Abstract: Purpose: Magnetic resonance imaging (MRI) screening enables early detection of breast cancers in women with an inherited predisposition. Interval cancers occurred in women with a BRCA1 mutation, possibly due to fast tumor growth. We investigated the effect of a BRCA1 or BRCA2 mutation and age on the growth rate of breast cancers, as this may influence the optimal screening frequency. Experimental Design: We reviewed the invasive cancers from the United Kingdom, Dutch, and Canadian MRI screening trials for women at hereditary risk, measuring tumor size at diagnosis and on preceding MRI and/or mammography. We could assess tumor volume doubling time (DT) in 100 cancers. Results: Tumor DT was estimated for 43 women with a BRCA1 mutation, 16 women with a BRCA2 mutation, and 41 women at high risk without an identified mutation. Growth rate slowed continuously with increasing age (P = 0.004). Growth was twice as fast in BRCA1 (P = 0.003) or BRCA2 (P = 0.03) patients as in high-risk patients of the same age. The mean DT for women with BRCA1/2 mutations diagnosed at ages ≤40, 41 to 50, and & gt;50 years was 28, 68, and 81 days, respectively, and 83, 121, and 173 days, respectively, in the high-risk group. Pathologic tumor size decreased with increasing age (P = 0.001). Median size was 15 mm for patients ages ≤40 years compared with 9 mm in older patients (P = 0.003); tumors were largest in young women with BRCA1 mutations. Conclusion: Tumors grow quickly in women with BRCA1 mutations and in young women. Age and risk group should be taken into account in screening protocols.

Abstract: Background: It is recommended that BRCA1/2 mutation carriers undergo breast cancer screening using MRI because of their very high cancer risk and the high sensitivity of MRI in detecting invasive cancers. Clinical observations suggest important differences in the natural history between breast cancers due to mutations in BRCA1 and BRCA2, potentially requiring different screening guidelines. Methods: Three studies of mutation carriers using annual MRI and mammography were analyzed. Separate natural history models for BRCA1 and BRCA2 were calibrated to the results of these studies and used to predict the impact of various screening protocols on detection characteristics and mortality. Results: BRCA1/2 mutation carriers (N = 1,275) participated in the studies and 124 cancers (99 invasive) were diagnosed. Cancers detected in BRCA2 mutation carriers were smaller [80% ductal carcinoma in situ (DCIS) or ≤10 mm vs. 49% for BRCA1, P & lt; 0.001]. Below the age of 40, one (invasive) cancer of the 25 screen-detected cancers in BRCA1 mutation carriers was detected by mammography alone, compared with seven (three invasive) of 11 screen-detected cancers in BRCA2 (P & lt; 0.0001). In the model, the preclinical period during which cancer is screen-detectable was 1 to 4 years for BRCA1 and 2 to 7 years for BRCA2. The model predicted breast cancer mortality reductions of 42% to 47% for mammography, 48% to 61% for MRI, and 50% to 62% for combined screening. Conclusions: Our studies suggest substantial mortality benefits in using MRI to screen BRCA1/2 mutation carriers aged 25 to 60 years but show important clinical differences in natural history. Impact: BRCA1 and BRCA2 mutation carriers may benefit from different screening protocols, for example, below the age of 40. Cancer Epidemiol Biomarkers Prev; 21(9); 1458–68. ©2012 AACR.

Abstract: Introduction: To reduce mortality, all guidelines advice women with very high breast cancer (BC) risk, due to a pathogenic variant (PV) in genes like BRA1/2 or chest wall irradiation between age 10-30 yrs., annual screening with Magnetic Resonance Imaging (MRI) and 2 or 3D mammography (Mm).1-6 For MRI, starting age for this group is usually 25 years. However for Mm some guidelines advise annual from age 30 yrs.1,2, others 10 yr. younger than the youngest family member 4,5, or for BRCA1 biennial from age 40 yrs.7 USA and Canadian but not European guidelines advice MRI screening also for women with a ≥ 20% lifetime breast cancer (BC) risk, while the European Eusobi guideline, unlike the US and Canadian, now advises to screen women with extremely dense breasts with MRI although not yearly.8 Considerations and evidence: We need to balance the possible benefit with the disadvantages of screening, like false positive rate, possible overdiagnosis and cost. We therefore have to use the optimal frequency of screening, depending on the expected tumor growth rate, which varies with a woman’s age and the cause of the increased risk.9 Two recent randomized trials one in women with familial risk the other for extremely dense breasts showed how much MRI advances BC detection compared to mammography, at which side effects.10,11 Observational and modelling studies show varying additional value of Mm to MRI-screening for different risk – and age groups.12-17 Conclusion: Screening for women at high risk can be better tailored to the age and risk-group. References: 1. American College of Radiology (ACR) Appropriateness Criteria. Breast Cancer Screening: High risk women. www. cancer.org. Assessed 2022-9-17 2. American Cancer Society Guideline High risk. Last Revised Jan. 2022. www.cancer.org 3. Mulder RL, Hudson MM, Bathia S et al. J Clin Oncol. 2020 Dec 10;38(35):4194-4207.Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group. 4. Cancer Care Ontario’s (CCO) “Magnetic Resonance Imaging Screening of Women at High Risk for Breast Cancer“, practice guideline; https://www.easternhealth.ca/wp-content/uploads/sites/2/2018/06/Breast-Magnetic-Resonance-MRI-and-High-Risk-Guideline_2017.pdf. and www.cancercare.on.ca 5. William J, Benjamin OA et al. Breast cancer screening and Diagnosis Version 1 2019.2. NCCN clinical practice guidelines in oncology. J Natl. ComprCaNetwork 2020;18(4):452-78. www.nccn.org. version 1 2022 6. National Institute for Health and Care Excellence (NICE). Familial breast cancer: Classification and care of people at risk of familial breast cancer and management of breast cancer and related risks in people with a family history of breast cancer. www.guidance.nice.org.uk/CG80/Guidance. 7.The Dutch guideline breast screening outside the National screening scheme: https://richtlijnendatabase.nl/richtlijn/borstkanker/screening/screening_buiten_het_bob/screening_buiten_het_bevolkingsonderzoek.html. Assessed 19 September 2022. 8. Mann EM, Athanasiou A, Baltzer PAT et al. Breast cancer screening in women with extremely dense breasts recommendations of the European Society of Breast Imaging (EUSOBI). European Radiology 2022;32: 4036-45. 9. Tilanus-Linthorst MMA, Obdeijn AIM, Hop WCJ et al. Age and a BRCA1 or-2 mutation predict breast cancer growth rates in the UK, Dutch and Canadian MRI-screening studies. Clin Ca Res 2007. 10. Saadatmand S, Geuzinge HA, Rutgers EJT, et al. MRI versus mammography for breast cancer screening in women with familial risk (FaMRIsc): a multicentre, randomised, controlled trial. Lancet Oncol. 2019;20(8):1136-1147. 11. Bakker MF, de Lange SV, Pijnappel RM et al. Supplemental MRI screening for women with extremely dense breast tissue. N Engl.J Med 2019; 381;22:2091-2102. 12. Geuzinge HA, Obdeijn IM, Rutgers EJT et al. Cost-effectiveness of breast cancer screening with magnetic resonance imaging for women at familial risk. JAMA Oncology 2020;6(9):13-81-1389. 13. Geuzinge HA, BakkerMF, Heijnsdijk EAM et al. Cost-Effectiveness of Magnetic Resonance Imaging Screening for Women With Extremely Dense Breast Tissue. J Natl Cancer Inst. 2021 Nov 2;113(11):1476-1483. 14. Chiarelli AM, Blackmore et al. Performance measures of MagneticResonanceImaging plus Mammography in the high risk Ontaria breast screening program. JNCI 2020;112(2):136-144. 15. Obdeijn IM, Heijnsdijk EA, Hunink MG et al. Mammographic screening in BRCA1 mutation carriers postponed until age 40: Evaluation of benefits, costs and radiation risks using models. Eur J Ca 2016; 63:135-42. 16. Obdeijn et al. The supplemental value of mammographic screening over MRI alone in BRCA2 screening. Br Ca Res Treat 2020 ; 181 :581-88. 17. Vreemann S, v Zelst JC, Mann RM et al. Breast Cancer Res 2018;20(1):84 The added value of mammography in different age-groups of women with and without BRCA mutation screened with MRI. Citation Format: Madeleine M.A. Tilanus-Linthorst. Screening for high risk patients: Does everyone need annual MRI with mammogram? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr ED2-2.

Abstract: Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143] , but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.