Precancerous Lesions: Timing and Biology

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1 February 3-5, 2016 Lansdowne Resort, Leesburg, VA Precancerous Lesions: Timing and Biology Victoria Seewaldt, M.D. City of Hope, Comprehensive Cancer Center, Beckman Institute

2 Early detection/prevention cancers w/ aggressive biology 18 FDG PET First pass 3T MRI Frequency BRCA1 mt - 60% Ashkenazi - 53% European American - 29% Hispanic American - 23% Asian - 20% African American Greenup et al. Ann Surg Onc 2013

3

4 PART 1 - One-size-all screening PART 2 - If you don t know what s broke its hard to fix it. PART 3 Prevention needs to make the whole body healthy

5 PART 1 - One-size-all screening fails

6 Failure of one-size-fits-all cancer screening

7 mammography Need tothinking use the about right tool for the job anatomy1.gif (GIF Image, pixels) Mammary Fat Mammary Fat A Lactiferous Duct ER+ breast cancer Calcifications - 79% HER2+ breast cancers Calcifications - 71% Subcutaneous Fat Subareolar Musculature B Epithelial cells A Lactiferous Duct Intralobular Connective Tissue Intralobular Connective Tissue Subcutaneous Fat Subareolar Musculature Lobe Adipose cells Triple-negative breast cancers Low frequency calcs - 15% No findings - 30% Mass/Focal asymmetry - 32% B Epithelial cells Stromal collagen Stromal Fibroblasts Adipose cells Endothelial cells Endothelial cells Basement Membrane Lobe Basement Membrane Stromal collagen Stromal Fibroblasts

8 Breast MRI in Underserved Durham Women 621 premenopausal high-risk women African American Caucasian 48 mos observation, 51 breast cancers - 22 Focal / Age shifted - 29 Non-focal / Accelerated 2005 S. Riley 0 mos 36 mos 48 mos ER/PR+ T1N0 Focal, non-accelerated 22/51 women

9

10

11 BRCA1 mutation 6 mos LN metastasis 09/2010 NL tissue 02/ cm 0.1 cm 0.4 cm 0.3 cm TNBC 2+LN

12 Age Shifted Accelerated (Interval TNBC BRCA1) Genomic instability Abnormal MRI Normal Bx TNBC Node + CHEMO PALPABLE TNBC Node + CHEMO 0 mos MRI 6 mos MRI 12 mos MRI Metastasis Multi-Focal 6 month screening interval NOT sufficient

13 PART 2 - If you don t know what s broke its hard to fix it. Dad

14 DU-268L DU-266L DU-295R DU-229.2L DU-256L DU-252L DU-294L DU-292R DU-277R DU-267R DU-168.5R DU-238.2L DU-228.3L DU-221.3R DU-254R DU-247R DU-255L DU-288R DU-280L DU-39.5L DU-96.5R DU-39.5R DU-287R DU-287L DU-258L DU-290R DU-249R DU-248L DU-248R DU-249L DU-238.2R ErbB3_Y1289 PKCpanBII.S660 pikb.s32.36 Paxillin.Y118 Vimentin IGF1R.IR_Y p70s6k.t389 ErbB3 pchk1.s345 p90.rsk.s380 Stat3 mtor.s2448 pacc.s79 patpcl.s454 p38mapkinase_t180.y182 X zeta..gamma..eta E.Cadherin perk.1.2.t202.y204 EGFR pcreb.s133 IGF1R.IR.YY.YY HIF1_alpha GSK2ab.S21.9 pgsk3.alpha.beta.y279.y216 pb.catenin.t41.s45 pakt.s473 MEK1.2.S217.S221 pegfr.y1068 ErbB2 cl.casp.7.d198 Bcl.xL VEGFR2 Bad PTEN pbad.s136 Bax pegfr.y1148 pstat3.s727 ppten.s380 pbcl2.s70 pirs1.s612 pret.y905 pvegfr2.y951 Src_Y416 p53.s15 prasgrf1.s916 ER.alpha cl.casp3.d175 Akt pnfkappa.bs536 pegfr.y992 peif4g.s1108 Alternative trial design with surrogate endpoint HIGH RISK YES ATYPIA R A N D O M I Z E YES AGENT n = 300 Time = 6-12 mos NO AGENT YES or NO ATYPIA Compare Signaling Networks

15 U01CA189283: City of Hope, Duke, Ohio State, U. Tennessee, U. Wisconsin, Emory - Combined MRI/proteomic profiling Combined Cohort n=2,1070; Preliminary Data Duke n=1,241/year Normal MRI (81% n=1005 ) MRI in 12 months Abnormal Screening MRI (19% n= 236 ) Abnormal Biopsy (2% n= 24) Normal Biopsy (6% n=76) 6 week MRI No Biopsy (11% n=133) Standard-of-Care Follow up MRI 6 months 37% African American 60% Caucasian 3% Other Normal MRI women/yr Interval Cancer % 5-7 women/yr

16 Cohort n Biopsy (6%) Abn. Biopsy (2%) Interval CA (0.5%) 36 months biopsy 36 months abn. biopsy 36 months Interval CA Duke + OSU U01 Cohort U01+ NCOR Core biopsy FFPE proteomic profiling stroma/epithelium RPPA (40-60 proteins) MALDI-TOFF MS Distal core biopsy (adipose, immune cell) WBC DNA Genetic analysis Serum for cell free analysis (exosomes)

17

18 Multidisciplinary Breast Mapping REFERENCE & MARKERS& Chris Sistrunk PhD DU-429 SLICE M 5 6 L DU-390 DU-468

19 Multi-Scale Modeling/Lineage Tracing of TNBC initiation SLICE SLICE REFERENCE & MARKERS& 6 U01CA189283: City of Hope, Duke, Ohio State, U. Tennessee, U. Wisconsin, Emory Dietze, Seewaldt Nature Reviews, 2015

20 PART 3 Prevention needs to make the whole body healthy

21 From female mortality increased in >50% of US counties vs. 3% counties for men - David Kindig and Erika Cheng, University of Wisconsin - Chris Murray, University of Washington

22 Obesity and insulin resistance Diabetes occurs when the pancreas burns out Insulin glucose Healthy HgbA1C = hr glucose glucose Insulin 2 hr Resistant HgbA1C = Insulin Diabetes HgbA1C > hr

23 Woman: Pre-Diabetic Insulin resistance, produces high insulin 18 FDG PET + + At risk breast tissue Increased insulin sensitivity Obesity is a risk factor TNBC Insulin stimulates signaling pathways that promotes the aggressive behavior of TNBC

24 Conclusions: One-size-all screening fails Need to understand the biology of cancer initiation. Prevention needs to make people healthier.

25 Thank you. 1R01CA A1 1R01CA U01CA A1

26

27 Mammographic density does not predict risk for individuals - only populations Model AUC (Cecchini) AUC (Chen) AUC (Tice) AUC (Barlow) Gail Gail + density Density GREEN LINE= No better than a coin flip Gail + Density Gail Density [Cecchini et al. Boyd Can. Prev. Res. 5(11), , 2012]

28 Mammographic Density and Individual Risk

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