ESMO PRECEPTORSHIP PROGRAMME BREAST CANCER€¦ · European Communities (2006), 4; th. ed. The screening exam has not been able ... Caumo F, et al. Digital Breast Tomosynthesis with

ESMO PRECEPTORSHIP PROGRAMME BREAST CANCERScreening

Name

Kristina Lång

Date 9 Nov 2018

DISCLOSURE OF INTEREST

Disclosure: • Received speaker’s fee and travel grant from Siemens

• Siemens Scientific Advisory Board (2017)

• Research collaboration with Philips

The aim of screening

• Detect a disease early in an asymptomatic stage

• Give early intervention and management

• Reduce the impact of a disease that has already occurred (secondary prevention)

Outcome is better because of early detection and intervention

Kristina Lång, ESMO 9 Nov 2018

Guidelines on the principles and practice of screeningaccording to Wilson and Jungner (WHO 1968)

The disease

• Severe

• High prevalence in a preclinical stage

• The natural history of the disease known

• Long period between between first sign and manifest disease

• Acceptable sensitivity and specificity

• Simple and cheap

• Safe and acceptable

• Possible treatment

• Effective, safe and acceptable

The test

The treatment


• New York HIP (1963)

• Malmö I and II (1976)

• Swedish Two County (1977)

• Edinburgh (1978)

• Canada I and II (1980)

• Stockholm (1981)

• Göteborg (1982)

• UK Age trial (1991)

www.mskcc.org

5

Early randomized controlled trials


Mammography screening in EUInitiation of a population based screening programmes

Sweden 1986

Finland 1987

UK 1988

The Netherlands 1988

Ireland 2000

Belgium 2001

Balticum 2002–2008

Hungary 2002

Germany 2005

Polen 2006

Malta 2008

Slovenia 2008

Altobelli and Lattanzi IJO 2014

Participation rate of

>70% acceptable


• Two-view mammography

• Target age 50–69

• Biennial screening intervals

• Double reading

mediolateral oblique craniocaudal

Typical mammography screening programme

Sweden: Age 40–74 with 1.5–2 year interval

UK: Age 50–70 with 3 year interval


The balance in screening

• Reduction in mortality

• Reduced suffering from metastatic disease

• Breast conserving surgery

• Feeling of security

• False positives

• Overdiagnosis

• Anxiety

• False negatives = false sense of security

Benefits Harms

8Kristina Lång, ESMO 9 Nov 2018

Reduction in breast cancer deaths

• In age group 40–49: 16% relative risk reduction

• 2057 women needs to be screened regularly to prevent one breast cancer death

• The effect of screening is lower in younger women:

• In age group 50–74: 23% relative risk reduction

• 760 women needs to be screened regularly to prevent one breast cancer death

- Lower prevalence

- Lower sensitivity of mammography (dense breasts)

Gotzsche, PC, Nielsen, M. Screening for breast cancer with mammography. Cochrane database of systematic reviews (2011)

Nationella riktlinjer för screening, Socialstyrelsen (2017)

0.049% absolute risk reduction

0.13% absolute risk reduction • In Europe: 50–69 år

IARC Working Group for Screening. NEJM (2015)

Benefit of screening


False positives

• 80–90% of recalled women are false positives

• Breast cancer-specific psychological distress that may endure for up to 3 years

• Recall rates: – prevalence screening

Overdiagnosis

• The detection of a cancer that would never have been found were it not for the screening test

• Two forms of overdiagnoses: 1. The detection of a lesion with essentially no malignant potential

2. The detection of a lesion that is slow-growing enough that the individual will go on to die of a competing cause of death first

• Women become cancer patients with psychological and treatment side effects

• A breast cancer diagnosis is associated with comorbidity: increased risk of dying of various causes (pulmonary circulation, suicide, heart failure, and gastrointestinal disease)

The consequences:

Riihimäki et al. Ann Oncol (2012)

Harm of screening


• Review of RCTs

• Screening is likely to reduce breast cancer mortality by about 15%

• But 30% overdiagnosis and overtreatment

Cochrane Database of Systematic Reviews 2011

• 2000 invited women screened for 10 years: 1 BC death prevented

10 women overdiagnosed and overtreated

200 women with FPs


• Review of the early mammography RCTs

• Reduction of breast cancer mortality about 20% (invited)

• Overdiagnosis rate: 11% (invited), 19% (attending)

• If 10,000 women aged 50 are invited to screening for 20 years:

1 breast cancer death prevented 3 women overdiagnosed and overtreated

43 breast cancer deaths prevented

129 women overdiagnosed and overtreated


Can we reduce overdiagnosis and overtreatment?

• Potential overdiagnosed cancer: low-grade DCIS and invasiv tubular cancer?

• Detection of DCIS has increased with screening (10–20%), 90% of DCIS do probably not evolve into invasive cancer

• Watchful waiting of low-grade DCIS vs. treatment (ongoing RCTs, The LORIS trial, the LORD trial mfl.)

Evans A and Vinnivombe S. Breast (2017)Francis A, et al. Clin Oncol (2015)Elshof LE, et al. Eur J Cancer. (2015)


Interval cancer

16

• Symptomatic cancers diagnosed in the interval between two screening examinations

• ”False” or ”true” interval cancers

• More aggressive with poorer prognosis

• Strong indicator on how successful your screening programme is


S C R E E N I N G B T

S C R E E N I N G D MS C R E E N I N G D M

2 0 1 3 2 0 1 4 2 0 1 4

Söker för knöl 3 månader senare

PAD: 12 mm IDC trippel negative G3

17

3 months later lump in the

breast

1000 screened women

30 recalls no recalls

true positives

false positives

true negatives

false negatives

clinically relevant cancers

overdiagnosed cancers

970

5 25 969

1 4

1

≈1/3 of all cancers are missed in screening

partly due to the limitation of the mammographic

technique

Birdwell et al. Radiology (2001)

Typical outcome of screening


Tomosynthesis in screening

• Caumo F, et al. Digital Breast Tomosynthesis with Synthesized Two-Dimensional Images versus Full-Field Digital Mammography for Population Screening: Outcomes from the Verona Screening Program. Radiology (2018)

• Hofvind S, et al. Digital Breast Tomosynthesis and Synthetic 2D Mammography versus Digital Mammography: Evaluation in a Population-based Screening Program. Radiology (2018)

• Skaane P, et al. Performance of breast cancer screening using digital breast tomosynthesis: results from the prospective population-based Oslo Tomosynthesis Screening Trial. Breast Cancer Research and Treatment. (2017)

• Bernardi D, et al. Breast cancer screening with tomosynthesis (3D mammography) with acquired or synthetic 2D mammography compared with 2D mammography alone (STORM-2): a population-based prospective study. Lancet Oncol. (2016)

• Lång K, et al. Performance of one-view breast tomosynthesis as a stand-alone breast cancer screening modality: results from the Malmö Breast Tomosynthesis Screening Trial, a population-based study. Eur. Radiol. (2016)

• Skaane P, et al. Prospective trial comparing full-field digital mammography (FFDM) versus combined FFDM and tomosynthesis in a population-based screening programme using independent double reading with arbitration. Eur. Radiol. (2013)

• Skaane P, et al. Comparison of Digital Mammography Alone and Digital Mammography Plus Tomosynthesis in a Population-based Screening Program. Radiology (2013)

• Ciatto S, et al. Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study. Lancet Oncol. (2013)

Prospective population-based screening trial (2013–2018)

19

• Incremental increase in breast cancer detection with

BT:2.2–2.7 per 1000 screens

• Mixed effect on recall rates


14,848 screened womenBT DM

Recall rate (%) 3.6 2.5

Detected cancers (n)* 131 97

CDR** 8.7/1000 6.5/1000

Sensitivity (%) 81 60

Specificity (%) 97 98

PPV (%) 24 26

* Bilateral cancers in two women

** Calculated per woman

+42 cancers (90% invasive)

+8 cancers (50% invasive)

+2.2 women with cancer per 1000 screened (CI: 1.2 to 3.2, p< 0.0001)

Malmö Breast Tomosynthesis Screening TrialOne-view tomosynthesis vs. two-view mammography


SCREENING DM

SCREENING BT

DM

PAD: 15 mm IDC G1, LN-

SCREENING DM SCREENING BT

• Today; outside rare very-high risk conditions, age is the sole risk factor considered in screening

• Individualized/risk-based screening may improve benefit/harm ratio

unsplash.com

‣ Earlier cancer detection and less intensive

treatments in high risk women ‣ Less false positives and overdiagnoses in

low risk women ‣ Increase the cost-efficacy

Individualized screening


• RCT, 7-year long European H2020 project ststarted 2018, including 5 countries (France, Italy, UK, Belgium and Israel)

• 85,000 women aged 40–70, 4-years follow-up

• Stratification based on personalized breast cancer risk (risk model, SNPs and breast density)

• Outcomes:

- Primary: Is risk-based screening non-inferior, and eventually superior, to conventional screening in terms of reduction of stage II or higher BC

- Secondary: Biopsy rates for benign breast lesions, rate of low-risk cancers in low-risk women in both arms, socio-psychological assessments, cost-effectiveness

MyPEBS (My Personalized Breast Screening)

25

https://cordis.europa.eu/project/rcn/212694_en.html

Personalized breast cancer screening trial


Additional imaging method for dense breasts

MRI

• Advantages: no ionizing radiation, high sensitivity

• Disadvantages: time, FP, cost, accessibility, contrast agent

• Abbreviated MRI protocol: 3D MIP image and first post-contrast T1 image (FAST)

• DWI-MRI (without Gd) a good alternative?

• The Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial:

Bickelhaupt, S et al. Radiology (2016)Kuhl CK, et al. Radiology (2017)

26

Emaus MJ et al. Radiology (2015)

- Women with extremely dense breast- RCT DM vs. DM + MRI- Primary outcome: proportion of IC rates


• Computer-aided-detection (CAD) has been used in mammography since the 90s

• To many false positives

• Recent improvements in AI, due to deep learning algorithms, is closing the gap between humans and computers

Lehman CD, et al. JAMA Intern Med (2015)

Fenton JJ, et al. NEJM (2007)

27

Artificial intelligence in screening

• Multicenter multireader-multicase study, 2,652 exams (653 malignant)

• 101 radiologist vs machine (Transpara)

• The performance of the AI system similar to the average radiologist

A Rodriguez-Ruiz et al. JNCI (2018)


• 9,588 double-read mammography screening exams (71 screen-detected cancers,187 FP)

• Images were analysed with a deep learning-based software (Transpara)

• Preselection tool that assigns 10 risk scores with an increasing likelihood of cancer

• The effect of excluding cases with low risk scores (≤5) from screen-reading was investigated

28

Can artificial intelligence reduce the workload in screening?


• Safely reduce the workload by 10%

29

AI score Normal cases (n) False positives (n) Cancer cases (n)1 1004 (10.4%) 6 (3.2%) 0 (0%)1–2 1830 (19.1%) 10 (5.4%) 1 (1.4%)1–3 2724 (28.4%) 19 (10.2%) 3 (4.2%)1–4 3996 (41.7%) 35 (18.7%) 5 (7.0%)1–5 5085 (53.0%) 52 (27.8%) 8 (11.3%)

K Lång et al. (ECR 2019) AI-score

N

• Adapt work effort to risk?

Sin

gle

read

ing

Dou

ble

read

ing

No

hum

an r

eade

rs

Can artificial intelligence reduce the workload in screening?


Workflow Efficiency.CAT – Computer Assisted Triage

Worklist A Worklist B Worklist C

Result from an AI or CAD solution automatically set on the exam and visible in the worklist in Sectra PACS.Single

readingDouble reading

AI

Breast cancer screeningSummary

31

• Implemented in most countries in Europe

• Screening interval: age 50–69, mammography with 2 year interval

• RCTs: Reduction in breast cancer mortality by 20%

• Overdiagnosis rate 11%

• False positives is a drawback in screening

• The screening policy will most likely be modified in the future with new imaging techniques, individualized screening and with the introduction of AI


Thank you for your attention

ESMO preceptorship programme Breast cancerDisclosure of interestThe aim of screeningGuidelines on the principles and practice of screeningaccording to Wilson and Jungner (WHO 1968)Early randomized controlled trialsMammography screening in EUTypical mammography screening programmeThe balance in screeningReduction in breast cancer deathsFalse positivesOverdiagnosisEstimates of overdiagnosis in screeningSlide Number 13Slide Number 14Can we reduce overdiagnosis and overtreatment?Interval cancerSlide Number 17Slide Number 18Tomosynthesis in screeningSlide Number 20Slide Number 21Slide Number 22Slide Number 23Individualized screeningPersonalized breast cancer screening trialAdditional imaging method for dense breastsSlide Number 27Can artificial intelligence reduce the workload in screening?Can artificial intelligence reduce the workload in screening?Workflow Efficiency. Breast cancer screeningSlide Number 32

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ESMO PRECEPTORSHIP PROGRAMME BREAST CANCER€¦ · European Communities (2006), 4; th. ed. The screening exam has not been able ... Caumo F, et al. Digital Breast Tomosynthesis with