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Evidence-based detection and management of hereditary breast cancer syndromes. Kristen Mahoney Shannon, MS, CGC Program Manager/Sr. Genetic Counselor MGH Center for Cancer Risk Assessment April 13, 2012. Date . Lecture Overview. Detection Identifying Risk Personal / Family history

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  1. Evidence-based detection and management of hereditary breast cancer syndromes Kristen Mahoney Shannon, MS, CGC Program Manager/Sr. Genetic Counselor MGH Center for Cancer Risk Assessment April 13, 2012 Date

  2. Lecture Overview • Detection • Identifying Risk • Personal / Family history • Genetic Testing • Syndromes • Hereditary Breast/Ovary Cancer Syndrome (HBOC) • Li-Fraumeni Syndrome (LFS) • Cowden Syndrome • Hereditary Diffuse Gastric Cancer (HDGC) • Peutz-Jeghers Syndrome (PJS) • Management • Cancer Screening • Cancer Risk Reducing Surgeries • Psychosocial Management

  3. Association between population frequencyand relative risk for breast cancer Relative Risk of Developing Cancer Frequency in the Population (Percent) Foulkes W. N Engl J Med 2008;359:2143-2153

  4. Detection of At-Risk Individuals

  5. Comprehensive Risk Assessment Family History Personal Medical History • Non-familial Risk Factors • Early menarche/late menopause • Nulliparity or late pregnancy • OCP use/hormonal exposures • Breast irradiation (during puberty) • Breast density • High BMI/Obesity • Atypical hyperplasia/ Lobular Carcinoma in Situ Physical Exam

  6. Genetic Testing Gene Panel Testing Single Gene Testing

  7. Hereditary Breast/Ovarian Cancer (HBOC) BRCA1 and BRCA2

  8. BRCA1 and BRCA2 phenotype • Breast Cancers • BRCA1 – 80% are triple negative • BRCA2 – garden variety • Ovarian Cancers • Endometriod, serous (BRCA1 and BRCA2) • Serous papillary (BRCA1) • NOT borderline tumors

  9. Identifying BRCA carriers

  10. HBOC Cancer Risks • Breast Cancer Risk • BRCA1: 50-80% • BRCA2: 40-70% • Ovarian Cancer Risk • BRCA1: 40-60% • BRCA2: 15-20% • Other Cancer Risk • Male Breast: <6-7% • Pancreatic: 1.3-7% • Prostate: <30-40%

  11. HBOC Cancer Risks Can Be Modified • Lifestyle factors • Location in the gene • “Modifier” gene allelotypes • Hormonal Interventions Chance of Remaining Cancer Free (Opposite Breast) Metcalfe K et al JCO 22:2328, 2004

  12. Li-Fraumeni Syndrome (TP53 gene) • Component Tumors: • Sarcoma • Breast Cancer • Brain tumors • Leukemia (childhood) • Adrenal cortical carcinoma

  13. Identifying LFS

  14. LFS Cancer Risks • ~75% of tumors are classic component tumors Other tumors: Colorectal cancer Endometrial cancer Esophageal cancer Gonadal germ cell tumor Hematopoietic malignancies (leukemias and lymphomas) Lung cancer Melanoma and non-melanoma skin cancer Neuroblastoma Ovarian cancer Pancreatic cancer Prostate cancer Stomach cancer Thyroid cancer Wilms’ tumor and other kidney cancers Risk of cancer 57% risk of 2nd primary 38% risk of 3rd primary Nichols, K.E., et al., Cancer Epidemiol Biomarkers Prev, 2001. 10(2): p. 83-7 Hwang, S.J., et al., Am J Hum Genet, 2003. 72(4): p. 975-83. . Chompret, A., et al., Br J Cancer, 2000. 82(12): p. 1932-7. Le Bihan, C., et al.,. Genet Epidemiol, 1995. 12(1): p. 13-25.

  15. Cowden Syndrome (PTEN gene) 91 yr 94 yr lung cancer 75 yr cancer, unspecified 65 yr colon polyps head circumference 62 cm oral mucosal papillomatosis 70 yr 67 yr 65 yr 56 yr 37 yr recurrent goiter since 16 yr DCIS, 35 oral mucosal papillomatosis head circumference 60 cm 32 yr 42 yr 40 yr 33 yr 35 yr enlarged thyroid Courtesy of G. Chan-Smutko, MGH

  16. Cowden Syndrome (PTEN gene) trichilemmoma • Cutaneous features (90-100%) • (Oral) mucosal papillomas  coalesce into “cobblestone” surface • Trichilemmomas (facial) • Acral keratoses (palmar/plantar) • Papillomatous lesions Images referenced from: Gene reviews: http://www.ncbi.nlm.nih.gov/books/NBK1488/ Emedicine: http://emedicine.medscape.com/article/1059940-overview

  17. Identifying Cowden Syndrome http://www.lerner.ccf.org/gmi/ccscore/

  18. Cowden Syndrome Cancer Risks

  19. Hereditary Diffuse Gastric Cancer • CDH1 gene Courtesy of D. Patel, MGH

  20. Identifying HDGC • The International Gastric Cancer Linkage Consortium (IGCLC) criteria: • Two gastric cancer (GC) cases in family, one individual under age 50 years with confirmed diffuse gastric cancer (DGC) • Three confirmed DGC cases in first- or second-degree relatives independent of age • Simplex case (i.e., a single occurrence in a family) of DGC occurring before age 40 years • Personal or family history of DGC and lobular breast cancer, one diagnosed before age 50 years Fitzgerald et al, 2010

  21. HDGC Cancer Risks Diffuse Gastric Cancer Risk in CDH1 carriers by Age Lobular Breast Cancer Risk = 39-51%

  22. Peutz-Jeghers Syndrome (PJS) • STK11 gene • Melanotic macules, intestinal polyps, increased cancer risk

  23. Identifying PJS • Two or more histologically confirmed PJ polyps • Any number of PJ polyps detected in one individual who has a family history of PJS in close relative(s) • Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in close relative(s) • Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation Clinical Diagnosis Beggs, et al (2010)

  24. PJS Cancer Risks • Cancer Risks: • Pancreas • Liver • Lungs • Breast • Ovaries • Uterus • Testicles • other

  25. Low-Moderate Penetrant Genes 2-4xRR of breast cancer

  26. Managing Breast Cancer Risk • Breast self-exam training and education and regular monthly BSE starting at age 18y • Semiannual clinical breast exam starting at age 25y • Annual mammogram and MRI screening starting at age 25 • Discuss option of prophylactic mastectomy on case-by-case basis • Consider chemoprevention options for breast and ovarian cancer • Consider investigational imaging and screening studies For BRCA carriers:

  27. High-Risk Patient With MRI detected Breast Cancer: Normal Mammogram Courtesy of Dr. Phoebe Freer, MGH

  28. MRI Detects an Apparent Cancer Courtesy of Dr. Phoebe Freer, MGH

  29. Risk Reducing Mastectomy • Bilateral prophylactic mastectomy decreases risk breast cancer ~90% • Prophylactic contralateral mastectomy decreases risk second breast cancer ~90% Hartmann L NEJM 2001; Seynaeve C ASCO abs #102962 2002; Rebbeck T JNCI 1999; NEJM 2002; Kauff N NEJM 2002 • Uptake ~50% • More often in women w/ sister or mother w/ breast ca • Less when mom or sister had ovarian cancer Skytte et al, Clin Genet 2010; Metcalfe et al Clin Genet 2008

  30. Managing Ovarian Cancer Risk • Recommend ovary/fallopian tube removal, ideally between 35 and 40 y, or upon completion of child-bearing • For those who have not elected ovary/fallopian tube removal, consider concurrent ultrasound + Ca-125 every 6 mo starting at age 35y or 5-10 y earlier than the earliest age of first diagnosis of ovarian cancer in the family • Consider chemoprevention options for breast and ovarian cancer • Consider investigational imaging and screening studies

  31. Risk Reducing Oophorectomy • Decreases risk of breast cancer ~50% • Decreases risk of ovarian cancer ~90% Hartmann L NEJM 2001; Seynaeve C ASCO abs #102962 2002; Rebbeck T JNCI 1999; NEJM 2002; Kauff N NEJM 2002 • Uptake ~90% • More often in women w/ mom or sister with ov cancer • BRCA2 carriers less Skytte et al, Clin Genet 2010; Metcalfe et al Clin Genet 2008

  32. Management – Other cancers

  33. Management – Other cancers (cont.)

  34. Other Management Issues • Education about signs and symptoms of cancer • Education about heritability / encourage family testing • Education about prenatal diagnosis / assisted reproduction • Psychosocial Management

  35. Summary • Detection & Management not straightforward • Multidisciplinary effort • Genetic Counselors / Specialists

  36. Acknowledgements MGH Center for Cancer Risk Assessment Breast/Ovarian Cancer Genetics Program Leif Ellisen, MD, PhD, Director Gayun Chan Smutko, MS, CGC Devanshi Patel, MS, CGC Michele Jacobs Gabree, MS, CGC Janette Lawrence, MS, CGC Erica Blouch, MS, CGC Meredeth Seidel, MS, CGC

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