Evidence map›Paper›PMID 35842520›Full record

Trial reportBreast cancer research and treatment2022

Factors affecting inter-individual variability in endoxifen concentrations in patients with breast cancer: results from the prospective TOTAM trial.

C Louwrens Braal, Justin D Westenberg, Sanne M Buijs, Steven Abrams, Tessa A M Mulder, Ron H N van Schaik, Stijn L W Koolen, Agnes Jager, Ron H J Mathijssen

Open access · hybridAbstract readClinical Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Breast cancer research and treatment, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
2.1field-weighted citation impact, top 13% 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

6 citing papers in PubMed, 11 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Observational
  5. Article
  6. Article
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

9 authors at 3 institutions in 2 countries.

C Louwrens Braal *Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands. c.braal@erasmusmc.nl.ORCID http://orcid.org/0000-0003-3600-9851
Justin D Westenberg *Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands.
Sanne M BuijsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands.
Steven AbramsData Science Institute, Interuniversity Institute for Biostatistics and Statistical Bioinformatics, UHasselt, Hasselt, Belgium.
Tessa A M MulderDepartment of Clinical Chemistry, Erasmus MC University Center, Rotterdam, The Netherlands.
Ron H N van SchaikDepartment of Clinical Chemistry, Erasmus MC University Center, Rotterdam, The Netherlands.
Stijn L W KoolenDepartment of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands.
Agnes JagerDepartment of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands.
Ron H J MathijssenDepartment of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, PO box 2040, 3015 CN, Rotterdam, The Netherlands.
Erasmus MC Cancer Institute · NLErasmus MC · NLUniversity of Antwerp · BE

Funding

Erasmus Universiteit Rotterdam 2017-17108
6 · The paper itself

Abstract

introductionEndoxifen-the principal metabolite of tamoxifen-is subject to a high inter-individual variability in serum concentration. Numerous attempts have been made to explain this, but thus far only with limited success. By applying predictive modeling, we aimed to identify factors that determine the inter-individual variability. Our purpose was to develop a prediction model for endoxifen concentrations, as a strategy to individualize tamoxifen treatment by model-informed dosing in order to prevent subtherapeutic exposure (endoxifen < 16 nmol/L) and thus potential failure of therapy.

methodsTamoxifen pharmacokinetics with demographic and pharmacogenetic data of 303 participants of the prospective TOTAM study were used. The inter-individual variability in endoxifen was analyzed according to multiple regression techniques in combination with multiple imputations to adjust for missing data and bootstrapping to adjust for the over-optimism of parameter estimates used for internal model validation.

resultsKey predictors of endoxifen concentration were CYP2D6 genotype, age and weight, explaining altogether an average-based optimism corrected 57% (95% CI 0.49-0.64) of the inter-individual variability. CYP2D6 genotype explained 54% of the variability. The remaining 3% could be explained by age and weight. Predictors of risk for subtherapeutic endoxifen (< 16 nmol/L) were CYP2D6 genotype and age. The model showed an optimism-corrected discrimination of 90% (95% CI 0.86-0.95) and sensitivity and specificity of 66% and 98%, respectively. Consecutively, there is a high probability of misclassifying patients with subtherapeutic endoxifen concentrations based on the prediction rule.

conclusionThe inter-individual variability of endoxifen concentration could largely be explained by CYP2D6 genotype and for a small proportion by age and weight. The model showed a sensitivity and specificity of 66 and 98%, respectively, indicating a high probability of (misclassification) error for the patients with subtherapeutic endoxifen concentrations (< 16 nmol/L). The remaining unexplained inter-individual variability is still high and therefore model-informed tamoxifen dosing should be accompanied by therapeutic drug monitoring.

Indexed as

Breast NeoplasmsAntineoplastic Agents, HormonalCytochrome P-450 CYP2D6FemaleGenotypeHumansProspective StudiesTamoxifen4-hydroxy-N-desmethyltamoxifenAntineoplastic Agents, HormonalCytochrome P-450 CYP2D6TamoxifenEarly breast cancerEndoxifenPredictive modelingTamoxifenTherapeutic drug monitoring

Identifiers

PMID35842520
PMCPMC9338137
OpenAlexW4285587382

What OpenQuestion holds

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LicenceCC BY
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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.