Evidence map›Paper›PMID 28893315›Full record

ArticleBreast cancer research : BCR2017

Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors.

Imke H Bartelink, Brendan Prideaux, Gregor Krings, Lisa Wilmes, Pei Rong Evelyn Lee, Pan Bo, Byron Hann, Jean-Philippe Coppé, Diane Heditsian, Lamorna Swigart-Brown and 18 more

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

Article in Breast cancer research : BCR, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.2field-weighted citation impact, top 19% 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

8 citing papers in PubMed, 23 citations in OpenAlex.

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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

28 authors at 5 institutions in 2 countries.

Imke H BartelinkDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA. i.h.bartelink@gmail.com.
Brendan PrideauxRutgers New Jersey Medical School, Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Ave, Newark, NJ, USA.
Gregor KringsDepartment of Pathology, University of California, San Francisco, CA, USA.
Lisa WilmesDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Pei Rong Evelyn LeeDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Pan BoDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Byron HannUCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Jean-Philippe CoppéDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Diane HeditsianPatient advocate University of California, San Francisco Breast Science Advocacy Core, San Francisco, CA, USA.
Lamorna Swigart-BrownDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Ella F JonesDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Sergey MagnitskyDepartment of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA.
Ron J KeizerDepartment of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, USA.
Niels de VriesDepartment of Clinical Pharmacy, Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, NKI-AVL, Amsterdam, The Netherlands.
Hilde RosingDepartment of Clinical Pharmacy, Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, NKI-AVL, Amsterdam, The Netherlands.
Nela PawlowskaDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA.
Scott ThomasDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA.
Mallika DhawanDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA.
Rahul AggarwalDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA.
Pamela N MunsterDepartment of Medicine, University of California San Francisco, 2340 Sutter Street, San Francisco, CA, 9411, USA.
Laura J EssermanUCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Weiming RuanDepartment of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
Alan H B WuDepartment of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
Douglas YeeDivision of Hematology Oncology, University of Minnesota, Minneapolis, MN, USA.
Véronique DartoisRutgers New Jersey Medical School, Public Health Research Institute, Rutgers, The State University of New Jersey, 225 Warren Ave, Newark, NJ, USA.
Radojka M SavicDepartment of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, USA.
Denise M WolfDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Laura van 't VeerDepartment of Laboratory Medicine, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
University of California, San Francisco · USUCSF Helen Diller Family Comprehensive Cancer Center · USRutgers, The State University of New Jersey · USThe Netherlands Cancer Institute · NLUniversity of Minnesota · US

Funding

CLINICAL, PHARMACOLOGY, DRUG ACTION &PHARMACOKINETICST32GM007546 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Radojka Savic · 1985 to 2026
$8.9M
A MALDI LTQ Orbitrap XL Mass Spectrometer for BioImagingS10OD018072 · OD · RBHS-NEW JERSEY MEDICAL SCHOOL · PI DARTOIS, VERONIQUE · 2015 to 2015
$418k
Targeted and regulation of flagellar dyneinF32GM075446 · NIGMS · EMORY UNIVERSITY · PI WIRSCHELL, MAUREEN E · 2005 to 2007
$143k
NIGMS NIH HHS F32 GM075446NIGMS NIH HHS T32 GM007546NIH HHS S10 OD018072
6 · The paper itself

Abstract

backgroundPoly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.

methodsMDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).

resultsVeliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R

conclusionsPARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.

Indexed as

AnimalsBenzimidazolesCarboplatinCell Line, TumorFemaleHumansLeukocytes, MononuclearMicePenetrancePoly(ADP-ribose) Polymerase InhibitorsSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationTriple Negative Breast NeoplasmsXenograft Model Antitumor AssaysBenzimidazolesCarboplatinPoly(ADP-ribose) Polymerase InhibitorsveliparibCarboplatinDrug penetrationInductively coupled plasma–mass spectrometryMatrix-assisted laser desorption/ionization mass spectrometric imagingPharmacokineticsPoly(ADP-ribose) polymerase inhibitorsSpatial heterogeneity

Identifiers

PMID28893315
PMCPMC5594551
OpenAlexW2755500181

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.