Advances in Breast Cancer

Advances in Breast Cancer Developed in collaboration Learning Objectives Upon completion, participants should be able to: Apply genomic medicine to treatment decisions for patients with HR+/HER2- early stage breast cancer Assess the range of radiotherapy doses and fractionation schemes that may be appropriate for patients with early stage breast cancer who undergo breast-conserving surgery Evaluate select clinical studies on the latest surgical techniques in breast cancer 1

Genomic Signatures: Changing the Face of HR+ Breast Cancer Jeremy Force, DO 21-Gene RS Assay 16 Breast Cancer Related Genes Estrogen Proliferation HER2 Invasion Others ER PR Bcl2 SCUBE2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GRB7 HER2 Stromelysin 3 Cathepsin L2 CD68 GSTM1 BAG1 5 Reference Genes Beta-actin GAPDH RPLPO GUS TFRC Paik S, et al. N Engl J Med. 2004;351:2817-26. 2

The RS Result Reveals Individual Tumor Biology for ER+, LN-Negative Breast Cancer Treated With ET Distant Recurrence at 10 Years Continuous Biology 40% 35% 30% 25% 20% 15% 10% 5% 0% 0 5 10 15 20 25 30 35 40 45 50 RS Value Low RS Disease Indolent Hormonal therapy sensitive Minimal, if any, chemotherapy benefit High RS Disease Aggressive Less sensitive to hormonal therapy Large chemotherapy benefit Paik S, et al. N Engl J Med. 2004;351:2817-26; Paik S, et al. J Clin Oncol. 2006;24:3726-34. The RS Result Identifies Patients With ER+ Tumors Who Would Derive the Greatest Benefit From Chemotherapy 1.0 Proportion Without Distant Recurrence 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 All patients RS < 18 RS 18-30 RS 31 *N = 651. Paik S, et al. J Clin Oncol. 2006;24:3726-34. Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen n* N Events 424 227 218 135 89 45 117 47 33 31 8 4 9 4 13 18 P =.02 P =.61 P =.39 P <.001 2 4 6 8 10 12 Years PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy 3

Background: Rationale for Adjusting RS Ranges in TAILORx: Large Chemotherapy Benefit in NSABP B-20 With RS > 25 Similar to RS 31 Patients 10-Year DRFS (%) Recurrence by Addition of Chemotherapy RS No. % Tam Tam+Chemo HR 95% CI P Value 0-10 177 27 98 95 1.788 0.360 to 8.868.471 11-25 279 43 95 94 0.755 0.313 to 1.824.531 26-100 195 30 63 88 0.285 0.148 to 0.551 <.0001 Sparano JA, et al. J Clin Oncol. 2008;26:721-8. TAILORx Methods: Treatment Assignment and Randomization Accrued Between April 2006 October 2010 Preregister: 21-Gene RS Assay (N = 11,232) Register (N = 10,273) ARM A: Low RS 0-10 (n = 1,619 evaluable) ASSIGN ET Mid-Range RS 11-25 (n = 6,711 evaluable) RANDOMIZE Stratification Factors: Menopausal Status, Planned Chemotherapy, Planned Radiation, and RS 11-15, 16-20, 21-25 ARM D: High RS 26-100 (n = 1,389 evaluable) ASSIGN ET + Chemo ARM B: Experimental Arm (n = 3,399) ET Alone ARM C: Standard Arm (n = 3,312) ET + Chemo Sparano JA, et al. N Engl J Med. 2018;379:111-21. 4

TAILORx: RS < 11 A IDFS 1.0 1.00 0.8 0.95 0.6 0.90 0.4 0.85 0.80 0.2 0.00 0.0 0 12 24 36 48 60 0 12 24 36 48 60 Months Probability of DFS C Freedom From Recurrence at Any Site 1.0 1.00 0.8 0.95 0.6 0.90 Probability of Freedom From Event 0.85 0.4 0.80 0.2 0.00 0 12 24 36 48 60 0.0 0 12 24 36 48 60 Months B Freedom From Recurrence of Breast Cancer at Distant Site 1.0 1.00 0.8 0.95 0.6 0.90 Probability of Freedom From Event D OS 1.0 0.85 0.4 0.80 0.2 0.00 0 12 24 36 48 60 0.0 0 12 24 36 48 60 Months From N Engl J Med, Sparano JA, et al. Prospective validation of a 21-gene expression assay in breast cancer, vol 373, p. 2005-2014. Copyright 2015. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Probability of Survival 0.8 0.6 1.00 0.95 0.90 0.85 0.4 0.80 0.2 0.00 0 12 24 36 48 60 0.0 0 12 24 36 48 60 Months ER/PR+ HER2- LN negative Tumor 1.1-5.0 cm or, if grade 3, 0.6-1.0 cm n = 1,626 99.3% 5-yr DFS 98.0% 5-yr OS TAILORx: RS 11-25 DFS Probability 1.0 0.8 0.6 0.4 0.2 Arm C Chemo + ET Arm B ET Alone P =.26 HR Arm B vs Arm C (95% CI) 1.08 (0.94, 1.24) 836 IDFS events after median of 7.5 years 338 of 836 (40.3%) with recurrence as first event 199 of 836 (23.8%) were distant recurrence 0.0 0 12 24 36 48 60 Months Number at Risk Arm C Chemo + ET 3,312 3,204 3,104 2,993 2,849 2,645 2,335 1,781 1,130 523 Arm B ET Alone 3,399 3,293 3,194 3,081 2,953 2,741 2,431 1,859 1,197 537 72 84 96 108 From N Engl J Med, Sparano JA, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer, vol 379, p. 111-121. Copyright 2018. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 5

TAILORx-Defined Cutoff for Definitively Determining Chemotherapy Benefit With the 21-Gene RS Assay (LN-Negative, HR+, HER2-) Subgroup Age 50 Years RS 0-10 RS 11-15 RS 16-20 RS 21-25 RS 26-100 No CT benefit No CT benefit ~1.5% CT benefit ~7% CT benefit Large CT benefit ~50% of patients 50 years have RS 0-15, 35% RS 16-25, and 15% RS 26-100 Sparano JA, et al. J Clin Oncol. 2018;36:abstract LBA1. Conclusion The 21-gene RS assay is a well-validated tool for use in women with HR+/HER2-, LN-negative breast cancer Postmenopausal women with HR+/HER2-, LN-negative breast cancer and RS 25 can safely forgo chemotherapy Premenopausal women with HR+/HER2-, LN-negative breast cancer and RS 20-25 warrant a conversation about potential chemotherapy benefit Please also see position statements and practice guidelines for warnings, efficacy, risks, and safety associated with the treatment strategies discussed. 6

Radiotherapy Fractionation for Early Stage Breast Cancer Rachel Blitzblau, MD, PhD Goals Focus: external beam options Brachytherapy options also available and appropriate for select patients 7

Radiotherapy Fractionation Radiotherapy is most often a series of daily treatments over a number of weeks Each of these treatments is a fraction of radiotherapy Number of fractions and final dose varies by cancer type and patient factors Historically, after breast-conserving surgery, breast cancer patients received 5-8 weeks of daily treatments to the entire breast Growing evidence shows that shorter fractionation schedules and/or treatment of just a part of the breast is equally effective for select breast cancer patients Smith BD, et al. Pract Radiat Oncol. 2018;8:145-52; Salerno KE. J Natl Compr Canc Netw. 2017;15:682-4. Hypofractionated Whole Breast Radiotherapy Local Recurrence, % Survival, % Cosmesis, % Follow-Up, Trial N Long Short Long Short Long Short Years Whelan et al 1,2 1,234 6.7 6.2 84.4 84.6 71.3 69.8 10 years START A 3,4 2,236 7.4 6.3; 8.8 80.2 81.6; 79.7 late 10 years START B 3,4 2,215 5.5 4.3 80.8 84.1 late 10 years 1. Whelan T, et al. J Natl Cancer Inst. 2002;94:1143-50. 2. Whelan TJ, et al. N Engl J Med. 2010;362:513-20. 3. START Trialists Group. Lancet Oncol. 2008;9:331-41. 4. Haviland JS, et al. Lancet Oncol. 2013;14:1086-94. 8

2018 ASTRO Consensus Statement HF-WBI Wider application of HF-WBI, shared decision making Age: any (prior: 50 years) Stage: any when intent is to treat entire breast without regional nodal fields (prior: T1/2 N0) Chemotherapy: any (prior: none) Dose homogeneity: minimize 105% for all fractionation (prior: +/- 7%) Also greater evidence now for use in DCIS patients Smith BD, et al. Pract Radiat Oncol. 2018;8:145-52. Partial Breast Irradiation 1 Preoperative Treat intact tumor before surgery Clinical trials published Ongoing clinical trials Intraoperative Single dose in OR after lumpectomy performed TARGIT and ELIOT trials 2-4 Postoperative 1 week Classic APBI 10 treatments, twice daily, 5 days External beam or brachytherapy NSABP B-39 and many other trials 5 Postoperative 3 weeks Mini tangents 15 fractions (START) 6 IMPORT LOW trial 7 1. Correa C, et al. Pract Radiat Oncol. 2017;7:73-9. 2. Veronesi U, et al. Lancet Oncol. 2013;14:1269-77. 3. Vaidya JS, et al. Lancet. 2010;376:91-102. 4. Vaidya JS, et al. Lancet. 2013;383:603-13. 5. ClinicalTrials.gov. NCT00103181. 6. Haviland JS, et al. Lancet Oncol. 2013;14:1086-94. 7. Coles CE, et al. Lancet. 2017;390:1048-60. 9

ASTRO Consensus Statement APBI Patients suitable for APBI if all criteria are present Factor Criterion Patient factors Age 60 y 50 y BRCA1/2 mutation Not present Pathologic factors Tumor size 2 cm T stage T1 Tis or T1 Margins Negative by at least 2 mm Grade Any LVSI No ER status Positive Multicentricity Unicentric only Multifocality Clinically unifocal with total size 2.0 cm Histology Invasive ductal or other favorable subtypes Pure DCIS Not allowed Low-risk DCIS EIC Not allowed RTOG 9804 Associated LCIS Allowed Nodal factors N stage pn0 (i-, i+) Nodal surgery SLNB or ALND Treatment factors Neoadjuvant therapy Not allowed Cautionary group: Any of these criteria should invoke caution and concern when considering APBI Factor Criterion Patient factors Age 50-59 y 40-49 y > 50 if don t meet suitable Pathologic factors Tumor size 2.1-3.0 cm T stage T0 or T2 Margins Close (< 2 mm) LVSI Limited/focal ER status Negative Multifocality Clinically unifocal with total size 2.1-3.0 cm Histology Invasive lobular Pure DCIS 3 cm And not in suitable EIC 3 cm Smith BD, et al. J Am Coll Surg. 2009;209:269-77; Correa C, et al. Pract Radiat Oncol. 2017;7:73-9. Patients unsuitable for APBI outside of a clinical trial if any of these criteria are present Factor Criterion Patient factors Age < 50 y < 40 y 40-49 if don t meet cautionary BRCA1/2 mutation Present Pathologic factors Tumor size > 3 cm T stage T3-4 Margins Positive LVSI Extensive Multicentricity Present Multifocality If microscopically multifocal > 3 cm in total size or if clinically multifocal Pure DCIS If > 3 cm in size EIC If > 3 cm in size Nodal factors N stage pn1, pn2, pn3 Nodal surgery None performed Treatment factors Neoadjuvant therapy If used UK IMPORT LOW Trial Multicenter, randomized, phase 3 noninferiority trial, 2007-2010 N = 2,018; women age > 50 years, pt1-2 (< 3 cm), pn0-1, margins 2 mm Procedures (all 15 fractions): 1: 40 Gy whole breast (control) 2: 36 Gy whole breast and 40 Gy partial breast (reduced-dose group) 3: 40 Gy partial breast (partial-breast group) Field-in-field, tangential beams (reduced tangents for partial breast) Primary: ipsilateral in breast relapse Relapse at 5 years: 1: 1.1%; 2: 0.2%; 3: 0.5% Conclusion: partial breast and reduced-dose whole breast radiotherapy are noninferior Coles CE, et al. Lancet. 2017;390:1048-60. 10

Conclusion Women with early stage, LN-negative breast cancer have many potentially appropriate radiotherapy treatment regimens Whereas historically the whole breast was treated for 5-7 weeks, there are now significant and growing data to support shorter treatment courses and partial breast regimens The vast majority of women with early stage breast cancer should now receive treatment courses of 1-4 weeks duration Please also see position statements and practice guidelines for warnings, efficacy, risks, and safety associated with the treatment strategies discussed. Hot Topics in Breast Cancer Surgery Jennifer K. Plichta, MD, MS 11

Lumpectomy Today Oncologically safe in the modern era Meta-analysis of nearly 7,000 patients with stage I-III breast cancer in 9 clinical trials Overall 5-year local recurrence rates after breast-conserving surgery: 4.2% (historical rates: 5%-10%) 7.0% 6.0% 5.0% 4.0% 3.0% 2.0% 1.0% 0.0% 5 Year Local Recurrence Rates 6.4% 4.9% 4.2% 3.2% 3.6% Neuman H, et al. 2018 American Society of Breast Surgeons Annual Meeting. Abstract 403956. NSM Oncologically safe in BRCA mutation carriers 1 548 risk-reducing NSMs in 346 patients at 9 institutions No breast cancers observed; median follow-up of 34 months (expected 22) Does not delay adjuvant therapy 2 NSM on 8,173 patients in NCDB: 8.7% N+, 10.6% triple negative,15.3% HER2+ Readmission rate; positive margin rate and time to chemotherapy; PMRT or hormonal therapy similar for NSM and SSM patients Photo from DellaCroce FJ, et al. Plast Reconstr Surg. 2015;136:1e. 1. Jakub JW, et al. JAMA Surg. 2018;153:123-9. 2. Albright EL, et al. Ann Surg Oncol. 2018;25:1928-35. 12

CPM Surgeons influence CPM choice Population-based survey 5,080 women, stages 0-II breast cancer treated 2013-2015 (70% response rate) 377 surgeons (77% response rate) Attending surgeon: explains 20% of variation in CPM rates Attending attitudes: explains 25% of surgeon influence CPM rate 34% vs 4% for surgeons who least favored vs most favored breast conservation Katz SJ, et al. JAMA Surg. 2018;153:29-36. In this scenario would you recommend Def. No Prob. No Prob. Def. Yes Def. No Prob. No Prob. Def. Yes 0 0.2 0.4 0.6 Fraction For CPM Against CPM For mastectomy For BCS Peace of Mind Avoid Surveillance Avoid Conflict Improve QOL (N = 370) If requested by patients Scenario (N = 370): A 55 year old with no family history of breast with no family history cancer has a normal screening mammogram. A bilateral screening ultrasound shows a 1.2-cm solid mass. Core biopsy demonstrates classic infiltrating ductal carcinoma. ER 95%, PR 90%, and HER2-negative. I might perform CPM for/to Cosmetic Reasons Avoid Losing Patient Reduce Recurrence Improve Survival 0 0.5 0.1 Fraction Very likely Quite likely Somewhat 0 0.5 0.1 A bit likely Not likely TAD TAD = SLNB + removal of clipped/biopsied node Removing the clipped/biopsied node improves axillary evaluation after NACT 1 208 patients, 191 ALND, residual disease in 120 (63%) FNR for clipped node alone: 4.2% (95% CI, 1.4 to 9.5) FNR for SLNB and ALND: 10.1% (95% CI, 4.2 to 19.8) Clipped node was not retrieved as SLN in 23% FNR TAD followed by ALND: 2.0% (1 of 50; 95% CI, 0.05 to 10.7) ACOSOG Z1071 (analysis of clipped nodes) 2 203 with clipped node, clinical T0-T4,N1-N2,M0 breast cancer, SLNB and ALND FNR for SLNB + clipped node: 6.8% (CI 1.9% to 16.5%; P =.20) 1. Caudle AS, et al. J Clin Oncol. 2016;34:1072-8. 2. Boughey JC, et al. Ann Surg. 2016;263:802-7. Figure reprinted with permission. 2016 American Society of Clinical Oncology. All rights reserved. 13

Timing of Surgery Higher local recurrence rates after breast-conserving therapy for tumor downsized by NACT 4,756 women in 10 randomized trials in early breast cancer, 1983-2002, median follow-up of 9 years 15-year local recurrence rate: NACT 21.4% vs ACT 15.9% (P =.0001) No significant differences in distant recurrence, breast cancer mortality, or death from any cause Local Recurrence, % 60 50 40 30 20 10 0 0 NACT ACT 4,756 women, 635 events 15-year loss: 5.5% (95% CI, 2.4-8.6) RR, 1.37 (95% CI, 1.17-1.16) Log-rank P =.0001 17.9% 15 20 Years Local Recurrence Crude Rates (Events per Woman-Years) and Log-Rank Analyses Years 0-4 Years 5-9 Years 10-14 Years 15 Neoadjuvant 2.58 (245/9,493) 1.43 (79/5528) 0.93 (26/2,784) 2.16 (16/740) Adjuvant 1.95 (185/9,477) 0.96 (54/5,618) 0.69 (19/2,769) 1.42 (11/772) Rate ratio 1.35 (1.11-1.64) 1.53 (1.08-2.17) 1.29 (0.70-2.38) 1.11 (0.48-2.57) (95% CI) from 30.4/102.0 13.6/31.8 2.7/10.3 0.6/5.4 (O-E)/V Early Breast Cancer Trialists Collaborative Group (EBCTCG). Lancet Oncol. 2018;19:27-39. 12.1% 9.0% 5 13.2% 21.4% 15.9% Avoiding Surgery? No surgery for pcr patients 1 Feasibility study of 40 patients with HER2+ or triple-negative T1-3/N0-1 Breast pcr rate: 48% Median initial tumor size was 3.3 cm; final tumor size was 1.1 cm FNA + vacuum-assisted core biopsy: accuracy 98%, FNR 5%, NPV 95% Active surveillance for DCIS 2 Comparison of Operative to Monitoring and Endocrine Therapy (COMET) Trial For Low Risk DCIS: A Phase III Prospective Randomized Trial Women 40 years; any grade I DCIS or any grade II DCIS without comedonecrosis; ER+ and/or PR+ Guideline-concordant care (surgery +/- radiation, ET) vs active surveillance (ET) Primary outcome: proportion of new ipsilateral breast cancers at 2 years follow-up 1. Kuerer HM, et al. Ann Surg. 2018;267:946-51. 2. ClinicalTrials.gov. NCT02926911. 14

Conclusion Contemporary local recurrence rates after breast-conserving therapy are lower today NSMs are oncologically safe in BRCA-mutation carriers and do not delay adjuvant therapies Targeted axillary dissections may become the standard of care for patients with excellent responses to NACT Some patients may have a higher risk of local recurrence after NACT and breast-conserving surgery Studies evaluating the possibility of omitting surgery for select breast cancer patients are ongoing; stay tuned! Please also see position statements and practice guidelines for warnings, efficacy, risks, and safety associated with the treatment strategies discussed. Contact Information Call (toll-free) 866 858 7434 Email info@med-iq.com Please visit us online at www.med-iq.com for additional activities provided by Med-IQ. 15

2018 Unless otherwise indicated, photographed subjects who appear within the content of this activity or on artwork associated with this activity are models; they are not actual patients or doctors. 16

Breast Cancer: Abbreviations and Acronyms ACT = adjuvant chemotherapy ALND = axillary lymphadenectomy APBI = accelerated partial breast irradiation BAG1 = Bcl-2 athanogene-1 Bcl2 = B-cell lymphoma 2 BRCA = breast cancer susceptibility gene CPM = contralateral prophylactic mastectomy CT = chemotherapy DCIS = ductal carcinoma in situ DFS = disease-free survival DRFS = distant recurrence free survival EIC = extensive intraductal component ER = estrogen receptor ET = endocrine therapy FNA = fine-needle aspiration FNR = false-negative rate GAPDH = glyceraldehyde 3-phosphate dehydrogenase GRB7 = growth factor receptor bound protein 7 GSTM1 = glutathione-s-transferase M1 HER2 = human epidermal growth factor receptor 2 HF-WBI = hypofractionated whole-breast irradiation HR = hormone receptor IDFS = invasive disease-free survival LCIS = lobular carcinoma in situ LN = lymph node LVSI = lymph-vascular space invasion MYBL2 = MYB proto-oncogene like 2 NACT = neoadjuvant chemotherapy NCDB = National Cancer Database NPV = negative predictive value NSABP = National Surgical Adjuvant Breast and Bowel Project NSM = nipple-sparing mastectomy OS = overall survival pcr = pathologic complete response PMRT = postmastectomy radiotherapy PR = progesterone receptor QOL = quality of life RPLPO = ribosomal protein lateral stalk subunit P0 RS = recurrence score SCUBE2 = signal peptide-cub-epidermal growth factor-like domain-containing protein 2 SLNB = sentinel lymph node biopsy SSM = skin-sparing mastectomy TAD = targeted axillary dissection TFRC = transferrin receptor