Breast Cancer New Approaches for Prevention and Early Detection

1. Breast CancerNew Approaches for Prevention and Early Detection Ozden Altundag, MD Baskent University Department of Medical Oncology Ankara/Turkey 10/9/2009 Batumi/Georgia

2. 2009 Estimated US Cancer Cases Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.5 million new cases of cancer will be diagnosed in 2009. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers in both men and in women. Now we will turn our attention to the number of new cancers anticipated in the US this year. It is estimated that about 1.5 million new cases of cancer will be diagnosed in 2009. Cancers of the prostate and breast will be the most frequently diagnosed cancers in men and women, respectively, followed by lung and colorectal cancers in both men and in women.

3. 2009 Estimated US Cancer Deaths Lung cancer is, by far, the most common fatal cancer in men (30%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death. Lung cancer is, by far, the most common fatal cancer in men (30%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death.

4. Cancer Incidence Rates* Among Women, US, 1975-2005

5. Cancer Incidence Rates* Among Women, US, 1975-2005 After increasing from 1994 to 1999, breast cancer incidence rates in women decreased by 2.2% per year from 1999 to 2005, likely due in part to a slight decline in mammography utilization and a reduction in use of hormone replacement therapy.

6. Lifetime Probability of Developing Cancer, Women, US, 2003-2005* Approximately one in three women in the United States will develop cancer over her lifetime. Approximately one in three women in the United States will develop cancer over her lifetime.

8. Risk Factors - Unchangeable

9. Risk Factors - Unchangeable/contd.

10. Risk Factors Associated with Lifestyle

11. Breast Cancer Screening Aim is to diagnose breast cancer at curative stage not showing any signs and symptoms of breast cancer.

12. Effective Screening Test Disease incidence should be high Diagnosed at early stage but without any signs Early diagnosis and treatment should be more effective than late treatment Benefit of early treatment should be higher than the cost and harmfulness of screening

13. Does Mammography Reduce Breast Cancer Mortality?

14. Mortality Reduction in Screening Patients Study Age Mortality reduction (%) HIP 40-64 24 Malm� 45-69 19 Sweeden 40-74 32 Edinburgh 45-64 21 Stockholm 40-64 26 Canada-1 40-49 -3 Canada-2 50-59 -2 Gothenburgh 39-59 16 All studies 39-74 24

15. Best Screening Method for Breast Cancer is Mammography? YES There is no place for US in screening

16. Mammography Standard positions are used in all over the world. It can be easily documented and repeated Cost-effective and non-invasive That is only method showing microcalcifications safely

17. At What Age Mammography Screening Should Start? All women starting at 40 years old should be screened with mammography

18. What Intervals Mammographic Screening Should be Done? EVERY YEAR

19. What is the Role of Breast Examination in Screening? Mammography is not sufficient alone for screening Some breast tumors not detected by mammograpy can be diagnosed with PE 5-7% of breast cancers are only detected with breast exam

20. Digital Mammography Provide equivalent detection level compared with conventional mammography Offers a lower average dose of radiation Easier access to images and computer-assisted diagnosis Superior in pre and postmenopausal women with dense breast and women under the age of 50

22. Breast MRI Expensive Higher sensitivity with lower spesificity Not safe for detection of microcalcification Useful for additional screening method for high risk women having mammography

23. MRI for Evaluation of the Breast Highly sensitive but high false positive rate Useful for screening BRCA patients May be useful in staging known breast cancer May become an important screening modality

24. MRI Screening for High Risk Women Evidence-based indications: With BRCA mutated women 1. degree relatives of BRCA mutated women Whole life risk of breast cancer about 20-25% according to family history Based on concensus indications: Women who received radiation to chest at the ages of 10-30 Li-Fraumeni syndrome patients and their first degree relatives There is some evidence based indications for MRI screening as you see in this slideThere is some evidence based indications for MRI screening as you see in this slide

25. Other Imaging Modalities Tc99m sestamibi scan (Miraluma) Tomosynthesis (variation of mammogram) These are not routinely used techniques but I would like to briefly give just their names here today.These are not routinely used techniques but I would like to briefly give just their names here today.

26. Breast Cancer Risk Factors Greatly increased risk RR>4.0 Inherited genetic mutations for breast cancer = 2 first degree relatives with breast cancer diagnosed at early age Personal history of breast cancer Age >65 (increasing risk with increasing age to 80) Who are the at high risk breast cancer women?Who are the at high risk breast cancer women?

27. Screening for High Risk Women Mammographic screening should be start at 30 years of age (rarely before this age) Screening interval can be shorter (e.g. 6 mos) MRI can be added US can be added There is a special group of women with high risk for breast cancer. These women need to be screened more intensively and at earlier age There is a special group of women with high risk for breast cancer. These women need to be screened more intensively and at earlier age

28. Screening Guidelines for the Early Detection of Breast Cancer, American Cancer Society Yearly mammograms are recommended starting at age 40. A clinical breast exam should be part of a periodic health examination, about every 3 years for women in their 20s and 30s. Asymptomatic women aged 40 and older should continue to undergo a clinical breast exam, preferably annually*. Beginning in their early 20s, women should be told about the benefits and limitations of breast-self examination. Women should know how their breasts normally feel and report any breast changes promptly to their health care providers. The American Cancer Society states that women aged 40 and older should have an annual mammogram and clinical breast exam (CBE) as part of a periodic health exam. Women should know how their breasts normally feel and report any changes to their health care provider. A breast self-examination (BSE) is an option for women starting in their 20s. The American Cancer Society states that women aged 40 and older should have an annual mammogram and clinical breast exam (CBE) as part of a periodic health exam. Women should know how their breasts normally feel and report any changes to their health care provider. A breast self-examination (BSE) is an option for women starting in their 20s.

29. PREVENTION Let`s move on to my another topic to discuss today which is chemopreventionLet`s move on to my another topic to discuss today which is chemoprevention

30. Why Do We Need Prevention? �Prevention is better than healing because it saves the labor of being sick� Thomas Adams 17th Century Physcian Limited efficacy of chemotherapies High morbidity and mortality of surgical and chemotherapeutic treatments Improved methods to predict cancer risk We can by developing predictive cancer risk models we can catch these women with high risk and treat them with chemopreventionWe can by developing predictive cancer risk models we can catch these women with high risk and treat them with chemoprevention

31. Cancer Prevention Research Cancer prevention is very complex area. As you see on this slide lots of research departments involve this research area.Cancer prevention is very complex area. As you see on this slide lots of research departments involve this research area.

32. Life Style Changes Observational studies suggest that ; Regular exercise Reducing body weight Decreasing or stopping alcohol intake may reduce the risk of breast cancer Increased dietary folate appears to reduce the increased risk of breast cancer due to alcohol intake Women`s Health Initiative found that a low fat diet was associated 9% risk reduction (but NS) Most very large prospective studies have found no association between intakes of fruits and vegetables and risk of breast cancer

33. Breast Cancer Development as a Long-term Process Breast cancer turn into invasive form in a long-term period One well-recognized hypothesis describes breast cancer development as a process wherein normal breast epithelium undergoes a series of pre-malignant and malignant changes. These changes include atypical hyperplasia, ductal carcinoma in situ and invasive breast cancer. One well-recognized hypothesis describes breast cancer development as a process wherein normal breast epithelium undergoes a series of pre-malignant and malignant changes. These changes include atypical hyperplasia, ductal carcinoma in situ and invasive breast cancer.

34. Invasive cancer is the end stage of a long process of tumorigenesis Since this is a long term process we can have a more chance to prevent invasive cancer development.Since this is a long term process we can have a more chance to prevent invasive cancer development.

35. Breast Cancer Initiation and Promotion There are lots of genetic changes happened during this long-term process of tumorigenesis.There are lots of genetic changes happened during this long-term process of tumorigenesis.

36. At-Risk Subjects Genetic (BRCA1 and 2, BRCA�?, p53) Pre-invasive breast lesions (DCIS, LCIS, AH) Previous breast cancer Gail Model So we have to find these group of patients at high risk for development of cancer. I would like to remind you again those risk factors here. As you can see here Gail model is most popular risk assessment model .So we have to find these group of patients at high risk for development of cancer. I would like to remind you again those risk factors here. As you can see here Gail model is most popular risk assessment model .

37. Breast Cancer Risk PredictionGail Model Age at menarche Age at first live birth Breast biopsies Presence of atypical hyperplasia Familial BC (mother/sisters) The Gail model a set of questions about risk factors for breast cancer has been the standard approaches to assessing risk However it has limited accuracy for estimating the risk of breast cancerThe Gail model a set of questions about risk factors for breast cancer has been the standard approaches to assessing risk However it has limited accuracy for estimating the risk of breast cancer

38. NCI Breast Cancer Risk Prediction Model  Age Breast cancer history of first degree relatives Age at first birth or nulliparity The number of breast biopsy Atypical hyperplasia Menarche age Race NCI breast cancer risk model is the modified Gail model and you can use it from NCI web site. Race is also added to this modelNCI breast cancer risk model is the modified Gail model and you can use it from NCI web site. Race is also added to this model

42. Breast Cancer: Risk-Treatment Options Follow-up may be the option Chemoprevention Prophylactic mastectomy Prophylactic oopherectomy

43. Chemoprevention Primary: Prevention of cancer at healthy women Secondary: Prevention of cancer at women with premalignant lesion Tertiary: Prevention of second cancer at women have a previous cancer

44. Tamoxifen in Breast Cancer Decrease risk of invasive breast cancer risk 43-49 % Primary prevention: Use for prevention with high risk women Secondary prevention: DCIS Tertiary prevention: Decreasing the incidence of contralaterally breast cancer

45. CHEMOPREVENTION Tamoxifen versus Placebo

46. There is a lots of prospective TMX chemoprevention studies showing superiority of tmx on placebo in reducing invasive breast cancer. The pivotal study is the NSABP-P1 studyThere is a lots of prospective TMX chemoprevention studies showing superiority of tmx on placebo in reducing invasive breast cancer. The pivotal study is the NSABP-P1 study

47. Tamoxifen Prevention Studies Breast Invazive cancer Women-annual f/uStudy Number risk Cancer Placebo Tam. Italian 5408 Low-Intermed 20,731 41 2.3 2.1 IBIS-I 7144 Not 29,718 70 6.8 4.6 reported NSABP-P1 13,388 High 52,401 264 6.8 3.4 (modified Gail model) In detailed table you can see the decrease risk of cancer with tamoxifenIn detailed table you can see the decrease risk of cancer with tamoxifen

48. NSABP-P1 I want to discuss NSABP-1 study more in detail A total of 13,388 women were randomized to receive tmx 20 mg/day or placebo for 5 years women with high risk according to the Gail model. I want to discuss NSABP-1 study more in detail A total of 13,388 women were randomized to receive tmx 20 mg/day or placebo for 5 years women with high risk according to the Gail model.

49. NSABP-P1 Cumulative Events

50. Greater benefit is seen in women at higher risk.Greater benefit is seen in women at higher risk.

51. NSABP-P1Adverse Effects of TMX Endometrial cancer (RR 2.5) Thromboembolic events Deep vein thrombosis Pulmonary embolus Cerebral vascular accident But it is known that the tmx has some common side effects which are shown hereBut it is known that the tmx has some common side effects which are shown here

52. CHEMOPREVENTION Tamoxifen versus Raloxifene

54. STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention LCIS, lobular carcinoma in situ Elevated risk = 5-year predicted breast cancer risk of = 1.66% according to the modified Gail model, or a history of lobular carcinoma in situ (LCIS) treated by excision LCIS, lobular carcinoma in situ Elevated risk = 5-year predicted breast cancer risk of = 1.66% according to the modified Gail model, or a history of lobular carcinoma in situ (LCIS) treated by excision

55. STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention Raloxifene is as effective as tamoxifen in reducing invasive breast cancer incidence Less effective in the prevention of the non-invasive breast cancer

56. STAR: Tamoxifen vs Raloxifen for Breast Cancer Prevention Women received raloxifen: Endometrial cancer: RR = 0.62 (% 95 CI: 0.35-1.08) Thromboembolic events: RR = 0.70 (% 95 CI: 0.54-0.91) Cataract: RR = 0.79 (% 95 CI: 0.68-0.92) Stroke, ishemic heart disease and bone fractures rates were similar in both groups

57. Chemoprevention-Ongoing Studies New Chemopreventive Agents Less toxic Effective for ER (-) breast cancer Short-term prevention studies

58. ATAC Trial: Study Design ATAC Trial The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial studied the efficacy and safety of the AI anastrozole compared with tamoxifen, either aloneor in combination as the initial adjuvant therapy for postmenopausal womenATAC Trial The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial studied the efficacy and safety of the AI anastrozole compared with tamoxifen, either aloneor in combination as the initial adjuvant therapy for postmenopausal women

59. ATAC Study: Contralaterally Breast Cancer Incidence in HR-Positive Patients ATAC Trial: Incidence of Contralateral Breast Cancer in HR-Positive Patients1,2 In the HR-positive population, anastrozole treatment resulted in a 53% reduction in the incidence of all contralateral breast cancers compared with tamoxifen; there was a 57% reduction in invasive contralateral breast cancers The decrease in the incidence of contralateral breast cancer, while intriguing in that it suggests a role for anastrazole in prevention, Results from clinical trials are neededATAC Trial: Incidence of Contralateral Breast Cancer in HR-Positive Patients1,2 In the HR-positive population, anastrozole treatment resulted in a 53% reduction in the incidence of all contralateral breast cancers compared with tamoxifen; there was a 57% reduction in invasive contralateral breast cancers The decrease in the incidence of contralateral breast cancer, while intriguing in that it suggests a role for anastrazole in prevention, Results from clinical trials are needed

60. SERMs in Breast Cancer Prevention:Proven Efficacy I would like to summarize SERM study results again with this slideI would like to summarize SERM study results again with this slide

61. Who can Receive SERM? LCIS DCIS Atypical ductal lobular hyperplasia BRCA-1? or BRCA-2 mutation 5-year breast cancer risk is > 1.66% according to the Gail model

62. Ongoing Breast Cancer Risk Reduction Studies with Aromatase Inhibitors

63. Ongoing Phase II Trials Periareolar fine needle aspiration model: Anastrozole Targretin Statins Curcumin Cyclooxygenase-2 inhibitors

64. THANK YOU