Evidence map›Paper›PMID 27472462›Full record

ArticleOncotarget2016

Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations.

Brendon Ladd, Anne Marie Mazzola, Teeru Bihani, Zhongwu Lai, James Bradford, Michael Collins, Evan Barry, Anne U Goeppert, Hazel M Weir, Kelly Hearne and 10 more

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

Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
2.3field-weighted citation impact, top 12% 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

20 citing papers in PubMed, 28 citations in OpenAlex.

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  17. Molecular mechanisms of therapy resistance in solid tumors: chasing "moving" targets.Virchows Archiv : an international journal of pathology · 2017
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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

20 authors at 2 institutions in 2 countries.

Brendon LaddOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Anne Marie MazzolaOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Teeru BihaniOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Zhongwu LaiOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
James BradfordOncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
Michael CollinsOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Evan BarryOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Anne U GoeppertOncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
Hazel M WeirOncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
Kelly HearneOncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
Jonathan G RenshawOncology iMed, AstraZeneca, Alderley Park, Macclesfield, UK.
Morvarid MohseniOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Elaine HurtOncology, Medimmune, Gaithersburg, MD, USA.
Sanjoo JallaOncology, Medimmune, Gaithersburg, MD, USA.
Haifeng BaoOncology, Medimmune, Gaithersburg, MD, USA.
Robert HollingsworthOncology, Medimmune, Gaithersburg, MD, USA.
Corinne ReimerOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Michael ZindaOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Stephen FawellOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
Celina M D'CruzOncology iMed, AstraZeneca, Gatehouse Park, Waltham, MA, USA.
AstraZeneca (United States) · USAstraZeneca (United Kingdom) · GB

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations.

Indexed as

MutationAnimalsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Drug Resistance, NeoplasmEstradiolEverolimusFemaleFulvestrantHumansMCF-7 CellsMicePiperazinesPyridinesCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6EstradiolEverolimusFulvestrantpalbociclibPiperazinesPyridinesReceptors, EstrogenTOR Serine-Threonine Kinasesadvanced metastatic breast cancercombination therapyendocrine resistanceER mutations

Identifiers

PMID27472462
PMCPMC5342331
OpenAlexW2480578469

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.