Breast Cancer Screening

Transcription

1 Breast Cancer Screening Eileen Rakovitch MD MSc FRCPC Sunnybrook Health Sciences Centre Medical Director, Louise Temerty Breast Cancer Centre LC Campbell Chair in Breast Cancer Research Associate Professor, Department of Radiation Oncology University of Toronto

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4 Early detection of invasive breast cancer will be associated with a lower risk of breast cancer related mortality.

5 Goal of Screening Clinical detectability Early detection Increased risk of death due to breast cancer

6 Screening Mammography Meta-analyses Between s 9 large RCTs Several meta-analyses

7 Meta-Analysis: Screening Mammography (Gøtzsche 2011).

8 Meta-analyses of Screening Mammography Summary risk ratio for breast cancer mortality reduction Median 11.4 years f/u RR= 0.81 (95% CI: )

9 Mammographic screening reduces the risk of breast cancer mortality

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11 Mammography Evidence Ping-Pong You could get a very sore neck watching all the claims and counter-claims about mammography zing back and forth. It s like a lot of evidence Ping-Pong matches. Sci American, 2014

12 Why is this still being debated?

13 Screening Mammography The benefit of screening mammography varies across studies

14 Screening Mammography The benefit of screening mammography varies across studies Variability in mammogram quality Variability in study methodologies invited to screen vs. attended screening Randomization methods contamination adherence ascertainment of breast cancer mortality

15 Screening Mammography The benefit of screening mammography varies across studies Variability in mammogram quality Variability in study methodologies invited to screen vs. attended screening Randomization methods contamination adherence ascertainment of breast cancer mortality Variability of trial inclusion in meta-analyses

16 Film vs. Digital mammography Would digital mammography be associated with an even greater benefit?

17 Does the early detection of invasive breast cancer lead to a lower incidence of locally advanced / advanced stage breast cancer?

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19 100/100,000 women 130/100,000 women

20 To benefit from screening mammography you have to attend screening

21 Meta-analysis of breast cancer mortality benefit and over diagnosis adjusted for adherence: Invited to screen analyses are helpful for planning policy Not ideal for individual decision-making How large is the benefit for women who attend screening? Meta-analysis adjusted by de-attenuation effect of risk estimates by women who do not attend screening Jacklyn, BJC 2016

22 Adjusting for Adherence Adherence rates across studies % of those randomized to screening % of controls De-attenuated risk of breast cancer mortality (95% CI: ) Over diagnosis 19% 30% Jacklyn, BJC 2016

23 To Benefit from Screening One Must Be Screened Breast cancer mortality reduction in women invited versus not invited 25% reduction in mortality Breast cancer mortality reduction in women screened versus not screened 38% reduction in mortality Broeders et al. J Med Screen 2012 Slide courtesy, Dr. Solveig Hofvind - Oslo

24 Study women who actually got screened Pan-Canadian Study of Mammography Screening and Mortality from Breast Cancer Region British Columbia Manitoba Ontario Quebec New Brunswick Nova Scotia Newfoundland and Labrador Summary (random) SMR % CI J Natl Cancer Inst (2014) 106(11) SMR 40% fewer breast cancer deaths

25 Guidelines Mammography Interval NCCN 2016 Age year ACP 2015 Age Individualize USPSTF 2016 Age Individualize years 2 years ACS 2015 Age year 45 to 54 2 years 55+ NICE 2010 Age years WHO 2013 Age years

26 Is the benefit big enough? Still more questions.

27 Screening Mammography Relative vs. Absolute Risk Reduction What age to start screening? Is mammography alone sufficient? Add ultrasound? Add MRI? How frequent? At what cost? What are the downsides of screening well women?

28 The Harms of Screening Mammography

29 Lead and Length time bias

30 False positives test result which incorrectly indicates that a particular condition or attribute is present. Does not result in a cancer diagnosis Welch, Passow JAMA Intern Med. 2014

31 False positives test result which incorrectly indicates that a particular condition or attribute is present. Does not result in a cancer diagnosis Unnecessary biopsies Psychological distress Welch, Passow JAMA Intern Med. 2014

32 False positives 7-10% of women experience unnecessary biopsies after 10 years of annual screening Breast Cancer Surveillance Consortium

33 False positives 7-10% of women experience unnecessary biopsies after 10 years of annual screening Among 10,000 women aged 50 yrs undergoing annual mammography x 10 years 6130 will have at least 1 FP Breast Cancer Surveillance Consortium

34 False positives 7-10% of women experience unnecessary biopsies after 10 years of annual screening Among 10,000 women aged 50 yrs undergoing annual mammography x 10 years 6130 will have at least 1 FP 10 yr cumulative risk of at least 1 FP by age start screening years: 61.3% years: 49.7% Breast Cancer Surveillance Consortium

35 Over diagnosis The detection of a tumor through screening that would not have become clinically evident in the absence of screening

36 Over diagnosis The detection of a tumor through screening that would not have become clinically evident in the absence of screening Can occur because tumor s indolent natural history Competing mortality risk (older age, comorbidities)

37 Over diagnosis Estimates of the extent of over diagnosis range from 5-50% Different populations, assumptions, measurement methods Includes diagnoses of DCIS and some invasive cancers Which ones are indolent? Among 10,000 women screened 302 DCIS or invasive cancers would be diagnosed Of these, 57 (19% estimate) may be over diagnosed Ranging from depending on risk estimate

38 Individualizing Screening Recommendations

39 Impact of Age Screening Women years old

40 Results of Randomized Trials for Women Age STUDY MORTALITY REDUCTION CONFIDENCE INTERVAL EDINBURGH 19% - 67% to 46% MALMO 36% - 11 % to 55% OSTERGOTLAND - 2% - 77% to 41% KOPPARBERG 33% 5% to 63% NBSS1-14% - 56% to 17% HIP 23% - 11% to 47% STOCKHOLM - 1% - 101% to 49% GOTHENBURG 44% 2% to 68% META ANALYSIS SUMMARY 18% 5% to 29% ** Hendrick et al: JNCI 22:87-92

41 Meta-analysis Mammographic screening reduces the risk of breast cancer mortality in younger women Pace, JAMA 2014

42 Why screen all women aged years? Breast cancer is single commonest cause of death in this age group Meta-analysis of 8 RCTs shows breast cancer mortality breast cancer mortality by 15% (CI 4% to 25%) Benefit underestimated: non-compliance and contamination Some service screening programs report 25% breast cancer mortality reduction More life-years lost in younger women Less aggressive treatment necessary Technology has greatly improved

43 Why not screen all women aged years? Mammography less sensitive breast density Lower cancer incidence compared to older women Smaller absolute benefit Treatment much more effective today Higher False positive rates Over diagnosis Radiation induced cancer (.005%)

44 Siu, Annals of Int Med, 2016 U.S. Preventive Services Task Force

45 Impact of Age Age years Meta-analyses Summary RR range: NNI = 1904 for women age yrs would need to be invited to prevent 1 breast cancer death 800 will have false positive result 100 will have a biopsy 35 will have cancer 1 (or 2) lives will be saved NNI= 307 for women aged Nelson,

46 Estimate of impact of screening by age Among 10,000 women aged 40 years undergoing annual mammography x 10 years 31 deaths would occur despite screening 5 deaths averted 50 years 62 deaths would occur despite screening 10 deaths averted 60 years 88 deaths would occur despite screening 42 averted Pace, 2014

47 Screening Women >70 years of age For Screening incidence of cancer mammogram sensitivity mammogram specificity Many have > 10yr. life expectancy Against Screening Only 2 RCTs included women both negative Higher proportion of slowgrowing ER+ tumors Competing causes of mortality Over diagnosis and unnecessary treatment

48 U.S. Preventive Services Task Force the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take into account patient context, including the patient s values regarding specific benefits and harms.

49 Screening High Risk Women

50 Breast Cancer Risk Factors Minor (1.5-2x population risk) o Age > 50 o Hormonal factors o Lifestyle (post-menopausal obesity, alcohol, lack of exercise, early smoking) o Minor family history o SNPs Moderate (2-4x) o o o o o o Previous breast cancer Very dense breasts Pre-malignant lesion (atypical hyperplasia, LCIS / lobular neoplasia) Moderate family history ATM, BRIP1, CHEK2, etc. Constellation of minor risk factors Major ( 5x) o BRCA1/2, TP53, PTEN, PALB2,CDH1 o 1 st degree relative mutation carrier o High risk family history o Breast radiation age 30 o Constellation of moderate risk factors

51 Breast Cancer Risk Groups Lifetime Risk Prevalence Average < 15% >80% Moderately Increased 15%-25% 10%-15% High >25% 1% - 2%

52 Breast Cancer Risk Groups Lifetime Risk Prevalence Average < 15% >80% Moderately Increased 15%-25% 10%-15% High >25% 1% - 2%

53 Screening High Risk Women Young women at high risk also have dense breasts Concern about long-term effect of ionizing radiation Individual patient data (IPD) meta-analysis six prospective MRI screening studies to determine if mammography screening in BRCA1/2 mutation carriers in addition to MRI improves screening accuracy effect differs between BRCA1 and BRCA2 gene mutation carriers age groups. Phi, BJC 2016

54 Breast Density Fibroglandular Tissue Non-Dense Dense Risk of Developing Cancer Mammography Sensitivity

55 Can MRI help?

56 MRI Advantages of MRI Disadvantages of MRI Less affected by breast density 3D imaging (tomographic slices) contrast agent (Gd DTPA) More sensitive than ultrasound, especially for DCIS costs Lower specificity Biopsies more difficult Logistics (2 nd week of cycle optimal) Claustrophobia iv for Gadolinium No ionizing radiation

57 Surveillance of BRCA1 and BRCA2 Mutation Carriers With Magnetic Resonance Imaging, Ultrasound, Mammography, and Clinical Breast Examination N= 236 Canadian women aged 25 to 65 years with BRCA1 or BRCA2 mutations who underwent 1 to 3 annual screening examinations, consisting of MRI, mammography, and ultrasound 1997, and March 31, 2003 On the day of imaging and at 6-month intervals, CBE was performed. Main Outcome Measures Sensitivity and specificity of each of the 4 surveillance modalities Mammography and Magnetic Resonance Imaging in BRCA2 Mutation Carrier With Less Than 25% Fibroglandular Density Warner, JAMA 2004

58 Results 22 cancers detected (16 invasive and 6 ductal carcinoma in situ). 17 (77%) were detected by MRI vs 8 (36%) by mammography, 7 (33%) by ultrasound, and 2 (9.1%) by CBE. Sensitivity and specificity (based on biopsy rates) were 77% and 95.4% for MRI 36% and 99.8% for mammography 33% and 96% for ultrasound 9.1% and 99.3% for CBE 1 interval cancer

59 Meta-analysis of MRI Screening Studies of High Risk Women Sensitivity* Specificity* Diagnostic Odds Ratio* Mammography 32% 99% 39 MRI 75% 96% 89 Both 84% 95% 125 * Using score of BI-RADS 4 or higher as cut-off Warner et al. Ann Int Med 2008

60 Conclusions In BRCA1 and BRCA2 mutation carriers, MRI is more sensitive for detecting breast cancers than mammography, ultrasound, or CBE alone. Whether surveillance regimens that include MRI will reduce mortality from breast cancer in high-risk women requires further investigation.

61 Breast Ultrasound Detects small invasive cancers not seen on mammography Reduced specificity Handheld ultrasound is user-dependent and very labor intensive May be beneficial in women with dense breasts May be beneficial in high risk women who cannot tolerate MRI Increased risk of False Positives US instead of mammography for screening not recommended

62 Research

63 Improving sensitivity and specificity Digital breast tomosynthesis Ultrasound Breast Screening Research Contrast imaging based on angiogenesis MRI Contrast-enhanced digital mammography Risk based screening Breast MRI for High-Risk Women Individualize screening recommendations for subgroups (very low risk, intermediate risk)

64 Tomosynthesis

65 POTENTIAL ADVANTAGES OF TOMOSYNTHESIS lesion conspicuity sensitivity overlap of tissues specificity Provide better depiction of extent of disease Better imaging of the moderately dense breast Reduced abnormal recall rate when no cancer present Improved detection of small invasive cancers Better characterization of cancers

66 Comparison of Full-Field Digital Mammography with Digital Breast Tomosynthesis: TMIST study RCT digital mammography vs. tomosynthesis 165,000 women Tomosynthesis vs. Digital Mammography Outcomes: significant cancer detection rate interval cancer rate patient preferences & QoL false +ve recalls and biopsies

67 3D Automated Breast US Faster for patient Operator-independent Need not be read in real time 3 vs. 20 min radiologist time Gives tomographic images

68 Contrast-Enhanced Digital Mammography (IV Iodine Contrast)

69 Contrast-enhanced Digital Mammography vs MRI Both have superior sensitivity to mammography No claustrophobia More accessible More specific? Patient preference May be useful for imaging women with dense breasts and for screening those at intermediate risk of developing breast cancer

70 Summary Screening Mammography reduces the risk of breast cancer mortality Relative risk reduction ~20% Currently, costs are high False positives (improve imaging) Over diagnosis (improved risk assessment of pathological entities) Assess individual s risk of breast cancer Screening recommendations should differ for risk groups Optimize risk/ benefits for each individual Elicit patient preferences and values

71 Summary of Screening Recommendations Average risk: Biennial mammography age individualize age and 75+ Moderate risk: annual mammography, CBE ± ultrasound age 40+ High risk: annual mammography + MRI age Mammography alone age 70+

72 Canadian Cancer Society Guidelines Age 40 to 49: Talk to your doctor about your risk of breast cancer, along with the benefits and risks of mammography. 50 to 69: Have a mammogram every 2 years. 70 or older: Talk to your doctor about how often you should have a mammogram. Your doctor may also do a physical examination of your breasts (a clinical breast examination) to check for signs of cancer

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74 Thank you