1. Breast Cancer Screening Steven Stanten MD Rupert Horoupian MD AltaBates Summit Medical Center Oakland, California

3. Incidence USA - 2008 USA - 2008 184,450 new cases of invasive ca 184,450 new cases of invasive ca 40,930 deaths 40,930 deaths 3 decade increase 3 decade increase Wide spread screening Wide spread screening Increased dx of non-invasive and pre- malignant lesions Increased dx of non-invasive and pre- malignant lesions

4. BREAST CANCER BURDEN Breast cancer is the most common malignancy diagnosed in women (excluding cancers of the skin) Breast cancer is the most common malignancy diagnosed in women (excluding cancers of the skin) In the United States breast cancer is the second most common cause of death from cancer In the United States breast cancer is the second most common cause of death from cancer

5. BREAST CANCER SCREENING IS AN INTEGRAL PART OF WOMEN’S PREVENTATIVE HEALTH BREAST CANCER SCREENING IS AN INTEGRAL PART OF WOMEN’S PREVENTATIVE HEALTH

6. Signs and Symptoms The earliest sign is an abnormality that shows up on a mammogram before it can be felt by the woman or health care provider. The earliest sign is an abnormality that shows up on a mammogram before it can be felt by the woman or health care provider. Early stages of breast cancer usually do not produce symptoms. Early stages of breast cancer usually do not produce symptoms.

7. Signs and Symptoms When breast cancer grows to the point where physical symptoms exist, these may include: When breast cancer grows to the point where physical symptoms exist, these may include: - A painless mass (up to 10 percent of patients have breast pain and no mass). - A painless mass (up to 10 percent of patients have breast pain and no mass). - Breast changes: thickening, swelling, and skin irritation or distortion. - Breast changes: thickening, swelling, and skin irritation or distortion. - Nipple changes: discharge, erosion, inversion, or tenderness. - Nipple changes: discharge, erosion, inversion, or tenderness.

8. Treatment Treatment Treatment - most successful when the cancer is detected early, before it has spread. Treatment Treatment -depends on the situation and the patient’s choices. Surgery Surgery - Breast conservation surgery (lumpectomy) removes the tumor and surrounding tissue. - Breast conservation surgery (lumpectomy) removes the tumor and surrounding tissue. - Mastectomy removes the breast. - Mastectomy removes the breast.

9. Treatment Radiation therapy Radiation therapy Chemotherapy Chemotherapy Hormone therapy Hormone therapy Monoclonal antibody therapy Monoclonal antibody therapy Often, two or more methods are used in Often, two or more methods are used in combination with each other. combination with each other.

10. Mortality One in six diagnosed with breast cancer will die from it One in six diagnosed with breast cancer will die from it Directly related to stage of disease Directly related to stage of disease Varies according to geography, culture, ethnicity, race, and socioeconomic status Varies according to geography, culture, ethnicity, race, and socioeconomic status

11. Deaths An estimated 40,200 deaths will occur from breast cancer in 2003. An estimated 40,200 deaths will occur from breast cancer in 2003. More than 39,000 of these deaths will be among women. More than 39,000 of these deaths will be among women. Only lung cancer accounts for more cancer deaths in women. Only lung cancer accounts for more cancer deaths in women.

12. Survival 020406080100 Switzerland Finland France Italy Netherlands Germany Denmark England Spain Scotland Estonia Poland Five-year survival (%) J Nat Cancer Inst 1995; 87: 1209 5-year survival (%) No. of patients75.773.571.470.869.968.468.162.562.561.858.843.92,24311,1232,4983,5952,6533,35917,49860,3901,04311,2612,3871,089

14. Survival Five-year localized survival rate…….97% Five-year localized survival rate…….97% Five-year regional survival rate…..…78% Five-year regional survival rate…..…78% Five-year distant survival rate……….21% Five-year distant survival rate……….21% Five-year overall survival rate….……..86% Five-year overall survival rate….……..86% Ten-year overall survival rate..……….76% Ten-year overall survival rate..……….76%

15. Risk Factors Direct Direct Age Age Family hx Family hx Early menarche Early menarche Late 1 st birth Late 1 st birth Proliferative benign breast disease Proliferative benign breast disease Thoracic radiation Thoracic radiation

16. Risk Factors As age increases, so does risk. Of all the women with breast cancer, 77% are 50+ years old. As age increases, so does risk. Of all the women with breast cancer, 77% are 50+ years old. Genetic risk factors/personal or family history. Genetic risk factors/personal or family history. Early menarche ( 55 years) Early menarche ( 55 years) Late age at first full-term pregnancy (> 30 years). Late age at first full-term pregnancy (> 30 years).

17. Risk Factors No children/not breast feeding = slight risk. No children/not breast feeding = slight risk. Oral contraceptives use or hormone replacement therapy = slightly greater risk. Oral contraceptives use or hormone replacement therapy = slightly greater risk. Risks increase with alcohol consumption. Risks increase with alcohol consumption. Even moderate physical activity can decrease risk. Even moderate physical activity can decrease risk. Obesity = increased risk in post- menopausal women. Obesity = increased risk in post- menopausal women.

18. Risk Factors Associations Associations Radiographically dense breasts Radiographically dense breasts Obesity Obesity Alcohol intake Alcohol intake Menopausal hormone use Menopausal hormone use

19. Risk Factors for Breast Cancer Family History/genetic factors Family History/genetic factors Reproductive/hormonal Reproductive/hormonal Proliferative benign breast disease Proliferative benign breast disease Mammographic density Mammographic density

20. Risk Assessment FACTORS USED IN NCI BREAST CANCER RISK PREDICTION MODEL FACTORS USED IN NCI BREAST CANCER RISK PREDICTION MODEL -Age -Age -Number of 1st degree female relatives with a history of breast cancer -Number of 1st degree female relatives with a history of breast cancer -Number of breast biopsies -Number of breast biopsies -Age at first live birth or nulliparity -Age at first live birth or nulliparity -History of atypical hyperplasia -History of atypical hyperplasia -Age at menarche -Age at menarche -Race -Race

21. Risk Assessment ORIGINAL GAIL MODEL ORIGINAL GAIL MODEL Gail et al Journal National Cancer Institute 1989; 81: 1879-1886 Gail et al Journal National Cancer Institute 1989; 81: 1879-1886 Model based and derived from extremely large data sets Model based and derived from extremely large data sets Estimates the risk of: Estimates the risk of: invasive invasive in situ (DCIS) in situ (DCIS) or lobular carcinoma in situ (LCIS) or lobular carcinoma in situ (LCIS) over a defined interval in women having annual screening over a defined interval in women having annual screening

22. Risk Assessment LIMITATIONS OF GAIL MODEL – LIMITATIONS OF GAIL MODEL – MAY OVERPREDICT RISK IN PRE- MENOPAUSAL WOMEN WHO DO NOT ADHERE TO GUIDELINES FOR ANNUAL SCREENING

23. Risk Assessment CLAUS MODEL - CLAUS MODEL - The Claus model takes into account 1st and 2nd degree relatives effected by breast cancer and accounts for their ages at the time of diagnosis

24. Concepts of Screening Merely finding a cancer earlier does not mean the patient will benefit Merely finding a cancer earlier does not mean the patient will benefit A different level of proof is required for a screening test as compared to applying a test to someone who is already ill, because the vast majority of those who will be screened will not have the disease most will not benefit from the test, but many may have false positives studies which may ‘harm them’. A different level of proof is required for a screening test as compared to applying a test to someone who is already ill, because the vast majority of those who will be screened will not have the disease most will not benefit from the test, but many may have false positives studies which may ‘harm them’. Since there are cancers that never kill and cancers that are Since there are cancers that never kill and cancers that are destined to kill before they can be discovered only a randomized control trial (RCT) in which one group is screened and the other has the ‘usual’ care can prove a screening test is efficacious destined to kill before they can be discovered only a randomized control trial (RCT) in which one group is screened and the other has the ‘usual’ care can prove a screening test is efficacious

25. RCT The statistical power of the RCT is crucial.

26. Screening Current screening methodologies rely heavily on imaging with proof from RCTs

27. Calcifications

30. Screening Cancers detected by periodic screening are likely to be slower growing, more indolent cancers. Faster, more aggressive cancers become clinically evident between screens. Cancers detected by periodic screening are likely to be slower growing, more indolent cancers. Faster, more aggressive cancers become clinically evident between screens.

31. Sojourn Time The period of time during which a cancer is detectable by a test before it is clinically evident is called the ‘sojourn time’. The period of time during which a cancer is detectable by a test before it is clinically evident is called the ‘sojourn time’.

32. Sojourn Time In order to intercept the most cancers earlier, the screening interval should be less than half the sojourn time In order to intercept the most cancers earlier, the screening interval should be less than half the sojourn time

33. Screening Mammography Basic definitions Basic definitions Uses Uses Specificity Specificity Sensitivity Sensitivity

34. Mammography Basics Basics Identify breast cancer too small to palpate Identify breast cancer too small to palpate Identify non-invasive and pre-malignant lesions Identify non-invasive and pre-malignant lesions Ionizing radiation Ionizing radiation Medial-lateral oblique view Medial-lateral oblique view Cranial-caudal view Cranial-caudal view Nipple to pectoralis Nipple to pectoralis FDA approved sites FDA approved sites Screen film vs. digital Screen film vs. digital

35. Mammography Category Assessment Follow-up Category Assessment Follow-up Breast Imaging Reporting and Database System (BI-RADS) Breast Imaging Reporting and Database System (BI-RADS)

36. Mammography BIRADS BIRADS 0 – more info 1 – normal 2 – benign 3 – probably benign 4 – suspicious 5 - malignant

37. Mammography Uses Uses Diagnose small, early stage breast ca Diagnose small, early stage breast ca Favorable clinical course Favorable clinical course Better cancer related survival Better cancer related survival Interpreting studies has some biases Interpreting studies has some biases Lead-time bias Lead-time bias Length bias Length bias Overdiagnosis bias Overdiagnosis bias Healthy volunteer bias Healthy volunteer bias

38. Mammography CAD – computer aided diagnosis CAD – computer aided diagnosis -Aids radiologist in detecting abnormalities -3 available commercial systems -500 CAD systems in US Clinical Trial – - Increase overall recall rate - Increase in # of detected cancers

39. Considerations in Choosing a Mammography Site - FDA certification of technician, medical physicist, radiologist - BIRAD reporting - CAD system - Digital Mammography

40. MAMMOGRAPHY DIGITAL VS FILM

41. Mammography Specificity Specificity Likelihood of test being normal when cancer is absent Likelihood of test being normal when cancer is absent We want this high We want this high If low then false positives lead to unnecessary tests. If low then false positives lead to unnecessary tests. Exceeds 90% Exceeds 90% BIRADS categories BIRADS categories

42. Mammography Sensitivity Sensitivity Proportion of breast cancer detected when cancer is present Proportion of breast cancer detected when cancer is present Lesion size Lesion size Lesion conspicuity Lesion conspicuity Breast tissue density Breast tissue density Patient age Patient age Hormone status of tumor Hormone status of tumor Image quality Image quality Skill of radiologist Skill of radiologist

43. Mammography Sensitivity Sensitivity Overall 75% Overall 75% 54-58% in age <40 54-58% in age <40 81-94% in age >65 81-94% in age >65

44. Mammography Factors influencing Specificity and Sensitivity Factors influencing Specificity and Sensitivity Radiologist interpretation Radiologist interpretation High breast density High breast density Centralized screening systems Centralized screening systems National QA programs National QA programs Interval between mammograms Interval between mammograms Post-menopausal hormone use Post-menopausal hormone use Prior breast surgery Prior breast surgery BMI BMI

45. Mammography Evidence of Benefit Evidence of Benefit Randomized controlled studies Randomized controlled studies 4 countries 4 countries 500,000 women 500,000 women 9 studies 9 studies Different designs Different designs Effect on mortality Effect on mortality Conflicting results Conflicting results

46. Mammography Harms of screening Harms of screening False negatives False negatives False positives False positives Radiation exposure Radiation exposure Anxiety Anxiety Over diagnosis Over diagnosis

47. Mammography Cochrane Review - Review of 7 trials - Screening mammography likely reduces breast cancer mortality - magnitude uncertain - ~20% reduction – or 15% relative risk reduction - screening leads to over diagnosis and over treatment

48. Mammography For 2000 women invited to screening for 10 years For 2000 women invited to screening for 10 years 1 will have her life prolonged 1 will have her life prolonged 10 will be treated unnecessarily 10 will be treated unnecessarily Conclusion – “It is thus not clear whether screening does more good than harm. Woman invited to screening should be fully informed of both benefits and harms.”

49. UTZ As adjunct to mammography As adjunct to mammography Inexpensive Inexpensive Widely available Widely available Targeted evaluation Targeted evaluation Solid vs. cyst Solid vs. cyst Benign vs. malignant Benign vs. malignant

50. UTZ Image guided biopsy Image guided biopsy Limited screening use Limited screening use Needs a skilled operator Needs a skilled operator Lack of standard exam techniques Lack of standard exam techniques Lack of standard interpretation criteria Lack of standard interpretation criteria No microcalcifications No microcalcifications

51. BREAST MRI THE BASIC STRENGTH OF BREAST MRI LIES IN THE DETECTION OF CANCER THAT IS OCCULT ON CONVENTIONAL IMAGING SUCH AS MAMMOGRAPHY AND SONOGRAPHY THE BASIC STRENGTH OF BREAST MRI LIES IN THE DETECTION OF CANCER THAT IS OCCULT ON CONVENTIONAL IMAGING SUCH AS MAMMOGRAPHY AND SONOGRAPHY

52. Background: What is MRI? Uses magnetic fields to produce detailed cross- sectional images of tissue structures Uses magnetic fields to produce detailed cross- sectional images of tissue structures Uses injected contrast agents to distinguish fat, glandular tissue, lesions, etc. in the breast Uses injected contrast agents to distinguish fat, glandular tissue, lesions, etc. in the breast Different factors contribute to the measured signal that determines the brightness of the tissues in the image Different factors contribute to the measured signal that determines the brightness of the tissues in the image Contrast agent provides reliable detection of cancers and other lesions. Contrast agent provides reliable detection of cancers and other lesions. Screening MRI requires appropriate techniques and equipment (including dedicated breast MRI equipment) and experienced staff Screening MRI requires appropriate techniques and equipment (including dedicated breast MRI equipment) and experienced staff

53. MRI MRI is not a screening technique for average risk patients MRI is not a screening technique for average risk patients

54. MRI With IV gadolinium With IV gadolinium 83-100% sensitive with cancer above a few mm 83-100% sensitive with cancer above a few mm Average 96% sensitive Average 96% sensitive

55. MRI Pros and cons Pros and cons Cost Cost Lack of standard exam Lack of standard exam Lack of standard interpretation criteria Lack of standard interpretation criteria No micro Ca++ No micro Ca++ Variability of equipment Variability of equipment Increase in false + rate Increase in false + rate Availability of equipment Availability of equipment

56. MRI Sensitivity - 71-100% Sensitivity - 71-100% Specificity - 37 - 97% Specificity - 37 - 97% Not recommended for screening Not recommended for screening Breast implants Breast implants Masses after surgery or XRT Masses after surgery or XRT Occult lesions with metastasis Occult lesions with metastasis Pre-operative planning? Pre-operative planning?

60. Rationale New evidence supporting MRI screening New evidence supporting MRI screening Ability of MRI to detect cancers is much higher (double) than mammography Ability of MRI to detect cancers is much higher (double) than mammography MRI plus mammography detects more cancers than MRI alone MRI plus mammography detects more cancers than MRI alone High false positive rate of MRI makes it inappropriate for screening women at average risk High false positive rate of MRI makes it inappropriate for screening women at average risk Strong evidence for MRI screening of women at increased risk based on family history/genetics Strong evidence for MRI screening of women at increased risk based on family history/genetics Insufficient evidence to recommend for or against MRI screening of women at moderately increased risk based on clinical factors Insufficient evidence to recommend for or against MRI screening of women at moderately increased risk based on clinical factors Insufficient evidence for other technologies Insufficient evidence for other technologies

61. Limitations and Potential Harms False negatives False negatives False positives False positives Anxiety, psychological distress Anxiety, psychological distress More call-backs More call-backs More biopsies More biopsies Cost Cost Limited access to high quality MRI screening and MRI-guided biopsies Limited access to high quality MRI screening and MRI-guided biopsies Variation in performance, interpretation, recall rates, and expertise Variation in performance, interpretation, recall rates, and expertise Little or no data on recurrence, survival rates, age, when to start and stop screening, screening intervals Little or no data on recurrence, survival rates, age, when to start and stop screening, screening intervals Variation in insurance coverage Variation in insurance coverage

62. BREAST CANCER SCREENING WITH MRI Individuals with BRCA1 or BRCA2 mutation Individuals with BRCA1 or BRCA2 mutation Individuals with a 1st degree relative of a BRCA1 or BRCA2 carrier but have not been tested Individuals with a 1st degree relative of a BRCA1 or BRCA2 carrier but have not been tested Individuals with a lifetime risk of breast cancer of >20% Individuals with a lifetime risk of breast cancer of >20% Individuals that have had radiation therapy to the chest between the ages of 10 and 30 years old Individuals that have had radiation therapy to the chest between the ages of 10 and 30 years old Breast cancer in a male relative Breast cancer in a male relative One first degree relative with bilateral breast cancer One first degree relative with bilateral breast cancer Individuals consider at high familial risk: Individuals consider at high familial risk: Two or more first degree relatives with breast cancer or Two or more first degree relatives with breast cancer or One 1st degree relative and two or more 2nd or 3rd degree relatives with breast cancer or One 1st degree relative and two or more 2nd or 3rd degree relatives with breast cancer or One 1st degree relative with breast cancer before the age of 45 years and one other relative with breast cancer or One 1st degree relative with breast cancer before the age of 45 years and one other relative with breast cancer or One first degree relative with breast cancer and one or more relatives with ovarian One first degree relative with breast cancer and one or more relatives with ovarian

63. Other modalities Not FDA-approved for screening Not FDA-approved for screening Ductoscopy/ductal lavage Ductoscopy/ductal lavage Tomography Tomography Scinitimammography Scinitimammography PET PET Elastography Elastography Spectroscopy Spectroscopy Optical imaging Optical imaging Electrical impendence measurements Electrical impendence measurements Thermography Thermography Etc. Etc.

64. Ductoscopy/Lavage The majority of breast cancers originate in the breast duct system so evaluating this system visually with ductoscopy, or studies to evaluate the cells from the ducts may help detect transformation from healthy to malignant cells. The majority of breast cancers originate in the breast duct system so evaluating this system visually with ductoscopy, or studies to evaluate the cells from the ducts may help detect transformation from healthy to malignant cells.

65. Ductal Lavage Asymptomatic women Asymptomatic women High risk High risk Use alone or in combination with mammography Use alone or in combination with mammography

66. High Risk Patients Identify High Risk patients Identify High Risk patients 2 or more relatives with breast or ovarian ca 2 or more relatives with breast or ovarian ca Breast ca before age 50 in a relative Breast ca before age 50 in a relative Male relative with breast ca Male relative with breast ca Genetic profiles Genetic profiles Chest radiation Chest radiation

67. Who is at High Risk? Three approaches: Three approaches: #1 - Family history suggestive of inherited gene mutation; risk is calculated by assessment models/tools #2 - Genetic testing for mutation in BRCA1/2, TP53, or PTEN #3 - Review of clinical history -Treated for Hodgkin disease -LCIS, ALH -LCIS, ALH -ADH, DCIS -High mammographic density -Personal history of breast cancer

68. High Risk Screening options Screening options Initiate screening at age 30 Initiate screening at age 30 Shorter intervals Shorter intervals MRI MRI UTZ UTZ Insufficient evidence exists

69. High Risk Who is at high risk? Who is at high risk? Family History Family History Clinical Indicators Clinical Indicators MRI screening studies MRI screening studies Evidence of efficacy Evidence of efficacy Benefits, limitations, and potential harms Benefits, limitations, and potential harms

70. Evidence Since the 2003 guideline, at least 6 prospective, non- randomized studies were conducted, in 6 different countries Since the 2003 guideline, at least 6 prospective, non- randomized studies were conducted, in 6 different countries All studies measured benefit of adding annual MRI to mammography All studies measured benefit of adding annual MRI to mammography All study participants had either a BRCA mutation or a strong family history All study participants had either a BRCA mutation or a strong family history Some studies included women with a personal history of breast cancer Some studies included women with a personal history of breast cancer Some studies also included ultrasound and/or CBE Some studies also included ultrasound and/or CBE All 6 studies reported significantly higher sensitivity for MRI compared to mammography (and US, CBE), and lower specificity (i.e. more false positives) All 6 studies reported significantly higher sensitivity for MRI compared to mammography (and US, CBE), and lower specificity (i.e. more false positives)

71. High Risk Current ACS Recommendation for Women at Increased Risk for Breast Cancer (2003) Current ACS Recommendation for Women at Increased Risk for Breast Cancer (2003) -In the absence of sufficient evidence to recommend specific screening strategies that might benefit women at increased risk, options are provided: -In the absence of sufficient evidence to recommend specific screening strategies that might benefit women at increased risk, options are provided: -earlier initiation of screening (30 years or younger) -earlier initiation of screening (30 years or younger) -the addition of MRI and/or Ultrasound to screening mammography and physical examination. -the addition of MRI and/or Ultrasound to screening mammography and physical examination.

72. Early Detection There is no certain way to prevent breast cancer. There is no certain way to prevent breast cancer. The best plan for women at average risk is to follow the American Cancer Society guidelines for early detection. The best plan for women at average risk is to follow the American Cancer Society guidelines for early detection. Nine out of 10 women can survive breast cancer simply by detecting it early Nine out of 10 women can survive breast cancer simply by detecting it early

73. Bottom Line Age and gender are the main risk factors. Age and gender are the main risk factors. Early detection increases survival and treatment options. Early detection increases survival and treatment options. All women 40+ should talk to their doctors All women 40+ should talk to their doctors about annual mammograms and CBEs. They about annual mammograms and CBEs. They can also perform monthly BSEs. can also perform monthly BSEs. Mammograms can save lives. Mammograms can save lives.

74. Early Detection/Guidelines Age 40+: Annual mammogram, annual clinical breast exam (CBE) by a health care professional, and an optional monthly breast self-exam (BSE). Age 40+: Annual mammogram, annual clinical breast exam (CBE) by a health care professional, and an optional monthly breast self-exam (BSE). Ages 20-39: Every three years a CBE by a health care professional and an optional monthly BSE. Ages 20-39: Every three years a CBE by a health care professional and an optional monthly BSE. Women with a family history of breast cancer should talk to their doctor about when to start screening Women with a family history of breast cancer should talk to their doctor about when to start screening

75. American Cancer Society GUIDELINES FOR THE EARLY DETECTION OF CANCER GUIDELINES FOR THE EARLY DETECTION OF CANCER -Yearly mammograms are recommended starting at age 40 and continuing for as long as a woman is in good health. -Clinical breast exam (CBE) should be part of a periodic health exam, about every 3 years for women in their 20s and 30s and every year for women 40 and over. -Women should know how their breasts normally feel and report any breast change promptly to their health care providers. Breast self-exam (BSE) is an option for women starting in their 20s. - Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year. Women at moderately increased risk (15% to 20% lifetime risk) should talk with their doctors about the benefits and limitations of adding MRI screening to their yearly mammogram. Yearly MRI screening is not recommended for women whose lifetime risk of breast cancer is less than 15%.