The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Linda A.J. Hendricks; Katja C.J. Verbeek; Janneke H.M. Schuurs-Hoeijmakers; Mirjam M. de Jong; Thera P. Links; Hilde Brems; Mio Aerden; Joan Brunet; Roser Lleuger-Pujol; Robert Hüneburg; Stefan Aretz; Chrystelle Colas; Marie Charlotte Villy; Emma R. Woodward; D. Gareth Evans; Daniëlle G.M. Bosch; Stephany H. Donze; Lenka Foretová; Ana Blatnik; Edward M. Leter; Marc Tischkowitz; Arne Jahn; Robin de Putter; Juliette Dupont; Siri Briskemyr; Verena Steinke-Lange; Margherita Baldassarri; Violetta C. Anastasiadou; Arvīds Irmejs; Carla Oliveira; Rachel S. van der Post; Arjen R. Mensenkamp; Bianca Tesi; Ninni Mu; Patrick R. Benusiglio; Anna Gerasimenko; Giovanni Innella; Daniela Turchetti; Claude Houdayer; Maud Branchaud; Hildegunn Høberg Vetti; Marianne Tveit Haavind; Judith Balmaña; Maite Torres; Maurizio Genuardi; Arianna Panfili; Kjersti Jørgensen; Lovise Mæhle; Nicoline Hoogerbrugge; Janet R. Vos

doi:10.1016/j.gim.2025.101467

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Linda A.J. Hendricks
, Katja C.J. Verbeek
, Janneke H.M. Schuurs-Hoeijmakers
, Mirjam M. de Jong
, Thera P. Links
, Hilde Brems
, Mio Aerden
, Joan Brunet
, Roser Lleuger-Pujol
, Robert Hüneburg
, Stefan Aretz
, Chrystelle Colas
, Marie Charlotte Villy
, Emma R. Woodward
, D. Gareth Evans
, Daniëlle G.M. Bosch
, Stephany H. Donze
, Lenka Foretová
, Ana Blatnik
, Edward M. Leter

Marc Tischkowitz, Arne Jahn, Robin de Putter, Juliette Dupont, Siri Briskemyr, Verena Steinke-Lange, Margherita Baldassarri, Violetta C. Anastasiadou, Arvīds Irmejs, Carla Oliveira, Rachel S. van der Post, Arjen R. Mensenkamp, Bianca Tesi, Ninni Mu, Patrick R. Benusiglio, Anna Gerasimenko, Giovanni Innella, Daniela Turchetti, Claude Houdayer, Maud Branchaud, Hildegunn Høberg Vetti, Marianne Tveit Haavind, Judith Balmaña, Maite Torres, Maurizio Genuardi, Arianna Panfili, Kjersti Jørgensen, Lovise Mæhle, Nicoline Hoogerbrugge, Janet R. Vos^*

^*Corresponding author for this work

Clinical Genetics

Radboud University Medical Center
University Medical Centre Groningen
KU Leuven
University Hospitals Leuven
Centro de Investigación Biomédica en Red (CIBER)
University Hospital Bonn
University of Bonn
Institut Curie (Paris)
Equipe Labellisée Par la Ligue Nationale Contre le Cancer
University of Manchester
Masaryk Memorial Cancer Institute
Institute of Oncology Ljubljana
Maastricht University
University of Cambridge
The Carl Gustav Carus Hospital
Hereditary Cancer Syndrome Center (Dresden)
German Cancer Research Center
National Center for Tumour Diseases (NCT); partner site Dresden
Ghent University Hospital
Unidade Local de Saúde Santa Maria
University Hospital of North Norway
Klinikum der Universität München
University of Siena
Azienda Ospedaliera Universitaria Senese
Nicosia Cyprus and Archbishop Makarios III Children's Hospital
Riga Stradins University
Paula Stradina Clinical University Hospital
University of Porto
Karolinska University Hospital
Karolinska Institutet
Sorbonne Université
University of Bologna
University Hospital S. Orsola
Université de Rouen Normandie
University of Bergen
VID Specialized University
Hospital Vall d'Hebron & ARADyAL research network
Catholic University of the Sacred Heart
Agostino Gemelli University Hospital Foundation IRCCS
University of Oslo

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

64 Downloads (Pure)

Abstract

Purpose:

Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk.

Methods:

This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires.

Results:

Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively.

Conclusion:

This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

Original language	English
Article number	101467
Journal	Genetics in Medicine
Volume	27
Issue number	10
DOIs	https://doi.org/10.1016/j.gim.2025.101467
Publication status	Published - Oct 2025

Bibliographical note

Publisher Copyright:
© 2025 The Authors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)Final published version, 714 KBLicence: CC BY

Cite this

Hendricks, L. A. J., Verbeek, K. C. J., Schuurs-Hoeijmakers, J. H. M., de Jong, M. M., Links, T. P., Brems, H., Aerden, M., Brunet, J., Lleuger-Pujol, R., Hüneburg, R., Aretz, S., Colas, C., Villy, M. C., Woodward, E. R., Evans, D. G., Bosch, D. G. M., Donze, S. H., Foretová, L., Blatnik, A., ... Vos, J. R. (2025). The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS). Genetics in Medicine, 27(10), Article 101467. https://doi.org/10.1016/j.gim.2025.101467

@article{394b725ddb1e4cd2bc868841645ceeba,

title = "The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)",

abstract = "Purpose: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. Methods: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. Results:Overall, 279 adult PHTS patients with (a history of) cancer were included (80\% female). Among females, 106 (54\%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29\%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5\% (95\% CI = 18.1-32.5) and 45.7\% (95\% CI = 36.9-55.4) in females and 14.5\% (95\% CI = 5.7-34.1) and 19.8\% (95\% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3\% (95\% CI = 14.9-35.2) and 45.6\% (95\% CI = 33.0-60.2) in females, respectively. Conclusion: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.",

author = "Hendricks, \{Linda A.J.\} and Verbeek, \{Katja C.J.\} and Schuurs-Hoeijmakers, \{Janneke H.M.\} and \{de Jong\}, \{Mirjam M.\} and Links, \{Thera P.\} and Hilde Brems and Mio Aerden and Joan Brunet and Roser Lleuger-Pujol and Robert H{\"u}neburg and Stefan Aretz and Chrystelle Colas and Villy, \{Marie Charlotte\} and Woodward, \{Emma R.\} and Evans, \{D. Gareth\} and Bosch, \{Dani{\"e}lle G.M.\} and Donze, \{Stephany H.\} and Lenka Foretov{\'a} and Ana Blatnik and Leter, \{Edward M.\} and Marc Tischkowitz and Arne Jahn and \{de Putter\}, Robin and Juliette Dupont and Siri Briskemyr and Verena Steinke-Lange and Margherita Baldassarri and Anastasiadou, \{Violetta C.\} and Arvīds Irmejs and Carla Oliveira and \{van der Post\}, \{Rachel S.\} and Mensenkamp, \{Arjen R.\} and Bianca Tesi and Ninni Mu and Benusiglio, \{Patrick R.\} and Anna Gerasimenko and Giovanni Innella and Daniela Turchetti and Claude Houdayer and Maud Branchaud and \{H{\o}berg Vetti\}, Hildegunn and \{Tveit Haavind\}, Marianne and Judith Balma{\~n}a and Maite Torres and Maurizio Genuardi and Arianna Panfili and Kjersti J{\o}rgensen and Lovise M{\ae}hle and Nicoline Hoogerbrugge and Vos, \{Janet R.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = oct,

doi = "10.1016/j.gim.2025.101467",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "10",

}

Hendricks, LAJ, Verbeek, KCJ, Schuurs-Hoeijmakers, JHM, de Jong, MM, Links, TP, Brems, H, Aerden, M, Brunet, J, Lleuger-Pujol, R, Hüneburg, R, Aretz, S, Colas, C, Villy, MC, Woodward, ER, Evans, DG, Bosch, DGM , Donze, SH, Foretová, L, Blatnik, A, Leter, EM, Tischkowitz, M, Jahn, A, de Putter, R, Dupont, J, Briskemyr, S, Steinke-Lange, V, Baldassarri, M, Anastasiadou, VC, Irmejs, A, Oliveira, C, van der Post, RS, Mensenkamp, AR, Tesi, B, Mu, N, Benusiglio, PR, Gerasimenko, A, Innella, G, Turchetti, D, Houdayer, C, Branchaud, M, Høberg Vetti, H, Tveit Haavind, M, Balmaña, J, Torres, M, Genuardi, M, Panfili, A, Jørgensen, K, Mæhle, L, Hoogerbrugge, N & Vos, JR 2025, 'The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)', Genetics in Medicine, vol. 27, no. 10, 101467. https://doi.org/10.1016/j.gim.2025.101467

TY - JOUR

T1 - The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

AU - Hendricks, Linda A.J.

AU - Verbeek, Katja C.J.

AU - Schuurs-Hoeijmakers, Janneke H.M.

AU - de Jong, Mirjam M.

AU - Links, Thera P.

AU - Brems, Hilde

AU - Aerden, Mio

AU - Brunet, Joan

AU - Lleuger-Pujol, Roser

AU - Hüneburg, Robert

AU - Aretz, Stefan

AU - Colas, Chrystelle

AU - Villy, Marie Charlotte

AU - Woodward, Emma R.

AU - Evans, D. Gareth

AU - Bosch, Daniëlle G.M.

AU - Donze, Stephany H.

AU - Foretová, Lenka

AU - Blatnik, Ana

AU - Leter, Edward M.

AU - Tischkowitz, Marc

AU - Jahn, Arne

AU - de Putter, Robin

AU - Dupont, Juliette

AU - Briskemyr, Siri

AU - Steinke-Lange, Verena

AU - Baldassarri, Margherita

AU - Anastasiadou, Violetta C.

AU - Irmejs, Arvīds

AU - Oliveira, Carla

AU - van der Post, Rachel S.

AU - Mensenkamp, Arjen R.

AU - Tesi, Bianca

AU - Mu, Ninni

AU - Benusiglio, Patrick R.

AU - Gerasimenko, Anna

AU - Innella, Giovanni

AU - Turchetti, Daniela

AU - Houdayer, Claude

AU - Branchaud, Maud

AU - Høberg Vetti, Hildegunn

AU - Tveit Haavind, Marianne

AU - Balmaña, Judith

AU - Torres, Maite

AU - Genuardi, Maurizio

AU - Panfili, Arianna

AU - Jørgensen, Kjersti

AU - Mæhle, Lovise

AU - Hoogerbrugge, Nicoline

AU - Vos, Janet R.

PY - 2025/10

Y1 - 2025/10

N2 - Purpose: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. Methods: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. Results:Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively. Conclusion: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

AB - Purpose: Patients with PTEN Hamartoma Tumor Syndrome (PHTS) have high hereditary cancer risks for breast, endometrial, and thyroid cancer. Patients develop multiple primary cancers, but these risks remain uncertain. We aimed to provide the second primary cancer risk. Methods: This European cohort study assessed second primary cancer risks with Kaplan-Meier analyses using data from medical files, registries and/or patient questionnaires. Results:Overall, 279 adult PHTS patients with (a history of) cancer were included (80% female). Among females, 106 (54%) developed a PHTS-related second primary cancer after a PHTS-related first primary cancer, whereas 10 (29%) males developed a PHTS-related second primary cancer after a PHTS-related first primary cancer. The 5- and 10-year PHTS-related second primary cancer risks were 24.5% (95% CI = 18.1-32.5) and 45.7% (95% CI = 36.9-55.4) in females and 14.5% (95% CI = 5.7-34.1) and 19.8% (95% CI = 8.6-41.9) in males, respectively. Furthermore, 5- and 10-year risks for a second primary breast cancer after a first primary breast cancer were 23.3% (95% CI = 14.9-35.2) and 45.6% (95% CI = 33.0-60.2) in females, respectively. Conclusion: This study demonstrated that PHTS patients have high second primary cancer risks, which is driven by breast cancer in females. Hence, identifying patients with PHTS before or at first primary cancer diagnosis is essential to enable potential early detection or prevention of a second primary cancer through surveillance or risk-reducing surgery.

UR - https://www.scopus.com/pages/publications/105014595428

U2 - 10.1016/j.gim.2025.101467

DO - 10.1016/j.gim.2025.101467

M3 - Article

C2 - 40433764

AN - SCOPUS:105014595428

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 10

M1 - 101467

ER -

The risk of a second primary cancer in PTEN Hamartoma Tumor Syndrome (PHTS)

Abstract

Bibliographical note

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