|
1
|
Wang Z, Hong H. Anti‑HER2‑targeted therapies for the treatment of advanced HER2‑positive breast cancer with brain metastases (Review). Mol Clin Oncol 2025; 22:45. [PMID: 40170686 PMCID: PMC11959222 DOI: 10.3892/mco.2025.2840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 02/17/2025] [Indexed: 04/03/2025] Open
Abstract
Compared with other metastatic sites, breast cancer brain metastases (BCBMs) are associated with the shortest survival time. In addition, human epidermal growth factor receptor 2 (HER2) is observed to be amplified in 20-25% of breast cancer cases where it is a poor prognostic factor for brain metastases. Various anti-HER2 targeted therapies have brought both new opportunities and challenges to patients with HER2-positive BCBM over the past decade. However, prolonging survival time and improving quality of life of patients have become controversial issues in the field of clinical research on BCBMs. On the basis of the latest literature, the present review documents the anti-HER2 targeted drugs applied in patients with HER2-positive BCBM. Further studies on the efficacy and safety of novel HER2-targeted drugs and combined or sequential therapy in clinical treatment are expected to provide more effective strategies for the treatment of patients with HER2-positive BCBM.
Collapse
Affiliation(s)
- Zhangyan Wang
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
| | - Huangming Hong
- Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610041, P.R. China
| |
Collapse
|
|
2
|
von Arx C, Calderaio C, Calabrese A, Marciano B, Martinelli C, Di Lauro V, Cerillo I, Cianniello D, De Laurentiis M. The multidisciplinary management of HER2-positive breast cancer brain metastases: from new biological insights to future therapeutic options. Front Oncol 2024; 14:1447508. [PMID: 39749036 PMCID: PMC11693720 DOI: 10.3389/fonc.2024.1447508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 12/02/2024] [Indexed: 01/04/2025] Open
Abstract
The advent and success of new drugs for treating HER2-positive metastatic breast cancer has led to a constant improvement in disease and progression-free survival as well as overall survival. Despite these advantages, the overall survival and quality of life of patients with HER2-positive breast cancer brain metastases are significantly worse than the ones of patients with HER2-positive breast cancer metastases outside the brain. For this reason, prevention and treatment of brain metastasis remain a major clinical challenge and the keys to further improving the clinical and survival outcomes of HER2-positive breast cancer patients. This review discusses the etiopathogenesis of brain metastasis, the currently available treatments, and the future perspective on new treatment strategies and diagnostic tools.
Collapse
Affiliation(s)
- Claudia von Arx
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Claudia Calderaio
- Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Naples, Italy
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Alessandra Calabrese
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Benedetta Marciano
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Claudia Martinelli
- Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Naples, Italy
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Vincenzo Di Lauro
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Ivana Cerillo
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Daniela Cianniello
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
| | - Michelino De Laurentiis
- Department of Breast and Thoracic Oncology, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples, Italy
- Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Naples, Italy
| |
Collapse
|
|
3
|
Li J, Zhen J, Ai R, Lai M, Wang H, Cai L. Intracranial management of HER-2 overexpression breast cancer with extensive volume or symptomatic brain metastases. Front Oncol 2024; 14:1386909. [PMID: 39011485 PMCID: PMC11246875 DOI: 10.3389/fonc.2024.1386909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/03/2024] [Indexed: 07/17/2024] Open
Abstract
Objectives This study aimed to evaluate the impact of high intracranial burden and symptomatic presentation of brain metastases on treatment outcomes in patients with HER-2 positive breast cancer. Through a retrospective analysis, we explored the intracranial responses following the application of HER-2 targeted therapy alone or in combination with other modalities and further elucidated the relationship between treatment efficacy, intracranial progression-free survival (PFS), overall survival (OS), and the burden of intracranial lesions and symptomatic presentations. Methods A retrospective analysis was conducted on cases of HER-2 overexpressing breast cancer patients with brain metastases. Clinical records were reviewed to extract patient demographics, treatment modalities, and intracranial disease characteristics. Intracranial tumor burden was quantified at diagnosis and post-initial treatment. High intracranial tumor burden was defined as either total metastatic volume >15 cc, or the largest lesion >3 cm. Responses were assessed using established criteria. The correlation between intracranial disease parameters and intracranial progression-free survival (PFS) and overall survival (OS) was determined. Results The study comprised 65 patients with HER-2 overexpression breast cancer and brain metastases. Symptomatic presentation was observed in 69.2% of patients at the diagnosis of brain metastases. Treatment with HER-2 target therapy alone or in combination with other modalities resulted in substantial intracranial responses, with 81.5% achieving at least a partial response at 3 months from therapy initiation. Median intracranial PFS and OS for patients with high intracranial burden were 9 and 22 months, respectively. Patients with high intracranial burden and symptomatic presentation at diagnosis demonstrated worse PFS and OS to those with lower burden and absence of symptoms (p < 0.05 for each). Conclusions Her-2 overexpressing breast cancer and brain metastases face significant challenges, particularly those with high intracranial tumor burden, which correlates with poorer outcomes and higher incidence of leptomeningeal metastasis. Most patients responded positively to initial therapies, especially anti-HER-2 treatments combined with radiotherapy. Larger tumors necessitated more comprehensive treatment approaches, such as WBRT and SRS. Key factors influencing intracranial tumor control included the Ki-67 index, intracranial tumor burden, and continuous use of HER-2 targeted therapy post-diagnosis.
Collapse
Affiliation(s)
- Juan Li
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| | - Junjie Zhen
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| | - Ruyu Ai
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| | - Mingyao Lai
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| | - Hui Wang
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| | - Linbo Cai
- Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou, China
| |
Collapse
|
|
4
|
Amouzegar A, Haig S, Kahn AM, Tawbi HA, Jones JA, Goldberg SB. Navigating the Complexities of Brain Metastases Management. Am Soc Clin Oncol Educ Book 2024; 44:e433694. [PMID: 38781565 DOI: 10.1200/edbk_433694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
The management of brain metastases, a potentially devastating complication of advanced cancers, has become increasingly complex with advancements in local and systemic therapies. Improved outcomes and extended survival for patients with metastatic solid tumors have led to a surge in the prevalence and possibly incidence of brain metastases, affecting up to 40% of individuals with solid tumors. Enhanced imaging technologies contribute to more accurate and early detection, shaping the understanding of the intricate landscape of this condition. Traditionally, surgery and radiation stood as the mainstays of treatment because of the limited efficacy of systemic therapies within the brain. However, emerging clinical data, particularly in melanoma, lung, and breast cancers, reveal promising results with novel systemic treatments such as immunotherapy and targeted therapies. Despite the historical exclusion of patients with active brain metastases from clinical trials, a shift is occurring toward a more inclusive approach. This chapter delves into the multifaceted challenges associated with managing brain metastases, with a focus on the evolving landscape of systemic approaches as well as the intricacies of shared decision making, providing a comprehensive overview of the current state and future directions in navigating the complexities of brain metastases management.
Collapse
Affiliation(s)
- Afsaneh Amouzegar
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shannon Haig
- Lake Erie College of Osteopathic Medicine, Greensburg, PA
| | - Adriana M Kahn
- Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Hussein A Tawbi
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Joshua A Jones
- Department of Oncology, Division of Radiation Oncology and Division of Palliative Medicine, Rochester Regional Health System, Rochester, NY
| | - Sarah B Goldberg
- Section of Medical Oncology, Department of Medicine, Yale School of Medicine, New Haven, CT
| |
Collapse
|
|
5
|
Karthik J, Sehrawat A, Kapoor M, Sundriyal D. Navigating breast cancer brain metastasis: Risk factors, prognostic indicators, and treatment perspectives. World J Clin Oncol 2024; 15:594-598. [PMID: 38835846 PMCID: PMC11145961 DOI: 10.5306/wjco.v15.i5.594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 01/24/2024] [Accepted: 04/15/2024] [Indexed: 05/21/2024] Open
Abstract
In this editorial, we comment on the article by Chen et al. We specifically focus on the risk factors, prognostic factors, and management of brain metastasis (BM) in breast cancer (BC). BC is the second most common cancer to have BM after lung cancer. Independent risk factors for BM in BC are: HER-2 positive BC, triple-negative BC, and germline BRCA mutation. Other factors associated with BM are lung metastasis, age less than 40 years, and African and American ancestry. Even though risk factors associated with BM in BC are elucidated, there is a lack of data on predictive models for BM in BC. Few studies have been made to formulate predictive models or nomograms to address this issue, where age, grade of tumor, HER-2 receptor status, and number of metastatic sites (1 vs > 1) were predictive of BM in metastatic BC. However, none have been used in clinical practice. National Comprehensive Cancer Network recommends screening of BM in advanced BC only when the patient is symptomatic or suspicious of central nervous system symptoms; routine screening for BM in BC is not recommended in the guidelines. BM decreases the quality of life and will have a significant psychological impact. Further studies are required for designing validated nomograms or predictive models for BM in BC; these models can be used in the future to develop treatment approaches to prevent BM, which improves the quality of life and overall survival.
Collapse
Affiliation(s)
- Jayalingappa Karthik
- Department of Medical Oncology Haematology, All India Institute of Medical Sciences Rishikesh, Rishikesh 249203, Uttarakhand, India
| | - Amit Sehrawat
- Department of Medical Oncology Haematology, All India Institute of Medical Sciences Rishikesh, Rishikesh 249203, Uttarakhand, India
| | - Mayank Kapoor
- Department of Medical Oncology Haematology, All India Institute of Medical Sciences Rishikesh, Rishikesh 249203, Uttarakhand, India
| | - Deepak Sundriyal
- Department of Medical Oncology Haematology, All India Institute of Medical Sciences Rishikesh, Rishikesh 249203, Uttarakhand, India
| |
Collapse
|
|
6
|
Liang K, Feliciano JL, Marrone KA, Murray JC, Hann CL, Anagnostou V, Tackett SA, Shin EJ, Hales RK, Voong KR, Battafarano RJ, Yang SC, Broderick SR, Ha JS, Forde PM, Brahmer JR, Lam VK. Clinical features and outcomes of advanced HER2+ esophageal/GEJ cancer with brain metastasis. ESMO Open 2024; 9:102199. [PMID: 38071928 PMCID: PMC10837776 DOI: 10.1016/j.esmoop.2023.102199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 10/30/2023] [Accepted: 11/15/2023] [Indexed: 01/26/2024] Open
Abstract
BACKGROUND Brain metastasis (BRM) is uncommon in gastroesophageal cancer. As such, clinicopathologic and molecular determinants of BRM and impact on clinical outcome remain incompletely understood. METHODS We retrospectively analyzed clinicopathologic data from advanced esophageal/gastroesophageal junction (E/GEJ) patients at Johns Hopkins from 2003 to 2021. We investigated the association between several clinical and molecular features and the occurrence of BRM, with particular focus on human epidermal growth factor receptor 2 (HER2) overexpression. Survival outcomes and time to BRM onset were also evaluated. RESULTS We included 515 patients with advanced E/GEJ cancer. Tumors were 78.3% esophageal primary, 82.9% adenocarcinoma, 31.0% HER2 positive. Cumulative incidence of BRM in the overall cohort and within HER2+ subgroup was 13.8% and 24.3%, respectively. HER2 overexpression was associated with increased risk of BRM [odds ratio 2.45; 95% confidence interval (CI) 1.10-5.46]. On initial presentation with BRM, 50.7% had a solitary brain lesion and 11.3% were asymptomatic. HER2+ status was associated with longer median time to onset of BRM (14.0 versus 6.3 months, P < 0.01), improved median progression free survival on first-line systemic therapy (hazard ratio 0.35, 95% CI 0.16-0.80), and improved median overall survival (hazard ratio 0.20, 95% CI 0.08-0.54) in patients with BRM. CONCLUSION HER2 overexpression identifies a gastroesophageal cancer molecular subtype that is significantly associated with increased risk of BRM, though with later onset of BRM and improved survival likely reflecting the impact of central nervous system-penetrant HER2-directed therapy. The prevalence of asymptomatic and solitary brain lesions suggests that brain surveillance for HER2+ patients warrants prospective investigation.
Collapse
Affiliation(s)
- K Liang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - J L Feliciano
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - K A Marrone
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - J C Murray
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - C L Hann
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - V Anagnostou
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - S A Tackett
- Department of Medicine, Biostatistics, Epidemiology and Data Management (BEAD) Core, Johns Hopkins University School of Medicine, Baltimore, USA
| | - E J Shin
- Department of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - R K Hales
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
| | - K R Voong
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, USA
| | - R J Battafarano
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - S C Yang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - S R Broderick
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - J S Ha
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - P M Forde
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - J R Brahmer
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - V K Lam
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA.
| |
Collapse
|
|
7
|
Fares J, Petrosyan E, Kanojia D, Dmello C, Cordero A, Duffy JT, Yeeravalli R, Sahani MH, Zhang P, Rashidi A, Arrieta VA, Ulasov I, Ahmed AU, Miska J, Balyasnikova IV, James CD, Sonabend AM, Heimberger AB, Lesniak MS. Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases. J Clin Invest 2023; 133:e161142. [PMID: 37847564 PMCID: PMC10721147 DOI: 10.1172/jci161142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 10/12/2023] [Indexed: 10/18/2023] Open
Abstract
A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.
Collapse
Affiliation(s)
- Jawad Fares
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Edgar Petrosyan
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Deepak Kanojia
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Crismita Dmello
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Alex Cordero
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Joseph T. Duffy
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ragini Yeeravalli
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Mayurbhai H. Sahani
- Dr. Vikram Sarabhai Institute of Cell and Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
| | - Peng Zhang
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Aida Rashidi
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Victor A. Arrieta
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ilya Ulasov
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Atique U. Ahmed
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Jason Miska
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Irina V. Balyasnikova
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - C. David James
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Adam M. Sonabend
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Amy B. Heimberger
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Maciej S. Lesniak
- Department of Neurological Surgery, and
- Northwestern Medicine Malnati Brain Tumor Institute, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| |
Collapse
|
|
8
|
Giordano G, Griguolo G, Landriscina M, Meattini I, Carbone F, Leone A, Del Re M, Fogli S, Danesi R, Colamaria A, Dieci MV. Multidisciplinary management of HER2-positive breast cancer with brain metastases: An evidence-based pragmatic approach moving from pathophysiology to clinical data. Crit Rev Oncol Hematol 2023; 192:104185. [PMID: 37863404 DOI: 10.1016/j.critrevonc.2023.104185] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 10/02/2023] [Accepted: 10/16/2023] [Indexed: 10/22/2023] Open
Abstract
INTRODUCTION About 30-50 % of stage IV HER2+ breast cancers (BC) will present brain metastases (BMs). Their management is based on both local treatment and systemic therapy. Despite therapeutic advances, BMs still impact on survival and quality of life and the development of more effective systemic therapies represents an unmet clinical need. MATERIALS AND METHODS A thorough analysis of the published literature including ongoing clinical trials has been performed, investigating concepts spanning from the pathophysiology of tumor microenvironment to clinical considerations with the aim to summarize the current and future locoregional and systemic strategies. RESULTS Different trials have investigated monotherapies and combination treatments, highlighting how the blood-brain barrier (BBB) represents a major problem hindering diffusion and consequently efficacy of such options. Trastuzumab has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab, and trastuzumab emtansine, as well as more recently neratinib, tucatinib, and trastuzumab deruxtecan, have been introduced in clinical practice after showing promising results in randomized controlled trials. CONCLUSIONS We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2 + BCs patients with BMs.
Collapse
Affiliation(s)
- Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences - Policlinico Riuniti, University of Foggia, Foggia 71122, Italy.
| | - Gaia Griguolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35128, Italy; Division of Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padova 35128, Italy
| | - Matteo Landriscina
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences - Policlinico Riuniti, University of Foggia, Foggia 71122, Italy
| | - Icro Meattini
- Radiation Oncology Unit, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences M Serio, University of Florence, Florence, Italy, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Florence, Italy
| | - Francesco Carbone
- Department of Neurosurgery, Städtisches Klinikum Karlsruhe, Karlsruher Neurozentrum, Karlsruhe 76133, Germany
| | - Augusto Leone
- Department of Neurosurgery, Städtisches Klinikum Karlsruhe, Karlsruher Neurozentrum, Karlsruhe 76133, Germany; Faculty of Human Medicine, Charité Universitätsmedizin Berlin, Berlin 10117, Germany
| | - Marzia Del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Stefano Fogli
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Romano Danesi
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Antonio Colamaria
- Division of Neurosurgery, Policlinico Riuniti Foggia, Foggia 71122, Italy
| | - Maria Vittoria Dieci
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35128, Italy; Division of Oncology 2, Veneto Institute of Oncology IOV - IRCCS, Padova 35128, Italy
| |
Collapse
|
|
9
|
Warrior S, Cohen-Nowak A, Kumthekar P. Modern Management and Diagnostics in HER2+ Breast Cancer with CNS Metastasis. Cancers (Basel) 2023; 15:cancers15112908. [PMID: 37296873 DOI: 10.3390/cancers15112908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/09/2023] [Accepted: 05/23/2023] [Indexed: 06/12/2023] Open
Abstract
Patients with HER2-positive breast cancer have seen improved survival and outcomes over the past two decades. As patients live longer, the incidence of CNS metastases has increased in this population. The authors' review outlines the most current data in HER2-positive brain and leptomeningeal metastases and discuss the current treatment paradigm in this disease. Up to 55% of HER2-positive breast cancer patients go on to experience CNS metastases. They may present with a variety of focal neurologic symptoms, such as speech changes or weakness, and may also have more diffuse symptoms related to high intracranial pressure, such as headaches, nausea, or vomiting. Treatment can include focal treatments, such as surgical resection or radiation (focal or whole-brain radiation), as well as systemic therapy options or even intrathecal therapy in the case of leptomeningeal disease. There have been multiple advancements in systemic therapy for these patients over the past few years, including the availability of tucatinib and trastuzumab-deruxtecan. Hope remains high as clinical trials for CNS metastases receive greater attention and as other HER2-directed methods are being studied in clinical trials with the goal of better outcomes for these patients.
Collapse
Affiliation(s)
- Surbhi Warrior
- Department of Hematology, Oncology Northwestern Memorial Hospital, Chicago, IL 60611, USA
| | - Adam Cohen-Nowak
- Department of Internal Medicine, Northwestern Memorial Hospital, Chicago, IL 60611, USA
| | - Priya Kumthekar
- Department of Neuro-Oncology, Northwestern Memorial Hospital, Chicago, IL 60611, USA
| |
Collapse
|
|
10
|
Mandó P, Waisberg F, Pasquinelli R, Rivero S, Ostinelli A, Perazzo F. HER2-Directed Therapy in Advanced Breast Cancer: Benefits and Risks. Onco Targets Ther 2023; 16:115-132. [PMID: 36844609 PMCID: PMC9948634 DOI: 10.2147/ott.s335934] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/20/2023] [Indexed: 02/20/2023] Open
Abstract
Around 20% of breast cancers are associated with amplification or overexpression of human epidermal growth factor receptor 2 (HER2). In this setting, anti-HER2-targeted agents are the cornerstone of cancer therapeutic strategies. This includes monoclonal antibodies, tyrosine kinase inhibitors (TKIs) and, recently, antibody-drug conjugates (ADCs). With the advent of these new alternatives, the decision-making process has become more complex, especially with regard to the treatment sequence possibilities. In spite of the fact that overall survival has significantly improved accordingly, resistance to treatment remains a challenge in HER2-positive breast cancer. The introduction of new agents has created awareness regarding new potential specific adverse events, and consequently, their increasing application pose major challenges in daily patient care. This review describes the therapeutic landscape for HER2-positive advanced breast cancer (ABC) and evaluates its benefits and risks in the clinical setting.
Collapse
Affiliation(s)
- Pablo Mandó
- Clinical Oncology Department, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Ciudad Autónoma de Buenos Aires, Argentina
| | - Federico Waisberg
- Clinical Oncology Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, Argentina
| | - Rosario Pasquinelli
- Clinical Oncology Department, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Ciudad Autónoma de Buenos Aires, Argentina
| | - Sergio Rivero
- Clinical Oncology Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, Argentina
| | - Alexis Ostinelli
- Clinical Oncology Department, Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, Argentina
| | - Florencia Perazzo
- Clinical Oncology Department, Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno” (CEMIC), Ciudad Autónoma de Buenos Aires, Argentina
| |
Collapse
|
|
11
|
Fleege NMG, Pierce-Gjeldum D, Swartz LK, Verbal K, Merajver S, Friese CR, Kiyota A, Heth J, Leung D, Smith SR, Gabel N, Kim MM, Morikawa A. IMPACT the Brain: A Team-Based Approach to Management of Metastatic Breast Cancer With CNS Metastases. JCO Oncol Pract 2023; 19:e67-e77. [PMID: 36223556 PMCID: PMC9870235 DOI: 10.1200/op.22.00291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
PURPOSE CNS metastases are associated with decreased survival and quality of life for patients with metastatic breast cancer (MBC). Team-based care can optimize outcomes. IMPACT the Brain is a care coordination program that aims to improve access to team-based care for patients with MBC and CNS metastases. MATERIALS AND METHODS Patients with MBC and CNS metastases were eligible for enrollment in this care coordination program. A team of specialists supported a dedicated program coordinator who provided navigation, education, specialty referral, and clinical trial screening. A unique intake form developed for the program created personalized, coordinated, and expedited specialty referrals. Patient-reported outcomes and caregiver burden assessments were collected on a voluntary basis throughout enrollment. Data were analyzed using descriptive statistics. RESULTS Sixty patients were referred, and 53 were enrolled (88%). The median time to program enrollment was 1 day (range, 0-11) and to first visit was 5 days (range, 0-25). On the basis of the program intake form, 47 referrals were made across six specialties, most commonly physical medicine and rehabilitation (n = 10), radiation oncology (n = 10), and neuropsychology (n = 10). Nineteen patients (36%) consented to enroll in clinical trials. CONCLUSION A tailored team-based care coordination program for patients with MBC and CNS metastases is feasible. Use of a unique intake screening form by a dedicated program coordinator resulted in faster time to first patient visit, enabled access to subspecialist care, and supported enrollment in clinical trials. Future research should focus on intervention development using PRO data collected in this care coordination program.
Collapse
Affiliation(s)
- Nicole M. Grogan Fleege
- University of Michigan Health System, Ann Arbor, MI,Nicole M. Grogan Fleege, MD, 1500 E. Medical Center Dr, Ann Arbor, MI 48109 Twitter: @NicoleFleege; e-mail:
| | | | | | - Kait Verbal
- University of Michigan Health System, Ann Arbor, MI
| | | | | | - Ayano Kiyota
- University of Michigan Health System, Ann Arbor, MI
| | - Jason Heth
- University of Michigan Health System, Ann Arbor, MI
| | - Denise Leung
- University of Michigan Health System, Ann Arbor, MI
| | | | | | | | - Aki Morikawa
- University of Michigan Health System, Ann Arbor, MI
| |
Collapse
|
|
12
|
Sun H, Xu J, Dai S, Ma Y, Sun T. Breast cancer brain metastasis: Current evidence and future directions. Cancer Med 2023; 12:1007-1024. [PMID: 35822637 PMCID: PMC9883555 DOI: 10.1002/cam4.5021] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/26/2022] [Accepted: 06/28/2022] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most common cancer in women and the second leading cause of cancer-related deaths after lung cancer. Metastasis of the central nervous system is a terrible event for breast cancer patients, affecting their survival and quality of life. Compared with hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients, brain metastases are more likely to affect patients with triple-negative breast cancer and human epidermal growth factor receptor 2-positive breast cancer. The treatment of breast cancer has improved greatly in the last two decades. However, brain metastases from breast cancer remain the leading cause of morbidity and mortality. Patients with breast cancer brain metastasis have been in an inferior position due to the lack of clinical research in this field, and they are often explicitly excluded from almost all clinical trials. The occurrence and progression of brain metastases will result in severe cognitive impairment and adverse physical consequences, so we must have a good understanding of the molecular mechanisms of breast cancer brain metastasis. In this article, we have retrieved the latest literature of molecules and pathways associated with breast cancer brain metastasis, summarized common therapy strategies, and discussed the prospects and clinical implications of targeting the molecules involved.
Collapse
Affiliation(s)
- Hongna Sun
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Junnan Xu
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Shuang Dai
- Department of Medical Oncology, Lung cancer center, West China HospitalSichuan UniversityChengduChina
| | - Yiwen Ma
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| | - Tao Sun
- Department of Medical Oncology, Liaoning Cancer Hospital & InstituteCancer Hospital of China Medical UniversityShenyangChina
| |
Collapse
|
|
13
|
Edavettal S, Cejudo-Martin P, Dasgupta B, Yang D, Buschman MD, Domingo D, Van Kolen K, Jaiprasat P, Gordon R, Schutsky K, Geist B, Taylor N, Soubrane CH, Van Der Helm E, LaCombe A, Ainekulu Z, Lacy E, Aligo J, Ho J, He Y, Lebowitz PF, Patterson JT, Scheer JM, Singh S. Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis. MED 2022; 3:860-882.e15. [PMID: 36257298 DOI: 10.1016/j.medj.2022.09.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 06/28/2022] [Accepted: 09/22/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. METHODS Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. FINDINGS We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. CONCLUSIONS Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. FUNDING This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.
Collapse
Affiliation(s)
| | | | | | - Danlin Yang
- Janssen Research and Development, Spring House, PA 19477, USA
| | | | | | | | | | - Renata Gordon
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Keith Schutsky
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Brian Geist
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Natalie Taylor
- Janssen Research and Development, San Diego, CA 92121, USA
| | | | | | - Ann LaCombe
- Janssen Research and Development, San Diego, CA 92121, USA
| | | | - Eilyn Lacy
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Jason Aligo
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Jason Ho
- Janssen Research and Development, Spring House, PA 19477, USA
| | - Yingbo He
- Janssen Research and Development, San Diego, CA 92121, USA
| | | | | | - Justin M Scheer
- Janssen Research and Development, Spring House, PA 19477, USA.
| | - Sanjaya Singh
- Janssen Research and Development, Spring House, PA 19477, USA
| |
Collapse
|
|
14
|
Tincknell G, Naveed A, Nankervis J, Mukhtiar A, Piper AK, Becker TM, Chantrill L, Aghmesheh M, Vine KL, Ranson M, Brungs D. HER2-Positive Gastroesophageal Cancers Are Associated with a Higher Risk of Brain Metastasis. Cancers (Basel) 2022; 14:5754. [PMID: 36497236 PMCID: PMC9735596 DOI: 10.3390/cancers14235754] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/09/2022] [Accepted: 11/17/2022] [Indexed: 11/25/2022] Open
Abstract
Brain metastasis from gastroesophageal adenocarcinomas (GOCs) is a rare but a devastating diagnosis. Human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker in GOCs. The association of HER2 with GOC brain metastasis is not known. We performed a retrospective analysis of patients with GOCs with known HER2 status between January 2015 and November 2021. HER2 was assessed on either the primary tumour or metastasis by immunohistochemistry or in situ hybridization. The diagnosis of brain metastasis was made on standard imaging techniques in patients with symptoms or signs. HER2 results were available for 201 patients, with 34 patients (16.9%) HER2 positive. A total of 12 patients developed symptomatic brain metastasis from GOCs, of which 7 (58.3%) were HER2 positive. The development of symptomatic brain metastasis was significantly higher in the HER2-positive GOCs (OR8.26, 95%CI 2.09-35.60; p = 0.0009). There was no significant association of HER2 status and overall survival in patients with brain metastasis. Although the rate of brain metastasis remains low in GOCs, the incidence of symptomatic brain metastasis was significantly higher in patients with HER2-positive tumours.
Collapse
Affiliation(s)
- Gary Tincknell
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Cancer Care Centre, Illawarra Shoalhaven Local Health District, Wollongong, NSW 2500, Australia
- School of Chemistry and Molecular Biosciences, University of Wollongong, Wollongong, NSW 2522, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Asma Naveed
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- NSW Health Pathology, Wollongong, NSW 2522, Australia
- Southern IML, Wollongong, NSW 2500, Australia
| | | | | | - Ann-Katrin Piper
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Therese M. Becker
- Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
- UNSW Medicine, University of New South Wales, Kensington, NSW 2052, Australia
- School of Medicine, Western Sydney University, Sydney, NSW 2560, Australia
| | - Lorraine Chantrill
- Illawarra Cancer Care Centre, Illawarra Shoalhaven Local Health District, Wollongong, NSW 2500, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Morteza Aghmesheh
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Cancer Care Centre, Illawarra Shoalhaven Local Health District, Wollongong, NSW 2500, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Kara Lea Vine
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- School of Chemistry and Molecular Biosciences, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Marie Ranson
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- School of Chemistry and Molecular Biosciences, University of Wollongong, Wollongong, NSW 2522, Australia
| | - Daniel Brungs
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
- Illawarra Cancer Care Centre, Illawarra Shoalhaven Local Health District, Wollongong, NSW 2500, Australia
- School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia
| |
Collapse
|
|
15
|
Che W, Liu J, Fu T, Wang X, Lyu J. Recent Trends in Synchronous Brain Metastasis Incidence and Mortality in the United States: Ten-Year Multicenter Experience. Curr Oncol 2022; 29:8374-8389. [PMID: 36354720 PMCID: PMC9689090 DOI: 10.3390/curroncol29110660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 10/29/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Large epidemiological studies describing the trends in incidence rates and mortality of synchronous brain metastases (SBMs) are lacking. The study aimed to provide a comprehensive understanding of the changes in the incidence and mortality of SBMs over the previous ten years. METHODS Trends in the incidence of solid malignancies outside of the CNS in patients with SBMs and incidence-based mortality rates were assessed using data from the Surveillance, Epidemiology, and End Results database. Joinpoint analyses were used to calculate annual percent changes (APCs) and 95% CIs. RESULTS Between 2010 and 2019, 66,655 patients, including 34,821 (52.24%) men and 31,834 (47.76%) women, were found to have SBMs, and 57,692 deaths occurred over this period. Lung cancer SBMs, melanoma SBMs, and breast cancer SBMs were ranked in the top three, having the highest age-standardized incidence rates. The incidence of SBMs decreased significantly with an APC of -0.6% from 2010 to 2019, while the APC was 1.2% for lung cancer SBMs, 2.5% for melanoma SBMs, and 0.6% for breast cancer SBMs. The SBM mortality first experienced a rapid increase (APC = 28.6%) from 2010 to 2012 and then showed a significant decline at an APC of -1.8% from 2012 to 2019. Lung cancer SBMs showed similar trends, while melanoma SBM and breast cancer SBM mortality increased continuously. CONCLUSIONS SBMs incidence (2010-2019) and incidence-based mortality (2012-2019) declined significantly. These findings can advance our understanding of the prevalence of SBMs.
Collapse
Affiliation(s)
- Wenqiang Che
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Jie Liu
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Tengyue Fu
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Xiangyu Wang
- Department of Neurosurgery, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Jun Lyu
- Department of Clinical Research, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| |
Collapse
|
|
16
|
Avila J, Leone JP. Advances in the Management of Central Nervous System Metastases from Breast Cancer. Int J Mol Sci 2022; 23:12525. [PMID: 36293379 PMCID: PMC9604332 DOI: 10.3390/ijms232012525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/17/2022] [Accepted: 10/17/2022] [Indexed: 11/24/2022] Open
Abstract
Central nervous system (CNS) metastases are common in breast cancer (BC) patients and are particularly relevant as new treatments for BC are prolonging survival. Here, we review advances in the treatment of CNS metastases from BC, including radiotherapy, systemic therapies, and the evolving role of immunotherapy. The use of radiotherapy and chemotherapy is the cornerstone of treatment for CNS metastases. However, new targeted therapies have recently been developed, including anti-HER2 agents and antibody-drug conjugates that have presented promising results for the treatment of these patients.
Collapse
Affiliation(s)
- Jorge Avila
- Department of Internal Medicine, St Elizabeth’s Medical Center, 736 Cambridge St., Boston, MA 02135, USA
- Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA
| | - José Pablo Leone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA 02215, USA
| |
Collapse
|
|
17
|
Bhargava P, Rathnasamy N, Shenoy R, Gulia S, Bajpai J, Ghosh J, Rath S, Budrukkar A, Shet T, Patil A, Desai S, Nair N, Joshi S, Popat P, Wadasadawala T, Pathak R, Sarin R, Kannan S, Badwe R, Gupta S. Clinical Profile and Outcome of Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer With Brain Metastases: Real-World Experience. JCO Glob Oncol 2022; 8:e2200126. [PMID: 36130155 PMCID: PMC9812453 DOI: 10.1200/go.22.00126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
PURPOSE There are sparse data in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases from real-world settings, especially where access to newer targeted therapies is limited. METHODS This was a single institution, retrospective cohort study of patients with HER2-positive breast cancer diagnosed between January 2013 and December 2017 to have brain metastases and treated with any HER2-targeted therapy. The main objectives were to estimate progression-free survival (PFS) and overall survival (OS) from the time of brain metastases. RESULTS A total of 102 patients with a median age of 52 (interquartile range, 45-57) years were included, of whom 63 (61.8%) had received one line and 14 (13.7%) had received two lines of HER2-targeted therapies before brain metastasis, 98 (96.1%) were symptomatic at presentation, 22 (25.3%) had solitary brain lesion, 22 (25.3%) had 2-5 lesions, and 43 (49.4%) had ≥ 5 lesions. Local treatment included surgical resection in nine (8.9%) and radiotherapy in all (100%) patients. The first HER2-targeted therapy after brain metastasis was lapatinib in 71 (68.6%), trastuzumab in 19 (18.6%), lapatinib and trastuzumab in three (2.9%), trastuzumab emtansine in four (3.9%), and intrathecal trastuzumab in five (4.9%) patients. At a median follow-up of 13.9 months, the median PFS and OS were 8 (95% CI, 6.2 to 9.8) months and 14 (95% CI, 10.8 to 17.2) months, respectively, with a 2-year OS of 25% (95% CI, 16.7 to 34.4). The median PFS in patients who received lapatinib-capecitabine regimen (n = 62) was 9.0 (95% CI, 7.3 to 10.7) months. CONCLUSION There was a substantial clinical benefit of local and systemic therapy in patients with brain metastases and HER2-positive disease in a real-world setting with limited access to newer HER2-targeted drugs.
Collapse
Affiliation(s)
- Prabhat Bhargava
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Narmadha Rathnasamy
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Ramnath Shenoy
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Seema Gulia
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Jyoti Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Jaya Ghosh
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sushmita Rath
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Ashwini Budrukkar
- Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Tanuja Shet
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Asawari Patil
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sangeeta Desai
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Nita Nair
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Shalaka Joshi
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Palak Popat
- Department of Biostatistics, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Tabassum Wadasadawala
- Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Rima Pathak
- Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Rajiv Sarin
- Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sadhana Kannan
- Department of Biostatistics, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Rajendra Badwe
- Department of Surgical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Sudeep Gupta
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India,Sudeep Gupta, MD, MBBS, DM, Department of Medical Oncology, Tata Memorial Centre, Mumbai 400012, India; Twitter: @ACTREC_TMC; e-mail:
| |
Collapse
|
|
18
|
Cai SL, Wang ZH, Chen XG, Han L, Gong GX, Chen YP, Lin XQ, Ma T, Chen HD. Risk Factors of Brain Metastasis and Prognosis in HER2-Positive Breast Cancer: A Single-Institution Retrospective Analysis from China. Front Oncol 2022; 12:905065. [PMID: 35832552 PMCID: PMC9271963 DOI: 10.3389/fonc.2022.905065] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundBrain metastasis (BM) frequently occurs in HER2-positive breast cancer (BC) patients, but the risk factors of BM in this type of patients are still unknown. Our study aims to assess the risk factors of BM and prognostic analysis in HER2-positive BC patients.MethodsUnivariate analysis used t-test, chi-square test, and Fisher’s exact test to find out the risk factors for BM, and multivariable analysis was done with stepwise logistic regression analysis. Prognostic data analysis was estimated by the Kaplan–Meier method.ResultsA total of 228 HER2-positive BC patients were included, of whom 214 patients were postoperative metastatic patients and 14 patients were de novo stage IV patients. Through comparing the stratified variables between 51 postoperative metastatic patients with BM and 163 postoperative metastatic patients without BM, the multivariate analysis showed that age ≤40 years (OR 2.321, 95% CI: 1.089 to 4.948) and first metastatic site with lung metastasis (OR 2.168, 95% CI: 1.099 to 4.274) were independent risk factors for BM in HER2-positive BC patients. Prognostic data of all 65 HER2-positive BC patients with BM showed that the time from the diagnosis of BC to the development of breast cancer brain metastasis (BCBM) was 36.3 months (95% CI: 30.0 to 42.1 months). The time from the diagnosis of first recurrence and metastasis stage to the diagnosis of BCBM was 11.35 months (95% CI: 7.1 to 18.4 months). The time from the diagnosis of BCBM to the time of follow-up was 24.1 months (95% CI: 13.9 to 37.5 months). Up until the time of follow-up data, a total of 38 patients had died, and the time from the diagnosis of BM of these 38 patients to death was 11.0 months (95% CI: 9.0 to 20.4 months).ConclusionThe prognosis of HER2-positive BC patients with BM was poor due to the lack of effective treatments for BM. Age ≤40 years and first metastatic site with lung metastasis were the independent risk factors for BM in HER2-positive BC patients. Future research about pre-emptive medical interventions may help to improve the prognosis of HER2-positive BC patients with high risk to develop BM.
Collapse
Affiliation(s)
- Shuang-Long Cai
- Department of Oncological Surgery, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Zhi-Hong Wang
- Department of Hematology, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Xiao-Geng Chen
- Department of Oncological Surgery, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Lei Han
- Department of Oncological Surgery, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Guo-Xian Gong
- Department of UItrasonic Diagnosis, Fujian Provincial Hospital, Fuzhou, China
| | - Yan-Ping Chen
- Department of Obstetrics and Gynecology, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Xiu-Quan Lin
- Department for Chronic and Noncommunicable Disease Control and Prevention, Fujian Provincial Center for Disease Control and Prevention, Fuzhou, China
| | - Tao Ma
- Third Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China
| | - Hong-Dan Chen
- First Department of Cadre Clinic, Provincial Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
- *Correspondence: Hong-Dan Chen,
| |
Collapse
|
|
19
|
Michel A, Dinger TF, Santos AN, Pierscianek D, Darkwah Oppong M, Ahmadipour Y, Dammann P, Wrede KH, Hense J, Pöttgen C, Iannaccone A, Kimmig R, Sure U, Jabbarli R. Time interval between the diagnosis of breast cancer and brain metastases impacts prognosis after metastasis surgery. J Neurooncol 2022; 159:53-63. [PMID: 35672530 PMCID: PMC9325855 DOI: 10.1007/s11060-022-04043-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 05/21/2022] [Indexed: 11/29/2022]
Abstract
Abstract
Purpose
Breast cancer (BC) is the most frequently diagnosed tumor entity in women. Occurring at different time intervals (TI) after BC diagnosis, brain metastases (BM) are associated with poor prognosis. We aimed to identify the risk factors related to and the clinical impact of timing on overall survival (OS) after BM surgery.
Methods
We included 93 female patients who underwent BC BM surgery in our institution (2008–2019). Various clinical, radiographic, and histopathologic markers were analyzed with respect to TI and OS.
Results
The median TI was 45.0 months (range: 9–334.0 months). Fifteen individuals (16.1%) showed late occurrence of BM (TI ≥ 10 years), which was independently related to invasive lobular BC [adjusted odds ratio (aOR) 9.49, 95% confidence interval (CI) 1.47–61.39, p = 0.018] and adjuvant breast radiation (aOR 0.12, 95% CI 0.02–0.67, p = 0.016). Shorter TI (< 5 years, aOR 4.28, 95% CI 1.46–12.53, p = 0.008) was independently associated with postoperative survival and independently associated with the Union for International Cancer Control stage (UICC) III–IV of BC (aOR 4.82, 95% CI 1.10–21.17, p = 0.037), midline brain shift in preoperative imaging (aOR10.35, 95% CI 1.09–98.33, p = 0.042) and identic estrogen receptor status in BM (aOR 4.56, 95% CI 1.35–15.40, p = 0.015).
Conclusions
Several factors seem to influence the period between BC and BM. Occurrence of BM within five years is independently associated with poorer prognosis after BM surgery. Patients with invasive lobular BC and without adjuvant breast radiation are more likely to develop BM after a long progression-free survival necessitating more prolonged cancer aftercare of these individuals.
Collapse
Affiliation(s)
- Anna Michel
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany.
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany.
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany.
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, University Duisburg-Essen, Hufelandstraße 55, 45147, Essen, Germany.
| | - Thiemo Florin Dinger
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Alejandro N Santos
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Daniela Pierscianek
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Marvin Darkwah Oppong
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Yahya Ahmadipour
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Philipp Dammann
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Karsten H Wrede
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Jörg Hense
- Department of Medical Oncology, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Christoph Pöttgen
- Department of Radiotherapy, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Antonella Iannaccone
- Department of Obstetrics and Gynecology, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Rainer Kimmig
- Department of Obstetrics and Gynecology, University Hospital Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Ulrich Sure
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| | - Ramazan Jabbarli
- Department of Neurosurgery and Spine Surgery, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- & Behavioral Sciences (C-TNBS), University Duisburg Essen, Essen, Germany
- German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, 45147, Essen, Germany
| |
Collapse
|
|
20
|
Li AY, Gaebe K, Jerzak KJ, Cheema PK, Sahgal A, Das S. Intracranial Metastatic Disease: Present Challenges, Future Opportunities. Front Oncol 2022; 12:855182. [PMID: 35330715 PMCID: PMC8940535 DOI: 10.3389/fonc.2022.855182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 02/16/2022] [Indexed: 11/13/2022] Open
Abstract
Intracranial metastatic disease (IMD) is a prevalent complication of cancer that significantly limits patient survival and quality of life. Over the past half-century, our understanding of the epidemiology and pathogenesis of IMD has improved and enabled the development of surveillance and treatment algorithms based on prognostic factors and tumor biomolecular characteristics. In addition to advances in surgical resection and radiation therapy, the treatment of IMD has evolved to include monoclonal antibodies and small molecule antagonists of tumor-promoting proteins or endogenous immune checkpoint inhibitors. Moreover, improvements in the sensitivity and specificity of imaging as well as the development of new serological assays to detect brain metastases promise to revolutionize IMD diagnosis. In this review, we will explore current treatment principles in patients with IMD, including the emerging role of targeted and immunotherapy in select primary cancers, and discuss potential areas for further investigation.
Collapse
Affiliation(s)
- Alyssa Y Li
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Karolina Gaebe
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Katarzyna J Jerzak
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Division of Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Parneet K Cheema
- Division of Oncology, William Osler Health System, Brampton, ON, Canada
| | - Arjun Sahgal
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Sunit Das
- Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.,Division of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
| |
Collapse
|
|
21
|
Wang L, Zeng D, Wang Q, Liu L, Lu T, Gao Y. Screening and Identification of Novel Potential Biomarkers for Breast Cancer Brain Metastases. Front Oncol 2022; 11:784096. [PMID: 35096583 PMCID: PMC8792448 DOI: 10.3389/fonc.2021.784096] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/09/2021] [Indexed: 12/29/2022] Open
Abstract
Brain metastases represent a major cause of mortality among patients with breast cancer, and few effective targeted treatment options are currently available. Development of new biomarkers and therapeutic targets for breast cancer brain metastases (BCBM) is therefore urgently needed. In this study, we compared the gene expression profiles of the brain metastatic cell line MDA-MB-231-BR (231-BR) and its parental MDA-MB-231, and identified a total of 84 genes in the primary screening through a series of bioinformatic analyses, including construction of protein-protein interaction (PPI) networks by STRING database, identification of hub genes by applying of MCODE and Cytohubba algorithms, identification of leading-edge subsets of Gene Set Enrichment Analysis (GSEA), and identification of most up-regulated genes. Eight genes were identified as candidate genes due to their elevated expression in brain metastatic 231-BR cells and prognostic values in patients with BCBM. Then we knocked down the eight individual candidate genes in 231-BR cells and evaluated their impact on cell migration through a wound-healing assay, and four of them (KRT19, FKBP10, GSK3B and SPANXB1) were finally identified as key genes. Furthermore, the expression of individual key genes showed a correlation with the infiltration of major immune cells in the brain tumor microenvironment (TME) as analyzed by Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA), suggesting possible roles of them in regulation of the tumor immune response in TME. Therefore, the present work may provide new potential biomarkers for BCBM. Additionally, using GSEA, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, we determined the top enriched cellular functions or pathways in 231-BR cells, which may help better understand the biology governing the development and progression of BCBM.
Collapse
Affiliation(s)
- Lulu Wang
- Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China.,Cancer Institute of Capital Medical University, Beijing, China
| | - Dan Zeng
- Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Qi Wang
- Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Li Liu
- Department of Experimental Center for Basic Medical Teaching, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Tao Lu
- Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Yan Gao
- Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing, China.,Cancer Institute of Capital Medical University, Beijing, China
| |
Collapse
|
|
22
|
CXCR2 Mediates Distinct Neutrophil Behavior in Brain Metastatic Breast Tumor. Cancers (Basel) 2022; 14:cancers14030515. [PMID: 35158784 PMCID: PMC8833752 DOI: 10.3390/cancers14030515] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/06/2023] Open
Abstract
Brain metastasis is one of the main causes of mortality among breast cancer patients, but the origins and the mechanisms that drive this process remain poorly understood. Here, we report that the upregulation of certain CXCR2-associated ligands in the brain metastatic variants of the breast cancer cells (BrM) dynamically activate the corresponding CXCR2 receptors on the neutrophils, thereby resulting in the modulation of certain key functional neutrophil responses towards the BrM. Using established neutrophil-tumor biomimetic co-culture models, we show that the upregulation of CXCR2 increases the recruitment of Tumor-Associated Neutrophils (TANs) towards the BrM, to enable location-favored formation of Neutrophil Extracellular Traps (NETs). Inhibition of CXCR2 using small molecule antagonist AZD5069 reversed this behavior, limiting the neutrophil responses to the BrM and retarding the reciprocal tumor development. We further demonstrate that abrogation of NETs formation using Neutrophil Elastase Inhibitor (NEI) significantly decreases the influx of neutrophils towards BrM but not to their parental tumor, suggesting that CXCR2 activation could be used by the brain metastatic tumors as a mechanism to program the tumor-infiltrating TANs into a pro-NETotic state, so as to assume a unique spatial distribution that assists in the subsequent migration and invasion of the metastatic tumor cells. This new perspective indicates that CXCR2 is a critical target for suppressing neutrophilic inflammation in brain metastasis.
Collapse
|
|
23
|
Bachelot T, Bailleux C, Darlix A, Jacot W. Aspects cliniques : Cancers HER2 et atteinte du système nerveux central, que faire en 2021 ? Bull Cancer 2022; 108:11S26-11S34. [PMID: 34969513 DOI: 10.1016/s0007-4551(21)00634-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context.
Collapse
Affiliation(s)
- Thomas Bachelot
- Département de cancérologie médicale, centre Léon-Bérard, 28 rue Laennec, 69373 Lyon, France.
| | - Caroline Bailleux
- Département de cancérologie médicale, centre Antoine-Lacassagne, 33 avenue Valombrose, 06100 Nice, France
| | - Amélie Darlix
- Département d'oncologie médicale, Institut régional du cancer de Montpellier, université de Montpellier, Montpellier, France ; Institut de génomique fonctionnelle, INSERM, CNRS, université de Montpellier, Montpellier, France
| | - William Jacot
- Département d'oncologie médicale, Institut régional du cancer de Montpellier, université de Montpellier, Montpellier, France ; Institut de recherche en cancérologie de Montpellier (IRCM) INSERM U1194, Montpellier, France
| |
Collapse
|
|
24
|
Corti C, Antonarelli G, Criscitiello C, Lin NU, Carey LA, Cortés J, Poortmans P, Curigliano G. Targeting brain metastases in breast cancer. Cancer Treat Rev 2021; 103:102324. [PMID: 34953200 DOI: 10.1016/j.ctrv.2021.102324] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/09/2021] [Accepted: 12/11/2021] [Indexed: 12/19/2022]
Abstract
Brain metastases (BMs) are an important source of morbidity and mortality in patients with metastatic breast cancer (BC). As survival of patients with advanced BC considerably improved thanks to research advancements and new therapeutic approaches, the apparent incidence of BMs is increasing. Local interventions, in the form of either surgical resection or radiation therapy, remain the mainstay in the management of BMs. Systemic treatments are typically used to complement local strategies to further improve and maintain control of central nervous system (CNS) disease. Although high-level evidence data about the impact of the blood-brain barrier (BBB), as well as the efficacy of anti-cancer agents on BMs and differentials between the systemic compartment and CNS are still scant, our understanding of the activity of systemic treatments with impact on BMs is rapidly evolving. Novel anti-HER2 agents, such as tucatinib, ado-trastuzumab emtansine, trastuzumab deruxtecan and neratinib, have shown intracranial efficacy. Current research efforts are ongoing not only to clarify the activity of existing treatments on the CNS, as well as to develop new drugs and innovative multi-modality approaches. This review will encompass the current treatment landscape of BMs arising from BC, with a focus on recent advancements in the field and investigational approaches.
Collapse
Affiliation(s)
- Chiara Corti
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy.
| | - Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
| | - Nancy U Lin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Lisa A Carey
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
| | - Javier Cortés
- Oncology Department, International Breast Cancer Center (IBCC), Quiron Group, Barcelona, Spain; Medica Scientia Innovation Research (MedSIR), Barcelona, Spain; Medica Scientia Innovation Research (MedSIR), Ridgewood, NJ, USA; Breast Cancer Research program, Vall d́Hebron Institute of Oncology (VHIO), Barcelona, Spain; Universidad Europea de Madrid, Faculty of Biomedical and Health Sciences, Department of Medicine, Madrid, Spain
| | - Philip Poortmans
- Iridium Netwerk and University of Antwerp, Wilrijk-Antwerp, Belgium
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Haematology (DIPO), University of Milan, Milan, Italy
| |
Collapse
|
|
25
|
Lin NU, Pegram M, Sahebjam S, Ibrahim N, Fung A, Cheng A, Nicholas A, Kirschbrown W, Kumthekar P. Pertuzumab Plus High-Dose Trastuzumab in Patients With Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study. J Clin Oncol 2021; 39:2667-2675. [PMID: 33945296 PMCID: PMC8376355 DOI: 10.1200/jco.20.02822] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/26/2021] [Accepted: 03/04/2021] [Indexed: 01/26/2023] Open
Abstract
PURPOSE Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab. METHODS In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety. RESULTS Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent. CONCLUSION Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.
Collapse
Affiliation(s)
| | - Mark Pegram
- Stanford Comprehensive Cancer Institute, Palo Alto, CA
| | - Solmaz Sahebjam
- Moffitt Cancer Center, University of South Florida, Tampa, FL
| | | | | | | | | | | | | |
Collapse
|
|
26
|
Di Nunno V, Franceschi E, Tosoni A, Mura A, Minichillo S, Di Battista M, Gatto L, Maggio I, Lodi R, Bartolini S, Brandes AA. Is Molecular Tailored-Therapy Changing the Paradigm for CNS Metastases in Breast Cancer? Clin Drug Investig 2021; 41:757-773. [PMID: 34403132 DOI: 10.1007/s40261-021-01070-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2021] [Indexed: 11/28/2022]
Abstract
Breast cancer (BC) is the second most common tumour spreading to the central nervous system (CNS). The prognosis of patients with CNS metastases depends on several parameters including the molecular assessment of the disease. Although loco-regional treatment remains the best approach, systemic therapies are acquiring a role leading to remarkable long-lasting responses. The efficacy of these compounds diverges between tumours with different molecular assessments. Promising agents under investigation are drugs targeting the HER2 pathways such as tucatinib, neratinib, pyrotinib, trastuzumab deruxtecan. In addition, there are several promising agents under investigation for patients with triple-negative brain metastases (third-generation taxane, etirinotecan, sacituzumab, immune-checkpoint inhibitors) and hormone receptor-positive brain metastases (CDK 4/5, phosphoinositide-3-kinase-mammalian target of rapamycin [PI3K/mTOR] inhibitors). Also, the systemic treatment of leptomeningeal metastases, which represents a very negative prognostic site of metastases, is likely to change as several compounds are under investigation, some with interesting preliminary results. Here we performed a comprehensive review focusing on the current management of CNS metastases according to molecular subtypes, site of metastases (leptomeningeal vs brain), and systemic treatments under investigation.
Collapse
Affiliation(s)
- Vincenzo Di Nunno
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy.
| | - Enrico Franceschi
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Alicia Tosoni
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Antonella Mura
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Santino Minichillo
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Monica Di Battista
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Lidia Gatto
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Ilaria Maggio
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Raffaele Lodi
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Stefania Bartolini
- Department of Oncology, AUSL Bologna, Via Altura 3, 40139, Bologna, Italy
| | | |
Collapse
|
|
27
|
Abstract
Brain metastasis continues to be a devastating complication of systemic malignancy, affecting approximately 20% of all patients suffering from cancer. Despite being a major source of morbidity and mortality for this patient population, a nationwide, systematic mechanism for reporting of brain metastases does not exist. Better understanding the epidemiology of brain metastases will help identify individuals who are at greatest risk of developing them and guide clinicians in selecting patients who are most likely to benefit from brain metastasis surveillance and prophylaxis.
Collapse
Affiliation(s)
- Patricia Sacks
- Lillian S. Wells Department of Neurosurgery, UF Brain Tumor Immunotherapy Program, University of Florida, PO Box 100265, Gainesville, FL 32610, USA
| | - Maryam Rahman
- Lillian S. Wells Department of Neurosurgery, UF Brain Tumor Immunotherapy Program, University of Florida, PO Box 100265, Gainesville, FL 32610, USA.
| |
Collapse
|
|
28
|
Garcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies. Cancers (Basel) 2021; 13:2927. [PMID: 34208287 PMCID: PMC8230933 DOI: 10.3390/cancers13122927] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 01/08/2023] Open
Abstract
Development of brain metastases can occur in up to 30-50% of patients with breast cancer, representing a significant impact on an individual patient in terms of survival and quality of life. Patients with HER2-positive breast cancer have an increased risk of developing brain metastases; however, screening for brain metastases is not currently recommended due to the lack of robust evidence to support survival benefit. In recent years, several novel anti-HER2 agents have led to significant improvements in the outcomes of HER2-positive metastatic breast cancer. Despite these advances, brain and leptomeningeal metastases from HER2-positive breast cancer remain a significant cause of morbidity and mortality, and their optimal management remains an unmet need. This review presents an update on the current and novel treatment strategies for patients with brain metastases from HER2-positive breast cancer and discusses the open questions in the field.
Collapse
Affiliation(s)
| | - Andri Papakonstantinou
- Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain;
- Department of Oncology-Pathology, Karolinska Institute, 17177 Stockholm, Sweden
- Department of Breast Cancer, Endocrine Tumors and Sarcoma, Karolinska University Hospital, 17176 Stockholm, Sweden
| | - Mafalda Oliveira
- Medical Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain;
- Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain;
| |
Collapse
|
|
29
|
Ko HM, Kim JR, Lee JS. The current status of cancer survivorship care and a consideration of appropriate care model in Korea. KOREAN JOURNAL OF CLINICAL ONCOLOGY 2020; 16:110-118. [PMID: 36945714 PMCID: PMC9942731 DOI: 10.14216/kjco.20017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 11/29/2020] [Accepted: 12/08/2020] [Indexed: 11/07/2022]
Abstract
Purpose Breast cancer patients with a human epidermal growth factor receptor 2 (HER2) enriched subtype are known to have higher rates of brain metastases (BM) than other patients. This study aimed to evaluate treatment options and survival outcomes. Methods A total of 115 breast cancer brain metastases (BCBM) patients with nearly complete medical records were retrospectively analyzed. Additionally, 36 patients were HER2 enriched types according to histological subtypes. The BM was found by brain magnetic resonance imaging in patients who had neurologic symptoms or by regular screening. Age, breast tumor size, number of BM, histological subtypes, first treatment of breast cancer, estrogen receptor, and HER2 status, stage, local treatment of BM were analyzed. Median overall survival, 5-year survival were analyzed from the data. Results The median survival time after BM was 6 months, the mean survival time was 16.3 months, and the 5-year survival after BM was only 8.0%. Factors that significantly affect the survival of BCBM patients include histological subtype, number of BM, use of lapatinib in multivariate analysis. A total of 19 out of 36 HER2 enriched patients were treated with lapatinib or capecitabine. For the treatment of HER2 enriched patients, additional use of blood-brain barrier (BBB) crossing substances, as well as local treatment for BM, significantly improve the survival rate in the Kaplan-Meier method (P=0.001). Conclusion A combination of local treatment modality for BCBM and the use of substances that cross the BBB for the HER2 enriched patient improved the survival rate.
Collapse
Affiliation(s)
- Hye Mi Ko
- Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University College of Medicine, Daejeon, Korea
| | - Je-Ryong Kim
- Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University College of Medicine, Daejeon, Korea
| | - Jin Sun Lee
- Department of Surgery and Research Institute for Medicinal Sciences, Chungnam National University College of Medicine, Daejeon, Korea
| |
Collapse
|
|
30
|
Bailleux C, Eberst L, Bachelot T. Treatment strategies for breast cancer brain metastases. Br J Cancer 2020; 124:142-155. [PMID: 33250512 PMCID: PMC7782834 DOI: 10.1038/s41416-020-01175-y] [Citation(s) in RCA: 147] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 10/25/2020] [Accepted: 11/03/2020] [Indexed: 12/22/2022] Open
Abstract
Brain metastases from breast cancer (BCBM) constitute the second most common cause of brain metastasis (BM), and the incidence of these frequently lethal lesions is currently increasing, following better systemic treatment. Patients with ER-negative and HER2-positive metastatic breast cancer (BC) are the most likely to develop BM, but if this diagnosis remains associated with a worse prognosis, long survival is now common for patients with HER2-positive BC. BCBM represents a therapeutic challenge that needs a coordinated treatment strategy along international guidelines. Surgery has always to be considered when feasible. It is now well established that stereotaxic radiosurgery allows for equivalent control and less-cognitive toxicities than whole-brain radiation therapy, which should be delayed as much as possible. Medical treatment for BCBM is currently a rapidly evolving field. It has been shown that the blood-brain barrier (BBB) is often impaired in macroscopic BM, and several chemotherapy regimens, antibody-drug conjugates and tyrosine-kinase inhibitors have been shown to be active on BCBM and can be part of the global treatment strategy. This paper provides an overview of the therapeutic option for BCBM that is currently available and outlines potential new approaches for tackling these deadly secondary tumours.
Collapse
Affiliation(s)
- Caroline Bailleux
- Department of Medical Oncology, Centre Antoine Lacassagne, 33 avenue Valombrose, 06100, Nice, France
| | - Lauriane Eberst
- Department of Medical Oncology, Institut de Cancérologie Strasbourg Europe, 17 rue Albert Calmette, 67200, Strasbourg, France
| | - Thomas Bachelot
- Department of Medical Oncology, Centre Leon Berard, 28 rue Laënnec, 69373, Lyon, France.
| |
Collapse
|
|
31
|
Khan M, Zhao Z, Arooj S, Zheng T, Liao G. Lapatinib Plus Local Radiation Therapy for Brain Metastases From HER-2 Positive Breast Cancer Patients and Role of Trastuzumab: A Systematic Review and Meta-Analysis. Front Oncol 2020; 10:576926. [PMID: 33240815 PMCID: PMC7677410 DOI: 10.3389/fonc.2020.576926] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 09/30/2020] [Indexed: 01/11/2023] Open
Abstract
Background Intracranial activity of lapatinib has been demonstrated in several studies in patients with human epidermal growth factor receptor-2 positive breast cancers (HER-2+ BC). Stereotactic radiosurgery (SRS) has been increasingly used as the local therapy for brain metastases in breast cancer patients. Increased objective response rate was observed for lapatinib plus whole brain radiotherapy (WBRT) is such patients with high toxicity. Objective We seek to obtain clinical evidence of synergistic efficacy of lapatinib in combination with radiation therapy, in particular, SRS. Materials and methods We carried out a comprehensive research using the following databases: PubMed; Medline; EMBASE; Cochrane library. These databases were searched until 10 June 2020. PRISMA guidelines were followed step by step for carrying out this systematic review and meta-analysis. Review Manager v 5.4 software was used for statistical evaluation of data. Results Overall 6 studies with 843 HER-2 positive breast cancer patients (442 HER-2 amplified disease, 399 luminal B disease) were included in this systematic review and meta-analysis. A total 279 patients had received lapatinib in addition to HER-2 antibody (trastuzumab) plus/minus chemoradiotherapy, while 610 patients had received trastuzumab-based management or only chemoradiotherapy. Lapatinib-based management of BM was associated with significant increase in overall survival (HR 0.63 [0.52, 0.77], p < 0.00001). Combination of the two (trastuzumab plus lapatinib) was associated with increased survival advantage compared to each agent alone (0.55 [0.32, 0.92], p = 0.02). SRS in combination with lapatinib was associated with increased local control (HR 0.47 [0.33, 0.66], p = 0.0001). Ever use of lapatinib with SRS was associated an increased survival as reported in two studies (Shireen et al.: 27.3 vs. 19.5 months, p = 0.03; Kim et al.: 33.3 vs. 23.6 months, p = 0.009). Kim et al. also revealed significant increase in intracranial activity with concurrent lapatinib reporting 57% complete response compared to 38% (p < 0.001) and lower progressive disease rate of 11 vs. 19% (p < 0.001). Risk of radiation necrosis was decreased with lapatinib use. Conclusions Lapatinib has shown intracranial activity and yielded better survival for HER-2+ BC patients with BMs. SRS in combination with ever use of lapatinib had better local control and were associated with better survival. Radiation necrosis risk was reduced with the use of lapatinib.
Collapse
Affiliation(s)
- Muhammad Khan
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.,Department of Oncology, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhihong Zhao
- Department of Nephrology, Shenzhen People's Hospital, Second Clinical Medicine Centre, Jinan University, Shenzhen, China
| | - Sumbal Arooj
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China.,Department of Biochemistry, University of Sialkot, Sialkot, Pakistan
| | - Tao Zheng
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| | - Guixiang Liao
- Department of Radiation Oncology, Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, China
| |
Collapse
|
|
32
|
Ataee Dizaji P, Vasheghani Farahani M, Sheikhaliyan A, Biglarian A. Application of additive hazards models for analyzing survival of breast cancer patients. JOURNAL OF RESEARCH IN MEDICAL SCIENCES : THE OFFICIAL JOURNAL OF ISFAHAN UNIVERSITY OF MEDICAL SCIENCES 2020; 25:99. [PMID: 33273944 PMCID: PMC7698387 DOI: 10.4103/jrms.jrms_701_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 01/28/2020] [Accepted: 06/29/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Survival rates for breast cancer (BC) are often based on the outcomes of this disease. The aim of this study was to compare the performance of three survival models, namely Cox regression, Aalen's, and Lin and Ying's additive hazards (AH) models for identifying the prognostic factors regarding the survival time of BC patients. MATERIALS AND METHODS This study was a historical cohort study which used 1025 females' medical records that underwent modified radical mastectomy or breast saving. These patients were admitted to Besat and Chamran Hospitals, Tehran, Iran, during 2010-2015 and followed until 2017. The Aalen's and Lin and Ying's AH models and also traditional Cox model were applied for analysis of time to death of BC patients using R 3.5.1 software. RESULTS In Aalen's and also Lin and Ying's AH models, age at diagnosis, history of disease, number of lymph nodes, metastasis, hormonal therapy, and evacuation lymph nodes were prognostic factors for the survival of BC patients (P < 0.05). In addition, in the Lin and Ying's AH model tumor size (P = 0.048) was also identified as a significant factor. According to Aalen's plot, metastasis, age at diagnosis, and number of lymph nodes had a time-varying effect on survival time. These variables had a different slope as the times go on. CONCLUSION AH model may yield new insights in prognostic studies of survival time of patients with BC over time. Because of the positive slope of estimated cumulative regression function in Aalen's plot, metastasis, higher age at diagnosis, and high number of lymph nodes are important factors in reducing the survival BC, and then based on these factors, the therapists should consider a special therapeutic protocol for BC patients.
Collapse
Affiliation(s)
- Parisa Ataee Dizaji
- Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | | | - Ayeh Sheikhaliyan
- Department of Industrial Engineering, Malek Ashtar University of Technology, Tehran, Iran
| | - Akbar Biglarian
- Department of Biostatistics, Social Determinants of Health Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| |
Collapse
|
|
33
|
Montemurro F, Delaloge S, Barrios C, Wuerstlein R, Anton A, Brain E, Hatschek T, Kelly C, Peña-Murillo C, Yilmaz M, Donica M, Ellis P. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial☆. Ann Oncol 2020; 31:1350-1358. [DOI: 10.1016/j.annonc.2020.06.020] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 06/04/2020] [Accepted: 06/25/2020] [Indexed: 10/23/2022] Open
|
|
34
|
Aoyagi K, Higuchi Y, Matsunaga S, Serizawa T, Yomo S, Aiyama H, Nagano O, Kondoh T, Kenai H, Shuto T, Kawagishi J, Jokura H, Sato S, Nakazaki K, Nakaya K, Hasegawa T, Kawashima M, Kawai H, Yamanaka K, Nagatomo Y, Yamamoto M, Sato Y, Aoyagi T, Matsutani T, Iwadate Y. Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702). Breast Cancer Res Treat 2020; 184:149-159. [PMID: 32737714 DOI: 10.1007/s10549-020-05835-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 07/22/2020] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.
Collapse
Affiliation(s)
- Kyoko Aoyagi
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.
- Gamma Knife House, Chiba Cerebral and Cardiovascular Center, 575 Tsurumai, Ichihara, Chiba, 290-0512, Japan.
| | - Yoshinori Higuchi
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Shigeo Matsunaga
- Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan
| | - Toru Serizawa
- Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan
| | - Shoji Yomo
- Division of Radiation Oncology, Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | | | - Osamu Nagano
- Gamma Knife House, Chiba Cerebral and Cardiovascular Center, 575 Tsurumai, Ichihara, Chiba, 290-0512, Japan
| | - Takeshi Kondoh
- Department of Neurosurgery, Shinsuma General Hospital, Kobe, Japan
| | - Hiroyuki Kenai
- Department of Neurosurgery, Nagatomi Neurosurgical Hospital, Oita, Japan
| | - Takashi Shuto
- Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan
| | - Jun Kawagishi
- Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan
| | - Hidefumi Jokura
- Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan
| | - Sonomi Sato
- Department of Neurosurgery, Southern Tohoku General Hospital, Ōkuma, Fukushima, Japan
| | - Kiyoshi Nakazaki
- Department of Neurosurgery, Brain Attack Center Ota Memorial Hospital, Fukuyama, Japan
| | - Kotaro Nakaya
- Department of Neurosurgery, Atami Tokoro Memorial Hospital, Atami, Japan
| | | | - Mariko Kawashima
- Department of Neurosurgery, The University of Tokyo Hospital, Tokyo, Japan
| | - Hideya Kawai
- Department of Surgical Neurology, Research Institute for Brain and Blood Vessels-Akita, Akita, Japan
| | - Kazuhiro Yamanaka
- Department of Neurosurgery, Osaka City General Hospital, Osaka, Japan
| | - Yasushi Nagatomo
- Department of Neurosurgery, Koseikai Takai Hospital, Tenri, Japan
| | | | - Yasunori Sato
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Aoyagi
- Department of Breast Surgery, Funabashi Municipal Medical Center, Funabashi, Japan
| | - Tomoo Matsutani
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasuo Iwadate
- Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
| |
Collapse
|
|
35
|
Wu XX, Yue GGL, Dong JR, Lam CWK, Wong CK, Qiu MH, Lau CBS. Actein Inhibits Tumor Growth and Metastasis in HER2-Positive Breast Tumor Bearing Mice via Suppressing AKT/mTOR and Ras/Raf/MAPK Signaling Pathways. Front Oncol 2020; 10:854. [PMID: 32547952 PMCID: PMC7269144 DOI: 10.3389/fonc.2020.00854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 04/29/2020] [Indexed: 12/20/2022] Open
Abstract
HER2-positive breast cancer accounts for 15–20% in breast cancer and 50% of the metastatic HER2-positive breast cancer patients died of central nervous system progression. The present study investigated the effects of actein (a natural cycloartane triterpene) on cells adhesion, migration, proliferation and matrix degradation, and its underlying mechanism in HER2-positive breast cancer cells. The in vivo effect of actein on tumor growth and metastasis in MDA-MB-361 tumor-bearing mice as well as the anti-brain metastasis in tail vein injection mice model were also investigated. Our results showed that actein inhibited HER2-positive breast cancer cells viability, proliferation and migration. Actein also induced MDA-MB-361 cells G1 phase arrest and inhibited the expressions of cyclins and cyclin-dependent kinases. For intracellular mechanisms, actein inhibited the expressions of molecules in AKT/mTOR and Ras/Raf/MAPK signaling pathways. Furthermore, actein (15 mg/kg) was shown to exhibit anti-tumor and anti-metastatic activities in MDA-MB-361 breast tumor-bearing mice, and reduced brain metastasis in tail vein injection mice model. All these findings strongly suggested that actein is a potential anti-metastatic agent for HER2-positive breast cancer.
Collapse
Affiliation(s)
- Xiao-Xiao Wu
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Grace Gar-Lee Yue
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China
| | - Jin-Run Dong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
| | - Christopher Wai-Kei Lam
- State Key Laboratory of Quality Research in Chinese Medicines, Faculty of Medicine, Macau University of Science and Technology, Macau, China
| | - Chun-Kwok Wong
- Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong, China.,Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China.,Li Dak Sum Yip Yio Chin R & D Centre for Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming-Hua Qiu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
| | - Clara Bik-San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China.,State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China.,Li Dak Sum Yip Yio Chin R & D Centre for Chinese Medicine, The Chinese University of Hong Kong, Hong Kong, China
| |
Collapse
|
|
36
|
Mills MN, Figura NB, Arrington JA, Yu HHM, Etame AB, Vogelbaum MA, Soliman H, Czerniecki BJ, Forsyth PA, Han HS, Ahmed KA. Management of brain metastases in breast cancer: a review of current practices and emerging treatments. Breast Cancer Res Treat 2020; 180:279-300. [PMID: 32030570 DOI: 10.1007/s10549-020-05552-2] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/30/2020] [Indexed: 12/21/2022]
Abstract
PURPOSE Breast cancer brain metastases (BCBM) are becoming an increasingly common diagnosis due to improved systemic control and more routine surveillance imaging. Treatment continues to require a multidisciplinary approach managing systemic and intracranial disease burden. Although, improvements have been made in the diagnosis and management of BCBM, brain metastasis patients continue to pose a challenge for practitioners. METHODS In this review, a group of medical oncologists, radiation oncologists, radiologists, breast surgeons, and neurosurgeons specializing in the treatment of breast cancer reviewed the available published literature and compiled a comprehensive review on the current state of BCBM. RESULTS We discuss the pathogenesis, epidemiology, diagnosis, treatment options (including systemic, surgical, and radiotherapy treatment modalities), and treatment response evaluation for BCBM. Furthermore, we discuss the ongoing prospective trials enrolling BCBM patients and their biologic rationale. CONCLUSIONS BCBM management is an increasing clinical concern. Multidisciplinary management combining the strengths of surgical, systemic, and radiation treatment modalities with prospective trials incorporating knowledge from the basic and translational sciences will ultimately lead to improved clinical outcomes for BCBM patients.
Collapse
Affiliation(s)
- Matthew N Mills
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL, 33612, USA
| | - Nicholas B Figura
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL, 33612, USA
| | - John A Arrington
- Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Hsiang-Hsuan Michael Yu
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL, 33612, USA
| | - Arnold B Etame
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Michael A Vogelbaum
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Hatem Soliman
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Brian J Czerniecki
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Peter A Forsyth
- Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Hyo S Han
- Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Kamran A Ahmed
- Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL, 33612, USA.
| |
Collapse
|
|
37
|
Integrated Transcriptomics, Proteomics, and Glycomics Reveals the Association between Up-regulation of Sialylated N-glycans/Integrin and Breast Cancer Brain Metastasis. Sci Rep 2019; 9:17361. [PMID: 31758065 PMCID: PMC6874669 DOI: 10.1038/s41598-019-53984-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 11/07/2019] [Indexed: 12/21/2022] Open
Abstract
Breast cancer brain metastasis has been recognized as one of the central issues in breast cancer research. The elucidation of the processes and pathways that mediate this step will provide important clues for a better understanding of breast cancer metastasis. Increasing evidence suggests that aberrant glycosylation patterns greatly contribute to cell invasion and cancer metastasis. Herein, we combined next-generation RNA sequencing with liquid chromatography-tandem mass spectrometry-based proteomic and N-glycomic analysis from five breast cancer cell lines and one brain cancer cell line to investigate the possible mechanisms of breast cancer brain metastasis. The genes/proteins associated with cell movement were highlighted in breast cancer brain metastasis. The integrin signaling pathway and the up-regulation of α-integrin (ITGA2, ITGA3) were associated with the brain metastatic process. 12 glycogenes showed unique expression in 231BR, which could result in an increase of sialylation during brain metastasis. In agreement with the changes of glycogenes, 60 out of 63 N-glycans that were identified exhibited differential expression among cell lines. The correlation between glycogenes and glycans revealed the importance of sialylation and sialylated glycans in breast cancer brain metastasis. Highly sialylated N-glycans, which were up-regulated in brain-seeking cell line 231BR, likely play a role in brain metastasis.
Collapse
|
|
38
|
Zahid KF, Kumar S, Al-Bimani K, Ahmed T, Al-Ajmi A, Burney IA, Al-Moundhri M. Outcome of Omani Women with Breast Cancer-associated Brain Metastases Experience from a University Hospital. Oman Med J 2019; 34:412-419. [PMID: 31555417 PMCID: PMC6745425 DOI: 10.5001/omj.2019.76] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Objectives Breast cancer (BC) is the leading cancer among women. Almost 20% of patients develop brain metastases (BM) and die shortly afterward. There is a dearth of data on the survival outcome of BC patients with BM from the Arab world. Methods Consecutive women diagnosed with BC who developed radiologically-confirmed BM during their illness were identified through the hospital’s electronic patient’s records. Clinicopathological features and treatment outcomes were recorded. Survival was calculated using the Kaplan-Meier method, and factors affecting survival were studied using log-rank analysis. Results Between January 2003 and June 2015, a total of 692 patients were treated for BC at our institute. Forty-eight (6.9%) developed BM. The median age at the diagnosis of BM was 45.2 years. More than half of cohort (54.2%) had HER2 positive disease, while 27.1% had the triple-negative disease. The median time interval between the diagnosis of BC and the development of BM was 21 months, and median survival after development of brain disease was seven months. On univariate analysis, pathological grade, previous systemic treatment, brain as the first site of metastases, brain as the only site of metastases, treatment of BM, systemic treatment after BM, and diagnosis-specific graded prognostic assessment (DS-GPA) score significantly affected survival. On multivariate Cox regression analysis, the brain as the first site of metastases, treatment for brain disease, treatment type, and DS-GPA score significantly affected survival post-BM. Conclusions Our data indicate that Omani women are diagnosed with BC at a younger age, develop BM earlier, and carry a poor outcome.
Collapse
Affiliation(s)
- Khawaja F Zahid
- Oncology Department, Castle Hill Hospital, Cottingham, East Riding of Yorkshire, UK
| | - Shiyam Kumar
- Unit of Medical Oncology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Khalid Al-Bimani
- Unit of Medical Oncology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Tanweer Ahmed
- Unit of Medical Oncology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Adil Al-Ajmi
- Department of Surgery, Sultan Qaboos University Hospital, Muscat, Oman
| | - Ikram A Burney
- Unit of Medical Oncology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Mansour Al-Moundhri
- College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| |
Collapse
|
|
39
|
Mayinger M, Reibelt A, Borm KJ, Ettl J, Wilkens JJ, Combs SE, Oechsner M, Duma MN. MRI based neuroanatomical segmentation in breast cancer patients: leptomeningeal carcinomatosis vs. oligometastatic brain disease vs. multimetastastic brain disease. Radiat Oncol 2019; 14:170. [PMID: 31533742 PMCID: PMC6749713 DOI: 10.1186/s13014-019-1380-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 09/11/2019] [Indexed: 11/30/2022] Open
Abstract
Purpose Pathogenesis of brain metastases/meningeal cancer and the emotional and neurological outcomes are not yet well understood. The hypothesis of our study is that patients with leptomeningeal cancer show volumetric differences in brain substructures compared to patients with cerebral metastases. Methods Three groups consisting of female breast cancer patients prior to brain radiotherapy were compared. Leptomeningeal cancer patients (LMC Group), oligometastatic patients (1–3 brain metastases) prior to radiosurgery (OMRS Group) and patients prior to whole brain radiation (WB Group) were included. All patients had MRI imaging before treatment. T1 MRI sequences were segmented using automatic segmentation. For each patient, 14 bilateral and 11 central/median subcortical structures were tested. Overall 1127 structures were analyzed and compared between groups using age matched two-sided t-tests. Results The average age of patients in the OMRS group was 60.8 years (± 14.7), 65.3 (± 10.3) in the LMC group and 62.6 (± 10.2) in the WB group. LMC patients showed a significantly larger fourth ventricle compared to OMRS (p = 0.001) and WB (p = 0.003). The central corpus callosum appeared smaller in the LMC group (LMC vs OMRS p = 0.01; LMC vs WB p = 0.026). The right amygdala in the WB group appeared larger compared with the OMRS (p = 0.035). Conclusions Differences in the size of brain substructures of the three groups were found. The results appear promising and should be taken into account for further prospective studies also involving healthy controls. The volumetrically determined size of the fourth ventricle might be a helpful diagnostic marker in the future.
Collapse
Affiliation(s)
- Michael Mayinger
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Department of Radiation Oncology, University of Zurich, Zurich, Switzerland
| | - Antonia Reibelt
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Kai Joachim Borm
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Johannes Ettl
- Department of Obstetrics and Gynecology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Jan J Wilkens
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Stephanie Elisabeth Combs
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Deutsches Konsortium für Translationale Krebsforschung (DKTK)-Partner Site Munich, Munich, Germany.,Institute of Innovative Radiotherapy, Helmholtzzentrum München, Munich, Germany
| | - Markus Oechsner
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Marciana Nona Duma
- Department of Radiation Oncology, Medical School, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. .,Department of Radiotherapy and Radiation Oncology, University Hospital of the Friedrich-Schiller-University, Bachstr. 18, 07745, Jena, Germany.
| |
Collapse
|
|
40
|
Survival and prognostic factors in surgically treated brain metastases. J Neurooncol 2019; 143:359-367. [DOI: 10.1007/s11060-019-03171-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/09/2019] [Indexed: 12/26/2022]
|
|
41
|
|
|
42
|
Hurvitz SA, O'Shaughnessy J, Mason G, Yardley DA, Jahanzeb M, Brufsky A, Rugo HS, Swain SM, Kaufman PA, Tripathy D, Chu L, Li H, Antao V, Cobleigh M. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res 2018; 25:2433-2441. [PMID: 30593513 DOI: 10.1158/1078-0432.ccr-18-2366] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 11/19/2018] [Accepted: 12/21/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE Patients with HER2-positive metastatic breast cancer (MBC) with central nervous system (CNS) metastasis have a poor prognosis. We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). EXPERIMENTAL DESIGN SystHERs (NCT01615068) was a prospective, U.S.-based, observational registry of patients with newly diagnosed HER2-positive MBC. Study endpoints included treatment patterns, clinical outcomes, and patient-reported outcomes (PRO). RESULTS Among 977 eligible patients enrolled (2012-2016), CNS metastasis was observed in 87 (8.9%) at initial MBC diagnosis and 212 (21.7%) after diagnosis, and was not observed in 678 (69.4%) patients. White and younger patients, and those with recurrent MBC and hormone receptor-negative disease, had higher risk of CNS metastasis. Patients with CNS metastasis at diagnosis received first-line lapatinib more commonly (23.0% vs. 2.5%), and trastuzumab less commonly (70.1% vs. 92.8%), than patients without CNS metastasis at diagnosis. Risk of death was higher with CNS metastasis observed at or after diagnosis [median overall survival (OS) 30.2 and 38.3 months from MBC diagnosis, respectively] versus no CNS metastasis [median OS not estimable: HR 2.86; 95% confidence interval (CI), 2.05-4.00 and HR 1.94; 95% CI, 1.52-2.49]. Patients with versus without CNS metastasis at diagnosis had lower quality of life at enrollment. CONCLUSIONS Despite advances in HER2-targeted treatments, patients with CNS metastasis continue to have a poor prognosis and impaired quality of life. Observation of CNS metastasis appears to influence HER2-targeted treatment choice.
Collapse
Affiliation(s)
- Sara A Hurvitz
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
| | - Joyce O'Shaughnessy
- Baylor University Medical Center, Texas Oncology and US Oncology, Dallas, Texas
| | - Ginny Mason
- Inflammatory Breast Cancer Research Foundation, West Lafayette, Indiana
| | - Denise A Yardley
- Breast Cancer Research Program, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, Tennessee
| | - Mohammad Jahanzeb
- Sylvester Comprehensive Cancer Center, University of Miami, Deerfield Campus, Deerfield Beach, Florida
| | - Adam Brufsky
- University of Pittsburgh Cancer Institute, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
| | - Hope S Rugo
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
| | - Sandra M Swain
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia
| | - Peter A Kaufman
- Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
| | - Debu Tripathy
- The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Laura Chu
- Genentech, Inc., South San Francisco, California
| | - Haocheng Li
- F. Hoffmann-La Roche, Mississauga, ON, Canada
| | | | - Melody Cobleigh
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois
| |
Collapse
|
|
43
|
Maurer C, Tulpin L, Moreau M, Dumitrescu C, de Azambuja E, Paesmans M, Nogaret JM, Piccart MJ, Awada A. Risk factors for the development of brain metastases in patients with HER2-positive breast cancer. ESMO Open 2018; 3:e000440. [PMID: 30425844 PMCID: PMC6212674 DOI: 10.1136/esmoopen-2018-000440] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/11/2018] [Accepted: 09/13/2018] [Indexed: 12/02/2022] Open
Abstract
Background Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) frequently experience brain metastases (BM). We aimed to define risk factors for the development of BM in patients with HER2+ BC and to report on their outcome. Methods This is a retrospective analysis of patients diagnosed with HER2+ BC between January 2000 and December 2014 at Institut Jules Bordet, Belgium. Statistical analyses were conducted with SAS V.9.4 using Kaplan-Meier method and Cox regression analyses. Results A total of 483 patients were included of whom 108 (22.4%) developed metastases and 52 (10.8%) BM. Among 96 metastatic patients without BM at diagnosis, 40 (41.7%) developed BM in the course of their disease. In multivariate analysis, risk factors for the development of BM were age ≤40 years (HR 2.10, 95 % CI 1.02 to 4.36), tumour size >2 cm (HR 4.94, 95% CI 1.69 to 14.47), nodal involvement (HR 3.48, 95% CI 1.47 to 8.25), absence or late start (≥6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79, 95% CI 1.52 to 9.43 or HR 2.65, 95% CI 1.03 to 6.82) and the development of lung metastases as first site of relapse (HR 6.97, 95% CI 3.41 to 14.24). Twenty-two patients with HER2+ BC and BM sent to our institute for further treatment were included in the outcome analysis. Asymptomatic patients at the time of BM diagnosis showed a better overall survival than symptomatic patients (HR 0.49, 95% CI 0.25 to 0.94). Conclusion A considerable number of patients with metastatic HER2+ BC will develop BM. Screening of patients with risk factors for BM might lead to early detection and better outcome. However, randomised controlled trials examining the use of MRI as a screening method for BM in patients with metastatic BC are warranted before such an approach can be recommended.
Collapse
Affiliation(s)
- Christian Maurer
- Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany.,Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Lorraine Tulpin
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Michel Moreau
- Unité de Gestion de l'Information, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Cristina Dumitrescu
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium.,Medical Oncology Clinic, Charleroi Universitary Hospital, Université Libre de Bruxelles (U.L.B.), Charleroi, Belgium
| | - Evandro de Azambuja
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Marianne Paesmans
- Unité de Gestion de l'Information, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Jean-Marie Nogaret
- Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Martine J Piccart
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Ahmad Awada
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| |
Collapse
|
|
44
|
Kozak MM, Jacobson CE, von Eyben R, Walck E, Pollom EL, Telli M, Horst KC. Patterns of Distant Failure by Intrinsic Breast Cancer Subtype in Premenopausal Women Treated With Neoadjuvant Chemotherapy. Clin Breast Cancer 2018; 18:e1077-e1085. [DOI: 10.1016/j.clbc.2018.04.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 04/04/2018] [Accepted: 04/27/2018] [Indexed: 12/30/2022]
|
|
45
|
Assi HI, Mahmoud T, Saadeh FS, El Darsa H. Management of leptomeningeal metastasis in breast cancer. Clin Neurol Neurosurg 2018; 172:151-159. [PMID: 30015053 DOI: 10.1016/j.clineuro.2018.07.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 06/22/2018] [Accepted: 07/01/2018] [Indexed: 10/28/2022]
Abstract
Leptomeningeal metastasis (LM), which occurs when malignant cells spread to the central nervous system, is becoming an increasingly common complication in patients with breast cancer. Diagnosis and treatment of LM is challenging. Moreover, prognosis of patients with LM is poor, with a median survival of 6 months after diagnosis. This review highlights the strengths and limitations of currently available diagnostic tools and therapies for LM. The current treatments for LM, including radiotherapy, systemic therapy, and intrathecal treatment, aim to maintain the quality of life of patients by correcting neurological deficits and arresting neurological degeneration. However, there is no standardized therapy for LM because of a lack of randomized trials on this condition.
Collapse
Affiliation(s)
- Hazem I Assi
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Lebanon.
| | - Tala Mahmoud
- Faculty of Medicine, University of Balamand, Lebanon.
| | - Fadi S Saadeh
- Faculty of Medicine, American University of Beirut, Lebanon.
| | - Haidar El Darsa
- Department of Internal Medicine, Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Lebanon.
| |
Collapse
|
|
46
|
Huang Z, Sun B, Wu S, Meng X, Cong Y, Shen G, Song S. A nomogram for predicting survival in patients with breast cancer brain metastasis. Oncol Lett 2018; 15:7090-7096. [PMID: 29725432 PMCID: PMC5920309 DOI: 10.3892/ol.2018.8259] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 01/18/2018] [Indexed: 12/27/2022] Open
Abstract
Brain metastasis (BM) is common in patients with breast cancer. Predicting patient survival is critical for the clinical management of breast cancer brain metastasis (BCBM). The present study was designed to develop and evaluate a prognostic model for patients with newly diagnosed BCBM. Based on the clinical data of patients with BCBM treated in the Affiliated Hospital of Academy of Military Medical Sciences (Beijing, China) between 2002 and 2014, a nomogram was developed to predict survival using proportional hazards regression analysis. The model was validated internally by bootstrapping, and the concordance index (c-index) was calculated. A calibration curve and c-index were used to evaluate discriminatory and predictive ability, in order to compare the nomogram with widely used models, including recursive partitioning analysis (RPA), graded prognostic assessment (GPA) and breast-graded prognostic assessment (Breast-GPA). A total of 411 patients with BCBM were included in the development of this predictive model. The median overall survival time was 14.1 months. Statistically significant predictors for patient survival included biological subtype, Karnofsky performance score, leptomeningeal metastasis, extracranial metastasis, the number of brain metastases and disease-free survival. A nomogram for predicting 1- and 2-year overall survival rates was constructed, which exhibited good accuracy in predicting overall survival with a concordance index of 0.735. This model outperformed RPA, GPA and Breast-GPA, based on the comparisons of the c-indexes. The nomogram constructed based on a multiple factor analysis was able to more accurately predict the individual survival probability of patients with BCBM, compared with existing models.
Collapse
Affiliation(s)
- Zhou Huang
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China.,Department of Radiation Oncology, National Cancer Center/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, P.R. China
| | - Bing Sun
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Shikai Wu
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Xiangying Meng
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Yang Cong
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Ge Shen
- Department of Radiation Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Santai Song
- Department of Breast Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| |
Collapse
|
|
47
|
Gohari MR, Khodabakhshi R, Shahidi J, Fard ZM, Foadzi H, Soleimani F, Biglarian A. The Impact of Multiple Recurrences in Disease-Free Survival of Breast Cancer: An Extended Cox Model. TUMORI JOURNAL 2018; 98:428-33. [DOI: 10.1177/030089161209800405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and background Identifying the risk factors of recurrence of breast cancer is important for both the physician and patient. Analysis of the first recurrence may lead to an inaccurate evaluation of the factor's effects because it does not completely reflect the history of the disease and may result in the loss of valuable information. The present study aimed to determine the factors that influence breast cancer recurrence and to estimate disease-free survival, adjusting for multiple metastases in breast cancer patients. Methods and study design Patients were selected from a longitudinal study carried out at Fayazabakhsh Hospital in Tehran, Iran. Women who were diagnosed with breast cancer and who underwent either modified radical mastectomy or breast-conserving surgery between January 2006 and April 2008 were recruited to take part in the study. Breast cancer recurrence was defined as the occurrence of a tumor in the contralateral breast, local-regional relapse, or distant metastasis to other organs. Using an extended Cox model, the effect of age, tumor size, estrogen receptors, HER2, progesterone receptors as well as lymph node ratio was analyzed. Results Over a 5833 person-month follow-up, 25 of 133 patients (18.8%) had died and 108 patients (81.2%) were still alive, 9 of them with metastasis. Thirty-four patients (25.6%) experienced their first disease recurrence. A total of 11 patients had a second metastasis. The mean time to first metastasis was 19.93 months, and mean gap time between two metastases was 7.15 months. Risk of experiencing a metastasis or death in the third and fifth year after surgery was approximately 22% and 28%, respectively. Fitting multiple recurrent regression shows that high lymph node ratio, high histologic grade, large tumor size and HER2-positive tumors are prognostic factors for shorter disease-free survival. Conclusions Our novel approach might be helpful in clinical practice to predict breast cancer recurrence after surgery and might be adapted to be used in other malignancies as well.
Collapse
Affiliation(s)
- Mahmood Reza Gohari
- Department of Biostatistics, Hospital Management Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Reza Khodabakhshi
- Department of Radiation Oncology, Fayazbakhsh Hospital, Tehran, Iran
| | - Javad Shahidi
- Grad Dip (Clinical Research), Research Program Coordinator, the Élisabeth Bruyère Research Institute, Ottawa, Ontario, Canada
| | | | | | - Farin Soleimani
- Pediatric Neurorehabilitation Research Center, University of Social Welfare and Rehabilitation Sciences (USWRS), Tehran, Iran
| | - Akbar Biglarian
- Department of Biostatistics, University of Social Welfare and Rehabilitation Sciences (USWRS), Tehran, Iran
| |
Collapse
|
|
48
|
Morikawa A, Wang R, Patil S, Diab A, Yang J, Hudis CA, McArthur HL, Beal K, Seidman AD. Characteristics and Prognostic Factors for Patients With HER2-overexpressing Breast Cancer and Brain Metastases in the Era of HER2-targeted Therapy: An Argument for Earlier Detection. Clin Breast Cancer 2017; 18:353-361. [PMID: 29337140 DOI: 10.1016/j.clbc.2017.12.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 11/24/2017] [Accepted: 12/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Although brain metastases (BM) are associated with poor prognosis, patients with human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) breast cancer (BC) with BM who are treated with anti-HER2 therapy have a relatively longer survival after BM diagnosis compared with other subtypes and HER2+ patients previously untreated with anti-HER2 therapy. It is unclear if previously reported prognostic factors are applicable to patients with HER2+ BC in the era of HER2-targeted therapy. PATIENTS AND METHODS We evaluated 100 consecutive patients with HER2+ BC with BM who underwent radiation therapy as primary BM treatment from January 2001 to December 2011 at Memorial Sloan Kettering Cancer Center by retrospective review. Patient characteristics at the time of BM diagnosis and their associations with time from BM to death were evaluated by Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS Significantly better survival from BM was noted for patients with higher performance status, fewer BM lesions, continued use of HER2-targeted therapy after BM diagnosis, and better controlled extracranial metastatic disease. Absence of neurologic symptoms at BM diagnosis was significantly associated with fewer lesions, decreased use of whole brain radiotherapy, and longer survival in univariate and multivariate analysis (multivariate hazard ratio, 3.69; 95% confidence interval, 1.69-8.07). CONCLUSION Our finding supports the continued use of HER2-targeted therapy after BM diagnosis. In addition, future research on the clinical impact of detecting asymptomatic BM in patients with HER2+ BC, in terms of improving prognosis, quality of life, and avoidance of whole brain radiotherapy, is warranted.
Collapse
Affiliation(s)
- Aki Morikawa
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rui Wang
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sujata Patil
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Adi Diab
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jonathan Yang
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Clifford A Hudis
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Heather L McArthur
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Kathryn Beal
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrew D Seidman
- Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, NY.
| |
Collapse
|
|
49
|
Altundag K. Her2 positive subtype and breast cancer brain metastasis: any effect of anti-Her2 targeted therapy? J Neurooncol 2017; 135:639. [PMID: 28900780 DOI: 10.1007/s11060-017-2623-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 09/09/2017] [Indexed: 11/27/2022]
Affiliation(s)
- Kadri Altundag
- MKA Breast Cancer Clinic, Tepe Prime, Cankaya, 06800, Ankara, Turkey.
| |
Collapse
|
|
50
|
Lewis Phillips GD, Nishimura MC, Lacap JA, Kharbanda S, Mai E, Tien J, Malesky K, Williams SP, Marik J, Phillips HS. Trastuzumab uptake and its relation to efficacy in an animal model of HER2-positive breast cancer brain metastasis. Breast Cancer Res Treat 2017; 164:581-591. [PMID: 28493046 PMCID: PMC5495871 DOI: 10.1007/s10549-017-4279-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/04/2017] [Indexed: 12/04/2022]
Abstract
Purpose The extent to which efficacy of the HER2 antibody Trastuzumab in brain metastases is limited by access of antibody to brain lesions remains a question of significant clinical importance. We investigated the uptake and distribution of trastuzumab in brain and mammary fat pad grafts of HER2-positive breast cancer to evaluate the relationship of these parameters to the anti-tumor activity of trastuzumab and trastuzumab emtansine (T-DM1). Methods Mouse transgenic breast tumor cells expressing human HER2 (Fo2-1282 or Fo5) were used to establish intracranial and orthotopic tumors. Tumor uptake and tissue distribution of systemically administered 89Zr-trastuzumab or muMAb 4D5 (murine parent of trastuzumab) were measured by PET and ELISA. Efficacy of muMAb 4D5, the PI3K/mTOR inhibitor GNE-317, and T-DM1 was also assessed. Results 89Zr-trastuzumab and muMAb 4D5 exhibited robust uptake into Fo2-1282 brain tumors, but not normal brains. Uptake into brain grafts was similar to mammary grafts. Despite this, muMAb 4D5 was less efficacious in brain grafts. Co-administration of muMAb 4D5 and GNE-317, a brain-penetrant PI3K/mTOR inhibitor, provided longer survival in mice with brain lesions than either agent alone. Moreover, T-DM1 increased survival in the Fo5 brain metastasis model. Conclusions In models of HER2-positive breast cancer brain metastasis, trastuzumab efficacy does not appear to be limited by access to intracranial tumors. Anti-tumor activity improved with the addition of a brain-penetrant PI3K/mTOR inhibitor, suggesting that combining targeted therapies is a more effective strategy for treating HER2-positive breast cancer brain metastases. Survival was also extended in mice with Fo5 brain lesions treated with T-DM1. Electronic supplementary material The online version of this article (doi:10.1007/s10549-017-4279-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
| | | | | | - Samir Kharbanda
- Calico Labs, 1170 Veterans Blvd, South San Francisco, CA, 94080, USA
| | - Elaine Mai
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Janet Tien
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | - Kimberly Malesky
- Novartis Institutes for BioMedical Research, 250 Massachusetts Ave, Cambridge, MA, 02139, USA
| | | | - Jan Marik
- Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA
| | | |
Collapse
|