Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumour Syndrome (PHTS)-a European cohort study

Linda A J Hendricks^#^{1

2}, Katja C J Verbeek^#^{1

2}, Janneke H M Schuurs-Hoeijmakers¹, Robin de Putter^{3

4}, Hilde Brems^{4

5}, Sien H Van Daele⁵, Violetta C Anastasiadou^{4

6}, Lenka Foretová^{4

7}, Patrick R Benusiglio⁸, Anna Gerasimenko^{9

10}, Chrystelle Colas^{4

11

12}, Marie-Charlotte Villy¹¹, Claude Houdayer^{4

13}, Maud Branchaud¹³, Robert Hüneburg^{14

15}, Stefan Aretz^{4

14

16}, Arne Jahn^{17

18

19

20}, Verena Steinke-Lange^{4

21}, Giovanni Innella^{22

23}, Daniela Turchetti^{4

22

23}, Valeria Barili²⁴, Maurizio Genuardi^{4

25

26}, Arianna Panfili²⁵, Margherita Baldassarri^{27

28

29}, Arvīds Irmejs^{4

30

31}, Mirjam M de Jong^{4

32}, Thera P Links³³, Edward M Leter³⁴, Daniëlle G M Bosch³⁵, Stephany H Donze³⁵, Rachel S van der Post^{2

36}, Arjen R Mensenkamp^{1

2}, Harm Westdorp³⁷, Hildegunn Høberg-Vetti^{4

38

39}, Marianne Tveit Haavind³⁸, Kjersti Jørgensen⁴⁰, Lovise Mæhle⁴⁰, Siri Briskemyr⁴¹, Juliette Dupont Garcia⁴², Ana Blatnik^{4

43}, Judith Balmaña^{4

44}, Maite Torres⁴⁴, Joan Brunet^{4

45}, Roser Lleuger-Pujol⁴⁵, Emma Tham^{4

46

47}, Marc Tischkowitz^{4

48}, D Gareth Evans^{4

49}, Zerin Hyder⁴⁹, Nicoline Hoogerbrugge^{1

2

4}, Janet R Vos^{50

51}

Affiliations

¹ Department of Human Genetics, Radboudumc expert centre for PHTS, Radboud university medical centre, Nijmegen, the Netherlands.
² Radboud Institute for Medical Innovation, Radboud university medical centre, Nijmegen, the Netherlands.
³ Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
⁴ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, the Netherlands.
⁵ Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁶ Karaiskakio Foundation, Nicosia Cyprus, and Archbishop Makarios III Children's Hospital, Nicosia, Cyprus.
⁷ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁸ Department of Medical Genetics, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
⁹ Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, 75013, Paris, France.
¹⁰ APHP Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Departement of Genetics, Centre de référence "déficiences intellectuelles de causes rares", Paris, France.
¹¹ Institut Curie, Service de Génétique, Paris, France.
¹² Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France.
¹³ Univ Rouen Normandie, Inserm U1245, FHU-G4 Génomique and CHU Rouen, Department of Genetics, 76000, Rouen, France.
¹⁴ Centre for Hereditary Tumour Syndromes, University Hospital of Bonn, Bonn, Germany.
¹⁵ Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
¹⁶ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁷ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁸ ERN-GENTURIS, Hereditary Cancer Syndrome Centre Dresden, Dresden, Germany.
¹⁹ German Cancer Consortium (DKTK), Dresden, Germany.
²⁰ National Centre for Tumour Diseases (NCT), Partner Site Dresden, Dresden, Germany.
²¹ Medical Genetics Centre, Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV - Campus Innenstadt, Klinikum der Universität München, München, Germany.
²² Department of Medical and Surgical Sciences, Centre for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy.
²³ Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
²⁴ Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy.
²⁵ Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²⁶ Medical Genetics Section, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁷ Medical Genetics, University of Siena, Siena, Italy.
²⁸ Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, Siena, 53100, Italy.
²⁹ Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, 53100, Italy.
³⁰ Institute of Oncology, Riga Stradins University, Riga, Latvia.
³¹ Breast Unit, Pauls Stradins Clinical University Hospital, Riga, Latvia.
³² Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
³³ Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
³⁴ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
³⁵ Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, the Netherlands.
³⁶ Department of Pathology, Radboud university medical centre, Nijmegen, the Netherlands.
³⁷ Department of Medical Oncology, Radboud university medical centre, Nijmegen, the Netherlands.
³⁸ Western Norway Familial Cancer Centre, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
³⁹ Faculty of Health Studies, VID Specialized University, Bergen, Norway.
⁴⁰ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁴¹ Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
⁴² Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
⁴³ Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁴⁴ Medical Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴⁵ Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL-IDIBGI, Barcelona-, Girona, Spain.
⁴⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁴⁷ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴⁸ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
⁴⁹ Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
⁵⁰ Department of Human Genetics, Radboudumc expert centre for PHTS, Radboud university medical centre, Nijmegen, the Netherlands. janet.vos@radboudumc.nl.
⁵¹ Radboud Institute for Medical Innovation, Radboud university medical centre, Nijmegen, the Netherlands. janet.vos@radboudumc.nl.

^# Contributed equally.

PMID: 40468016
PMCID: PMC12137667
DOI: 10.1038/s44276-025-00157-y

Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumour Syndrome (PHTS)-a European cohort study

Linda A J Hendricks et al. BJC Rep. 2025.

. 2025 Jun 4;3(1):42.

doi: 10.1038/s44276-025-00157-y.

Authors

Affiliations

¹ Department of Human Genetics, Radboudumc expert centre for PHTS, Radboud university medical centre, Nijmegen, the Netherlands.
² Radboud Institute for Medical Innovation, Radboud university medical centre, Nijmegen, the Netherlands.
³ Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
⁴ European Reference Network for Genetic Tumour Risk Syndromes (ERN GENTURIS), Nijmegen, the Netherlands.
⁵ Department of Human Genetics, University of Leuven, Leuven, Belgium.
⁶ Karaiskakio Foundation, Nicosia Cyprus, and Archbishop Makarios III Children's Hospital, Nicosia, Cyprus.
⁷ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
⁸ Department of Medical Genetics, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.
⁹ Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière, 75013, Paris, France.
¹⁰ APHP Sorbonne Université, GH Pitié Salpêtrière et Trousseau, Departement of Genetics, Centre de référence "déficiences intellectuelles de causes rares", Paris, France.
¹¹ Institut Curie, Service de Génétique, Paris, France.
¹² Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France.
¹³ Univ Rouen Normandie, Inserm U1245, FHU-G4 Génomique and CHU Rouen, Department of Genetics, 76000, Rouen, France.
¹⁴ Centre for Hereditary Tumour Syndromes, University Hospital of Bonn, Bonn, Germany.
¹⁵ Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany.
¹⁶ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁷ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁸ ERN-GENTURIS, Hereditary Cancer Syndrome Centre Dresden, Dresden, Germany.
¹⁹ German Cancer Consortium (DKTK), Dresden, Germany.
²⁰ National Centre for Tumour Diseases (NCT), Partner Site Dresden, Dresden, Germany.
²¹ Medical Genetics Centre, Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV - Campus Innenstadt, Klinikum der Universität München, München, Germany.
²² Department of Medical and Surgical Sciences, Centre for Studies on Hereditary Cancer, University of Bologna, Bologna, Italy.
²³ Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
²⁴ Medical Genetics, Department of Medicine and Surgery, University of Parma, Parma, Italy.
²⁵ Department of Laboratory and Infectious Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.
²⁶ Medical Genetics Section, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
²⁷ Medical Genetics, University of Siena, Siena, Italy.
²⁸ Med Biotech Hub and Competence Centre, Department of Medical Biotechnologies, University of Siena, Siena, 53100, Italy.
²⁹ Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, 53100, Italy.
³⁰ Institute of Oncology, Riga Stradins University, Riga, Latvia.
³¹ Breast Unit, Pauls Stradins Clinical University Hospital, Riga, Latvia.
³² Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
³³ Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
³⁴ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
³⁵ Department of Clinical Genetics, Erasmus MC Rotterdam, Rotterdam, the Netherlands.
³⁶ Department of Pathology, Radboud university medical centre, Nijmegen, the Netherlands.
³⁷ Department of Medical Oncology, Radboud university medical centre, Nijmegen, the Netherlands.
³⁸ Western Norway Familial Cancer Centre, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
³⁹ Faculty of Health Studies, VID Specialized University, Bergen, Norway.
⁴⁰ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
⁴¹ Department of Medical Genetics, University Hospital of North Norway, Tromsø, Norway.
⁴² Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.
⁴³ Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
⁴⁴ Medical Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴⁵ Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL-IDIBGI, Barcelona-, Girona, Spain.
⁴⁶ Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
⁴⁷ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
⁴⁸ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
⁴⁹ Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK.
⁵⁰ Department of Human Genetics, Radboudumc expert centre for PHTS, Radboud university medical centre, Nijmegen, the Netherlands. janet.vos@radboudumc.nl.
⁵¹ Radboud Institute for Medical Innovation, Radboud university medical centre, Nijmegen, the Netherlands. janet.vos@radboudumc.nl.

^# Contributed equally.

PMID: 40468016
PMCID: PMC12137667
DOI: 10.1038/s44276-025-00157-y

Abstract

Background: PTEN hamartoma tumour syndrome (PHTS) patients have a high hereditary risk of cancer, especially breast (BC), endometrial (EC), and thyroid cancer (TC). However, the prognosis of PHTS-related cancers is unknown.

Methods: This European cohort study included adult PHTS patients with data from medical files, registries, and/or questionnaires. Overall survival (OS) was assessed using Kaplan-Meier analyses and were compared with sporadic cancer and the general population using standardized mortality (SMR) and relative survival rates (RSR). Survival bias was addressed using left-truncation.

Results: Overall, 147 BC patients were included. The 10y-OS was 77% (95%CI = 66-90), decreasing with increasing stage from 90% (95%CI = 73-100) for stage 0 to 0% (95%CI = 0-0) for stage IV. BC relative survival was comparable to sporadic BC in the first two years (2y-RSR = 1.1; 95%CI = 1.1-1.1) and increasing thereafter (5y-RSR = 1.7; 95%CI = 1.6-1.7). For TC (N = 56) and EC (N = 35), 10y-OS was 87% (95%CI = 74-100) and 64% (95%CI = 38-100), respectively. Overall and cancer-specific mortality in female PHTS patients exceeded general population rates (SMR = 3.7; 95%CI = 2.6-5.0 and SMR = 2.7; 95%CI = 1.6-4.4).

Conclusions: The prognosis of PHTS-related cancers was comparable to the general population. The higher overall mortality in PHTS patients is presumably related to their higher cancer incidence. These findings, and the high survival observed in early-stage cancer, emphasise the importance of recognising PHTS early to facilitate cancer surveillance.

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Conflict of interest statement

Competing interests: A.R.M. received funds from AstraZeneca for contribution to sponsored quality assessment and variant interpretation of VUS in BRCA1 and BRCA2. This funding was not related to this study. J.B. received funding support from GSK for an educational activity unrelated to this study. MT is the Editor-in-Chief of BJC Reports, he was not involved in any aspect of the handling of this manuscript or any editorial decisions. The remaining authors have no competing interests to declare. Ethics approval and consent to participate: This study was performed in accordance with the Declaration of Helsinki. The Research Ethics Committee of the Radboud university medical centre (file number 2018-5056) approved this study and the institutional ethics committees approved this study. Written informed consent was obtained when indicated by the ethics committee.

Figures

**Fig. 1. Schematic presentation of the total PHTS cohort and cancer patient cohort.**
The total PHTS cohort consisted of patients who were recruited based on their PHTS diagnosis, with or without (a history of) cancer (n = 513). The PHTS cancer patient cohort consisted of PHTS patients with a history of cancer (n = 249). Data for patients only included in the cancer patient cohort were obtained from centres that only provided data on PHTS patients with cancer (n = 25).

**Fig. 2. Survival per cancer type.**
The survival probability per cancer type in percentages (%) on the y-axis is presented for the left-truncated analyses. The x-axis represents the number of years after cancer diagnosis. The dashed lines represent 95% confidence intervals. The number of patients at risk (Nrisk) and the cumulative number of events (Nevent) are presented in the risk tables. Survival for breast and endometrial cancer is presented only for females. Overall survival (OS) is presented for female breast, endometrial, thyroid, colorectal, renal cancer, and melanoma (a, e, i, m, o, p). The cancer-specific survival (CSS) is presented for female breast, endometrial, thyroid, and colorectal cancer (b, f, j, n). Disease-free survival (DFS) is presented for female breast, endometrial, and thyroid cancer (c, g, k). The metastasis-free survival (MFS) is presented for breast, endometrial, and thyroid cancer (d, h, l). The 5- and 10-year survival per cancer type is presented in Supplementary Table 2.

**Fig. 3. Relative survival rates for breast cancer, endometrial cancer, and thyroid cancer.**
Comparison of observed survival in PHTS cancer patients with expected survival in the general population is presented as the relative survival rates (RSR). Comparison of observed survival in PHTS cancer patients with expected survival in sporadic cancer is presented as RSR_ca. RSR is presented on the y-axis for 1 to 5 years after cancer diagnosis (x-axis). Error bars represent the 95% confidence intervals. For breast and endometrial cancer, the RSR_ca is additionally presented by stage (**b, d**). Breast cancer stage 0 refers to carcinoma in situ (b).

See this image and copyright information in PMC

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Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumour Syndrome (PHTS)-a European cohort study

Affiliations

Cancer prognosis and treatment results in patients with PTEN Hamartoma Tumour Syndrome (PHTS)-a European cohort study

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials