Case Presentation and Discussion: Breast Cancer. Madhuri Rao, MD PGY-5 SUNY Downstate Medical Center
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1 Case Presentation and Discussion: Breast Cancer Madhuri Rao, MD PGY-5 SUNY Downstate Medical Center
2 Case Presentation 37 y/o female PMH/PSH: nil Meds: nil NKDA Family Hx: Sister died in early 30 s from cancer (type unknown) Gyn Hx o o o o Age at menarche: years Para 3, 1 st live birth at 20 years + breast feeding Denies HRT Social Hx: Denies ETOH, smoking, illicit drug use
3 Case Presentation Presentation Brownish left nipple discharge 2011 Mammogram Normal Bloody discharge with palpable mass 2013 Sonogram 1.9 x 1.9 x 1.1cm mass at 5 o'clock Core needle biopsy Infiltrating ductal cancer On Examination Bilateral breasts symmetrical No discharge Left breast Firm retroareolar nodule No lymphadenopathy Clinical Stage: T1aN0M0
4 Case Presentation Management MRI Surgery o Partial mastectomy with needle localization and sentinel lymph node biopsy Pathology o 2 foci of infiltrating ductal carcinoma, 2.1cm, 0.5cm Micropapillary type o Sentinel lymph node Isolated tumor cells o pt1an0(i+)mx
5 Case Presentation Management Referral to medical and radiation oncology Genetic testing BRCA-Variant of Unknown Significance
6 BRCA Variant of Unknown Significance (VUS) What does it mean and what to do next
7 What is BRCA VUS? Allelic variants of the BRCA genes Include o Missense mutations, in-frame deletions o Non-synonymous nucleotide substitutions o Alterations in non coding sequences and untranslated regions Cancer risk cannot be established through case-control association studies
8 Incidence 15% of BRCA1 and BRCA 2 DNA tests African Americans highest rate (16.5%) Asian, Middle Eastern and Hispanic (10-14%) Decreasing rate with improving mutation classification Nanda R, et al. Genetic testing in an ethnically diverse cohort of high-risk women: a comparative analysis of BRCA1 and BRCA2 mutations in American families of European and African ancestry. JAMA 294 (15): , Hall MJ, et al. BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breastovarian cancer. Cancer 115 (10): ,2009.
9 Cancer risk Implications Surgical decision making Genetic counseling Follow up
10 Combination of Cancer Risk o Genetic o Familial o Epidemiological o In vitro and in silico data o Histopathological features Integrated studies from large databases (ENIGMA, IARC, BIC)
11 Cancer Risk
12 Surgical Decision Making Ambiguity Difficulty in patient understanding Timing of decision and reclassification of VUS o Upto 9 years after initial testing Role of risk reducing mastectomy/ oophorectomy Mitzi L. Murray, et al. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions. Genetics IN Medicine :Vol. 13, Dec 2011
13 Surgical Decision Making Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions Mitzi L. Murray, et al., Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 107 women with BRCA-VUS counseled between 1998 and 2009 Risk Reducing Mastectomy 11/107 (10.3%) Risk Reducing Oophorectomy 22/107 (20.6%) Only 2 cases reported VUS as sole reason for surgery
14 Surgical Decision Making Other studies Women with pathogenic BRCA mutations o RRM 0-54% o RRO 12-74% Tested for but no mutation o RRM 2-24% o RRO 2-23%
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16 Genetic Counseling Uncertainty, distress? only communicate class III and above (clinical genetics departments in the Netherlands) Subjective interpretation of data influencing surgical decisions Testing offered to selected relatives
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19 Follow Up Have access to organized UV databases Establish tracking system Communicate reclassification information
20 Summary VUS Genetic sequence change whose association with disease risk is unknown Decreasing incidence with improved reclassification Interpret VUS with all available information o Family history o Pathological characteristics o Functional studies o In vitro and in silico studies Establish reliable tracking system
21 References P. Radice, et al. Unclassified variants in BRCA genes: guidelines for Interpretation, Annals of Oncology 22 (Supplement 1): i18 i23, 2011 S. Moghadasi, et al. Variants of Uncertain Significance in BRCA1 and BRCA2 Assessment of in Silico Analysis and a Proposal for Communication in Genetic Counseling. J Med Gen et. 2013; 50(2): Mitzi L. Murray, et al. Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: Variant reclassification and surgical decisions. Genetics IN Medicine :Vol. 13, Dec 2011 Joan Brune. Hereditary breast cancer and genetic counseling in young women. Received: 30 June 2010 / Accepted: 6 July 2010 / Published online: 14 August 2010 Genetics of Breast and Ovarian Cancer (PDQ ) National Cancer Institute
22 Thank You
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