BCCF03B_Moran_NCCNbc22_v2.pdf

1. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. NCCN.org – For Clinicians │ NCCN.org/patients – For Patients NCCN 2022 Breast Cancer Congress Radiation Therapy Meena S. Moran, MD Yale Cancer Center/Smilow Cancer Hospital Locoregional Management of Non-Metastatic Breast Cancer with SABCS Updates

2. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. BINV‐2: Modifications to Local‐regional Management

3. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. 8.2021

4. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Node+/high‐risk N0 s/p BCS + ALND Poortsman P, Lancet Oncology 2020 WBI WBRT + RNI* Regional Nodal RT for “Higher Risk Patients” • 10% N0 w/ high risk features • ~50% had 1+ LN • ~50% T1 (<2cm) tumors • ~75% ER+ • Only 10% did not receive chemotherapy • 25% did not receive HTWhelan T, NEJM 2015 *SC/IMN +/‐axilla MA‐20 Node+/high‐risk N0 s/p BCS or MRM + ALND WBI or PMRT WBRT/PMRT + RNI* *SC/IMN +/-axilla • 76% BCS, 24% MRM • Medially/centrally N0 (pN0 44%) • Chemo 25%, • HT 30% • Chemo + HT 30% EORTC 22922 Poortmans P, NEJM 2015 Whelan T, NEJM 2015

5. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Results MA‐20 & EORTC 22922 10 yr Distant Cancer Free Survival 10 yr Breast Cancer Specific Survival Whelan T, NEJM 2015 Poortmans P, NEJM 2015 Poortsman P, Lancet Oncology 2020 15 yr Breast Cancer Mortality 10 yr Isolated LRR‐Free Survival 10 yr Distant Cancer Free Survival 10 yr Disease Free Survival HR 0.81 p=0.0055 HR 0.82 p=0.018 HR 0.86 p=0.020 HR 0.76 p=0.010 HR 0.76 p=0.030 HR 0.59 p=0.009

6. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Who Were The High‐Risk Patients Included in these Trials? • 85% N+ (1‐3+) •<5% had 4+ nodes •~10% N0 w/‘high‐risk’ features: • pN0 w/ primary tumor >5 cm • pN0 with Tumors >2 cm and <10 axillary nodes removed with >1 following: • grade 3 histology • ER‐negativity • Extensive LVI • 55% N+ with pT1‐pT3 tumors located in the UOQ/LOQ of the breast •45% were N0 patients : pT1‐pT3 centrally or medially located tumors MA‐20 EORTC 22922

7. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. 2022 Modification: Refining Patients in pN0 Cohort for Consideration of RNI

9. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. BINV‐2: Modifications to 1‐3+ nodes after BCS

10. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. ACOSOG Z0011 10 yr. Outcomes Primary Endpoints: • Overall Survival • Morbidity • LR and nodal rec *Protocol: Tangents only 10 yr LR recurrence: (p = 0.36) 6.2% ALND vs. 5.3% SLND 10 yr nodal recurrences: (p = 0.28) 0.5% ALND vs. 1.5% in the SLND cN0T1/T2 Up to 2+ SLN SLN → ALND → WBRT SLN → ALND → WBRT SLN alone → WBRT SLN alone → WBRT

11. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. ACOSOG Z0011 10 yr. Outcomes Primary Endpoints: • Overall Survival • Morbidity • LR and nodal rec *Protocol: Tangents only 10 yr LR recurrence: (p = 0.36) 6.2% ALND vs. 5.3% SLND 10 yr nodal recurrences: (p = 0.28) 0.5% ALND vs. 1.5% in the SLND cN0T1/T2 Up to 2+ SLN SLN → ALND → WBRT SLN → ALND → WBRT SLN alone → WBRT SLN alone → WBRT • Low burden of disease in N+ • No Mastectomy patients, only BCS • Limited RT details

13. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. SINODAR‐ONE Trial Preliminary Results: SABC 2021 T1/T2 N1*(< 2+) BCT or Mastectomy ALND SLNB alone N=889 52 Italian centers *Required macrometastatic LN involvement (>2mm) • 20‐23% Mastectomy • RT details >75% • Reported: Outcomes @ Median f/u 34months 5 yr projected Gentile, D. et al SABC 2021 Outcomes ALND (n) SLNB (n) P value Mortality 4 4 0.984 Ax Recurrence 1 1 0.489 IBTR 0 3 0.169 Distant recurrence 7 8 0.815

14. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. SINODAR‐ONE Trial Preliminary Results: SABC 2021 Results: 5 yr RFS, OS reported Analyzed by intention to treat and per protocol No difference in RFS, OS Gentile, D. et al SABC 2021

15. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Patients Enrolled on SINODAR‐ONE vs. ACOSOG Z‐0011: From: Gentile, D. et al SABC 2021

16. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Key Points SINODAR‐ONE: The preliminary findings of SINODAR‐ONE confirm Z‐0011 findings: • T1‐T2 patients with up to 2 macromets, no ALND is needed • Regardless of whether axilla is targeted with RT, axillary event rare In addition, this trial may allow for future: • Broadening of criteria to include mastectomy pts (in addition to BCS pts) • Deeper delve into RT treatment details to further guide RT field decisions Need to further refine axillary RT fields for non‐Z0011

17. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Review of RT Breast Treatment Fields • Z‐0011 protocol specified “Tangents Only” • 3‐‐field (intended to treat SC/III AX nodes)prohibited • Z11 was surgical study (No RT QA) • ? High tangent use? • ? 3‐field use? Standard tangent Superior Border High Tangent Significant RT deviations in subset analyzed: • >20% used 3 field • >50% high tangents • Deviations in both arms Ragsi, et al. JCO 3 Field Technique Axial Projection En Face Projection

18. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. AMAROS = After Mapping of the Axilla, RT or Surgery? AMAROS Donkers, Lancet Onc 2014 N=5000 •80% BCT 20% mastectomy •Arms balanced •Median SLN removed=2 •Median nodes removed(ALND)=15 Tumors <5cm, cN0

19. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. 5 year (median 6.2 yr) publication: • Axillary recurrences: RT 1.2 % vs. ALND 0.4% p=NS • Lymphedema: 23% (ALND) vs. 11% (Ax‐RT)p=0.0001 AMAROS results: Donkers, Lancet Onc 2014 10 year Abstract Only: • Axillary recurrences: RT 1.8% vs. ALND 0.93% p=NS • No difference in OS, DMFS or LRR SABC, Donkers, 2019 Abstract GS4‐01

20. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. OTOASAR TRIAL Optimal Treatment Of the Axilla: Surgery Or Radiotherapy N=2,100 •~80% BCT ~20% mastectomy •Median SLN removed=2 •Median nodes removed(ALND)=15 < Savolt A, et al. Eur. J. Surg Onco 2017;43(4):672‐9

21. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. OTOASAR TRIAL Savolt A, et al. Eur. J. Surg Onco 2017;43(4):672‐9 • No difference in ALND compared with SLNBx and RT to axilla • RT to axilla is an alternative treatment to ALND in selected patients • Majority of patients in AMAROS and OTOASAR had tumors <3cm and 1‐2+ nodes

23. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Modifications to the Definition of RNI: BINV 2, BINV 3

24. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. 8.2021 8.2021 © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

25. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Node+/high-risk N0 s/p BCS + ALND WBI WBRT + RNI* RNI for “Higher Risk Patients” T, NEJM 2015 *SC/IMN +/-axilla MA-20 Node+/high-risk N0 s/p BCS or MRM + ALND WBI or PMRT WBRT/PMRT + RNI* *SC/IMN +/-axilla EORTC 22922 • Recommendation to ‘Strongly consider RNI with WBRT’ based on MA‐20 and EORTC 22922 which demonstrated improved long‐term BC‐specific outcomes when RNI added to PMRT or WBRT • Results suggest RNI (in select higher‐risk pts) results in ↓LRR , and aﬀects distant breast cancer‐ specific outcomes • RNI was defined in the 2021 NCCN guideline based on these 2 trials as supra/infraclavicular nodes, internal mammary chain, and undissected axilla

26. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. KROG 08‐06 Study Question: Independent effects of IMN‐RT on DFS as a component of RNI (when added to tangents + SC/Ax) after BCS or Mastectomy for pN+ Kim YB, et al. JAMA Oncology. 2021 T1-T3, N+ s/p BCS or Mastectomy RT+*RNI+ IMN RT RT +*RNI without IMN RT Stratified by N1,N2, N3 & surgery type N=747

27. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Korean IM study KROG 08‐06 • Underpowered to detect a Δ10% in outcomes Subset analysis (unplanned): • Patients with medial or centrally located tumors had a 10% ↑DFS • HR 0.42 (0.22‐0.82) p=0.03 HR 0.80 (CI:0.57-1.14 p=0.22) HR 0.81 (CI:0.56-1.16 p=0.25) HR 0.87 (CI:0.57-1.31 p=0.50) Kim YB, et al. JAMA Oncology. 2021

28. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

29. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Key Points: • Large PIII trials (MA‐20/EORTC22922) have demonstrated a modest but statistically significant improvement in the long term (10+ years) outcomes with RNI (which in these studies included IMN chain) • IMN RT associated with higher risk of heart/lung toxicity, thus its routine inclusion remains somewhat controversial • Appears the inclusion of IM nodes contributes to the benefits of RNI for N+ centrally/medial tumors • The contribution of including the IM nodal chain to RNI in other subsets of patients needs further refinement

30. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Key Points: • When determining inclusion of the IMN chain with RNI, clinical judgement needed • Patient selection should consider risks vs. benefits for IMN inclusion including: • Long term cardiac and lung toxicities • Existing/competing co‐morbidities of the patient • Age/life expectancy • Meticulous treatment planning observing normal tissue dose constraints is mandatory

31. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. BINV‐I4: LR Management After Pre‐operative Systemic Therapy

32. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. Local‐regional Management After Pre‐operative Systemic Treatment

33. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. Local‐regional Management After Pre‐operative Systemic Treatment

34. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. BINV‐D: Axillary Staging Considerations

37. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. kIn the mastectomy setting, in patients who were initially cN0 who have pN+SLNB, and have no axillary dissection, RT to the chest wall should include the undissected axilla at risk +/- RNI

38. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Major Shift in NCCN Treatment Algorithm for Axillary Management • Shift in paradigm for radiation oncologists for patients treated with cT1/T2, cN0 treated without pre‐operative systemic treatment • Contemporary data from AMAROS and OTOASAR now confirm no difference in long‐term outcomes with either ALND or RT to the axilla this subgroup after BCT or Mastectomy, with less morbidity with RT • A reasonable approach to T1/T2 cN0 pts without pre‐operative systemic therapy is to forgo ALND in patients with up to 2+ nodes after Mastectomy and use PMRT with intentional inclusion of the axilla • Considerations should shift away from classical thinking of ALND recommendations based on ‘estimated residual disease burden in the axilla’, and more towards careful patient selection for ALND omission and inclusion of RT to axilla

39. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. BINV‐I: Principles of Radiation Therapy

40. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. 8.2021 © 2022 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.

41. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. age >50 s/p BCS Invasive BC <3cm, pN0 Primary Cosmesis End‐point: 3‐yr physician assessed moderate to severe breast adverse effects: Pts requiring PMRT, RNI, boost or chemotherapy were ineligible Agarwal, et al. Radiother Oncol. 2011 Jul;100(1):93‐100 Brunt AM, et al JCO July 2020 FAST Trial (CRUKE/04/015)

42. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Brunt AM, et al JCO July 2020 Mod/Marked Br Shrinkage Mod/Marked Br Edema Mod/Marked Br Induration 10 Year Cum LR 1.3% FAST Trial (CRUKE/04/015): 10 Year Follow‐up

43. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. FAST Forward Trial 40 Gy in 15 (2.67 Gy fx) 27 Gy in 5 (5.4 Gy fx) 26 Gy in 5 (5.2 Gy fx) ‐Invasive cancers ‐Age >18 years ‐(pT1–3, pN0–1) ‐BCT or Mastectomy ‐chemotherapy allowed (NAC or adjuvant) • Breast or CW • Protocol mandated 3D‐CT planning Brunt AM, et al Lancet April 2020 Dose constraints (5 fx): PTV: 95% of PTV should get 95% prescribed dose V 8 Gy ipsilateral lung: <15% V 7 Gy heart: <5 % and V1,5 Gy heart: < 30% Dmax of < 110% 40 Gy in 15 (2.67 Gy fx) 27 Gy in 5 (5.4 Gy fx) 26 Gy in 5 (5.2 Gy fx)

44. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. • Local relapse: Non‐inferiority bt 3 arms (<2% in all arms) • Patient & clinician‐assessed normal tissue effects: • 26 Gy arm was equivalent to 40 Gy/15 • 27 Gy arm did worse than 40 Gy/15 • 26 Gy arm had less mod/severe toxicity overall than 27 Gy arm FAST‐Forward Trial: 5 yr. Outcomes Brunt AM, et al Lancet April 2020

49. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. CMF: • CMF has been used with RT in both prospective & retrospective studies • A large body of published data of clinical experience of CMF + RT delivered concomitantly Endocrine therapy: • Multiple retrospective analyses of patients treated w/ET before, during of after RT either from clinical trials or institutional experiences suggest no difference in outcomes or toxicity • Meta‐analysis (Li F, et al, Breast 2016) Sequencing of Systemic Agents with RT (BINV‐I) CMF/Endocrine Therapy

50. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. CMF: • CMF has been used with RT in both prospective & retrospective studies • A large body of published data of clinical experience of CMF + RT delivered concomitantly Endocrine therapy: • Multiple retrospective analyses of patients treated w/ET before, during of after RT either from clinical trials or institutional experiences suggest no difference in outcomes or toxicity • Meta‐analysis (Li F, et al, Breast 2016) Sequencing of Systemic Agents with RT (BINV‐I) CMF/Endocrine Therapy

51. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Capecitabine: • CREATE X established the benefit of capecitabine for patients with TNBC and residual disease after surgery in NAC setting • Capecitabine is a known radiosensitizing agent with potential to ↑ cell kill/normal tissue toxicity • Capecitabine was not given concomitantly with RT in CREATE X Olaparib: • OlympiA trial did not include any patients who received olaparib and cRT • Similar to other trials, protocol not designed to assess the safety data of this combination w/ RT • Ongoing small trial (RADIOPARP Phase I) combination of olaparib +RT for LABC or metastatic TNBC • Feasibility study; Small number of patients (N=24) • Full doses not given (400 BID OlympiA and max dose 200 BID in 5/24 pts) Sequencing of Systemic Agents with RT (BINV‐I) Capecitabine and Olaparib

52. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Capecitabine: • CREATE X established the benefit of capecitabine for patients with TNBC and residual disease after surgery in NAC setting • Capecitabine is a known radiosensitizing agent with potential to ↑ cell kill/normal tissue toxicity • Capecitabine was not given concomitantly with RT in CREATE X Olaparib: • OlympiA trial did not include any patients who received olaparib and cRT • Similar to other trials, protocol not designed to assess the safety data of this combination w/ RT • Ongoing small trial (RADIOPARP Phase I) combination of olaparib +RT for LABC or metastatic TNBC • Feasibility study; Small number of patients (N=24) • Full doses not given (400 BID OlympiA and max dose 200 BID in 5/24 pts) Sequencing of Systemic Agents with RT (BINV‐I) Capecitabine and Olaparib

53. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Sequencing HER‐2 Targeted Therapies and RT • PIII trials that established the routine use of HER2+ agents did not assess the independent contributions of sequencing RT • Existing published data mainly on Trastuzumab….Lapatinib • Some clinical data to suggest that anti‐HER2 +cRT may be radiosensitizing • ↑ response rates in locally advanced, gross disease Horton J, Int J Rad Onc Bio Phy 2010 • Cardiac toxicity (+cRT) from retrospective reviews suggest equivalence to historic controls (Trastuzumab PIII trials) • Published retrospec ve & small prospec ve clinical series → • No difference in toxicities (skin/soft tissue, lung, esophagus, etc) • Systematic review suggests no appreciable difference in toxicities Mignot F, Rad & Onc 2017 • TDM‐1, Pertuzumab likely to be safe, though available data are much more limited • Some sugges on of ↑ toxicity of cRT w/TDM‐1 & Pertuzumab to other sites (brain, GI) caution with RT to other sites • These recommendations pertain only to breast/post‐mastectomy RT

54. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. Sequencing HER‐2 Targeted Therapies and RT • PIII trials that established the routine use of HER2+ agents did not assess the independent contributions of sequencing RT • Existing published data mainly on Trastuzumab….Lapatinib • Some clinical data to suggest that anti‐HER2 +cRT may be radiosensitizing • ↑ response rates in locally advanced, gross disease Horton J, Int J Rad Onc Bio Phy 2010 • Cardiac toxicity (+cRT) from retrospective reviews suggest equivalence to historic controls (Trastuzumab PIII trials) • Published retrospec ve & small prospec ve clinical series → • No difference in toxicities (skin/soft tissue, lung, esophagus, etc) • Systematic review suggests no appreciable difference in toxicities Mignot F, Rad & Onc 2017 • TDM‐1, Pertuzumab likely to be safe, though available data are much more limited • Some sugges on of ↑ toxicity of cRT w/TDM‐1 & Pertuzumab to other sites (brain, GI) caution with RT to other sites • These recommendations pertain only to breast/post‐mastectomy RT

55. © National Comprehensive Cancer Network, Inc. 2022, All Rights Reserved. No part of this publication may be reproduced or transmitted in any other form or by any means, electronic or mechanical, without first obtaining express written permission from NCCN®. Contact education@nccn.org with any questions. NCCN.org – For Clinicians │ NCCN.org/patients – For Patients NCCN Member Institutions Who We Are An alliance of leading cancer centers devoted to patient care, research, and education Our Mission To improve and facilitate quality, effective, equitable, and accessible cancer care cancer care so all patients can live better lives Our Vision To define and advance high- quality, high-value, patient- centered cancer care globally

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