The Trials and Tribulations of Chasing a COMET

Transcription

1 The Trials and Tribulations of Chasing a COMET AUS/NZ Breast Cancer Trials Group 39 th Annual Scientific Meeting July 28, 2017 E. Shelley Hwang MD MPH Duke University Medical Center

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4 This is DCIS 67 year old woman 5 mm ductal carcinoma in situ Low grade Cribriform without necrosis ER/PR positive Margins negative at 3 mm Outcome with BCT alone 1%/yr IBTR risk through 7 years No increase in breast cancer death McCormick et al, J Clin Oncol, 2015

5 But this is also DCIS 64 year old woman 1.2 cm ductal carcinoma in situ High grade Solid type with necrosis ER/PR positive Declined surgery Outcome after observation for 3 years:

6 What is the evidence for overdiagnosis and overtreatment of DCIS?

7 Epidemiology of DCIS Ductal carcinoma in situ, precancer, preinvasive cancer Estimated incidence of DCIS: over 60,000 new cases annually Usually diagnosed by calcifications on mammography in asymptomatic patient DCIS now comprises over 20% of all mammographically detected breast cancers Nonobligate precursor of invasive cancer; rate and likelihood of progression are unknown American Cancer Society. Cancer Facts and Figures Ernster VL, et al. J Natl Cancer Inst Ward EM et al, CA Cancer J Clin 2015.

8 Colon Cancer Incidence and Mortality Rates ( per 100,000)

9 DCIS Incidence continues to rise ( ) DCIS INVASIVE Screening mammograms introduced WHI data published

10 DCIS and competing causes of mortality All age groups Overall Survival Breast Cancer Survival Worni M et al, JNCI 2015

11 RTOG 9804: RCT of lumpectomy vs lumpectomy/rt for low risk DCIS McCormick B et al, JCO 2015

12 Breast Cancer Risk with LCIS MSKCC Cohort , n= breast cancers 1/3 invasive 2% annual risk of cancer King et al, JCO 2015

13 What are the tradeoffs of surveillance for DCIS? Are there predictors of invasive progression? Trials of active surveillance

14 Modeling Study Objective Perform a quantitative comparison between: Usual Care (UC) Current standard of care Immediate treatment vs. Active Surveillance (AS) Regular follow-up screening Treatment upon diagnosis of invasive disease Main outcome measures 10-year disease-specific cumulative mortality (DSCM) (i.e. probability of breast cancer death at 10 years) Number needed to treat to avert one breast cancer death at 10 years

15 Results I: Age 40 at Diagnosis Median AS projection 95% projection range (PR) of AS projection 95%-CI competing risks estimate 95%-CI UC estimate AS = active surveillance UC = usual care Baseline screening parameters Ryser M et al, JNCI 2016

16 Results I: Age 40 at Diagnosis Difference AS-UC: 2.6% ( ) AS = active surveillance UC = usual care Baseline screening parameters Ryser M et al, JNCI 2016

17 Results II: Age 55 at Diagnosis Difference AS-UC: 1.5% ( ) AS = active surveillance UC = usual care Baseline screening parameters Ryser M et al, JNCI 2016

18 Results III: Age 70 at Diagnosis Competing 10 years: 16.5 (95% CI: ) Difference AS-UC: 0.2% ([-0.9]-2.2) AS = active surveillance UC = usual care Baseline screening parameters Ryser M et al, JNCI 2016

19 Comparison Rates DCIS Upstaging Variable Nuclear grade MSKCC:LORIS eligible (n=296) n (%) Duke Cohort (n=307) n (%) COMET eligible (n=81) n (%) LORIS eligible (n=74) n (%) LORD eligible (n=10) n (%) Low 53 (18) 15 (5) 12 (15) 12 (16) 10 (100) Intermediate 244 (82) 95 (31) 69 (85) 62 (84) 0 (0) High 0 (0) 197 (64) 0 (0) 0 (0) 0 (0) Comedonecrosis (51) 0 (0) 0 (0) 0 (0) Upgrade (4) 8 (10) 7 (9) 3 (30) Upstage 57 (18) 53 (17) 5 (6) 5 (7) 1 (10) Grimm L et al, Ann Surg Onc 2017

20 Procedures in 10 years (1,000 women) n=1083 RTOG Lx+RT (n=592) Lx (n=155) Usual Care 2+ Tx (n=44) Mx bi (n=109) Active Surveillance No Tx (n=840) Mx uni (n=227) n=160 10% Progression 20% Progression No Tx (n=790) n=260 Lx (n=5) Mx bi (n=15) Mx uni (n=40) Lx+RT (n=100) Mx bi (n=27) Mx uni (n=60) Lx+RT (n=170) Lx (n=5)

21 n=110 Invasive events in 10 years (1,000 women) RTOG Usual Care Contra (n=48) Ipsi (n=62) None (n=890) n=110 n=148 n=248 Active Surveillance 10% Progression 20% Progression Contra (n=48) Contra (n=48) Ipsi (n=200) Ipsi (n=100) None (n=852) None (n=752)

22 Individual and Health System trade-offs (annual national US data) USUAL CARE 34,000 lumpectomy 23,000 radiation 10,000 unilateral mastectomy 4000 bilateral mastectomy + 20,000 endocrine therapy > = < SURVEILLANCE % 10-year disease-specific mortality benefit

23 What are the tradeoffs of surveillance for DCIS? Are there predictors of invasive progression? Trials of active surveillance

24 Digital mammogram feature extraction Extract features from both individual calcifications and clusters (i) shape: MCs heterogeneous morphology (e.g., round, oval, elongated) and size; (ii) topological: topological relations between MCs from weighted graphs associated to clusters; (iii) texture: from both original and preprocessed raw images, such as MC pixel values, contrast and statistical measures of Gray Level Cooccurrence Matrices Cluster: Individual features computed for all calcifications in cluster, then 4 global statistical measures (Mean, STD, Min, and Max) describe the cluster. Overall, currently we have 134 features to describe one cluster: 29 *4 individual MC-level + 18 cluster-level Shi B. et al., Acad Radiol 2017

25 Calcification Cluster Segmentation Original digital mag view Shi B. et al., Can occult invasive disease in ductal carcinoma in situ be predicuted using computer-extracted mammographic features? Acad Radiol

26 Calcification Cluster Segmentation Cluster segmented by algorithm (weighted graph and convex hull) Shi B. et al., Can occult invasive disease in ductal carcinoma in situ be predicuted using computer-extracted mammographic features? Acad Radiol

27 Development of an Imaging Classifier for Invasive Progression Heterogeneity of micro-calcifications (MCs) and the texture features in the neighborhood can be used to predict the aggressiveness of DCIS. Tuning algorithm parameters based on cluster-level ground truth from radiologists

28 Performance of Digital Image Classifier Shi B. et al., Acad Radiol 2017

29 The DCIS Score: 10-year Ipsilateral Breast Events ANY IBE INVASIVE IBE Solin L, et al., JNCI 2013

30 Molecular phenotypes of DCIS predict overall and invasive recurrence Disease-free Survival Invasive Disease-free Survival Williams, K. Ann Oncol 2015

31 IHC Automated Image Analysis Pathological image registration to align serial sections, enabling studies using readily generated pathological samples to investigate intra-tumor heterogeneity.

32 IHC Automated Image Analysis epithelial cell fibroblast lymphocyte H&E

33 Phenotypic IHC Markers of Heterogeneity Double Stains Functional Category Cell Type Scoring ALDH1A1 Stem Cell Marker Epithelia Intensity + Distribution Ki-67 Proliferation Epithelia Distribution COL15A1 Basement Membrane BM Presence around DCIS ESR1 Hormone Signaling Epithelia Intensity + Distribution p=0.027 Phospho-FAK Cell Adhesion Epithelia Intensity + Distribution CD68 Macrophage Macrophage Distribution CA9 Hypoxia Epithelia Intensity + Distribution FOXP3 T Regulatory Cells Lymphocyte Distribution p=0.045 ERBB2 Oncogenic Signaling Epithelia Intensity + Distribution P63 Basal Cells Myoepithelia Presence around DCIS RANK Inflammatory Signaling Epithelia Intensity + Distribution PGR Hormone Signaling Epithelia Intensity + Distribution Single Stains GLUT1 Glucose Transport Epithelia Intensity + Distribution p=0.046 p=0.059 CD31 Blood Vessels Endothelia Distribution Rho A Motility Epithelia Intensity + Distribution

34 NGS analysis: depth of coverage

35 Number of variants detected in pure DCIS and synchronous DCIS/invasive samples

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38 What are the tradeoffs of surveillance for DCIS? Are there predictors of invasive progression? Trials of active surveillance

39 Trials of Active Surveillance for DCIS UK and EORTC trials have been initiated (LORD, LORIS studies) Newly diagnosed clinically low risk DCIS Primary outcome: ipsilateral invasive cancer-free survival Randomization: usual care (surgery and/or RT) vs. active surveillance Annual mammography Intervene if evidence of progression to invasive cancer

40 COMET (Comparison of Operative to Monitoring and Endocrine Therapy) Trial for low risk DCIS Trial Schema Registered and randomized (n=900) GROUP 1: Usual Treatment (n=450) Surgery, Radiation or both choice for endocrine therapy Mammogram every 12 months for 5 years GROUP 2: Close Monitoring (n=450) choice for endocrine therapy Mammogram every 6 months for 5 years Eligiblity criteria: Age 40 Grade I/II DCIS without invasive cancer Diagnosed confirmed by core or surgical biopsy ER(+) and/or PR(+), HER2(-) if tested No mass on PE or imaging Endpoints: 2, 5, 7-year invasive cancer dx 2, 5, 7-year OS, DSS PRO endpoints (QOL, fear of cancer recurrence, body image)

41 COMET Trial for low risk DCIS Eligibility Criteria Age >40 at diagnosis; agree to randomization Pathologic confirmation of grade I/II DCIS without invasion (microinvasion not allowed) ER(+) and/or PR(+); HER2-negative (0, 1+, or 2+ if testing performed) No evidence of other breast disease on physical examination and breast imaging within 6 months of registration Available for follow up examinations Ability to read, understand and evaluate study materials Speaks Spanish or English, or availability of an appropriate professional interpreter at enrollment

42 COMET Trial for low risk DCIS Clinical Endpoints Project 1: Compare cancer outcomes and clinical outcomes between patients who are treated with GCC versus AS for core biopsy-proven DCIS. Primary outcome: 2, 5, and 7-year diagnosis of invasive cancer Additional secondary endpoints: 2, 5, and 7-year receipt of mastectomy, radiation, chemotherapy 2, 5, and 7-year overall mortality and breast cancer specific mortality Project 2: Compare patient reported outcomes (PRO) between GCC and AS groups. PRO measures will include both psychosocial outcomes (QOL, emotional/psychological outcomes, body image and sexual function) as well as decision quality (knowledge of DCIS, decision-making and decision regret, and risk perception).

43 Which Patients are NOT Candidates for Active Surveillance? High grade or extensive DCIS Palpable disease, other breast signs or symptoms Mass on imaging NOT encouraged outside of a clinical trial context

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45 Future validation in prospective randomized trials n~900 (UK) n~1,200 (EORTC) n~900 (US) Low grade DCIS ~3,000 women R Standard treatment (~1,500 women): Surgery +/- radiotherapy Active surveillance (~1,500 women) No treatment Annual mammography For 10 years Annual mammography For 10 years 45

46 Conclusions All health care decisions involve trade-offs and uncertainty Reducing overtreatment of DCIS will require many tools, including better approaches to diagnosis, treatment, risk communication Patient participation in evaluation of trade-offs is crucial Future trials will include studying active surveillance for low risk lesions We must REFRAME the goals of treatment of DCIS Risk of invasive cancer and breast cancer mortality impact on QOL and breast cancer free survival

47 DCISoptions.org

48 Acknowledgments Hwang/Marks lab Wash U genome sequencing center University of Arizona Center for Evolutionary Biology COMET Team International PPRECISION Team Duke Breast Oncology Team Duke Math/Biostatistics Team UCSF Breast Oncology Program Funders (NCI, DOD, BCRP, Komen, PCORI, BCRF/TBCRC/Alliance) Patients, Advocates and their families

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50 Final Model: Table Format 5-Year Absolute Risk of breast cancer in ADH Age Group # foci of AH < (0.00) 1.95 (0.13) 2.96 (0.35) 4.10 (0.70) 5.19 (1.11) 6.01 (1.40) 6.37 (1.66) 6.19 (2.02) 5.52 (2.40) 4.50 (2.48) 3.35 (2.67) 2.28 (2.53) (0.00) 2.89 (0.13) 4.37 (0.35) 6.04 (0.70) 7.62 (1.11) 8.81 (1.40) 9.33 (1.66) 9.08 (2.02) 8.10 (2.40) 6.62 (2.48) 4.95 (2.67) 3.38 (2.53) (0.00) 2.89 (0.13) 6.44 (0.35) 8.85 (0.70) (1.11) (1.40) (1.66) (2.02) (2.40) 9.69 (2.48) 7.27 (2.67) 4.99 (2.53) Degnim, A. Breast ASCO 2015

51 Incidence of stage-specific breast cancer after introduction of mammographic screening Breast Cancer Incidence, All Breast Cancer Incidence in Women <40y Bleyer A, Welch HG NEJM 2013

52 SEER data L R D Ryser M et al, JNCI 2016

53 Surgical Treatment Patterns for DCIS and LCIS Ward E, Cancer J Clin 2015

54 IHC Automated Image Analysis Final Markers: ALDH1A (stem)+ Ki-67 (proliferation) COL15A1 (specialized BM) + ESR1 CD68 (macrophage) + COX2 (inflammatory) RHOA (migration) + FOXP3 (T-Reg) PR P16 CA9 (hypoxia) Pathological image registration to align serial sections, enabling studies using readily generated ERBB2 pathological samples to investigate intra-tumor heterogeneity. CD31 (blood vessel) Cleaved Caspase (apoptosis)

55 Mammographic Predictors of Invasion Inclusion >=40 yo Underwent stereotactic Bx: only DCIS, only calcs Digital mag view avail Exclusion Presence of mass, asymmetry, distortion Hx of breast cancer or prior surgery Presence of microinvasion at initial Bx Final: 99 cases, 25 upstaged Another 140 withheld for final testing Shi B. et al., Acad Radiol

56 ECOG 5194: Prospective Single Arm Study of Excision alone for DCIS: 12-year update Solin L et al, JCO 2015

57 Increasing Incidence of Thyroid Cancer Ahn HS, NEJM 2014