D. Lawrence Wickerham, MD,1,17 Norman Wolmark, MD1,17 San Antonio Breast Cancer Symposium - December 6-10, 2016 A Randomized, Double-blinded, Placebo-controlled Clinical Trial of Extended Adjuvant Endocrine Therapy with Letrozole in Postmenopausal Women with Hormone-receptor (+) Breast Cancer who have Completed Previous Adjuvant Tx with an Aromatase Inhibitor: Results from NRG Oncology/NSABP B-42 Eleftherios P. Mamounas, MD,1,2 Hanna Bandos, PhD1,3 Barry C. Lembersky, MD,1,4 Charles E. Geyer, Jr., MD,1,5 Louis Fehrenbacher, MD,1,6 Mark L. Graham, MD,1,7 Stephen L. Chia, MD, FRCPC1,8 Adam M. Brufsky, MD, PhD,1,4 Bryan T. Hennessy, MD,1,9 Gamini S. Soori, MD,1,10 Shaker R. Dakhil, MD,1,11 Thomas E. Seay, MD,1,12 James L. Wade, III, MD,1,13 Edward C. McCarron, MD,1,14 Soonmyung Paik, MD,1,15 Sandra M. Swain, MD,1,16 D. Lawrence Wickerham, MD,1,17 Norman Wolmark, MD1,17 1NRG Oncology/NSABP (NSABP Legacy trials are now part of the NRG Oncology portfolio), Pittsburgh, PA; 2UF Cancer Center at Orlando Health, Orlando, FL; 3University of Pittsburgh, Pittsburgh, PA; 4University of Pittsburgh Cancer Institute, Pittsburgh, PA; 5Massey Cancer Center, Virginia Commonwealth University, Richmond, VA; 6Kaiser Permanente Oncology Clinical Trials Norther California, Vallejo, CA; 7Southeast Cancer Control Consortium, Goldsboro, NC; 8British Columbia Cancer Agency (BCCA),Vancouver, British Columbia, Canada; 9Cancer Trials Ireland (Formerly known as Irish Clinical Oncology Research Group - ICORG), Dublin, Ireland; 10Missouri Valley Cancer Consortium, Omaha, NE; 11CCOP, Wichita Cancer Center of Kansas, Wichita, KS; 12Georgia NCI Community Oncology Research Program, Atlanta, GA; 13CCOP, Central Illinois, Decatur, IL; 14MedStar Franklin Square Medical Center/Weinberg Cancer Institute, Baltimore, MD; 15Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea; 16Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC; 17Allegheny Health Network Cancer Institute, Pittsburgh, PA This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Background/Rationale San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Background/Rationale Extended adjuvant endocrine therapy after 5 years of tamoxifen with either an aromatase inhibitor or tamoxifen improves disease-free survival in early-stage breast cancer Optimal duration of adjuvant aromatase inhibitor therapy beyond 5 years is unknown NSABP B-42 aimed to determine whether 5 years of letrozole vs. placebo improves disease-free survival in patients who have completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

R NSABP B-42: Schema or Stratification: San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Schema Postmenopausal Pts with ER+ or PR+ Breast Cancer Stage I, II, or IIIa invasive BC at diagnosis Disease-free After 5 Years of Endocrine Therapy or AI X 5 yrs TAM X < 3 yrs  AI to Complete 5 yrs Stratification: Pathological nodal status (Negative, Positive) Prior adjuvant TAM (Yes, No) Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD) R Letrozole X 5 yrs Placebo X 5 yrs This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute.

San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Endpoints Primary endpoint: Disease-free Survival (DFS): Local, regional, distant recurrence, opposite BC, 2nd non-breast primary cancer, and death from any cause as first event Secondary endpoints: Overall survival Breast Cancer-Free Interval (BCFI): Recurrence or opposite BC as first event Distant Recurrence (DR) Osteoporotic fractures (OF) Arterial thrombotic events (AT) This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Patient Population San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Patient Population From September 2006 to January 2010, 3966 pts were randomized 43 patients excluded: 36 no follow-up; 7 not at risk for the primary endpoint Median follow-up for 3923 pts included in efficacy analyses was 6.9 years The required 631 DFS events for definitive analysis occurred by August 2016 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Patient Characteristics San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Patient Characteristics No significant differences in the distribution of patient, tumor, and prior treatment characteristics between the two treatment groups: 34-35% <60 years of age 57-58% node-negative 39% received prior tamoxifen 61% breast-conserving surgery This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Treatment Compliance San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Treatment Compliance Median duration of treatment was 59.8 months in both groups Overall, 62.5% of placebo patients and 60.3% of letrozole patients completed 5 years of therapy Main reasons for letrozole treatment discontinuation: Patient withdrawal/refusal: 13.8% Adverse Event: 9.6% Disease Progression: 4.1% This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium - December 6-10, 2016 Results This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Disease-Free Survival San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Disease-Free Survival Letrozole Placebo 100 80 60 40 20 0 2 4 6 7 8 Years After Randomization Disease-Free Survival Letrozole 1959 1813 1644 1225 216 Placebo 1964 1814 1639 1208 210 HR=0.85 (0.73-0.999) P = 0.048 84.7% 81.3% # Events 292 339 *P-value did not reach statistical significance level of 0.0418 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: DFS First Events by Treatment San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: DFS First Events by Treatment   Placebo (n=1964) Letrozole (n=1959) First event # % Distant Recurrence 87 4.4 61 3.1 Local Recurrence 33 1.7 36 1.8 Second Primary Ca 171 8.7 134 6.8 Opposite Breast 59 3.0 30 1.5 Non-Breast 112 5.7 104 5.3 Death 48 2.4 Total First Event 339 17.3 292 14.9 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Cumulative Incidence of BCFI Event San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Cumulative Incidence of BCFI Event Letrozole Placebo Cumulative Incidence of BCFI Event 12 10 8 6 4 2 0 2 4 6 7 8 Years After Randomization 10.0% 6.7% HR=0.71 (0.56-0.89) P=0.003 # Pts # Events 1959 127 1964 179 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Cumulative Incidence of Distant Recurrence San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Cumulative Incidence of Distant Recurrence Letrozole Placebo Cumulative Incidence of DR 12 10 8 6 4 2 0 2 4 6 7 8 5.8% 3.9% HR=0.72 (0.53-0.97) P=0.03 Years After Randomization # Pts # Events 73 1964 102 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Overall Survival San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Overall Survival Letrozole Placebo 100 80 60 40 20 0 2 4 6 8 Years After Randomization Disease-Free Survival 0 2 4 6 7 8 Letrozole 1959 1902 1781 1499 287 Placebo 1964 1902 1791 1528 291 Overall Survival 92.3% 91.8% HR=1.15 (0.99-1.44) P=0.22 # Deaths 164 146 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Cumulative Incidence of Osteoporotic Fx San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Cumulative Incidence of Osteoporotic Fx Letrozole Placebo Cumulative Incidence of Osteoporotic Fx 12 10 8 6 4 2 0 2 4 6 7 8 5.4% HR=1.19 (0.88-1.60) P=0.27 Years After Randomization 4.8 % # Events 91 78 This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Cum. Inc. of Arterial Thrombotic Events San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Cum. Inc. of Arterial Thrombotic Events 12 10 8 6 4 2 # Events 71 59 Letrozole Placebo HR=1.21 (0.85-1.70) P=0.29 Cum. Inc. of Arterial Thrombotic Events 4.0% 3.4 % 0 2 4 6 7 8 Years After Randomization This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Summary The beneficial effect of extended letrozole therapy on DFS did not reach statistical significance (15% reduction) No significant difference in overall survival Extended letrozole provided: Statistically significant improvement in BCFI (29% reduction in BCFI event) Statistically significant reduction in the rate of DR (28% reduction in DR) Letrozole did not significantly increase risk of osteoporotic fractures but risk of arterial thrombotic events was elevated for letrozole after 2.5 years This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

NSABP B-42: Conclusions and Perspective San Antonio Breast Cancer Symposium - December 6-10, 2016 NSABP B-42: Conclusions and Perspective Our findings suggest that careful assessment of potential risks and benefits is required before recommending extended letrozole therapy in patients with early-stage BC, including: Patient and tumor characteristics (age, nodal status) Existing co-morbidities Information on bone mineral density Tolerance of the AI in the initial 5 years Genomic classifiers that predict risk of late recurrence and/or benefit from extended endocrine therapy may help to further individualize the recommendation for extended aromatase inhibitor therapy This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute

San Antonio Breast Cancer Symposium - December 6-10, 2016 Acknowledgements The 3,966 patients who participated in the trial The NSABP Investigators/Coordinators Hanna Bandos and Barry Lembersky The NSABP Operations and Biostatistics Center staff NCI CTEP and Novartis This presentation is the intellectual property of the author/presenter. Contact them at terry.mamounas@orlandohealth.com for permission to reprint and/or distribute