بنام خداوند جان و خرد

1. بنام خداوند جان و خرد

2. Management & Screening in High Risk Population for Breast Cancer Dr Ahmad Elahi Fellowship of Breast Surgical Oncology

3. Introduction

4. GLOBOCAN 2018: Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

7. Cancer Incidence, Female

8. Cancer Mortality, Female

11. Akbari Et Al.” Breast Cancer Status In Iran: Statistical Analysis Of 3010 Cases Between 1998 And 2014”. International Journal Of Breast Cancer. 2017

12. Population Pyramid in Iran

13. Population Pyramid in Developed Countries

14. Definition of Screening

15. PRINCIPLES OF CANCER SCREENING The goal: Early detection of disease. Target population: Subgroups of people who have a high probability of asymptomatic disease Screening tests: should be safe, easy, ethical andcost-effective (with acceptable level of accuracy) Followed by: Diagnostic tests to determine whether disease is truly present. Treatment: should be available, accessible.

16. 5 Years Survival Rates

17. Average Risk Screening

18. High risk populations

19. High Risk Populations Women with a Family History of Breast Cancer Genetic Mutations That Increase Breast Cancer Risk Women Who Received Thoracic Radiation at an Early (usually for treatment of Hodgkin lymphoma- especially before age 30). Those with LCIS or atypical hyperplasia

21. Special attention (Genetic counseling) • A personal or family history of cancer ageof<50 • Apersonal or family history of > one type of cancer • A personal or family history ofthe same cancer more than once, • Cancer in at least two generations in the family, • Malebreast cancer, • Family history of known hereditary pattern, • Breast and/or ovarian cancer.

23. Breast Cancer Risk Assessment Tool (BCRAT) BCRAT is not used for: • A prior diagnosis of breast cancer, DCIS, or LCIS • Received previous radiation to the chest • Gene mutations in BRCA1 or BRCA2 or other genetic syndromes Gail model The Gail model: Based on age at menarche, age at first live birth, number of previous breast biopsies, the presence or absence of atypical hyperplasia, and the number of first-degree female relatives with breast cancer • Accessed at www.cancer.gov/bcrisktool/ • NCCN Guidelines: any woman with a 5‑year risk of >1.7% determined can be considered for preventative therapy. ( >20%–25% lifetime risk )

24. Tyrer‑Cuzickmodel: Most sensitive of all the models for detecting the risk of breast cancer. accessed at: www.ems‑trials. org/riskevaluator The main limitation: when using for hereditary breast and ovarian cancers (HBOC).

25. Increased Risk

26. Management strategies available for high-risk women: Intensive surveillance Chemoprevention with endocrine agents Prophylactic surgery

27. Intensive surveillance The American Cancer Society, The American Congress of Obst & Gyn; All recommend that: If a woman, aged 30 or older, has >20% lifetime risk, should be offered: • Annual screening breast MRI • +Annual screening MG (scheduled 6 months apart from one another)

28. Chemoprevention Tamoxifen: • Reduced risk one‑half in both pre& post‑menopausal • Increased risk for developing: uterine cancer, cataracts venous thrombus event (stroke, pulmonary embolus and DVT) • Gommonside effects: Hot flashes, Vaginal discharge Raloxifene: • Similar benefit in the postmenopausal • Not known to incur an increased risk for uterine cancer • Lower risk profile for venous thromboembolic events. • Common side effects: hot flashes, vaginal dryness, leg cramps, weight gain

32. These are not currently FDA approved

33. Genetic Mutations that Increase Breast Cancer Risk Inherited genetic mutations: 5%–10% of all cancers. Mutations with an increased risk of breast cancer: - most common (50%) : BRCA1 and BRCA2 Hereditary cancer syndromes: Hereditary breast and ovarian cancers (HBOC): Mutations in the BRCA1 and BRCA2 genes ( 50%) Li–Fraumenisyndrome (TP53 gene) Cowden syndrome (PTEN gene) Peutz–Jegherssyndrome (STK11 gene) Hereditary diffuse gastric cancer syndrome (CDH1 gene). Other: PALB2, ATM, CHEK2 (14)

35. BRCA1 & BRCA2 mutations • AD, with hundreds of highly penetrant mutations • Cumulative risk of breast cancer by age 70: - 55% to 65% for carriers of BRCA1 - 45% to 47% for carriers of BRCA2 • BRCA1: discovered in 1994 on chromosome 17q (17q21) • BRCA2: discovered in 1995 on chromosome 13q (13q12-13)

36. BRCA1 or BRCA2 mutation: • Elevated risk of breast (7 times) and ovarian cancer (25 times). • increased risk of pancreatic, prostate, and male breast cancer. Breast cancer associated with BRCA1 mutation: • more likely to be hormone receptor negative & higher grade • more lymphocytic infiltration, more continuous pushing margins • more frequently have medullary or atypical medullary features Breast cancer associated with BRCA2 mutation: • May be associated with poorer survival. • Association with other cancer: prostate, melanoma, pancreas.

38. Genetic Assessments

39. ASBS Recommendations: (February 14, 2019) • Breast surgeons, genetic counselors:education, counseling, recommendation • Genetic testing (BRCA1/BRCA2 and PALB2) should beoffered to each patient with breast cancer (newly diagnosed or with a personal history). • Patients who had genetic testing previously specially prior to 2014 (without pathogenic variant) may benefit from updated testing. *may not have included testing for PALB2 and large genomic rearrangements in BRCA1 or BRCA2. • Genetic testing should be made available to patients who meet NCCN guidelines( preferably multi-gene panel )

40. Impact of genetic testing on treatment St. Gallen/Vienna 2017: Panelists believed that BRCA 1-2 mutations impact decisions on: • Breast surgery yes 88.5%, no 8% • Systemic therapies yes 73.1%, no 23.1% • Prophylactic interventions yes 94.1%, no 4% ASBS: • BRCA1 pathogenic variant benefit from PARP inhibitors in their adjuvant therapy regimen. • Radiation is relatively contraindicated in patients with TP53 pathogenic variants (Li-Fraumeni Syndrome).

41. Breast cancer risk reduction strategiesin High Risk Population

42. Lifestyle modifications • Intensive surveillance • Risk-reducing agents • Risk-reducing surgery

43. Lifestyle modifications • Breast feeding, • Regular exercise, • Maintaining healthy body weight, • Limiting alcohol consumption, • Avoiding of hormone replacement therapy.

44. Intensive surveillance

45. Screening recommendations for BRCA1/2 mutation carriers (by NCCN and ACS)

46. Screening in Elderly patients with breast cancer (older than 70 years) US Preventive Services Task Force: There is no sufficient data for effect of mammographic screening in decreasing mortality for women ≥70 years. The consequence is that: Diagnosis of BC in the elderly patients is late. More than one third of patients > 65 years have metastases. Decrease in mortality rate due to BC in recent years was smaller than younger ages (1.1% vs 2.5%) Recommendation: Continue screening MG in elderly women with a life expectancy of >10 years. ( MG q2yrs )

47. Risk-reducing agents • risk-reducing agents -Use of tamoxifen may be considered (LOE is weak)

48. Risk-reducing surgery • risk-reducing surgery (Bilat risk-reducing mastectomy- RRM) Include: Total mastectomy, SSM, NSM • Most effective method, reduces risk by ∼90%. *Routine SLNB is not indicated (possibility of occult breast cancer <5%)

49. Screening following risk-reducing surgery Following MST & SSM: • There is no currently recommended surveillance schedule after RRS. Following NSM : • Continued screening with annual breast MRI or ultrasound may be considered (due to tissue behind NAC).

50. Bilateral prophylactic mastectomy in BRCA carriers without breast cancer