Radiotherapy Management of Breast Cancer Treated with Neoadjuvant Chemotherapy Julia White MD Professor, Radiation Oncology
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 011202
What we know well. Efficacy of Radiotherapy for Breast Cancer Treatment in the Adjuvant Setting
Gains from RT in Overall Recurrence (local, regional, distant) Results in Improved Breast Cancer Survival Updated EBCTCG Meta analyses Lancet 2011- BCS (n=10,801) + RT: Lancet 2014- Mastectomy w/ AD (n=3,131) + RT: Local-regional Recurrence Overall (any) Recurrence 8.1% MAST + RT 26% MAST (p<0.00001) 17.9% Gain 10 year Local Control 19.3% BCS + RT 35.0% BCS (p<0.00001) 15.7% Gain 10 year Overall Control Overall (any) Recurrence Breast Cancer Mortality 51.9% MAST + RT 62.5% MAST (p<0.00001) 10.6% Gain 10 year Overall Control 21.4% BCS + RT 25.2% BCS (p<0.00005) 3.8% Improvement 15 year Survival Breast Cancer Mortality 58.3% MAST + RT 66.4% MAST (p<0.001) 8% Improvement 20 year Survival
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
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
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
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?
What is evolving. Efficacy of Radiotherapy for Breast Cancer Treatment in the Neo Adjuvant Chemotherapy Setting
NeoAdjuvant Chemotherapy and Breast Conservation
Neoadjuvant Chemotherapy: Breast Conserving Surgery and Radiation Therapy Study N BCT % F/U (yrs.) Clinical Stage % In-breast recurrence Phase III: NSABP B-18 763 68 16 NSABP B-27 2,411 49 8.5 EORTC 10902 350 28 4.7 87% T-1,2 74% N-0 71% T-1,2 70% N-0 73% T1,2 48% N-0 13 6 10.7* * Local regional recurrence
NSABP B18: Does Initial Surgical Intention Pre- NAC Affect Outcome? 1988 1993 AC x4 Surgery 9 years median F/U n = 1533 ct1-3, N0-1 R Surgery AC x4 % IBTR p Preop Chemo 10.7 0.12 Postop Chemo 7.6 MRM pre NAC Lumpectomy post NAC 15.9 0.04 Lumpectomy pre NAC- Same post NAC 9.9 Wolmark et al., JNCI 30:2001
MDACC Prognostic Index LRR after BCT or MRM treated with Neoadjuvant Chemotherapy 815 patients 1974-2000 331 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 0-4 1. Clinical N2 N3 disease 2. Lymphovascular invasion 3. Residual pathologic primary size > 2 cm 4. Pathologically multifocal residual disease Huang EH, IJROBP 66:2006
No Difference in Local Regional Control by MDAPI 0-1 but BCT Worse for Score > 2 Score % w/ BCT % w/ MRM 0-1 83% 58% 2 13% 28% 3-4 4% 14% Huang EH, IJROBP 66:2006
Breast Conserving Therapy after Neoadjuvant Chemotherapy 308 operable breast cancer patients Medical University Vienna 1995-2007 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
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
Impact of Multifocal or Multicentric Disease Treated with NAC 2002 2010: 6,143 breast cancer patients enrolled on multi institution clinical trials with NAC Gepar trio, Gepar quattro, Gepar quinto Unifocal Multifocal Multicentric p N 4,733 820 588 BCT % 71.6 58.5 30 pcr % 19.4 16.5 14.4 Local Recurrence All 7.1 4.9 9.6 Ataseven, Ann Surg Onc 2014 BCT 8.7 4.2 8.0 0.3 Mast 11 5.9 10 0.03
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
MDAPI in a More Modern Treatment Era: LRR Free Survival BCT vs. MRM 551 patients neoadjuvant chemotherapy 2001-2005 244 BCT and 327 MRM Median follow up 62 months Akay et al., Ann Surg Oncol 19:2012
MDAPI 0-2: No Difference in LRR Free Survival BCT vs. MRM Score % w/ BCT % w/ MRM 0-1 78% 44% 2 17% 38% 3-4 6% 18% Akay Ann Surg Oncol 19:2012
Breast Radiotherapy Methods for NAC Conventional WBI Hypofractionated WBI Boost 10-16 Gy/ 5-8 treatments Accelerated PBI 50 Gy/ 25 treatments 42.56 Gy/ 16 treatments 30-38 Gy/ 6-10 treatments
Regional Nodal Radiotherapy Regional nodes: Axilla (what did not get removed with dissection, undissected axilla ) Supraclavicular Internal mammary ( first three intercostal spaces)
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, 1990-2004 Median follow-up 88 months Davieau et a IJROBP 78:2011
No Difference in LRR or OS by Use of Nodal Radiotherapy in ypn0 Davieau et a IJROBP 78:2011
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
NeoAdjuvant Chemotherapy and Postmastectomy Radiotherapy
Local Regional Recurrence and Survival: Post-mastectomy Radiation 6 Prospective Neoadjuvant Chemotherapy Trials MDACC 1974-2000 n = 636 Mastectomy Radiation n = 542 No Radiation n = 134 Huang, et al., JCO, 22:2004
MDACC Benefit PMRT after NAC PMRT Improved 10 10 Year Local Cause Regional Specific Recurrence Survival Factor No RT % RT % p Clinical: Clinical: > IIIb T3 T4 T4 N2-3 N2-3 Pathological : Tsz 2.1-5 cm Pathological > 4 pos > nodes 5cm > 4 pos (ypn2) nodes. 22 22 44 8 0.002 0.002 46 24 15 45 < 0.001 0.007 40 27 12 49 <0.001 <0.024 31 14 0.002 52 18 13 44 <0.005 0.001 59 16 <0.0001 Huang, et al., JCO, 22:2004
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 7 33 0.04 % Cause Specific Survival 87 40 0.0014 McGuire, et al. IJROBP, 68:2007
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 1974-2000 676 RT 73 No RT 66 RT 14% No RT 8% II 30% III 70 % 11* 22 54 47 McGuire 1982-2002 106 62 100% pcr II 30% III 70 % 5 10 - LeScodan 1990-2004 134 91 100% ypn0 II 63% III 37% 4 12 88 94 Shim 1998-2009 151 57 100% ypn0 II 60% III 40% 2 8 93 90
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
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
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 40603 Carboplatin 60% Tryphaena * Trastuzumab + Pertuzumab 63% *Her2 TNBC
Should Down Staging of the Axilla with NeoAdjuvant Chemotherapy affect Delivery of Regional Nodal Radiotherapy?
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 4 2961 Patients - 318 LRR as First Events 1071 Mastectomy NO PMRT - 137 LRR first events
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 (1.12 2.23) 0.0095 Clin. nodal status: cn(+) vs. cn(-) 1.53 (1.08 2.18) 0.017 Breast/nodal pathologic status: ypn(-): No Breast pcr vs. Breast pcr 2.21 (0.77 6.30) 0.0002 ypnode(+) vs. ypnode(-)/breast pcr 4.48 (1.64 12.21) Lumpectomy Plus Breast XRT (1890 patients, 189 LRR Events) Age: 50 vs. age 50 0.71 (0.53 0.96) 0.025 Clin. nodal status: cn(+) vs. cn(-) 1.70 (1.26 2.31) 0.0005 Breast/nodal pathologic status: ypn(-): No Breast pcr vs. Breast pcr 1.44 (0.90 2.33) 0.0006 ypnode(+) vs. ypnode(-)/breast pcr 2.25 (1.41 3.59)
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
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
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
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)
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