damiano, Antonella Cannella, Marta Ribelli, Sara Pilotto, Michele Milella, Giampaolo Tortora and Emilio Bria

Cancers 2020, 12(5), 1196; https://doi.org/10.3390/cancers12051196 - 8 May 2020

Cited by 73 | Viewed by 7409

Abstract

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

12 pages, 813 KiB

Open AccessReview

Current Strategies and Future Perspectives for Precision Medicine in Pancreatic Cancer

by Ivonne Regel, Julia Mayerle and Mahajan Ujjwal Mukund

Cancers 2020, 12(4), 1024; https://doi.org/10.3390/cancers12041024 - 21 Apr 2020

Cited by 48 | Viewed by 7078

Abstract

Current standard-of-care for patients with pancreatic ductal adenocarcinoma (PDAC) focusses on chemotherapeutic regimens and pancreatic cancer surgery. However, limited treatment options, late diagnosis in advanced tumor stages and the aggressive behavior of PDAC contribute to the high mortality of the disease. Consequently, there is an urgent need of precision medicine for pancreatic cancer patients. All over the world, numerous initiatives started in recent years to translate novel scientific discoveries into prospective clinical trials. One major approach pursues the stratification of PDAC patients according the tumor transcriptome to predict treatment response. Other strategies concentrate on genomic alterations and the identification of individualized targeted therapies. Further experimental studies are ongoing to detect novel biomarkers for cancer diagnosis, subtyping, treatment response prediction or clinical outcome. However, the challenge remains to transfer the knowledge into clinical practice. In this review, we summarize current literature and knowledge and highlight novel concepts of basic and clinical research uncovering suitable biomarkers and targeted therapies. Thus, we provide an overview of preclinical and clinical efforts of precision medicine in pancreatic cancer. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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14 pages, 2506 KiB

Open AccessReview

Personalized Medicine: Recent Progress in Cancer Therapy

by Valentina Gambardella, Noelia Tarazona, Juan Miguel Cejalvo, Pasquale Lombardi, Marisol Huerta, Susana Roselló, Tania Fleitas, Desamparados Roda and Andres Cervantes

Cancers 2020, 12(4), 1009; https://doi.org/10.3390/cancers12041009 - 19 Apr 2020

Cited by 182 | Viewed by 23999

Abstract

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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27 pages, 332 KiB

Open AccessReview

Personalized Medicine—Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer

by Christine Koulis, Raymond Yap, Rebekah Engel, Thierry Jardé, Simon Wilkins, Gemma Solon, Jeremy D. Shapiro, Helen Abud and Paul McMurrick

Cancers 2020, 12(4), 812; https://doi.org/10.3390/cancers12040812 - 28 Mar 2020

Cited by 39 | Viewed by 5944

Abstract

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

Other

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20 pages, 687 KiB

Open AccessPerspective

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives

by Bas Weenink, Pim J. French, Peter A.E. Sillevis Smitt, Reno Debets and Marjolein Geurts

Cancers 2020, 12(3), 751; https://doi.org/10.3390/cancers12030751 - 22 Mar 2020

Cited by 76 | Viewed by 6678

Abstract

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells. Full article

(This article belongs to the Special Issue Personalized Medicine: Recent Progress in Cancer Therapy)

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