Comprehensive Inherited Risk Estimation for Risk-Based Breast Cancer Screening in Women
Authors: Nina Mars, Sini Kerminen, Max Tamlander, Matti Pirinen, Eveliina Jakkula, Kirsimari Aaltonen, Tuomo Meretoja, Sirpa Heinävaara, Elisabeth Widén, Samuli Ripatti, Aarno Palotie, Mark Daly, Bridget Riley-Gills, Howard Jacob, Dirk Paul, Athena Matakidou, Adam Platt, Heiko Runz, Sally John, George Okafo, Nathan Lawless, Robert Plenge, Joseph Maranville, Mark McCarthy, Julie Hunkapiller, Margaret G. Ehm, Kirsi Auro, Simonne Longerich, Caroline Fox, Anders Mälarstig, Katherine Klinger, Deepak Raipal, Eric Green, Robert Graham, Robert Yang, Chris O'Donnell, Tomi P. Mäkelä, Jaakko Kaprio, Petri Virolainen, Antti Hakanen, Terhi Kilpi, Markus Perola, Jukka Partanen, Anne Pitkäranta, Juhani Junttila, Raisa Serpi, Tarja Laitinen, Veli-Matti Kosma, Jari Laukkanen, Marco Hautalahti, Outi Tuovila, Raimo Pakkanen, Jeffrey Waring, Bridget Riley-Gillis, Fedik Rahimov, Ioanna Tachmazidou, Chia-Yen Chen, Heiko Runz, Zhihao Ding, Marc Jung, Shameek Biswas, Rion Pendergrass, Julie Hunkapiller, Margaret G. Ehm, David Pulford, Neha Raghavan, Adriana Huertas-Vazquez, Jae-Hoon Sul, Anders Mälarstig, Xinli Hu, Katherine Klinger, Robert Graham, Eric Green, Sahar Mozaffari, Dawn Waterworth, Nicole Renaud, Ma'en Obeidat, Samuli Ripatti, Johanna Schleutker, Markus Perola, Mikko Arvas, Olli Carpén, Reetta Hinttala, Johannes Kettunen, Arto Mannermaa, Katriina Aalto-Setälä, Mika Kähönen, Jari Laukkanen, Johanna Mäkelä, Reetta Kälviäinen, Valtteri Julkunen, Hilkka Soininen, Anne Remes, Mikko Hiltunen, Jukka Peltola, Minna Raivio, Pentti Tienari, Juha Rinne, Roosa Kallionpää, Juulia Partanen, Ali Abbasi, Adam Ziemann, Nizar Smaoui, Anne Lehtonen, Susan Eaton, Heiko Runz, Sanni Lahdenperä, Shameek Biswas, Julie Hunkapiller, Natalie Bowers, Edmond Teng, Rion Pendergrass, Fanli Xu, David Pulford, Kirsi Auro, Laura Addis, John Eicher, Qingqin S Li, Karen He, Ekaterina Khramtsova, Neha Raghavan, Martti Färkkilä, Jukka Koskela, Sampsa Pikkarainen, Airi Jussila, Katri Kaukinen, Timo Blomster, Mikko Kiviniemi, Markku Voutilainen, Mark Daly, Ali Abbasi, Jeffrey Waring, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, Tim Lu, Natalie Bowers, Rion Pendergrass, Linda McCarthy, Amy Hart, Meijian Guan, Jason Miller, Kirsi Kalpala, Melissa Miller, Xinli Hu, Kari Eklund, Antti Palomäki, Pia Isomäki, Laura Pirilä, Oili Kaipiainen-Seppänen, Johanna Huhtakangas, Nina Mars, Ali Abbasi, Jeffrey Waring, Fedik Rahimov, Apinya Lertratanakul, Nizar Smaoui, Anne Lehtonen, David Close, Marla Hochfeld, Natalie Bowers, Rion Pendergrass, Jorge Esparza Gordillo, Kirsi Auro, Dawn Waterworth, Fabiana Farias, Kirsi Kalpala, Nan Bing, Xinli Hu, Tarja Laitinen, Margit Pelkonen, Paula Kauppi, Hannu Kankaanranta, Terttu Harju, Riitta Lahesmaa, Nizar Smaoui, Alex Mackay, Glenda Lassi, Susan Eaton, Hubert Chen, Rion Pendergrass, Natalie Bowers, Joanna Betts, Kirsi Auro, Rajashree Mishra, Majd Mouded, Debby Ngo, Teemu Niiranen, Felix Vaura, Veikko Salomaa, Kaj Metsärinne, Jenni Aittokallio, Mika Kähönen, Jussi Hernesniemi, Daniel Gordin, Juha Sinisalo, Marja-Riitta Taskinen, Tiinamaija Tuomi, Timo Hiltunen, Jari Laukkanen, Amanda Elliott, Mary Pat Reeve, Sanni Ruotsalainen, Benjamin Challis, Dirk Paul, Julie Hunkapiller, Natalie Bowers, Rion Pendergrass, Audrey Chu, Kirsi Auro, Dermot Reilly, Mike Mendelson, Jaakko Parkkinen, Melissa Miller, Tuomo Meretoja, Heikki Joensuu, Olli Carpén, Johanna Mattson, Eveliina Salminen, Annika Auranen, Peeter Karihtala, Päivi Auvinen, Klaus Elenius, Johanna Schleutker, Esa Pitkänen, Nina Mars, Mark Daly, Relja Popovic, Jeffrey Waring, Bridget Riley-Gillis, Anne Lehtonen, Jennifer Schutzman, Julie Hunkapiller, Natalie Bowers, Rion Pendergrass, Diptee Kulkarni, Kirsi Auro, Alessandro Porello, Andrey Loboda, Heli Lehtonen, Stefan McDonough, Sauli Vuoti, Kai Kaarniranta, Joni A Turunen, Terhi Ollila, Hannu Uusitalo, Juha Karjalainen, Esa Pitkänen, Mengzhen Liu, Heiko Runz, Stephanie Loomis, Erich Strauss, Natalie Bowers, Hao Chen, Rion Pendergrass, Kaisa Tasanen, Laura Huilaja, Katariina Hannula-Jouppi, Teea Salmi, Sirkku Peltonen, Leena Koulu, Nizar Smaoui, Fedik Rahimov, Anne Lehtonen, David Choy, Rion Pendergrass, Dawn Waterworth, Kirsi Kalpala, Ying Wu, Pirkko Pussinen, Aino Salminen, Tuula Salo, David Rice, Pekka Nieminen, Ulla Palotie, Maria Siponen, Liisa Suominen, Päivi Mäntylä, Ulvi Gursoy, Vuokko Anttonen, Kirsi Sipilä, Rion Pendergrass, Hannele Laivuori, Venla Kurra, Laura Kotaniemi-Talonen, Oskari Heikinheimo, Ilkka Kalliala, Lauri Aaltonen, Varpu Jokimaa, Johannes Kettunen, Marja Vääräsmäki, Outi Uimari, Laure Morin-Papunen, Maarit Niinimäki, Terhi Piltonen, Katja Kivinen, Elisabeth Widen, Taru Tukiainen, Mary Pat Reeve, Mark Daly, Niko Välimäki, Eija Laakkonen, Jaakko Tyrmi, Heidi Silven, Eeva Sliz, Riikka Arffman, Susanna Savukoski, Triin Laisk, Natalia Pujol, Mengzhen Liu, Bridget Riley-Gillis, Rion Pendergrass, Janet Kumar, Kirsi Auro, Iiris Hovatta, Chia-Yen Chen, Erkki Isometsä, Kumar Veerapen, Hanna Ollila, Jaana Suvisaari, Thomas Damm Als, Antti Mäkitie, Argyro Bizaki-Vallaskangas, Sanna Toppila-Salmi, Tytti Willberg, Elmo Saarentaus, Antti Aarnisalo, Eveliina Salminen, Elisa Rahikkala, Johannes Kettunen, Kristiina Aittomäki, Fredrik Åberg, Mitja Kurki, Samuli Ripatti, Mark Daly, Juha Karjalainen, Aki Havulinna, Juha Mehtonen, Priit Palta, Shabbeer Hassan, Pietro Della Briotta Parolo, Wei Zhou, Mutaamba Maasha, Kumar Veerapen, Shabbeer Hassan, Susanna Lemmelä, Manuel Rivas, Mari E. Niemi, Aarno Palotie, Aoxing Liu, Arto Lehisto, Andrea Ganna, Vincent Llorens, Hannele Laivuori, Taru Tukiainen, Mary Pat Reeve, Henrike Heyne, Nina Mars, Joel Rämö, Elmo Saarentaus, Hanna Ollila, Rodos Rodosthenous, Satu Strausz, Tuula Palotie, Kimmo Palin, Javier Garcia-Tabuenca, Harri Siirtola, Tuomo Kiiskinen, Jiwoo Lee, Kristin Tsuo, Amanda Elliott, Kati Kristiansson, Mikko Arvas, Kati Hyvärinen, Jarmo Ritari, Olli Carpén, Johannes Kettunen, Katri Pylkäs, Eeva Sliz, Minna Karjalainen, Tuomo Mantere, Eeva Kangasniemi, Sami Heikkinen, Arto Mannermaa, Eija Laakkonen, Nina Pitkänen, Samuel Lessard, Clément Chatelain, Perttu Terho, Sirpa Soini, Jukka Partanen, Eero Punkka, Raisa Serpi, Sanna Siltanen, Veli-Matti Kosma, Teijo Kuopio, Anu Jalanko, Huei-Yi Shen, Risto Kajanne, Mervi Aavikko, Mitja Kurki, Juha Karjalainen, Pietro Della Briotta Parolo, Arto Lehisto, Juha Mehtonen, Wei Zhou, Masahiro Kanai, Mutaamba Maasha, Kumar Veerapen, Hannele Laivuori, Aki Havulinna, Susanna Lemmelä, Tuomo Kiiskinen, L. Elisa Lahtela, Mari Kaunisto, Elina Kilpeläinen, Timo P. Sipilä, Oluwaseun Alexander Dada, Awaisa Ghazal, Anastasia Kytölä, Rigbe Weldatsadik, Kati Donner, Timo P. Sipilä, Anu Loukola, Päivi Laiho, Tuuli Sistonen, Essi Kaiharju, Markku Laukkanen, Elina Järvensivu, Sini Lähteenmäki, Lotta Männikkö, Regis Wong, Auli Toivola, Minna Brunfeldt, Hannele Mattsson, Kati Kristiansson, Susanna Lemmelä, Sami Koskelainen, Tero Hiekkalinna, Teemu Paajanen, Priit Palta, Kalle Pärn, Mart Kals, Shuang Luo, Vishal Sinha, Tarja Laitinen, Mary Pat Reeve, Marianna Niemi, Kumar Veerapen, Harri Siirtola, Javier Gracia-Tabuenca, Mika Helminen, Tiina Luukkaala, Iida Vähätalo, Jyrki Pitkänen, Marco Hautalahti, Johanna Mäkelä, Sarah Smith, Tom Southerington
Journal: Journal of Clinical Oncology (2024)

PURPOSE Family history (FH) and pathogenic variants (PVs) are used for guiding risk surveillance in selected high-risk women but little is known about their impact for breast cancer screening on population level. In addition, polygenic risk scores (PRSs) have been shown to efficiently stratify breast cancer risk through combining information about common genetic factors into one measure. METHODS In longitudinal real-life data, we evaluate PRS, FH, and PVs for stratified screening. Using FinnGen (N = 117,252), linked to the Mass Screening Registry for breast cancer (1992-2019; nationwide organized biennial screening for age 50-69 years), we assessed the screening performance of a breast cancer PRS and compared its performance with FH of breast cancer and PVs in moderate- ( CHEK2 )- to high-risk ( PALB2 ) susceptibility genes. RESULTS Effect sizes for FH, PVs, and high PRS (&gt;90th percentile) were comparable in screening-aged women, with similar implications for shifting age at screening onset. A high PRS identified women more likely to be diagnosed with breast cancer after a positive screening finding (positive predictive value [PPV], 39.5% [95% CI, 37.6 to 41.5]). Combinations of risk factors increased the PPVs up to 45% to 50%. A high PRS conferred an elevated risk of interval breast cancer (hazard ratio [HR], 2.78 [95% CI, 2.00 to 3.86] at age 50 years; HR, 2.48 [95% CI, 1.67 to 3.70] at age 60 years), and women with a low PRS (&lt;10th percentile) had a low risk for both interval- and screen-detected breast cancers. CONCLUSION Using real-life screening data, this study demonstrates the effectiveness of a breast cancer PRS for risk stratification, alone and combined with FH and PVs. Further research is required to evaluate their impact in a prospective risk-stratified screening program, including cost-effectiveness.