In Honour of Dr. Neera Patel

In Honour of Dr. Neera Patel

Residual Cancer Burden (RCB) vs Pathologic Complete Response (pcr) as an End-point W. Fraser Symmans, M.D. Professor of Pathology UT M.D. Anderson Cancer Center

Pathologic Assessment Of The Primary Tumor Bed See downloadable protocol and illustrations at www.mdanderson.org/breastcancer_rcb

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Measure Residual Invasive Primary Tumor Bed: Macroscopic Findings Qualified By Microscopic Findings

Residual Cancer Burden (RCB) Primary Tumor Bed Lymph Nodes d 1 d met d 2 f inv d prim = d 1 d 2 f inv = % area with invasive CA LN = Number of Positive Nodes d met = size largest metastasis DRFS Following Neoadjuvant T/FAC Chemotherapy (N=241) Variable Hazard Ratio (95% CI) P value Primary tumor bed size (d prim ) 1.24 (1.04-1.48) 0.02 Fraction of invasive cancer (f inv ) 7.37 (2.16-25.1) 0.001 Number of positive lymph nodes (LN) 1.11 (1.04-1.19) 0.002 Size of largest metastasis (d met ) 1.17 (0.99-1.38) 0.06 Symmans et al JCO 2007;25:4414-22

Residual intralymphatic cancer in breast is measured as invasive cancer Residual isolated tumor cells in lymph node are measured as metastatic Google terms: residual cancer burden breast www.mdanderson.org/breastcancer_rcb

RCB Interpretation: Inter-Pathologist Reproducibility 100 cases of residual disease (invasive, metastatic, or in situ) Results from 5 pathologists 4 had no prior training or experience with RCB, but read manuscript and materials on the RCB website Followed the patients for 7 more years to a median follow up of 12 years RCB Index Score Overall concordance correlation coefficient: 0.93 (95% CI 0.91 to 0.95) Overall accuracy: 0.99 RCB Categories (pcr, RCB-I, RCB-II, RCB-III) Kappa coefficient for overall agreement: 0.58 (95% CI 0.54 to 0.63) Peintinger et al. Modern Pathology 2015 ;28:913-20

Multicenter I-SPY2 Trial - Prognosis of pcr TNBC HR+HER2- Yee D, et al. San Antonio Breast Cancer Symposium, December 5-9, 2017 This presentation is the intellectual property of the Douglas Yee. Contact them at yeexx006@umn.edu for permission to reprint and/or distribute.

Multicenter I-SPY2 Trial - Prognosis of pcr HER2+/HR- HER2+/HR+ Yee D, et al. San Antonio Breast Cancer Symposium, December 5-9, 2017 This presentation is the intellectual property of the Douglas Yee. Contact them at yeexx006@umn.edu for permission to reprint and/or distribute.

Residual Cancer Burden (RCB) Prognosis Single institution (MDACC), long follow-up

TNBC Multivariate Cox Regression TNBC Cases in MDACC RCB Study (n = 219) HR lower 95 upper 95 p = Age 0.99 0.97 1.01 NS Grade 3 0.96 0.54 1.69 NS c-stage III 1.19 0.73 1.96 NS RCB index 1.89 1.56 2.29 <0.01 Symmans et al JCO 2017;35:1049-60

HR+/HER2- Multivariate Cox Regression HR+/HER2- Cases in MDACC RCB Study (n = 501) HR lower 95 upper 95 p = Age 0.99 0.97 1.01 NS Grade 3 1.23 0.82 1.84 NS c-stage III 2.53 1.73 3.71 <0.01 RCB index 1.95 1.57 2.41 <0.01 Symmans et al JCO 2017;35:1049-60

HER2+ (H+T/FEC) Multivariate Cox Regression HER2+ Cases in MDACC RCB Study (n = 203) HR lower 95 upper 95 p = Age 1.02 0.99 1.06 NS Grade 3 0.56 0.29 1.10 NS c-stage III 1.33 0.70 2.55 NS Multifocal 1.48 0.72 3.07 NS pcr 0.34 0.08 1.35 NS RCB index 1.80 1.26 2.59 <0.01 Symmans et al JCO 2017;35:1049-60

HER2+/HR- (H+T/FEC) HER2+/HR+ (H+T/FEC) Symmans et al JCO 2017;35:1049-60

The Residual Cancer Burden Index is a Prognostic Surrogate in Every Subtype of Breast Cancer Cohorts N = Number Analyzed #1 to #3. Combined T/FAC Cohorts ^ 823 Triple-Negative 219 HR-Positive / HER2-Negative * 501 HER2-Positive 103 #5. HER2-targeted +T/FEC 203 Survivors: Median Follow up (Years) Relapse-Free Survival Distant Relapse-Free Survival Overall Survival Hazard Ratio (95% CI) C-Index (95% CI) Hazard Ratio (95% CI) C-Index (95% CI) Hazard Ratio (95% CI) C-Index (95% CI) 8.2 1.86 (1.68, 2.05) - 1.86 (1.68, 2.05) - 1.88 (1.68, 2.10) - 1.89 (1.56, 2.29) 0.74 (0.68, 0.80) 1.95 (1.60, 2.38) 0.75 (0.69, 0.81) 1.92 (1.58, 2.34) 0.76 (0.70, 0.82) 1.95 (1.57, 2.41) 0.71 (0.66, 0.76) 1.99 (1.60, 2.49) 0.72 (0.67, 0.77) 1.98 (1.55, 2.53) 0.73 (0.67, 0.78) 1.91 (1.45, 2.52) 0.75 (0.68, 0.83) 1.93 (1.44, 2.59) 0.76 (0.69, 0.84) 1.81 (1.32, 2.48) 0.72 (0.63, 0.82) 7.1 2.25 (1.73, 2.91) 0.73 (0.65, 0.82) 2.22 (1.72, 2.86) 0.73 (0.64, 0.81) 2.39 (1.72, 3.31) 0.72 (0.60, 0.84) Symmans et al JCO 2017;35:1049-60

Comparison In A Phase II Randomized Trial I-SPY2 Trial: Addition of Veliparib and Carboplatin to Weekly Paclitaxel Response Endpoint pcr OR = 4.56, p = 0.013 OR = 0.88, p = 1 pcr/rcb-i OR = 8.19, p = 0.0005 OR = 0.85, p = 1 Liu MC, et al. SABCS, 2015, abstract P3-07-49

Annals of Oncology 2015; 26: 1280-91 Modern Pathol 2015; 28: 1195-201

Recommendation Provide the following information: 1. pcr (ypt0 ypn0 and ypt0/is ypn0) versus residual disease, 2. ypt and ypn Stage using the current AJCC/UICC staging system, 3. Residual cancer burden (RCB) A single standardized approach to macroscopic and microscopic pathologic examination makes it easy to reliably provide all 3 results! Use of the RCB approach enhances the prognostic meaning of pcr

Excerpt From Our CAP Synoptic Report

Acknowledgements MD Anderson Multidisciplinary Team I-SPY Multidisciplinary Investigators Neoadjuvant Teams within the Alliance and BIG (Europe and rest of the world) Members of my lab at MDACC, Christos Hatzis and Lajos Pusztai, Fabrice Andre, Minetta Liu, Hongkun Wang, Flori Peintinger, and others Veerle Bossuyt (Yale) and Elena Provenzano (Cambridge), David Cameron (Edinburgh), and the NABG/BIG Residual Disease Working Group

Online Educational Resources Google Search Term: RCB Breast or Residual Cancer Burden Breast Educational Videos Macroscopic and Microscopic Evaluation Protocol for Pathologists Detailed SOP Document Calibration of Percent Cellularity by Area Computer Generated Examples https://www.mdanderson.org/for-physicians/clinical-tools-resources/clinicalcalculators/residual-cancer-burden.html https://www.mdanderson.org/education-and-research/resources-forprofessionals/clinical-tools-and-resources/clinical-calculators/calculators-rcbpathology-protocol2.pdf https://www.mdanderson.org/education-and-research/resources-forprofessionals/clinical-tools-and-resources/clinical-calculators/calculators-cellularityguide.pdf