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.

APHP Sorbonne Université GH Pitié Salpêtrière et Trousseau Departement of Genetics Centre de référence déficiences intellectuelles de causes rares Paris France

Breast Unit Pauls Stradins Clinical University Hospital Riga Latvia

Centre for Hereditary Tumour Syndromes University Hospital of Bonn Bonn Germany

Centre for Medical Genetics Ghent University Hospital Ghent Belgium

Centro Hospitalar Universitário Lisboa Norte Lisbon Portugal

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Cancer Genetics Institute of Oncology Ljubljana Ljubljana Slovenia

Department of Clinical Genetics Erasmus MC Rotterdam Rotterdam the Netherlands

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Genetics Maastricht University Medical Centre Maastricht the Netherlands

Department of Endocrinology University of Groningen University Medical Centre Groningen Groningen the Netherlands

Department of Genetics University of Groningen University Medical Centre Groningen Groningen the Netherlands

Department of Human Genetics Radboudumc expert centre for PHTS Radboud university medical centre Nijmegen the Netherlands

Department of Human Genetics University of Leuven Leuven Belgium

Department of Internal Medicine 1 University Hospital Bonn Bonn Germany

Department of Laboratory and Infectious Diseases Fondazione Policlinico Universitario A Gemelli IRCCS Rome Italy

Department of Medical and Surgical Sciences Centre for Studies on Hereditary Cancer University of Bologna Bologna Italy

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

Department of Medical Genetics Oslo University Hospital Oslo Norway

Department of Medical Genetics Pitié Salpêtrière Hospital APHP Sorbonne University Paris France

Department of Medical Genetics University Hospital of North Norway Tromsø Norway

Department of Medical Oncology Radboud university medical centre Nijmegen the Netherlands

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Pathology Radboud university medical centre Nijmegen the Netherlands

ERN GENTURIS Hereditary Cancer Syndrome Centre Dresden Dresden Germany

European Reference Network for Genetic Tumour Risk Syndromes Nijmegen the Netherlands

Faculty of Health Studies VID Specialized University Bergen Norway

Genetica Medica Azienda Ospedaliero Universitaria Senese Siena 53100 Italy

German Cancer Consortium Dresden Germany

Hereditary Cancer Program Catalan Institute of Oncology IDIBELL IDIBGI Barcelona Girona Spain

Inserm U830 DNA Repair and Uveal Melanoma Equipe Labellisée Par la Ligue Nationale Contre le Cancer Paris France

Institut Curie Service de Génétique Paris France

Institute for Clinical Genetics Faculty of Medicine Carl Gustav Carus Technische Universität Dresden Dresden Germany

Institute of Human Genetics Medical Faculty University of Bonn Bonn Germany

Institute of Oncology Riga Stradins University Riga Latvia

Karaiskakio Foundation Nicosia Cyprus and Archbishop Makarios 3 Children's Hospital Nicosia Cyprus

Manchester Centre for Genomic Medicine St Mary's Hospital Division of Evolution and Genomic Sciences School of Biological Sciences University of Manchester Manchester UK

Med Biotech Hub and Competence Centre Department of Medical Biotechnologies University of Siena Siena 53100 Italy

Medical Genetics Centre Germany; Arbeitsgruppe Erbliche Gastrointestinale Tumore Medizinische Klinik und Poliklinik 4 Campus Innenstadt Klinikum der Universität München München Germany

Medical Genetics Department of Medicine and Surgery University of Parma Parma Italy

Medical Genetics Section Department of Life Sciences and Public Health Università Cattolica del Sacro Cuore Rome Italy

Medical Genetics Unit IRCCS Azienda Ospedaliero Universitaria di Bologna Bologna Italy

Medical Genetics University of Siena Siena Italy

Medical Oncology Department Vall d'Hebron Hospital Universitari Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

National Centre for Tumour Diseases Partner Site Dresden Dresden Germany

Radboud Institute for Medical Innovation Radboud university medical centre Nijmegen the Netherlands

Sorbonne University Paris Brain Institute ICM Inserm CNRS Hôpital de la Pitié Salpêtrière 75013 Paris France

Univ Rouen Normandie Inserm U1245 FHU G4 Génomique and CHU Rouen Department of Genetics 76000 Rouen France

Western Norway Familial Cancer Centre Department of Medical Genetics Haukeland University Hospital Bergen Norway

Zobrazit více v PubMed

Brohet RM, Velthuizen ME, Hogervorst FB, Meijers-Heijboer HE, Seynaeve C, Collée MJ, et al. Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations. J Med Genet. 2014;51:98–107. PubMed

Kuchenbaecker KB, Hopper JL, Barnes DR, Phillips KA, Mooij TM, Roos-Blom MJ, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. Jama. 2017;317:2402–16. PubMed

Nelen MR, Kremer H, Konings IB, Schoute F, van Essen AJ, Koch R, et al. Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations. Eur J Hum Genet. 1999;7:267–73. PubMed

Pilarski R PTEN Hamartoma Tumor Syndrome: A Clinical Overview. Cancers (Basel). 2019;11. PubMed PMC

Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, Brunet J, Lleuger-Pujol R, Høberg-Vetti H, et al. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. J Natl Cancer Inst. 2023;115:93–103. PubMed

Malentacchi F, Turrini I, Sorbi F, Projetto E, Castiglione F, Fambrini M, et al. Pilot investigation of the mutation profile of PIK3CA/PTEN genes (PI3K pathway) in grade 3 endometrial cancer. Oncol Rep. 2019;41:1560–74. PubMed PMC

Smith IN, Briggs JM. Structural mutation analysis of PTEN and its genotype-phenotype correlations in endometriosis and cancer. Proteins. 2016;84:1625–43. PubMed PMC

Lebok P, Kopperschmidt V, Kluth M, Hube-Magg C, Özden C, B T, et al. Partial PTEN deletion is linked to poor prognosis in breast cancer. BMC Cancer. 2015;15:963. PubMed PMC

Beg S, Siraj AK, Prabhakaran S, Jehan Z, Ajarim D, Al-Dayel F, et al. Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer. Breast Cancer Res Treatment. 2015;151:541–53. PubMed

Tang L, Li X, Gao Y, Chen L, Gu L, Chen J, et al. Phosphatase and tensin homolog (PTEN) expression on oncologic outcome in renal cell carcinoma: A systematic review and meta-analysis. PLoS One. 2017;12:e0179437. PubMed PMC

Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA. 2007;104:7564–9. PubMed PMC

Deng F, Ma YX, Liang L, Zhang P, Feng J. The pro-apoptosis effect of sinomenine in renal carcinoma via inducing autophagy through inactivating PI3K/AKT/mTOR pathway. Biomed Pharmacother. 2018;97:1269–74. PubMed

Burrows N, Williams J, Telfer BA, Resch J, Valentine HR, Fitzmaurice RJ, et al. Phosphatidylinositide 3-kinase (PI3K) and PI3K-related kinase (PIKK) activity contributes to radioresistance in thyroid carcinomas. Oncotarget. 2016;7:63106–23. PubMed PMC

Wang J, Xu J, Fu J, Yuan D, Guo F, Zhou C, et al. MiR-29a regulates radiosensitivity in human intestinal cells by targeting PTEN gene. Radiat Res. 2016;186:292–301. PubMed

Sizemore GM, Balakrishnan S, Thies KA, Hammer AM, Sizemore ST, Trimboli AJ, et al. Stromal PTEN determines mammary epithelial response to radiotherapy. Nat Commun. 2018;9:2783. PubMed PMC

Brana I, Pham NA, Kim L, Sakashita S, Li M, Ng C, et al. Novel combinations of PI3K-mTOR inhibitors with dacomitinib or chemotherapy in PTEN-deficient patient-derived tumor xenografts. Oncotarget. 2017;8:84659–70. PubMed PMC

Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treatment. 2011;128:447–56. PubMed

National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020) [Available from: https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. PubMed

Di Carlo VRB, Bannon F, Woods LM, Maringe C, Bonaventure A, Coleman MP, et al. Life tables for the CONCORD programme. Available from: http://csg.lshtm.ac.uk/life-tables, downloaded on March 2023.

Belgian Cancer Registry, Brussels, 2023.

Dutch Cancer Registry. Dutch Cancer Figures 2023. www.cijfersoverkanker.nl.

Carbognin L, Miglietta F, Paris I, Dieci MV. Prognostic and Predictive Implications of PTEN in Breast Cancer: Unfulfilled Promises but Intriguing Perspectives. Cancers (Basel). 2019;11:1401. PubMed PMC

Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15:222–34. PubMed PMC

Öfverholm A, Einbeigi Z, Wigermo A, Holmberg E, Karsson P. Increased overall mortality even after risk reducing surgery for BRCA-positive women in Western Sweden. Genes (Basel). 2019;10:1046. PubMed PMC

Huszno J, Kołosza Z, Grzybowska E. BRCA1 mutation in breast cancer patients: Analysis of prognostic factors and survival. Oncol Lett. 2019;17:1986–95. PubMed PMC

Schmidt MK, van den Broek AJ, Tollenaar RA, Smit VT, Westenend PJ, Brinkhuis M, et al. Breast cancer survival of BRCA1/BRCA2 mutation carriers in a hospital-based cohort of young women. J Natl Cancer Inst. 2017;109. 10.1093/jnci/djw329. PubMed

Lee EH, Park SK, Park B, Kim SW, Lee MH, Ahn SH, et al. Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis. Breast Cancer Res Treat. 2010;122:11–25. PubMed

Forjaz de Lacerda G, Howlader N, Mariotto AB. Differences in cancer survival with relative versus cause-specific approaches: an update using more accurate life tables. Cancer Epidemiol Biomarkers Prev. 2019;28:1544–51. PubMed PMC

Withrow DR, Pole JD, Nishri ED, Tjepkema M, Marrett LD. Choice of relative or cause-specific approach to cancer survival analysis impacts estimates differentially by cancer type, population, and application: evidence from a Canadian population-based cohort study. Popul Health Metr. 2017;15:24. PubMed PMC

Howlader N, Ries LA, Mariotto AB, Reichman ME, Ruhl J, Cronin KA. Improved estimates of cancer-specific survival rates from population-based data. J Natl Cancer Inst. 2010;102:1584–98. PubMed PMC

Agarwal S, Pappas L, Neumayer L, Kokeny K, Agarwal J. Effect of breast conservation therapy vs mastectomy on disease-specific survival for early-stage breast cancer. JAMA Surg. 2014;149:267–74. PubMed

Corradini S, Reitz D, Pazos M, Schönecker S, Braun M, Harbeck N, et al. Mastectomy or breast-conserving therapy for early breast cancer in real-life clinical practice: outcome comparison of 7565 cases. Cancers (Basel). 2019;11:160. PubMed PMC

Emiroglu SÖE, Cabıoglu N, Igci A, Saip P, Yazici H, Ozmen T, et al. Is breast conserving surgery efficacious in breast cancer patients with BRCA1 or BRCA2 germline mutation? Breast Cancer (Dove Med Press). 2023;15:163–73. PubMed PMC

Metcalfe K, Gershman S, Ghadirian P, Lynch HT, Snyder C, Tung N, et al. Contralateral mastectomy and survival after breast cancer in carriers of BRCA1 and BRCA2 mutations: retrospective analysis. Bmj. 2014;348:g226. PubMed PMC

van den Broek AJ, Schmidt MK, van ‘t Veer LJ, Oldenburg HSA, Rutgers EJ, Russell NS, et al. Prognostic impact of breast-conserving therapy versus mastectomy of BRCA1/2 mutation carriers compared with noncarriers in a consecutive series of young breast cancer patients. Ann Surg. 2019;270:364–72. PubMed

Ngeow J, Stanuch K, Mester JL, Barnholtz-Sloan JS, Eng C. Second malignant neoplasms in patients with Cowden syndrome with underlying germline PTEN mutations. J Clin Oncol. 2014;32:1818–24. PubMed PMC

Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30:1194–220. PubMed

Friedenreich CM, Cook LS, Wang Q, Kokts-Porietis RL, McNeil J, Ryder-Burbidge C, et al. Prospective cohort study of pre- and postdiagnosis physical activity and endometrial cancer survival. J Clin Oncol. 2020;38:4107–17. PubMed PMC

Singer S, Husson O, Tomaszewska IM, Locati LD, Kiyota N, Scheidemann-Wesp U, et al. Quality-of-life priorities in patients with thyroid cancer: a multinational European Organisation for Research and Treatment of Cancer Phase I Study. Thyroid®. 2016;26:1605–13. PubMed

Steele SR, Park GE, Johnson EK, Martin MJ, Stojadinovic A, Maykel JA, et al. The impact of age on colorectal cancer incidence, treatment, and outcomes in an equal-access health care system. Dis Colon & Rectum. 2014;57:303–10. PubMed

Thorstenson A, Bergman M, Scherman-Plogell A-H, Hosseinnia S, Ljungberg B, Adolfsson J, et al. Tumour characteristics and surgical treatment of renal cell carcinoma in Sweden 2005–2010: a population-based study from the National Swedish Kidney Cancer Register. Scandinavian Journal of Urology. 2014;48:231–8. PubMed

Plym A, Ullenhag GJ, Breivald M, Lambe M, Berglund A. Clinical characteristics, management and survival in young adults diagnosed with malignant melanoma: A population-based cohort study. Acta Oncologica. 2014;53:688–96. PubMed

Tejerizo-García A, Jiménez-López JS, Muñoz-González JL, Bartolomé-Sotillos S, Marqueta-Marqués L, López-González G, et al. Overall survival and disease-free survival in endometrial cancer: prognostic factors in 276 patients. Onco Targets Ther. 2013;9:1305–13. PubMed PMC

Felix AS, Brinton LA. Cancer progress and priorities: uterine cancer. Cancer Epidemiol Biomarkers Prev. 2018;27:985–94. PubMed PMC

Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. Eur J Hum Genet. 2020;28:1387–93. PubMed PMC

Drissen M, Vos JR, van der Biessen-van Beek DTJ, van der Post RS, Nagtegaal ID, van Kouwen MCA, et al. Detection and yield of colorectal cancer surveillance in adults with PTEN hamartoma tumour syndrome. Cancers (Basel). 2022;14:4005. PubMed PMC

Smolarz B, Nowak AZ, Romanowicz H. Breast cancer-epidemiology, classification, pathogenesis and treatment (Review of Literature). Cancers (Basel). 2022;14:2569. PubMed PMC

Vaccarella S, Georges D, Bray F, Ginsburg O, Charvat H, Martikainen P, et al. Socioeconomic inequalities in cancer mortality between and within countries in Europe: a population-based study. Lancet Reg Health Eur. 2023;25:100551. PubMed PMC

Brandt J, Garne JP, Tengrup I, Manjer J. Age at diagnosis in relation to survival following breast cancer: a cohort study. World J Surg Oncol. 2015;13:33. PubMed PMC