Breast & Ovarian Cancer Inherited Predisposition

1. Breast & Ovarian Cancer Inherited Predisposition SDK December 17. 2013

2. Breast Cancer • Most common cancer (31%) in women • The second most common cause of cancer related mortality • Lifetime risk is 13.48 % (1 in 7) • One third of women with breast cancer die from breast cancer • 86% of women with breast cancer are alive 5 years after diagnosis (76% alive at 10 years). • 0.6% of all cases are in men

3. What causes breast and ovarian cancer? • There is no single cause. There are a number of factors (risk factors) which can influence an individual’s chance of developing breast and/or ovarian cancer. The most important are: • Being a woman • Getting older. Most women who develop breast and/or ovarian cancer are over the age of 50 • Having a family history of breast and/or ovarian cancer • The presence of Ashkenazi Jewish ancestry. Women with this background are more likely to carry specific types of faulty genes causing breast and/or ovarian cancer

4. Risk Factors for Breast Cancer • Female (1% male) • Aging • Relative (mother or sister) • Menstrual history • Early onset • Late menopause • Child birth • After the age of 30

5. Exogenous Estrogen • Hormonal replacement therapy(HRT) • 30% increased risk with long term use • Oral Contraceptives(OC) • Risk is slight & • risk returns to normal once the use of OC’s has been discontinued

6. Risk Factors for Breast Cancer • Radiation exposure • Breast disease • Obesity • Diet • Fat • Alcohol

7. Genetics • BRCA-1 • Familial breast cancers or breast cancers that seem to run in families have been linked to mutations in the BRCA-1 gene. • BRCA-1 mutations have also been linked to ovarian cancer • BRCA-2 • Mutations in BRCA-2 have been linked to both male and female familial breast cancers- but not ovarian cancer • P53, Rb-1 • P53 and Rb-1 are tumor suppressor genes • Her-2/neu, C-erB2, c-myc • C-erB2, Her-2/neu, and c-myc are oncogenes • Women with mutations in P53 and BRCA-1 have a lifetime risk of breast cancer of 85%.

8. What is meant by a family history of breast and/or ovarian cancer? A family history of cancer can occur: • Just by chance, because cancer is common • Because family members are exposed to the same environmental factors • Because an inherited predisposition to cancer is running in the family, though this is rare • A family history of breast and/or ovarian cancer means having one or more close blood relatives who have, or have had, breast and/or ovarian cancer. • These relatives could be on either the father’s or the mother’s side of the family. • Close blood relatives (not relatives by marriage) are: • Parents, siblings or children (first-degree relatives – 1o) • Aunts, uncles, nephews, nieces or grandparents (second-degree relatives – 2o)

9. Inherited predisposition to the development of breast and/ or ovarian cancer • The majority of breast and/or ovarian cancer cases are not due to an inherited predisposition to develop the condition. • A small number of the cases of breast and/or ovarian cancer (about 5%-10%) involve an inherited predisposition to develop the cancer. • In these cases, the women have inherited a faulty copy of a breast and/or ovarian ‘cancer protection’ gene that usually control cell division and growth in the cells in the breast and ovarian tissue .

11. Development of breast and/or ovarian cancer is not a quick or simple processWhy ???? • Because It is a progression involving a build-up of variations in a number of different ‘cancer protection’ genes in the cells of the breast and/or ovaries over a woman’s lifetime • This is why the development of breast and/or ovarian cancer can take many, many years and is often seen in older women. • Men who carry such changes may have a small increase in risk for developing cancer during their lifetime.

12. Development of breast and/or ovarian cancer is not a quick or simple processWhy ???? • Between 5% and 10% of all breast and ovarian cancers are believed to be due to having inherited a faulty copy of one of the ‘cancer protection’ genes that usually control cell division and growth in the cells in the breast and ovarian tissue. • From birth, the division and growth of cells in these women’s breast and ovarian cells is not as very tightly controlled as in other women in the population • Although these cells may be on the first step on the staircase towards becoming cancerous, the other copy of that ‘cancer protection’ gene and additional ‘cancer protection’ genes in the cells, are still working properly so the process of cell division and growth in the cells in the breast and ovarian tissue is still largely normal. • Further mutations occur over time in a number of other ‘cancer protection’ genes in breast or ovarian cells, and the cells become cancerous

13. Is it only one gene is involved in the development of breast and ovarian cancer No What Gets Inherited Cancer or Gene Breast and/or ovarian cancer itself is not inherited, although cancer that arises from an inherited faulty ‘cancer protection’ gene is sometimes called hereditary cancer.

14. What are the inherited faulty ‘cancer protection’ genes involved in predisposition to breast and/or ovarian cancer? Two of these genes that have been identified where (mutations) can contribute to the development of breast and/or ovarian cancer. • Breast Cancer 1 gene (BRCA1) • Breast Cancer 2 gene (BRCA2) • The BRCA1 and BRCA2 ‘cancer protection’ genes are known as tumour suppressor genes and their role is to act as the ‘brakes’ on uncontrolled cell growth. • Men and women both have the BRCA1 and BRCA2 genes in their cells and their role in the cell is to protect against cancer.

15. What is the pattern of inheritance in families • Two factors influence the pattern of inheritance • The faulty BRCA1 or BRCA2 gene(s) • The BRCA1 is located on chromosomes 17 • The BRCA2 is located on chromosomes 13 • Both of these chromosomes are autosomes • The effects of changes in the BRCA1 and BRCA2 genes are ‘dominant’ over the information in the working copy of the genes on the partner chromosomes 17 and 13. • The pattern of inheritance in families of the faulty genes causing predisposition to breast and/or ovarian cancer is will be Autosomal Dominant. What will be the pattern of inheritance ?

16. What will be the chance in every pregnancy, each of their children has • Where one of the parents has or had breast and/or ovarian cancer involving a faulty BRCA1 or BRCA2 gene, or is a carrier of a faulty BRCA1 or BRCA2 gene, in every pregnancy, each of their children has • 1 chance in 2 (50% chance) of inheriting the faulty gene from the affected parent • 1 chance in 2 (50% chance) of not inheriting the faulty gene and only inheriting a working copy of the gene from both parents

17. Chance of having breast cancer due to an inherited predisposition. • Based on the number of relatives with breast and/or ovarian cancer, the family relationship and the age of diagnosis, • Women are categorized into separate risk groups for developing breast and/or ovarian cancer. • The family relationship is classified as • First-degree relatives (10): parents, siblings or children • Second-degree relatives (20): aunts, uncles, nephews, nieces or grandparents

18. Chance of having breast cancer due to an inherited predisposition. Categorise a woman’s risks for developing Breast Cancer based on her family history of cancer into 3 groups • Category 1: At or slightly above average risk • Category 2: At moderately increased risk • Category 3: At potentially high risk The guidelines for doctors also categories a woman’s risks for developing ovarian cancer based on her family history of cancer into 2 groups Category 1 or Category 2: At average or moderately increased risk Category 3: At potentially high risk

22. Chance of having ovarian cancer due to an inherited predisposition.

23. Staging of Breast Cancer The American Joint Committee on Cancer (AJCC) has designated staging by TNM • T= Tumor size • N = Lymph node involvement • M = Metastasis

24. Stage 1 • Tumor < 2.0 cm in greatest dimension • No nodal involvement (N0) • No metastases (M0)

25. Stage II • Tumor > 2.0 < 5 cm • or • Ipsilateralaxillary lymph node (N1) • No Metastasis (M0)

26. Stage III • Tumor > 5 cm (T3) • or ipsilateralaxillary lymph nodes fixed to each other or other structures (N2) • involvement of ipsilateral internal mammary nodes (N3) • Inflammatory carcinoma (T4d)

27. Stage IV (Metastatic breast cancer) • Any T • Any N • Metastasis (M1) • Stage 4 means any metastatic breast cancer no matter what size the tumor or if there is nodal involvement or not. • If it is metastatic, it is stage 4. • In general, stage 4 is not considered curable. The goals are to increase the quality of life and extend survival time

28. Breast Cancer • Arises from the interaction of two processes • The cancer formation process • The process of development of the breast

29. Mutation • Invade & Spread • Mutation • Cancer Gene Latency Period, 20 years or more Malignant Tumor Unspecialized Cell Initiated Cell Benign Tumor Promotion Progression Initiation • Proliferation • Independence Stages of Cancer Formation

30. Development of the Breast Ductal Tree Differentiation Occurs With Pregnancy After Puberty After Pregnancy Birth 2 years Proliferation Differentiation Proliferation Proliferation

31. Proliferation – Cell Multiplication • Essential for normal growth & development of the breast • Important factor in breast cancer • The key event during tumor promotion • Allows less time for mutation repair

32. Proliferation Decreases Mutation Repair Time For Repair Before DNA Duplication Little Time For Repair Before DNA Duplication Within a Cell In Each Daughter Cell In Each Daughter Cell

33. Proliferation – Cell Multiplication Essential for normal growth & development of the breast Important factor in breast cancer • Decreases time for mutation repair • Key event during the tumor promotion • Proliferating cells at risk to undergo initiation, promotion and progression stages of cancer formation • Estrogen and other reproductive hormones cause proliferation of breast cells

34. Proliferation and Differentiation

35. Development of the Breast Ductal Tree Differentiation Occurs With Pregnancy After Puberty After Pregnancy Birth 2 years Lobules

36. Differentiation of A Breast Lobule Growth to a Functioning Entity Sexual Maturity Pregnancy Lactation Puberty Terminal End Bud Lobule Type 1 Lobule Type 2 Lobule Type 3 Lobule Type 4 Level of Proliferation 60 22 4 1

39. Carcinogens Cells at Risk Are Analogous to a Target’s Bull’s-eye • A larger number of cells at risk produces a larger (and easier to hit) bull’s-eye.

40. Interaction of a Cell at Risk with a Carcinogen Can Produce an Initiated Cell • An initiated cell is the firststep in formation of a tumor • For an initiated cell to become a tumor both the Promotion and Progression stages have to occur • The larger the number of initiated cells the higher the breast cancer risk