Screening and Cancer Screening: more complex than we Cancer site - - PDF document

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The WISDOM of Screening

May: Laura Esserman, MD MBA Professor , UCSF Departments of Surgery and Radiology June: Yiwey Shieh, MD Instructor , UCSF Division of General Internal Medicine A real world case: 39 year old woman undergoing in vitro fertilization (IVF) gets a mammogram as part of routine pre-IVF testing. She has no family history of cancer or personal history of breast disease. Mammogram shows microcalcifications (right). A biopsy is recommended.

Roadmap

• Screening: more complex than we

thought!

• Population-wide effects of screening

and the difficulty with guidelines

• Adopting precision (risk-based)

principles to screening

– Tools to risk-stratify patients – Changing our perception of “cancer” – Embracing the continuum of screening and prevention

Screening and Cancer

Cancer site Test(s) Breast Mammography Prostate PSA Colorectal Colonoscopy, FOBT, sigmoidoscopy Cervical Cytology (Pap smear) Lung Low-dose CT

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What should be the target of screening?

Detectable Metastases Normal Cell Atypical Cell Carcinoma In Situ Stage 1 Cancer Stage 2-3 Cancer Cancer death

Old Paradigm: inexorable progression

Early Detection Will Reduce Mortality

Esserman et al, Lancet Oncology May 2014

“cancer” is one disease . . .

For Both Breast and Prostate

Incidence Rates Have Risen and Remain Higher

8

BREAST PROSTATE

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Detectable Metastasis

New Paradigm: variable progression

Normal Cell Atypical Cell/CIS Stage 1 Cancer Stage 2-3 Cancer Cancer death Detectable Metastasis Normal Cell Stage 1-3 Cancer Cancer death Normal Cell Atypical Cell/CIS Stage 1 Cancer Systemic Therapy Key to Reducing Mortality Early Detection Will Not Impact Mortality Early Detection Reduce Mortality INDOLENT LESIONS RAPID PROGRESSION SLOW PROGRESSION

IDLE condition : Indolent lesions

• f epithelial origin

Indolent Tumors: Rare metastases, course Indolent

Overdiagnosis occurs when screening picks up IDLE or indolent disease

IDLE INDOLENT

What makes screening so complex?

• Benefits of screening are proportionate to

distribution of biologic tumor types

• Perceptions of screening benefit are also

proportionate to distribution of biologic tumor types

Screening and Treatment Are Necessarily Related

• Distribution of tumor types is changed by

screening

• Impact of screening changes with advances in

treatment

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Screening changes distribution of disease type

1 0 2 0 3 0 4 0 5 0 Fast Slow Ve ry Slow IDLE % of ove ra ll ca nce rs de te cte d

Breast

1 0 2 0 3 0 4 0 5 0 Fast Slow Ve ry Slow IDLE % of ove ra ll ca nce rs de te cte d

Colorectal & Cervical

1 0 2 0 3 0 4 0 5 0 Fast Slow Ve ry Slow IDLE % of ove ra ll ca nce rs de te cte d

Prostate

ARE THERE “IDLE” OR INDOLENT CANCERS? Defining indolent breast cancers using gene expression profiling

70 significant prognosis genes

Vant Veer Nature 2002

Ultralow Threshold

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Ultra Low risk: Threshold determination and locking

Ultra low group (yellow curve):

• Threshold at 0.7
• 100% overall survival @ 25 years (n=8)

Threshold different and refined from Esserman et al BCRT: Nature paper 5 yrs FU

Ultra Low Threshold determined using NEJM publication with 25 years FU data (van de Vijver et al, NEJM 2002; Drukker et al, BCRT 2014)

• Node negative at time of diagnosis
• 100% overall survival at 25 years
• Ultra low risk threshold locked at MP-score 0.7

Indolence = excellent survival absent screening, systemic treatment

94% Survival NO Systemic Tx 20 years 97% Survival 20 years

Evidence for indolent prostate cancers

Prostate cancer mortality in low risk (Gleason ≤ 6, PSA ≤ 10) lesions followed with active surveillance

Klotz JCO 2014

HAS THE DISTRIBUTION CHANGED OVER TIME?

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30% of Screen Detected Are Categorized as “Ultralow Risk” Cancers

Women aged 49-60

Esserman, Shieh, van’t Veer BCRT 2011

70-gene prognosis signature index score distribution

Women aged 49-60

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High Unscreened, symptomatic Screened, assymptomatic

DCIS Increased 500% after the Advent of Mammographic Screening . . .

10 20 30 40 50 60 70 80 90 100 1975 1980 1985 1990 1995 2000 2005 Incidence rate (per 100,000) Year of diagnosis

Figure 2. SEER9 Age-adjusted incidence rate of breast cancer by stage (1973-2005)

In situ Rate Localized Rate Regional Rate Distant Rate

Localized Regional In Situ Metastatic

Li CEBP 2005

Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ A Population-Based Cohort Study

Yasuaki Sagara, MD; Melissa Anne Mallory, MD; Stephanie Wong, MD; Fatih Aydogan, MD; Stephen DeSantis, BS; William T. Barry, PhD; Mehra Golshan, MD IMPORTANCE While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. OBJECTIVE To investigate the survival benefit of breast surgery for low-grade DCIS. A retrospective longitudinal cohort study using the Research

Original Investigation

• 57,222 women (SEER)
• 2% (1169) of women had observation only
• Survival in low grade DCIS IDENTICAL (98.6 vs 98.8%)

for surgery vs. not

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Precursor of Indolent tumor fits definition of IDLE

DCIS Dx IDLE Condition

Consequences: Treatment of DCIS

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J Am Coll Radiol. 2013 Dec;10(12):918-23. Evolving paradigm for imaging, diagnosis, and management of DCIS

Dictionary.com Definition

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can·cer noun 1.Pathology

• a. a malignant and invasive growth or tumor, especially one
• riginating in epithelium, tending to recur after excision

and to metastasize to other sites. b.any disease characterized by such growths.

• 2. any evil condition or thing that spreads destructively; blight.

“Cancer” today encompasses many diseases with distinct trajectories: Which should still be called “cancer”?

PATIENTS ASSUME THAT CANCER, LEFT UNTREATED , WILL KILL YOU

Physicians too

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The good and bad of screening

Mortality has declined

Incidence has increased (for certain cancers) Thyroid cancer incidence vsmortality in Korea

Ahn NEJM 2014

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What’s driving increase in incidence rates?

Esserman JAMA 2009

Is screening preventing metastatic disease at time of first presentation?

Welch NEJM 2015

How do we make screening better?

YES NO Early metastatic risk moderate/ high Chemo ê recurrence risk Metastatic risk extremely low Excellent outcome certain

Indolent T umor

Late metastatic risk moderate/ high Minimal chemo impact on recurrence Characteristics Clinical Implications Not a harbinger of distant disease Initial Treatment: Safe if less aggressive Early detection: Benefit minimal / none Harbinger of distant disease Distant recurrence fatal Initial Treatment: Maximized to reduce recurrence Early detection benefit most likely for late risk population

Recognize that tumor biology is complex: Use Diagnostic Tools To adjust treatment approaches

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NOMENCLATURE CHANGE When Nomenclature Changes . . . Treatment changes

• Cervical Cancer

– CIS à CIN 1, 2, & 3 (Bethesda System 1998) – CIN 1 now followed, 50% disappear by 1 year without treatment

• Bladder Cancer

– Superficial bladder cancer à papillary urothelial neoplasm of low malignant potential (PUNLMP)

• Thyroid Cancer

– encapsulated follicular variant of papillary thyroid carcinoma à noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Course correction

Nomenclature Revision for Encapsulated Follicular Variant

• f Papillary Thyroid Carcinoma

A Paradigm Shift to Reduce Overtreatment of Indolent Tumors

Yuri E. Nikiforov, MD, PhD; Raja R. Seethala, MD; Giovanni Tallini, MD; Zubair W. Baloch, MD, PhD; Fulvio Basolo, MD; Lester D. R. Thompson, MD; Justine A. Barletta, MD; Bruce M. Wenig, MD; Abir Al Ghuzlan, MD; Kennichi Kakudo, MD, PhD; Thomas J. Giordano, MD, PhD; Venancio A. Alves, MD, PhD; Elham Khanafshar, MD, MS; Sylvia L. Asa, MD, PhD; Adel K. El-Naggar, MD; William E. Gooding, MS; Steven P. Hodak, MD; Ricardo V. Lloyd, MD, PhD; Guy Maytal, MD; Ozgur Mete, MD; Marina N. Nikiforova, MD; Vania Nosé, MD, PhD; Mauro Papotti, MD; David N. Poller, MB, ChB, MD, FRCPath; Peter M. Sadow, MD, PhD; Arthur S. Tischler, MD; R. Michael Tuttle, MD; Kathryn B. Wall; Virginia A. LiVolsi, MD; Gregory W. Randolph, MD; Ronald A. Ghossein, MD Research Original Investigation

JAMA Oncology April 14, 2016

Other Indolent or IDLE conditions

Cancer site Corresponding IDLE condition Prostate Gleason 3+3 disease Breast Indolent invasive cancers Breast Low-grade DCIS

• Opportunity for watchful waiting or

prevention

• IDLE conditions:

– Should not be targets of screening

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Mammography guidelines, 2016

Organization Start screening at age Terminate screening at age Frequency of assessment United States Preventive Services Task Force (USPSTF) 50 74 Every 2 years (for women at average- risk of breast cancer) American Cancer Society (ACS) 45 As appropriate based on life expectancy Annually then biennially at 55 years of age and

• lder

American College of Obstetricians and Gynecologists (ACOG) 40 As appropriate based on life expectancy Annually American College of Radiology (ACR)/Society

• f Breast Imaging (SBI)

40 As appropriate based on life expectancy Annually

Screening Recommendations – Around the World

42

Country Start age Stop age Frequency US 40 NA Annually Sweden 45 74 Biennially UK 50 70 Triennially Netherlands/Italy/Germany 50 70 Biennially Australia 50 75 Biennially France 50 74 Biennially Israel 50* 40* 74 Bienneial *annually for high risk Switzerland recently considering ending mammography screening altogether because of lack of evidence that the benefits outweighs the harms. Biller-Andorno and Jüni, NEJM, 2014.

Some women screened too much, others too little Women are caught in the middle... and some are choosing not to screen at all

Unintended Consequences of the Screening Controversy

We already do risk-based screening

(to some extent)

• HPV-negative after age 30 à retest in 5 years
• Colonic polyps

– Few small, hyperplastic polyps à 10 years – T ubular adenomas à 5-10 years (depending on size, number) – Sessile serrated polyps à 3-5 years

Images from aafp.org

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Careful delineation of target population in lung cancer screening

• Age 55 to 80
• >30 pack-year smoking history
• If former smoker, quit within 15 years
• Asymptomatic

Other tools to assess risk

• Risk prediction models

– Breast: Gail model, BCSC risk model – Prostate: PCPT risk calculator

• Genetics

– Mutations – SNPs

1" 2" 4" 8" 16" 0.01" 0.1" 1" 10" 100" Rela%ve'''Risk' Allele'frequency'%''' Familial"Cancer" Syndromes" (BRCA1/2)" Common'variants' (SNPs)' Intermediate" Penetrance"(CHEK2)"

Women Informed to Screen Depending On Measures of risk WISDOM Study Design: Pragmatic Trial

48 Eligible Patients Consent

Randomized Cohort

Randomize

Annual Screening Personalized Screening Observational Cohort Annual Screening Personalized Screening

adapts over time

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Risk Calculator

USPST F

BCSC 9 genes Polygenic risk

Mammogram

• breast density

Athena Health Questionnaire

• family history,

comorbidities, previous biopsies, age, race/ethnic ity

Personalized Risk Profile: Risk Assignment notification, assigned screening frequency Genomic profiling

• BRCA, comprehensive

hereditary breast cancer risk gene panel, SNPs

• saliva collection

RBS trial consent RBS Consumer Engagement

Lowest risk Average risk Elevated risk Highest risk

BCSC

Follow-Up:

• Mammography

Frequency Assigned by Risk Profile

• Annual Athena Questionnaire to re-assess risk

Cancer detected: Molecular profiling

Breast Health Specialist counseling No cancer: repeat 49

Personalized Screening Arm

Shared Decision-Making Report

The Personalized Arm: Better Buckets

Age 40-49 with a <1.3% 5-year risk Repeat MMG at age 50 Age ≥50 *OR* >1.3% 5-year risk Biennial MMG Age 40-49 with

• ext. dense breasts

OR BCSC/SNPs 5year risk 4.5-6% Annual MMG Positive Genetic test OR >6% 5-year risk Annual MMG + MRI

All: yearly update of risk

Determine if personalized screening (as compared to annual screening):

• 1. Is as safe
• 2. Is less morbid
• 3. Is more accepted by women
• 4. Enables prevention
• 5. Has greater health care value

WISDOM Study Aims IBIS 2: Anastrazole

52

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Prevention Trials: Endocrine Risk Reduction

• Investment:

– 100’s of millions spent testing endocrine therapy in the setting of elevated risk in the U.S.; Italy; U.K.

• Impact:

– 50% risk reduction in population w/average Gail Risk (~ 3) – 85% reduction for women with atypia

• Agents

– Tamoxifen, Raloxifen, Exemestane, Arimidex

• Current Uptake:

– Likely less than 5% of eligible women

Lifestyle Modifications

• Lifestyle modifications are recommended as

potential risk reduction strategies for women

• ther than BRCA carriers and include:

– Weight control – No cigarette smoking – Decreased alcohol consumption – Exercise – Discontinue hormone therapy if appropriate

• Lifestyle modifications (especially optimal

weight maintenance after menopause and decreased animal fat) can decrease breast cancer risk by 30-45%

Ross D. 2000 San Antonio Breast Cancer Symposium…need abstract number of updated reference Vogel V. CA Cancer J Clin. 2000;50:156-170. Holmes MD et al. Breast Cancer Res 2004;6:170-178..

Integrating prevention into risk assessment

Risk category Average Above Average Moderate High Very High Genetic Information <20 th percentile based on PRS 20-40 th PRS 40-60 th PRS CHEK2, ATM, 60-80 th PRS PALB2, CDH1, STK11 >80 th PRS BRCA1/2, TP53, PTEN Screening Mammogram ≥50 years Every 2 years Mammogram ≥40 years Every 2 years Mammogram Yearly Mammogram MRI Yearly Mammogram MRI Yearly Medical & Lifestyle- based Risk Reduction Lifestyle Tamoxifen, Aromatase inhibitors, Lifestyle Tamoxifen, Aromatase inhibitors, Lifestyle Surgical Risk Reduction BSO BPM

Risk Based Screening Will Teach Us

Who is At Risk for What Kind of Cancer

LEARN

who gets what kind of cancer

CONTINUOUS IMPROVEMENT ADAPT/T AILOR

Prevention Biopsy Treatment Screening

PRACTICE GENERATING EVIDENCEà ADAPT

!

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Importance of communication

Fintelmann RSNA Radiographics 2015

Lung-RADS: defining the target in lung cancer screening

Fintelmann RSNA Radiographics 2015

Screening wisely

Shieh Nature Reviews Clin Onc 2016

Screening cascade, part 1

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Screening cascade, part 2

Recap: Complexity is driven by biology

• Benefits of screening are proportionate to

distribution of biologic tumor types

• Perceptions of screening benefit are also

proportionate to distribution of biologic tumor types

• Distribution changes by screening
• Impact of screening will change with advances

in treatment

How can generalists help?

• Understand why screening is complex

– Biology, and how screening changes it

• Join the search for a solution

– refer patients to WISDOM, enrolling Fall 2016 http://wisdomstudy.org

• Support patient-centered decision-making

– BCSC risk calculatorhttps://tools.bcsc- scc.org/bc5yearrisk/calculator.htm – Prostate cancer prevention trial risk calculator (PCPTR 2.0) – Guide your patients according to their risk

• Integrate Prevention into screening whenever possible