Cancers

Editorial

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3 pages, 178 KiB

Open AccessEditorial

Cerebral Metastasis of Common Cancers

by Johan M. Kros and Dana A. M. Mustafa

Cancers 2021, 13(1), 65; https://doi.org/10.3390/cancers13010065 - 29 Dec 2020

Viewed by 1700

Abstract

Blood-brain barrier The incidence of brain metastasis has risen dramatically over the last decades and has equaled that of primary brain tumors [...] Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

Research

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8 pages, 1058 KiB

Open AccessArticle

Stereotactic Radiation and Dual Human Epidermal Growth Factor Receptor 2 Blockade with Trastuzumab and Pertuzumab in the Treatment of Breast Cancer Brain Metastases: A Single Institution Series

by Edy Ippolito, Sonia Silipigni, Paolo Matteucci, Carlo Greco, Francesco Pantano, Giuliana D’Auria, Carlo Cosimo Quattrocchi, Barnaba Floreno, Michele Fiore, Teresa Gamucci, Giuseppe Tonini and Sara Ramella

Cancers 2022, 14(2), 303; https://doi.org/10.3390/cancers14020303 - 08 Jan 2022

Cited by 4 | Viewed by 1486

Abstract

(1) Background: This study aims to assess the safety and efficacy of fractionated SRT (fSRT) and pertuzumab–trastuzumab (PT) in patients with breast cancer brain metastases (BCBM). (2) Methods: Patients with HER2+ BCBM who received FSRT from 2015 to 2019 were identified. Patients were [...] Read more.

(1) Background: This study aims to assess the safety and efficacy of fractionated SRT (fSRT) and pertuzumab–trastuzumab (PT) in patients with breast cancer brain metastases (BCBM). (2) Methods: Patients with HER2+ BCBM who received FSRT from 2015 to 2019 were identified. Patients were included if they were treated with fSRT within 21 days of receiving PT. All lesions were treated with LINAC-based fSRT to a total dose of 27 Gy delivered in three consecutive fractions. All patients received concurrent PT. Patients were evaluated 4–6 weeks after SRS and subsequently every 2–3 months with MRI re-imaging (3) Results: A total of 49 patients with HER2+ brain metastases were identified. Of these patients, a total of 10 patients with 32 HER2+ BCBM were treated with concurrent SRT and PT and included in the analysis. No local progression was observed. Overall response rate was 68.7%. Only one patient developed asymptomatic radionecrosis. Median time to BM occurrence was 15.6 (range: 1–40.5 months). Distant intracranial failure occurred in 4/10 patients (40.0%). Overall BCBM median survival was 33.9 months (95%CI 24.1–43.6). Mean duration of PT treatment was 27.9 months (range: 10.1–53.7 months). (4) Conclusions: In our single institution experience, fSRT and PT showed to be a safe treatment for patients with BCBM with an adequate overall response rate. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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10 pages, 1037 KiB

Open AccessArticle

High Density of NRF2 Expression in Malignant Cells Is Associated with Increased Risk of CNS Metastasis in Early-Stage NSCLC

by Georgios Tsakonas, Alfonso Martín-Bernabé, Konstantinos Rounis, Pablo Moreno-Ruiz, Johan Botling, Luigi De Petris, Antti Ylipää, Artur Mezheyeuski, Patrick Micke, Arne Östman and Simon Ekman

Cancers 2021, 13(13), 3151; https://doi.org/10.3390/cancers13133151 - 24 Jun 2021

Cited by 2 | Viewed by 2578

Abstract

Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining [...] Read more.

Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64–33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70–37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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11 pages, 3292 KiB

Open AccessArticle

Differential Expression of BOC, SPOCK2, and GJD3 Is Associated with Brain Metastasis of ER-Negative Breast Cancers

by Rute M. S. M. Pedrosa, Leonoor V. Wismans, Renata Sinke, Marcel van der Weiden, Casper H. J. van Eijck, Johan M. Kros and Dana A. M. Mustafa

Cancers 2021, 13(12), 2982; https://doi.org/10.3390/cancers13122982 - 15 Jun 2021

Cited by 4 | Viewed by 2659

Abstract

Background: Brain metastasis is considered one of the major causes of mortality in breast cancer patients. To invade the brain, tumor cells need to pass the blood-brain barrier by mechanisms that are partially understood. In primary ER-negative breast cancers that developed brain metastases, [...] Read more.

Background: Brain metastasis is considered one of the major causes of mortality in breast cancer patients. To invade the brain, tumor cells need to pass the blood-brain barrier by mechanisms that are partially understood. In primary ER-negative breast cancers that developed brain metastases, we found that some of the differentially expressed genes play roles in the T cell response. The present study aimed to identify genes involved in the formation of brain metastasis independently from the T cell response. Method: Previously profiled primary breast cancer samples were reanalyzed. Genes that were found to be differentially expressed were confirmed by RT-PCR and by immunohistochemistry using an independent cohort of samples. Results: BOC, SPOCK2, and GJD3 were overexpressed in the primary breast tumors that developed brain metastasis. BOC expression was successfully validated at the protein level. SPOCK2 was validated at both mRNA and protein levels. SPOCK2 and GJD3 mRNA overexpression were also found to be associated with cerebral metastasis in an external online database consisting of 204 primary breast cancers. Conclusion: The overexpression of BOC, SPOCK2, and GJD3 is associated with the invasion of breast cancer into the brain. Further studies to determine their specific function and potential value as brain metastasis biomarkers are required. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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13 pages, 1958 KiB

Open AccessArticle

Correlation of Clinical Parameters with Intracranial Outcome in Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Pd-1/Pd-L1 Inhibitors as Monotherapy

by Konstantinos Rounis, Marcus Skribek, Dimitrios Makrakis, Luigi De Petris, Sofia Agelaki, Simon Ekman and Georgios Tsakonas

Cancers 2021, 13(7), 1562; https://doi.org/10.3390/cancers13071562 - 29 Mar 2021

Cited by 12 | Viewed by 2466

Abstract

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and [...] Read more.

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and University Hospital of Heraklion, Greece. The inclusion criteria for response assessment were brain metastases (BM) prior to ICI administration, radiological evaluation with CT or MRI for IC response assessment, PD-1/PD-L1 inhibitors as monotherapy, and no local central nervous system (CNS) treatment modalities for ≥3 months before ICI initiation. In the IC response analysis, 33 pts were included. Non-primary (BM not present at diagnosis) BM, odds ratio (OR): 13.33 (95% CI: 1.424–124.880, p = 0.023); no previous brain radiation therapy (RT), OR: 5.49 (95% CI: 1.210–25.000, p = 0.027); and age ≥70 years, OR: 6.19 (95% CI: 1.27–30.170, p = 0.024) were associated with increased probability of IC disease progression. Two prognostic groups (immunotherapy (I-O) CNS score) were created based on the abovementioned parameters. The I-O CNS poor prognostic group B exhibited a higher probability for IC disease progression, OR: 27.50 (95% CI: 2.88–262.34, p = 0.004). Age, CNS radiotherapy before the start of ICI treatment, and primary brain metastatic disease can potentially affect the IC outcome of NSCLC pts with BM. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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Review

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15 pages, 908 KiB

Open AccessReview

Integration of Systemic Therapy and Stereotactic Radiosurgery for Brain Metastases

by Raees Tonse, Martin C. Tom, Minesh P. Mehta, Manmeet S. Ahluwalia and Rupesh Kotecha

Cancers 2021, 13(15), 3682; https://doi.org/10.3390/cancers13153682 - 22 Jul 2021

Cited by 16 | Viewed by 3898

Abstract

Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), [...] Read more.

Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and resection. However, the increased availability of molecular-based therapies with central nervous system (CNS) penetration now permits the individualized selection of tailored systemic therapies to be used alongside local treatments. Moreover, the introduction of immune checkpoint inhibitors (ICIs), with demonstrated CNS activity has further revolutionized the management of BM patients. The rapid introduction of these cancer therapeutics into clinical practice, however, has led to a significant dearth in the published literature about the optimal timing, sequencing, and combination of these systemic therapies along with SRS. This manuscript reviews the impact of tumor biology and molecular profiles on the management paradigm for BM patients and critically analyzes the current landscape of SRS, with a specific focus on integration with systemic therapy. We also discuss emerging treatment strategies combining SRS and ICIs, the impact of timing and the sequencing of these therapies around SRS, the effect of corticosteroids, and review post-treatment imaging findings, including pseudo-progression and radiation necrosis. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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12 pages, 308 KiB

Open AccessReview

Molecular Profiles of Brain Metastases: A Focus on Heterogeneity

by Shan Ali, Zuzanna Górska, Renata Duchnowska and Jacek Jassem

Cancers 2021, 13(11), 2645; https://doi.org/10.3390/cancers13112645 - 28 May 2021

Cited by 15 | Viewed by 2941

Abstract

Brain metastasis is a common and devastating clinical entity. Intratumor heterogeneity in brain metastases poses a crucial challenge to precision medicine. However, advances in next-generation sequencing, new insight into the pathophysiology of driver mutations, and the creation of novel tumor models have allowed [...] Read more.

Brain metastasis is a common and devastating clinical entity. Intratumor heterogeneity in brain metastases poses a crucial challenge to precision medicine. However, advances in next-generation sequencing, new insight into the pathophysiology of driver mutations, and the creation of novel tumor models have allowed us to gain better insight into the genetic landscapes of brain metastases, their temporal evolution, and their response to various treatments. A plethora of genomic studies have identified the heterogeneous clonal landscape of tumors and, at the same time, introduced potential targets for precision medicine. As an example, we present phenotypic alterations in brain metastases originating from three malignancies with the highest brain metastasis frequency: lung cancer, breast cancer, and melanoma. We discuss the barriers to precision medicine, tumor heterogeneity, the significance of blood-based biomarkers in tracking clonal evolution, the phylogenetic relationship between primary and metastatic tumors, blood–brain barrier heterogeneity, and limitations to ongoing research. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

18 pages, 329 KiB

Open AccessReview

Brain Metastasis from Unknown Primary Tumour: Moving from Old Retrospective Studies to Clinical Trials on Targeted Agents

by Roberta Balestrino, Roberta Rudà and Riccardo Soffietti

Cancers 2020, 12(11), 3350; https://doi.org/10.3390/cancers12113350 - 12 Nov 2020

Cited by 14 | Viewed by 4009

Abstract

Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to [...] Read more.

Brain metastases (BMs) are the most common intracranial tumours in adults and occur up to 3–10 times more frequently than primary brain tumours. BMs may be the cause of the neurological presenting symptoms in patients with otherwise previously undiagnosed cancer. In up to 15% of patients with BMs, the primary tumour cannot be identified. These cases are known as BM of cancer of unknown primary (CUP) (BM-CUP). CUP has an early and aggressive metastatic spread, poor response to chemotherapy, and poor prognosis. The pathogenesis of CUP seems to be characterized by a specific underlying pro-metastatic signature. The understanding of BM-CUP, despite its relative frequency and unfavourable outcome, is still incomplete and clear indications on management are missing. Advances in diagnostic tools, molecular characterization, and target therapy have shifted the paradigm in the approach to metastasis from CUP: while earlier studies stressed the importance of finding the primary tumour and deciding on treatment based on the primary diagnosis, most recent studies focus on the importance of identifying targetable molecular markers in the metastasis itself. The aim of this review is to summarize current evidence on BM-CUP, from the diagnosis and pathogenesis to the treatment, with a focus on available studies and ongoing clinical trials. Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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Other

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20 pages, 1605 KiB

Open AccessSystematic Review

Efficacy and Safety of a Second Course of Stereotactic Radiation Therapy for Locally Recurrent Brain Metastases: A Systematic Review

by François Lucia, Ruben Touati, Nicolae Crainic, Gurvan Dissaux, Olivier Pradier, Vincent Bourbonne and Ulrike Schick

Cancers 2021, 13(19), 4929; https://doi.org/10.3390/cancers13194929 - 30 Sep 2021

Cited by 6 | Viewed by 2319

Abstract

Recent advances in cancer treatments have increased overall survival and consequently, local failures (LFs) after stereotactic radiotherapy/radiosurgery (SRS/SRT) have become more frequent. LF following SRS or SRT may be treated with a second course of SRS (SRS2) or SRT (SRT2). However, there is [...] Read more.

Recent advances in cancer treatments have increased overall survival and consequently, local failures (LFs) after stereotactic radiotherapy/radiosurgery (SRS/SRT) have become more frequent. LF following SRS or SRT may be treated with a second course of SRS (SRS2) or SRT (SRT2). However, there is no consensus on whenever to consider reirradiation. A literature search was conducted according to PRISMA guidelines. Analysis included 13 studies: 329 patients (388 metastases) with a SRS2 and 135 patients (161 metastases) with a SRT2. The 1-year local control rate ranged from 46.5% to 88.3%. Factors leading to poorer LC were histology (melanoma) and lack of prior whole-brain radiation therapy, large tumor size and lower dose at SRS2/SRT2, poorer response at first SRS/SRT, poorer performance status, and no controlled extracranial disease. The rate of radionecrosis (RN) ranged from 2% to 36%. Patients who had a large tumor volume, higher dose and higher value of prescription isodose line at SRS2/SRT2, and large overlap between brain volume irradiated at SRS1/SRT1 and SRS2/SRT2 at doses of 18 and 12 Gy had a higher risk of developing RN. Prospective studies involving a larger number of patients are still needed to determine the best management of patients with local recurrence of brain metastases Full article

(This article belongs to the Special Issue Metastatic Brain Tumors Research)

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