Evidence map›Paper›PMID 26547932›Full record

ArticleJournal of the National Cancer Institute2016

Preclinical Efficacy of Ado-trastuzumab Emtansine in the Brain Microenvironment.

Vasileios Askoxylakis, Gino B Ferraro, David P Kodack, Mark Badeaux, Ram C Shankaraiah, Giorgio Seano, Jonas Kloepper, Trupti Vardam, John D Martin, Kamila Naxerova and 9 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of the National Cancer Institute, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.

0numbers the graph read from it
0cells of the map it votes in
45citing papers in PubMed
3.9field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

45 citing papers in PubMed, 81 citations in OpenAlex.

  1. Trial
  2. Article
  3. Review
  4. Article
  5. Article
  6. Review
  7. Article
  8. Article
  9. Article
  10. Observational
  11. Article
  12. Review
  13. Article
  14. Article
  15. Review
  16. Review
  17. Review
  18. Article
  19. The blood-tumour barrier in cancer biology and therapy.Nature reviews. Clinical oncology · 2021
    Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 1 institution in 1 country.

Vasileios Askoxylakis: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Gino B Ferraro: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
David P Kodack: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Mark Badeaux: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Ram C Shankaraiah: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Giorgio Seano: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Jonas Kloepper: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Trupti Vardam: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
John D Martin: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Kamila Naxerova: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Divya Bezwada: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Xiaolong Qi: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Martin K Selig: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Elena Brachtel: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Dan G Duda: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Peigen Huang: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Dai Fukumura: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Jeffrey A Engelman: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA.
Rakesh K Jain: Edwin L. Steele Laboratories, Department of Radiation Oncology (VA, GBF, DPK, MB, RCS, GS, JK, TV, JDM, KN, DB, XQ, DGD, PH, DF, RKJ), Department of Pathology (MKS, EB), and Department of Medicine, Cancer Center (JAE), Massachusetts General Hospital and Harvard Medical School, Boston MA. jain@steele.mgh.harvard.edu.
Dana-Farber/Harvard Cancer Center · US

Funding

Vascular Normalization: Rolse of Perivascular CellsP01CA080124 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2000 to 2016
$35.0M
Probing Tumor Microenvironment Using NanotechnologyR01CA126642 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2008 to 2012
$8.3M
Dissecting Pediatric Brain Tumor Microenvironment to Improve TreatmentR35CA197743 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI JAIN, RAKESH K. · 2015 to 2020
$5.7M
NO in Tumor Angiogenesis,Microcirculation &Rad.TherapyR01CA096915 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2002 to 2012
$3.0M
Doppler Optical Frequency Domain Imaging InstrumentS10RR027070 · NCRR · MASSACHUSETTS GENERAL HOSPITAL · PI FUKUMURA, DAI · 2010 to 2010
$260k
NCI NIH HHS P01 CA080124NCI NIH HHS P01-CA080124NCI NIH HHS R01 CA096915NCI NIH HHS R01-CA096915NCI NIH HHS R01 CA126642NCI NIH HHS R01-CA126642NCI NIH HHS R35 CA197743NCRR NIH HHS S10 RR027070NCRR NIH HHS S10-RR027070
6 · The paper itself

Abstract

backgroundCentral nervous system (CNS) metastases represent a major problem in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer because of the disappointing efficacy of HER2-targeted therapies against brain lesions. The antibody-drug conjugate ado-trastuzumab emtansine (T-DM1) has shown efficacy in trastuzumab-resistant systemic breast cancer. Here, we tested the hypothesis that T-DM1 could overcome trastuzumab resistance in murine models of brain metastases.

methodsWe treated female nude mice bearing BT474 or MDA-MB-361 brain metastases (n = 9-11 per group) or cancer cells grown in organotypic brain slice cultures with trastuzumab or T-DM1 at equivalent or equipotent doses. Using intravital imaging, molecular techniques and histological analysis we determined tumor growth, mouse survival, cancer cell apoptosis and proliferation, tumor drug distribution, and HER2 signaling. Data were analyzed with one-way analysis of variance (ANOVA), Kaplan-Meier analysis, and Coefficient of Determination. All statistical tests were two-sided.

resultsT-DM1 delayed the growth of HER2-positive breast cancer brain metastases compared with trastuzumab. These findings were consistent between HER2-driven and PI3K-driven tumors. The activity of T-DM1 resulted in a survival benefit (median survival for BT474 tumors: 28 days for trastuzumab vs 112 days for T-DM1, hazard ratio = 6.2, 95% confidence interval = 6.1 to 85.84, P < .001). No difference in drug distribution or HER2-signaling was revealed between the two groups. However, T-DM1 led to a statistically significant increase in tumor cell apoptosis (one-way ANOVA for ApopTag, P < .001), which was associated with mitotic catastrophe.

conclusionsT-DM1 can overcome resistance to trastuzumab therapy in HER2-driven or PI3K-driven breast cancer brain lesions due to the cytotoxicity of the DM1 component. Clinical investigation of T-DM1 for patients with CNS metastases from HER2-positive breast cancer is warranted.

Indexed as

Ado-Trastuzumab EmtansineAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic AgentsApoptosisBiomarkers, TumorBlotting, WesternBrain NeoplasmsBreast NeoplasmsCell ProliferationDrug Administration ScheduleDrug Resistance, NeoplasmErb-b2 Receptor Tyrosine KinasesFemaleGene Expression ProfilingKaplan-Meier EstimateAdo-Trastuzumab EmtansineAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBiomarkers, TumorERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesMaytansineTrastuzumab

Identifiers

PMID26547932
PMCPMC4862418
OpenAlexW2374911498

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.