Radiotherapy Management of Breast Cancer Treated with Neoadjuvant Chemotherapy. Julia White MD Professor, Radiation Oncology

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1 Radiotherapy Management of Breast Cancer Treated with Neoadjuvant Chemotherapy Julia White MD Professor, Radiation Oncology

2 Agenda Efficacy of radiotherapy in the management of breast cancer in the Adjuvant setting Neoadjuvant Chemotherapy and breast conservation Neoadjuvant Chemotherapy and Post mastectomy radiotherapy and Clinical trials for local regional management post NAC: NSABP B51/ RTOG 1304 Alliance

3 What we know well. Efficacy of Radiotherapy for Breast Cancer Treatment in the Adjuvant Setting

4 Gains from RT in Overall Recurrence (local, regional, distant) Results in Improved Breast Cancer Survival Updated EBCTCG Meta analyses Lancet BCS (n=10,801) + RT: Lancet Mastectomy w/ AD (n=3,131) + RT: Local-regional Recurrence Overall (any) Recurrence 8.1% MAST + RT 26% MAST (p< ) 17.9% Gain 10 year Local Control 19.3% BCS + RT 35.0% BCS (p< ) 15.7% Gain 10 year Overall Control Overall (any) Recurrence Breast Cancer Mortality 51.9% MAST + RT 62.5% MAST (p< ) 10.6% Gain 10 year Overall Control 21.4% BCS + RT 25.2% BCS (p< ) 3.8% Improvement 15 year Survival Breast Cancer Mortality 58.3% MAST + RT 66.4% MAST (p<0.001) 8% Improvement 20 year Survival

5 Regional Nodal Radiotherapy Breast cancer metastases to 4 or more axillary lymph nodes has been an accepted indication for local and regional nodal radiotherapy post mastectomy or lumpectomy More recent evidence now supports that many women with 1-3 positive lymph nodes will benefit from local and regional nodal radiotherapy

6 Supports Local Regional Radiotherapy in Breast Cancer Patients with 1-3 Axillary Nodal Metastases Post Mastectomy Improve DFS/ OS EBCTCG Meta analysis Lancet 2014 EORTC 22922/10925 ECCO 2013 Post Lumpectomy Improve DFS NCIC MA.20 ASCO 2010 EORTC 22922/10925 ECCO 2013 Positive SNB Replace ALND EORTC AMOROS Lancet 2014

7 Radiotherapy when Surgery is First Line for Breast Cancer Treatment Has a large effect on reducing local regional recurrence after lumpectomy in nearly all patients and after mastectomy in node positive patients Yields smaller but consistent effect on reducing distant metastases and breast cancer mortality Indications for post mastectomy radiotherapy are expanding to include many patients with 1-3 positive axillary nodes Similarly, regional nodal radiotherapy more frequently indicated after breast conserving surgery when axillary nodes are positive

8 Challenge: None of the patients included in the Phase III RCT s analyzed in the EBCTCG meta analyses had neoadjuvant chemotherapy. Radiation therapy clinical decision making has been based on pathologic extent of disease from surgery as first line of breast cancer treatment. Radiation therapy indications in setting of neoadjuvant chemotherapy are evolving: is clinical stage, chemo response, or final pathologic extent of disease the key factor?

9 What is evolving. Efficacy of Radiotherapy for Breast Cancer Treatment in the Neo Adjuvant Chemotherapy Setting

10 NeoAdjuvant Chemotherapy and Breast Conservation

11 Neoadjuvant Chemotherapy: Breast Conserving Surgery and Radiation Therapy Study N BCT % F/U (yrs.) Clinical Stage % In-breast recurrence Phase III: NSABP B NSABP B-27 2, EORTC % T-1,2 74% N-0 71% T-1,2 70% N-0 73% T1,2 48% N * * Local regional recurrence

12 NSABP B18: Does Initial Surgical Intention Pre- NAC Affect Outcome? AC x4 Surgery 9 years median F/U n = 1533 ct1-3, N0-1 R Surgery AC x4 % IBTR p Preop Chemo Postop Chemo 7.6 MRM pre NAC Lumpectomy post NAC Lumpectomy pre NAC- Same post NAC 9.9 Wolmark et al., JNCI 30:2001

13 MDACC Prognostic Index LRR after BCT or MRM treated with Neoadjuvant Chemotherapy 815 patients BCT 485 mastectomy Prognostic Index Score: 0-4 Sum of each item scored 0 if absent or 1 if present for a total score of Clinical N2 N3 disease 2. Lymphovascular invasion 3. Residual pathologic primary size > 2 cm 4. Pathologically multifocal residual disease Huang EH, IJROBP 66:2006

14 No Difference in Local Regional Control by MDAPI 0-1 but BCT Worse for Score > 2 Score % w/ BCT % w/ MRM % 58% 2 13% 28% 3-4 4% 14% Huang EH, IJROBP 66:2006

15 Breast Conserving Therapy after Neoadjuvant Chemotherapy 308 operable breast cancer patients Medical University Vienna Received neoadjuvant therapy on 3 ABCSG studies AC, Taxane and Trastuzumab (ABCSG 7, 14, 24) LRFS 5 year All: MRM 91% BCT 89% Intention pre NAC: MRM - MRM 91% MRM - BCT 84% BCT-BCT 97% Adverse pathologic factors explain variation in LRFS T1-2 ER+ G3 24% 40% 50% 54% 53% 54% 98% 70% 38% Fitzal, Breast Cancer Res Treat,2011

16 Fitzal, Breast Cancer Res Treat,2011 Local Recurrence Free Survival: Intention of Mastectomy Pre NAC Not Associated with Worse Outcome MX = Mastectomy BCT= Lumpectomy + Breast XRT

17 Impact of Multifocal or Multicentric Disease Treated with NAC : 6,143 breast cancer patients enrolled on multi institution clinical trials with NAC Gepar trio, Gepar quattro, Gepar quinto Unifocal Multifocal Multicentric p N 4, BCT % pcr % Local Recurrence All Ataseven, Ann Surg Onc 2014 BCT Mast

18 Ataseven, Ann Surg Onc 2014 All All Local Recurrence Free Survival BCT pcr No significant difference unifocal, multifocal, multicentric for those treated with BCT or who achieve pcr

19 MDAPI in a More Modern Treatment Era: LRR Free Survival BCT vs. MRM 551 patients neoadjuvant chemotherapy BCT and 327 MRM Median follow up 62 months Akay et al., Ann Surg Oncol 19:2012

20 MDAPI 0-2: No Difference in LRR Free Survival BCT vs. MRM Score % w/ BCT % w/ MRM % 44% 2 17% 38% 3-4 6% 18% Akay Ann Surg Oncol 19:2012

21 Breast Radiotherapy Methods for NAC Conventional WBI Hypofractionated WBI Boost Gy/ 5-8 treatments Accelerated PBI 50 Gy/ 25 treatments Gy/ 16 treatments Gy/ 6-10 treatments

22 Regional Nodal Radiotherapy Regional nodes: Axilla (what did not get removed with dissection, undissected axilla ) Supraclavicular Internal mammary ( first three intercostal spaces)

23 Is Regional Nodal Irradiation Indicated for ypn0 Breast Conservation? 248 patient cn0 (n=164), cn1-n2 (n=84) All had lumpectomy and were ypn0, 90 Breast RT alone 158 Breast + Regional RT Centre Rene Huguenin, Median follow-up 88 months Davieau et a IJROBP 78:2011

24 No Difference in LRR or OS by Use of Nodal Radiotherapy in ypn0 Davieau et a IJROBP 78:2011

25 Neoadjuvant Chemotherapy and Radiotherapy: Breast Conservation Radiation therapy following breast conserving surgery results in acceptably low rates of in-breast recurrence. Advanced clinical stage, T3-4, N2-3, pathologic residual > 2 cm associated with increased rates of LRR due to adverse pathology / poor response. Conventional whole breast radiotherapy with boost to surgical cavity method of choice Role for regional radiotherapy for clinically node positive breast cancer that becomes node negative (ypn0) is evolving

26 NeoAdjuvant Chemotherapy and Postmastectomy Radiotherapy

27 Local Regional Recurrence and Survival: Post-mastectomy Radiation 6 Prospective Neoadjuvant Chemotherapy Trials MDACC n = 636 Mastectomy Radiation n = 542 No Radiation n = 134 Huang, et al., JCO, 22:2004

28 MDACC Benefit PMRT after NAC PMRT Improved Year Local Cause Regional Specific Recurrence Survival Factor No RT % RT % p Clinical: Clinical: > IIIb T3 T4 T4 N2-3 N2-3 Pathological : Tsz cm Pathological > 4 pos > nodes 5cm > 4 pos (ypn2) nodes < <0.001 < < < Huang, et al., JCO, 22:2004

29 Pathologic Complete Response from Neoadjuvant Chemotherapy: Post-mastectomy Radiation Improves Outcomes RT n = 72 No RT n = 34 p % Local regional recurrence All 5 10 ns Stage I-II 0 0 ns Stage III % Cause Specific Survival McGuire, et al. IJROBP, 68:2007

30 PMRT Benefit Less Pronounced in Clinical Stage II with pcr or ypn0 post NAC? Author/ treatment era n Follow up (mo.) Path response Clinical Stage LRR % OS % PMRT NoRT PMRT NoRT Huang RT 73 No RT 66 RT 14% No RT 8% II 30% III 70 % 11* McGuire % pcr II 30% III 70 % LeScodan % ypn0 II 63% III 37% Shim % ypn0 II 60% III 40%

31 Neoadjuvant Chemotherapy and Radiotherapy: Mastectomy Radiation can improve local regional recurrence and impact survival for patients with locally advance breast cancer who receive neoadjuvant chemotherapy and mastectomy Most Benefit Clinical stage III-IV, pathologic N2-3 Should be considered regardless of response to chemotherapy in Clinical Stage III Unclear role for PMRT in down staged patients to ypn0

32 Cortazar SABC 2012, Lancet 2014 Association of pcr to Event Free and Overall Survival CTNeoBC Pooled Analysis Meta analysis of 12 neoadjuvant randomized controlled trials

33 Trends in Pathologic Complete Response Rates from NAC Trial Additional Agents Path CR NSABP B18 AC 13% NSABP B27 Paclitaxel 26% NSABP B40 Bevacizumab 34.5% NOAH * Trastuzumab 43% NeoALTO * Trastuzumab + Lapatanib 53% CALGB Carboplatin 60% Tryphaena * Trastuzumab + Pertuzumab 63% *Her2 TNBC

34 Should Down Staging of the Axilla with NeoAdjuvant Chemotherapy affect Delivery of Regional Nodal Radiotherapy?

35 NSABP B18 and B27: Patterns of LRF B-18 B-27 Operable Breast Cancer R Mamounas et al, JCO, 2012 Operable Breast Cancer R Surgery AC x 4 AC x 4 AC x 4 AC x 4 AC x 4 Surgery Surgery Docetaxel x 4 Surgery Surgery Docetaxel x Patients LRR as First Events 1071 Mastectomy NO PMRT LRR first events

36 Multivariate Analysis of Independent Predictors of 10-year LRR According to Type of Surgery Mastectomy (1071 patients, 131 LRR Events) Variable Hazard Ratio (95% CI) P Clinical tumor size: 5 vs. 5 cm 1.58 ( ) Clin. nodal status: cn(+) vs. cn(-) 1.53 ( ) Breast/nodal pathologic status: ypn(-): No Breast pcr vs. Breast pcr 2.21 ( ) ypnode(+) vs. ypnode(-)/breast pcr 4.48 ( ) Lumpectomy Plus Breast XRT (1890 patients, 189 LRR Events) Age: 50 vs. age ( ) Clin. nodal status: cn(+) vs. cn(-) 1.70 ( ) Breast/nodal pathologic status: ypn(-): No Breast pcr vs. Breast pcr 1.44 ( ) ypnode(+) vs. ypnode(-)/breast pcr 2.25 ( )

37 10-Year Cumulative Incidence of LRR: Lumpectomy + Breast XRT > 50 yo < 50 yo n=122 n=154 n=58 n=84 n=31 n=57

38 10-Year Cumulative Incidence of LRR: Mastectomy T < 5 cm n=143 T > 5 cm n=128 n=37 n=33 n=21 n=11

39 Background With modern NAC regimens about 40% of pts with axillary nodal metastases at presentation are down-staged to pathologically negative axillary nodes at surgery (even higher proportion in TNBC or HER-2 neu + tumors) Several RCTs have consistently shown that achievement of pcr in the breast with negative axillary nodes predicts for excellent long-term outcomes both in terms of LRR and distant recurrence

40 NSABP B-51/RTOG 1304 Trial Phase III - Clinical T1-3N1M0 breast cancer - Pathology positive axillary node (FNA/Core) - Neoadjuvant CT + anti HER2 ypn0 at definitive Breast Surgery + AND or SNB Randomization Arm 1 Arm 2 No Regional Nodal XRT Regional Nodal XRT A. Lumpectomy: Breast XRT. A. Lump.: Breast/Nodal XRT B. Mastectomy: Observation B. Mast: Chestwall/ Nodal XRT Targeted accrual = 1636 Stratification: Type of Surgery (Mast v. Lump), ER-Status (+ v. ), HER2 Status (+ v. ), pcr in Breast (yes v. no)

41 Thank you!