Breast Cancer Screening in the Precision Medicine Era: Risk-Based Screening in a Population-Based Trial

Ongoing controversy over the optimal approach to breast cancer screening has led to discordant professional society recommendations, particularly in women age 40 to 49 years. One potential solution is risk-based screening, where decisions around the starting age, stopping age, frequency, and modality of screening are based on individual risk to maximize the early detection of aggressive cancers and minimize the harms of screening through optimal resource utilization. We present a novel approach to risk-based screening that integrates clinical risk factors, breast density, a polygenic risk score representing the cumulative effects of genetic variants, and sequencing for moderate- and high-penetrance germline mutations. We demonstrate how thresholds of absolute risk estimates generated by our prediction tools can be used to stratify women into different screening strategies (biennial mammography, annual mammography, annual mammography with adjunctive magnetic resonance imaging, defer screening at this time) while informing the starting age of screening for women age 40 to 49 years. Our risk thresholds and corresponding screening strategies are based on current evidence but need to be tested in clinical trials. The Women Informed to Screen Depending On Measures of risk (WISDOM) Study, a pragmatic, preference-tolerant randomized controlled trial of annual vs personalized screening, will study our proposed approach. WISDOM will evaluate the efficacy, safety, and acceptability of risk-based screening beginning in the fall of 2016. The adaptive design of this trial allows continued refinement of our risk thresholds as the trial progresses, and we discuss areas where we anticipate emerging evidence will impact our approach.

[1]  H. Caron,et al.  A worldwide collaboration to harmonize guidelines for the long‐term follow‐up of childhood and young adult cancer survivors: A report from the international late effects of Childhood Cancer Guideline Harmonization Group , 2013, Pediatric blood & cancer.

[2]  R. Advani,et al.  ACR Appropriateness Criteria: follow-up of Hodgkin's lymphoma. , 2010, Current problems in cancer.

[3]  S. Friedman,et al.  NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2017. , 2017, Journal of the National Comprehensive Cancer Network : JNCCN.

[4]  D. Berry,et al.  Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. , 1997, Journal of the National Cancer Institute.

[5]  A Howell,et al.  Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme , 2003, Journal of medical genetics.

[6]  Rochelle Fu,et al.  Effectiveness of Breast Cancer Screening: Systematic Review and Meta-analysis to Update the 2009 U.S. Preventive Services Task Force Recommendation , 2016, Annals of Internal Medicine.

[7]  N. Powe,et al.  Diversity in Clinical and Biomedical Research: A Promise Yet to Be Fulfilled , 2015, bioRxiv.

[8]  H. Nelson,et al.  Screening for Breast Cancer: An Update for the U.S. Preventive Services Task Force , 2009, Annals of Internal Medicine.

[9]  Gillian D Sanders,et al.  Benefits and Harms of Breast Cancer Screening: A Systematic Review. , 2015, JAMA.

[10]  V. Moyer Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. , 2014, Annals of internal medicine.

[11]  Amy Cantor,et al.  Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation , 2016, Annals of Internal Medicine.

[12]  Gary K. Chen,et al.  A comprehensive examination of breast cancer risk loci in African American women. , 2014, Human molecular genetics.

[13]  R. Advani,et al.  Hodgkin lymphoma, version 2.2012 featured updates to the NCCN guidelines. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[14]  Sarah A. Edwards,et al.  Tumor characteristics associated with mammographic detection of breast cancer in the Ontario breast screening program. , 2011, Journal of the National Cancer Institute.

[15]  Ellen Warner,et al.  Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination , 2004, JAMA.

[16]  Practice bulletin no. 122: Breast cancer screening. , 2011, Obstetrics and gynecology.

[17]  J. Hopper,et al.  Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. , 2003, American journal of human genetics.

[18]  Magali Olivier,et al.  TP53 mutations in human cancers: origins, consequences, and clinical use. , 2010, Cold Spring Harbor perspectives in biology.

[19]  Nazneen Rahman,et al.  Gene-panel sequencing and the prediction of breast-cancer risk. , 2015, The New England journal of medicine.

[20]  W. Han,et al.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls. , 2013, Human molecular genetics.

[21]  G. Colditz,et al.  Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. , 2000, American journal of epidemiology.

[22]  J Benichou,et al.  Validation studies for models projecting the risk of invasive and total breast cancer incidence. , 1999, Journal of the National Cancer Institute.

[23]  Mark E. Robson,et al.  Counselling framework for moderate-penetrance cancer-susceptibility mutations , 2016, Nature Reviews Clinical Oncology.

[24]  C. Vachon,et al.  Breast Density and Benign Breast Disease: Risk Assessment to Identify Women at High Risk of Breast Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Orli G. Bahcall Common variation and heritability estimates for breast, ovarian and prostate cancers , 2013, Nature Genetics.

[26]  Patrick Neven,et al.  Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer , 2015 .

[27]  Stephen W Duffy,et al.  A breast cancer prediction model incorporating familial and personal risk factors , 2004, Hereditary Cancer in Clinical Practice.

[28]  E. Halperin,et al.  Presymptomatic Risk Assessment for Chronic Non-Communicable Diseases , 2010, PloS one.

[29]  L. Esserman,et al.  Population-based screening for cancer: hope and hype , 2016, Nature Reviews Clinical Oncology.

[30]  M. Yaffe,et al.  American Cancer Society Guidelines for Breast Screening with MRI as an Adjunct to Mammography , 2007 .

[31]  G. Anderson,et al.  Predicting risk of breast cancer in postmenopausal women by hormone receptor status. , 2007, Journal of the National Cancer Institute.

[32]  Richard D. Riley,et al.  A systematic review of breast cancer incidence risk prediction models with meta-analysis of their performance , 2012, Breast Cancer Research and Treatment.

[33]  Christopher R. Gignoux,et al.  Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25 , 2014, Nature Communications.

[34]  D. Easton,et al.  Polygenic susceptibility to prostate and breast cancer: implications for personalised screening , 2011, British Journal of Cancer.

[35]  The Polish Breast Cancer Consortium Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations , 2002 .

[36]  Michael Jones,et al.  Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  A. Jemal,et al.  Mammography Use and Physician Recommendation After the 2009 U.S. Preventive Services Task Force Breast Cancer Screening Recommendations. , 2016, American journal of preventive medicine.

[38]  A. Tosteson,et al.  Provider Attitudes and Screening Practices Following Changes in Breast and Cervical Cancer Screening Guidelines , 2015, Journal of General Internal Medicine.

[39]  Rongwei Fu,et al.  Use of Medications to Reduce Risk for Primary Breast Cancer: A Systematic Review for the U.S. Preventive Services Task Force , 2013, Annals of Internal Medicine.

[40]  C. Fox,et al.  Breast-cancer screening. , 1979, Lancet.

[41]  S. Gruber,et al.  Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome , 2006, Clinical Cancer Research.

[42]  J. Stockman Systematic Review: Surveillance for Breast Cancer in Women Treated With Chest Radiation for Childhood, Adolescent, or Young Adult Cancer , 2011 .

[43]  Jane E. Carpenter,et al.  Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants , 2015, JNCI Journal of the National Cancer Institute.

[44]  H. D. de Koning,et al.  Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. , 2004, The New England journal of medicine.

[45]  G. Giles,et al.  Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[46]  M. King,et al.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2 , 2014, Proceedings of the National Academy of Sciences.

[47]  J. Lortet-Tieulent,et al.  Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society , 2016 .

[48]  David A Mankoff,et al.  ACR Appropriateness Criteria Breast Cancer Screening. , 2016, Journal of the American College of Radiology : JACR.

[49]  S. Cummings,et al.  Personalizing Mammography by Breast Density and Other Risk Factors for Breast Cancer: Analysis of Health Benefits and Cost-Effectiveness , 2011, Annals of Internal Medicine.

[50]  Rebecca A Hubbard,et al.  Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. , 2013, JAMA internal medicine.

[51]  J. Chang-Claude,et al.  Gene–environment interaction and risk of breast cancer , 2016, British Journal of Cancer.

[52]  M. Gail,et al.  Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. , 1989, Journal of the National Cancer Institute.

[53]  Jacques Simard,et al.  Incorporating Truncating Variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model , 2016, Genetics in Medicine.

[54]  T. Wilt,et al.  Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement , 2011 .

[55]  D Spiegelman,et al.  Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. , 2001, Journal of the National Cancer Institute.

[56]  L. Shulman,et al.  Prevention of Breast Cancer in Postmenopausal Women: Approaches to Estimating and Reducing Risk , 2009 .

[57]  C. Begg,et al.  Breast cancer after chest radiation therapy for childhood cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  C. Vachon,et al.  Genetic susceptibility to triple-negative breast cancer. , 2013, Cancer research.

[59]  Graham A Colditz,et al.  Risk factors for breast cancer according to estrogen and progesterone receptor status. , 2004, Journal of the National Cancer Institute.

[60]  Lesley McGuffog,et al.  Cancer risks and mortality in heterozygous ATM mutation carriers. , 2005, Journal of the National Cancer Institute.

[61]  R. Birdwell,et al.  Prospective study of the efficacy of breast magnetic resonance imaging and mammographic screening in survivors of Hodgkin lymphoma. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  M. Intra,et al.  CDH1 germline mutations and hereditary lobular breast cancer , 2016, Familial Cancer.

[63]  S. Cummings,et al.  Breast cancer risk prediction using a clinical risk model and polygenic risk score , 2016, Breast Cancer Research and Treatment.

[64]  V Shane Pankratz,et al.  Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Jaana M. Hartikainen,et al.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk , 2013, Nature Genetics.

[66]  C. Eng,et al.  Lifetime Cancer Risks in Individuals with Germline PTEN Mutations , 2012, Clinical Cancer Research.

[67]  Karla Kerlikowske,et al.  Using Clinical Factors and Mammographic Breast Density to Estimate Breast Cancer Risk: Development and Validation of a New Predictive Model , 2008, Annals of Internal Medicine.

[68]  V. Moyer Medications for Risk Reduction of Primary Breast Cancer in Women: U.S. Preventive Services Task Force Recommendation Statement , 2013, Annals of Internal Medicine.

[69]  Peter Kraft,et al.  Interactions between genetic variants and breast cancer risk factors in the breast and prostate cancer cohort consortium. , 2011, Journal of the National Cancer Institute.

[70]  Jinbo Chen,et al.  Projecting absolute invasive breast cancer risk in white women with a model that includes mammographic density. , 2006, Journal of the National Cancer Institute.

[71]  E Stephens,et al.  Cancer screening , 2002, Journal of epidemiology and community health.

[72]  S. Feig,et al.  Personalized Screening for Breast Cancer: A Wolf in Sheep's Clothing? , 2015, AJR. American journal of roentgenology.

[73]  David A. Hinds,et al.  Assessment of Clinical Validity of a Breast Cancer Risk Model Combining Genetic and Clinical Information , 2010, Journal of the National Cancer Institute.

[74]  Oguzhan Alagoz,et al.  Collaborative Modeling of the Benefits and Harms Associated With Different U.S. Breast Cancer Screening Strategies , 2016, Annals of Internal Medicine.

[75]  Karla Kerlikowske,et al.  The contributions of breast density and common genetic variation to breast cancer risk. , 2015, Journal of the National Cancer Institute.

[76]  R. Nussbaum,et al.  Genetic/familial high-risk assessment: breast and ovarian. , 2010, Journal of the National Comprehensive Cancer Network : JNCCN.

[77]  J. Lortet-Tieulent,et al.  Breast Cancer Screening for Women at Average Risk: 2015 Guideline Update From the American Cancer Society. , 2015, JAMA.