Marc Tischkowitz1, Judith Balmaña2, William D Foulkes3, Paul James4,5, Joanne Ngeow6,7, Rita Schmutzler8,9, Nicoleta Voian10, Myra J Wick11, Douglas R Stewart12, Tuya Pal13. 1. Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK. 2. Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO) and Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Hospital Campus, Barcelona, Spain. 3. Departments of Human Genetics, Oncology and Medicine, McGill University, Montréal, QC, Canada. 4. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia. 5. Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 6. Genomic Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. 7. Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre, Singapore, Singapore. 8. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. 9. University Hospital of Cologne, Center of Integrated Oncology, CIO and Center of Familial Breast and Ovarian Cancer, Cologne, Germany. 10. Genetic Risk Clinic, Providence Cancer Institute, Portland, OR, USA. 11. Departments of Obstetrics and Gynecology and Clinical Genomics, Mayo Clinic, Rochester, MN, USA. 12. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. 13. Department of Medicine, Vanderbilt University Medical Center/Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
Abstract
PURPOSE: PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited. METHODS: A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors. RESULTS: PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2. CONCLUSION: This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.
PURPOSE: PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited. METHODS: A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors. RESULTS: PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2. CONCLUSION: This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis.
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