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

5/26/16 A real world case: 39 year old woman undergoing in vitro fertilization (IVF) gets a mammogram as part of routine pre-IVF testing. The WISDOM of Screening She has no family history of cancer or personal history of breast disease. Mammogram shows May: Laura Esserman, MD MBA microcalcifications ( right ). Professor , UCSF Departments of Surgery and Radiology A biopsy is recommended. June: Yiwey Shieh, MD Instructor , UCSF Division of General Internal Medicine Roadmap Screening and Cancer • Screening: more complex than we Cancer site Test(s) thought! Breast Mammography • Population-wide effects of screening Prostate PSA and the difficulty with guidelines Colorectal Colonoscopy, FOBT, sigmoidoscopy • Adopting precision (risk-based) Cervical Cytology (Pap smear) principles to screening Lung Low-dose CT – Tools to risk-stratify patients – Changing our perception of “cancer” – Embracing the continuum of screening and prevention 1

5/26/16 Old Paradigm: inexorable progression Normal “cancer” is one disease . . . Cell Atypical Cell Carcinoma In Situ Stage 1 Cancer What should be the target of Stage 2-3 Cancer screening? Detectable Metastases Early Detection Will Cancer Reduce Mortality death Esserman et al, Lancet Oncology May 2014 For Both Breast and Prostate Incidence Rates Have Risen and Remain Higher BREAST PROSTATE 8 2

5/26/16 New Paradigm: variable progression Overdiagnosis occurs when screening INDOLENT RAPID SLOW picks up IDLE or indolent disease LESIONS PROGRESSION PROGRESSION Normal Normal Normal Cell Cell Cell Atypical Atypical Stage 1-3 Cell/CIS Cell/CIS Cancer Stage 1 Stage 1 Detectable Cancer Cancer Metastasis INDOLENT Cancer Stage 2-3 death Cancer IDLE condition : Indolent lesions Detectable IDLE of epithelial origin Metastasis Indolent Tumors: Cancer Rare metastases, course Indolent death Early Detection Will Early Detection Systemic Therapy Key Not Impact Mortality Reduce Mortality to Reducing Mortality Screening and Treatment Are What makes screening so complex? Necessarily Related • Benefits of screening are proportionate to • Distribution of tumor types is changed by distribution of biologic tumor types screening • Perceptions of screening benefit are also • Impact of screening changes with advances in proportionate to distribution of biologic treatment tumor types 3

5/26/16 Screening changes distribution of disease type Breast 5 0 nce rs de te cte d 4 0 3 0 ll ca 2 0 % of ove ra 1 0 0 Fast Slow Ve ry Slow IDLE Prostate Colorectal & Cervical ARE THERE “IDLE” OR INDOLENT 5 0 5 0 nce rs de te cte d nce rs de te cte d 4 0 4 0 CANCERS? 3 0 3 0 ll ca ll ca 2 0 2 0 % of ove ra % of ove ra 1 0 1 0 0 0 Fast Slow Ve ry Slow IDLE Fast Slow Ve ry Slow IDLE Defining indolent breast cancers using gene expression profiling 70 significant prognosis genes Ultralow Threshold Vant Veer Nature 2002 4

5/26/16 Indolence = excellent survival absent Ultra Low risk: Threshold determination and locking screening, systemic treatment 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 94% Survival • 100% overall survival at 25 years NO Systemic Tx • Ultra low risk threshold locked at MP-score 0.7 20 years 97% Survival Ultra low group (yellow curve): 20 years 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 Evidence for indolent prostate cancers Prostate cancer mortality in low risk (Gleason ≤ 6, PSA ≤ 10) lesions followed with active surveillance HAS THE DISTRIBUTION CHANGED OVER TIME? Klotz JCO 2014 5

5/26/16 30% of Screen Detected Are Categorized as 70-gene prognosis signature index score distribution “Ultralow Risk” Cancers Women aged 49-60 Women aged 49-60 High Unscreened, symptomatic Screened, assymptomatic 22 Esserman, Shieh, van’t Veer BCRT 2011 DCIS Increased 500% after the Advent of Research Mammographic Screening . . . Original Investigation Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ Figure 2. SEER9 Age-adjusted incidence rate of breast cancer by stage (1973-2005) A Population-Based Cohort Study 100 Yasuaki Sagara, MD; Melissa Anne Mallory, MD; Stephanie Wong, MD; Fatih Aydogan, MD; Stephen DeSantis, BS; William T. Barry, PhD; Mehra Golshan, MD 90 80 IMPORTANCE While the prevalence of ductal carcinoma in situ (DCIS) of the breast has Incidence rate (per 100,000) Localized increased substantially following the introduction of breast-screening methods, the clinical 70 significance of early detection and treatment for DCIS remains unclear. 60 OBJECTIVE To investigate the survival benefit of breast surgery for low-grade DCIS. In situ Rate Localized Rate 50 A retrospective longitudinal cohort study using the Regional Rate • 57,222 women (SEER) Distant Rate 40 Regional • 2% (1169) of women had observation only 30 20 • Survival in low grade DCIS IDENTICAL (98.6 vs 98.8%) In Situ 10 for surgery vs. not Metastatic 0 1975 1980 1985 1990 1995 2000 2005 Year of diagnosis Li CEBP 2005 6

5/26/16 Precursor of Indolent tumor fits Consequences: Treatment of DCIS definition of IDLE DCIS Dx IDLE Condition J Am Coll Radiol. 2013 Dec;10(12):918-23. Evolving paradigm for imaging, diagnosis, and management of DCIS 26 Dictionary.com Definition can·cer noun 1. Pathology a. a malignant and invasive growth or tumor, especially one originating in epithelium, tending to recur after excision and to metastasize to other sites. PATIENTS ASSUME THAT CANCER, b. any disease characterized by such growths. LEFT UNTREATED , WILL KILL YOU 2. any evil condition or thing that spreads destructively; blight. Physicians too “Cancer” today encompasses many diseases with distinct trajectories: Which should still be called “cancer”? 27 28 7

5/26/16 Mortality has declined The good and bad of screening Incidence has increased Thyroid cancer incidence vsmortality (for certain cancers) in Korea Ahn NEJM 2014 8

5/26/16 Is screening preventing metastatic disease What’s driving increase in incidence rates? at time of first presentation? Esserman JAMA 2009 Welch NEJM 2015 Recognize that tumor biology is complex: Use Diagnostic Tools To adjust treatment approaches Clinical Implications Characteristics Not a harbinger of distant disease Initial Treatment: Safe if less Metastatic risk extremely low aggressive Excellent outcome certain YES Early detection: Benefit minimal / none Indolent T umor Harbinger of distant disease Late metastatic risk moderate/ high How do we make screening better? NO Minimal chemo impact on recurrence Distant recurrence fatal Initial Treatment: Maximized Early metastatic risk moderate/ high to reduce recurrence Chemo ê recurrence risk Early detection benefit most likely for late risk population 9

5/26/16 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 NOMENCLATURE CHANGE – encapsulated follicular variant of papillary thyroid carcinoma à noninvasive follicular thyroid neoplasm with papillary-like nuclear features Course correction Other Indolent or IDLE conditions Cancer site Corresponding IDLE condition Research Prostate Gleason 3+3 disease Original Investigation Breast Indolent invasive cancers Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma Breast Low-grade DCIS 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; • Opportunity for watchful waiting or 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; prevention 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 • IDLE conditions: JAMA Oncology – Should not be targets of screening April 14, 2016 10