4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer.
Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, we performed high resolution proteomic analysis on two cohorts of ER positive breast tumors derived from patients who either manifested good or poor outcome to tamoxifen treatment upon recurrence. A total of 112 fresh frozen tumors were collected from multiple medical centers and divided into two sets: an in-house training and a multi-center test set. Epithelial tumor cells were enriched with LCM and analyzed by nano-LC Orbitrap mass spectrometry (MS), which yielded >3000 and >4000 quantified proteins in the training and test sets, respectively. Raw data are available via ProteomeXchange with identifiers PXD000484 and PXD000485. Statistical analysis showed differential abundance of 99 proteins, of which a subset of 4 proteins was selected through a multivariate step-down to develop a predictor for tamoxifen treatment outcome. The 4-protein signature significantly predicted poor outcome patients in the test set, independent of predictive histopathological characteristics (hazard ratio [HR] = 2.17; 95% confidence interval [CI] = 1.15 to 4.17; multivariate Cox regression p value = 0.017). Immunohistochemical (IHC) staining of PDCD4, one of the signature proteins, on an independent set of formalin-fixed paraffin-embedded tumor tissues provided and independent technical validation (HR = 0.72; 95% CI = 0.57 to 0.92; multivariate Cox regression p value = 0.009). We hereby report the first validated protein predictor for tamoxifen treatment outcome in recurrent ER-positive breast cancer. IHC further showed that PDCD4 is an independent marker.
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands; Postgraduate School of Molecular Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: t.demarchi@erasmusmc.nl.
Tommaso
T
De Marchi
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: n.liu@ncmls.ru.nl.
Ning Qing
NQ
Liu
Department of Neurology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: c.stingl@erasmusmc.nl.
Cristoph
C
Stingl
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: a.timmermans@erasmusmc.nl.
Mieke A
MA
Timmermans
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: m.smid@erasmusmc.nl.
Marcel
M
Smid
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: m.look@erasmusmc.nl.
Maxime P
MP
Look
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: milatjoa@hotmail.com.
Mila
M
Tjoa
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands; Postgraduate School of Molecular Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Electronic address: r.braakman@erasmusmc.nl.
Rene B H
RB
Braakman
Division of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Electronic address: m.opdam@nki.nl.
Mark
M
Opdam
Division of Medical Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Electronic address: s.linn@nki.nl.
Sabine C
SC
Linn
Department of Laboratory Medicine, Radboud University Medical Center, PO Box 9101, NL-6500 HB, Nijmegen, The Netherlands. Electronic address: f.sweep@labgk.umcn.nl.
Fred C G J
FC
Sweep
Department of Radiation Oncology, Radboud University Medical Center, PO Box 9101, NL-6500 HB, Nijmegen, The Netherlands. Electronic address: P.Span@rther.umcn.nl.
Paul N
PN
Span
Department of Pathology, Maasstad Hospital, Maasstadweg 21, 3079 DZ, Rotterdam, The Netherlands. Electronic address: KliffenM@maasstadziekenhuis.nl.
Mike
M
Kliffen
Department of Neurology, Erasmus MC, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: t.luider@erasmusmc.nl.
Theo M
TM
Luider
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: j.foekens@erasmsumc.nl.
John A
JA
Foekens
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands; Cancer Genomics Center Netherlands, Amsterdam, The Netherlands. Electronic address: j.martens@erasmusmc.nl.
John W M
JW
Martens
Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Wytemaweg 80, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: a.umar@erasmsumc.nl.
Arzu
A
Umar
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000145:classification / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D013629:Tamoxifen
Biomarker; Breast cancer; Mass spectrometry; Proteomics; Tamoxifen resistance