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Research Article
Volkmar Müller
University Medical Center Hamburg-Eppendorf
Corresponding Author
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Background: Breast cancer (BC) is the most frequent female cancer its which preferentially metastasizes to bone. Mechanisms of bone tropism are poorly understood, however, the transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism and thus of potential interest.
Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue from BC patients treated in the GAIN study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining.
Results: In 1197 samples, we found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly better disease-free (log-rank p 0.019) and overall survival (log-rank p = 0.018), but no association with time to bone metastasis as first site of relapse. Stratified univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: log-rank p = 0.009; OS: log-rank p = 0.008) and in the HER2-negative subgroup (DFS: log-rank p = 0.004; OS: log-rank p = 0.002).
Conclusions: Our findings suggest that a loss of TGIF expression is associated with BC progression, especially in luminal carcinomas.
Trial registration: This clinical trial has been registered with ClinicalTrials.gov; registration number: NCT00196872.
Keywords
Breast cancer, TGFB-induced factor homeobox 1, TGIF, Bone metastases
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Competing interest reported. V.M: Dr. Möbus received speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, Teva, and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics GmbH. V.M: Dr. Müller received speaker honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, Novartis, MSD, Daiichi-Sankyo and Eisai, Lilly, Tesaro and Nektar. Research support from Novartis, Roche, Seattle Genetics, Genentech. PAF: Dr. Fasching reports grants from Novartis, grants from Biontech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from Astra Zeneca, personal fees from Macrogenics, personal fees from Eisai, personal fees from Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, during the conduct of the study. ES: Dr. Stickeler reports personal fees from Roche Pharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Tesaro, personal fees from Astra Zeneca, outside the submitted work. CD: Dr. Denkert received honoraria from Novartis and Roche; Research funding from Myriad Genetics, reports consulting or advisory role for MSD Oncology and Daiichi Sankyo and stock and other ownership interest with Sividon Diagnostics (now Myriad and travel expenses from Roche. In addition, Dr. Denkert has patents, royalities and intellectual property with VMscopedigital pathology software: Patent application: EP18209672 - cancer immunotherapy; Patent application EP20150702464 - therapy response; Patent application EP20150702464 - therapy response. LH: Dr. Hanker received speaker honoraria from Astra Zeneca, Clovis, GSK/Tesaro Novartis, Roche, and consultancy honoraria from Astra Zeneca, Clovis, GSK/Tesaro and Roche. FM: Dr. Marmé reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, outside the submitted work. SL: Dr. Loibl reports grants and other from Abbvie , grants and other from Amgen, grants and other from Astra Zeneca, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from Seattle Genetics, other from PriME/ Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from Eirgenix, other from BMS, other from Puma, other from MSD, grants from Immunomedics, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. The other authors (CS; KML; SS; JR; RPH; TK; CS; CHK; LH; US; VV; VN) declare that they have no competing interests.
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View the published article at BMC Cancer.
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See the published version of this preprint at BMC Cancer.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Research Article
Volkmar Müller
University Medical Center Hamburg-Eppendorf
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Cancer.
Version 1
Posted 27 Jan, 2021
No community comments so far
Editorial decision: Major revision
On 19 Apr, 2021
Reviews received
Received 14 Apr, 2021
Reviewers agreed
On 19 Mar, 2021
Reviews received
Received 24 Feb, 2021
Reviewers agreed
On 19 Feb, 2021
Reviewers invited
Invitations sent on 06 Feb, 2021
Editor assigned
On 28 Jan, 2021
Editor invited
On 22 Jan, 2021
Submission checks complete
On 22 Jan, 2021
First submitted
On 18 Jan, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at BMC Cancer.
Background: Breast cancer (BC) is the most frequent female cancer its which preferentially metastasizes to bone. Mechanisms of bone tropism are poorly understood, however, the transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism and thus of potential interest.
Methods: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue from BC patients treated in the GAIN study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining.
Results: In 1197 samples, we found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly better disease-free (log-rank p 0.019) and overall survival (log-rank p = 0.018), but no association with time to bone metastasis as first site of relapse. Stratified univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: log-rank p = 0.009; OS: log-rank p = 0.008) and in the HER2-negative subgroup (DFS: log-rank p = 0.004; OS: log-rank p = 0.002).
Conclusions: Our findings suggest that a loss of TGIF expression is associated with BC progression, especially in luminal carcinomas.
Trial registration: This clinical trial has been registered with ClinicalTrials.gov; registration number: NCT00196872.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Competing interest reported. V.M: Dr. Möbus received speaker honoraria from Amgen, Astra Zeneca, Celgene, Roche, Teva, and consultancy honoraria from Roche, Amgen, Tesaro and Myelo Therapeutics GmbH. V.M: Dr. Müller received speaker honoraria from Amgen, Astra Zeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, and consultancy honoraria from Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, Novartis, MSD, Daiichi-Sankyo and Eisai, Lilly, Tesaro and Nektar. Research support from Novartis, Roche, Seattle Genetics, Genentech. PAF: Dr. Fasching reports grants from Novartis, grants from Biontech, personal fees from Novartis, personal fees from Roche, personal fees from Pfizer, personal fees from Celgene, personal fees from Daiichi-Sankyo, personal fees from Astra Zeneca, personal fees from Macrogenics, personal fees from Eisai, personal fees from Merck Sharp & Dohme, grants from Cepheid, personal fees from Lilly, during the conduct of the study. ES: Dr. Stickeler reports personal fees from Roche Pharma, personal fees from Novartis, personal fees from Pfizer, personal fees from Tesaro, personal fees from Astra Zeneca, outside the submitted work. CD: Dr. Denkert received honoraria from Novartis and Roche; Research funding from Myriad Genetics, reports consulting or advisory role for MSD Oncology and Daiichi Sankyo and stock and other ownership interest with Sividon Diagnostics (now Myriad and travel expenses from Roche. In addition, Dr. Denkert has patents, royalities and intellectual property with VMscopedigital pathology software: Patent application: EP18209672 - cancer immunotherapy; Patent application EP20150702464 - therapy response; Patent application EP20150702464 - therapy response. LH: Dr. Hanker received speaker honoraria from Astra Zeneca, Clovis, GSK/Tesaro Novartis, Roche, and consultancy honoraria from Astra Zeneca, Clovis, GSK/Tesaro and Roche. FM: Dr. Marmé reports personal fees from Roche, personal fees from AstraZeneca, personal fees from Pfizer, personal fees from Tesaro, personal fees from Novartis, personal fees from Amgen, personal fees from PharmaMar, personal fees from GenomicHealth, personal fees from CureVac, personal fees from EISAI, outside the submitted work. SL: Dr. Loibl reports grants and other from Abbvie , grants and other from Amgen, grants and other from Astra Zeneca, grants and other from Celgene, grants and other from Novartis, grants and other from Pfizer, grants and other from Roche, other from Seattle Genetics, other from PriME/ Medscape, personal fees from Chugai, grants from Teva, grants from Vifor, grants and other from Daiichi-Sankyo, other from Lilly, other from Samsung, other from Eirgenix, other from BMS, other from Puma, other from MSD, grants from Immunomedics, outside the submitted work; In addition, Dr. Loibl has a patent EP14153692.0 pending. The other authors (CS; KML; SS; JR; RPH; TK; CS; CHK; LH; US; VV; VN) declare that they have no competing interests.
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