Radiation after Neoadjuvant Systemic Therapy: Are the Rules Different? Julia S. Wong MD Department of Radiation Oncology Dana-Farber Cancer Institute Brigham and Women's Hospital

I have no conflicts of interest

Background Rationale for neoadjuvant chemotherapy (NAC)/preoperative systemic therapy: Prognostic information Evaluate new drugs/protocol therapies Convert mastectomy to breast-conserving therapy Possibly decrease extent of axillary surgery By assessing response, gain prognostic info….

Questions How do we interpret post-chemotherapy pathology to make radiation therapy decisions? Postmastectomy RT (PMRT): yes or no Extent of nodal RT In BCT setting: what is an acceptable margin

Rules for RT Based on Pathology after Initial Surgery Can we use the “old” rules (when surgery is first) or do we have enough data to change the rules? Pathologic findings (downstaging) after NAC may not have the same significance as those found at initial surgery Limited, retrospective data with NAC and RT

Rules for RT after Initial Surgery After mastectomy and chemotherapy, PMRT if >4 +LNs Often considered in 1-3 +LNs Infrequently recommended for node-negative After breast-conserving surgery (BCS), RT generally recommended provided negative margins achieved Nodal field used depending on extent of nodal involvement and extent of axillary surgery Margins: no tumor on ink

When to Consider Postmastectomy RT (PMRT) After Initial Surgery After MRM and adjuvant chemotherapy, LRR is related to # of positive nodes Data from ECOG and MDACC: # + nodes LRR (%) 0 3-5 1-3 10-13 >4 20-30 No PMRT; “…more modern series show lower LRR with modern systemic therapy” Recht A, JCO 1999; Katz A, JCO 2000

10-Year Risk of LRR After MRM and Adjuvant CT (ECOG) # + Nodes N LRR+/-D LRR 1-3 1018 13% 8% 4-7 62 29% 19% Initial surgery! Adj anthracycline, no PMRT Recht A, JCO 1999

LRR (NAC  Mastectomy) N = 150; no inflammatory breast CA Median FU 4.1 yrs Preop doxorubicin or paclitaxel No PMRT Clinical stage at diagnosis: I 1% II 43% III 48% IV 7% Much of our understanding of the results of NAC comes from the MDACC experience. This is one of their earlier series...looking at a subset of patients from their NAC trials…. Buchholz J Clin Oncol 2002

LRR (NAC  Mastectomy) 5 and 10 yr LRR: 27% LRR associated with: Increased T stage Increased clinical stage Size of residual tumor # involved LNs No tamoxifen LRR for pCR (n=18): 19% On logistic regression LRR associated with: CS IIIB (or higher), >4 +LNs, no tam Pretreatment factors and path/treatment factors These LRR rates are higher than those after initial surgery 19% LRR for pCR—small subset--these patients likely had more advanced stage/disease that in ECOG series Buchholz J Clin Oncol 2002

NAC vs Adjuvant Chemo (Mastectomy) Follow up study Same N = 150 (NAC group); N = 1031 (adjuvant) Clinical stage higher in NAC group Path tumor size and #+LNs less in NAC group 5 yr LRR 27% (NAC) vs 15% (adjuvant) LRR higher in NAC for: All tumor sizes > 4 +LNs T2 and 1-3 +LNs (32% vs 8%) Conclusion: PMRT should be recommended for all pts with >4+LNs, T3, clin stage IIIA or more, regardless of whether they got NAC or postop chemo Buchholz IJROBP 2002

PMRT after NAC N = 542 (compared with N = 134 without PMRT) Median FU 69 months Mainly Stage II/III (RT patients higher stage) LRR at 10 yrs: PMRT No PMRT Overall 11% 22% Stage III/IV + pCR 3% 33% PMRT benefit on MVA for LRR and CSS What do we know about the use of PMRT after NAC 6 trials Significant benefit for patients receiving PMRT and in particular those who achieved a pCR Huang J Clin Oncol 2004

PMRT after NAC with Pathologic Complete Response Mainly Stage II/III pCR after NAC Med FU 62 months LRR at 10 yrs: PMRT (n=72) No PMRT (n=34) Stage I/II 0% 0% Stage III 7% 33% (p=0.04) 92% anthracycline-based; 38% also got taxane Small numbers, big CIs on the stage III comparison Short FU HER2 not done McGuire IJROBP 2007

LRR after NAC in Stage II Stage I (5%) or II (95%) 1974 – 2001 Mastectomy, no RT; doxorubicin-based chemo Median FU 46 months LRR at 5 and 10 yrs: 10% LRR correlated with: clin T3N0, >4+LNs, age <40, no tamoxifen LRR at 5 yrs for clin T1-2, 1-3+ LNs (n=42): 5% Is there a favorable group that can potentially avoid PMRT Garg IJROBP 2004

Summary: Mastectomy after NAC Retrospective data with imbalances; higher stage that adjuvant studies LRR associated with higher stage, more residual disease, lack of pCR Benefit to PMRT in Stage III, any T3, any > 4+LNs PMRT benefit in limited nodal involvement and pCR in need of further study

Breast-Conserving Therapy: LR after Initial Surgery 1980s: LR approximately 10-15% (early-stage) Recent series: about 2-8% Better mammography, margins, systemic therapy Mention age (and subtype) (Arvold); included stage II patients; med FU 85 mos; age significant on MVA (not tumor size p.08 or #+LNs p.059) No Herceptin ??

Planning for BCT after NAC Pre- and post-NAC imaging Assess extent of calcifications if present Clip placement at time of initial core bx Axillary ultrasound and FNA if indicated (also for PMRT considerations)

BCT after NAC N = 340 1987 – 2000 Stage I: 4%, II: 58%, III: 38% Positive margins in 4% Median follow up: 60 months (10-180) IBTR-free: 94%; LRR-free: 91% Predictive of IBTR and RNF: clin N2/3, path size >2cm, multifocal residual, LVI Predictive on logistic regression Chen J Clin Oncol 2004

“Concentric” vs. “Splotchy” Response to CT As Dr. Singletary described in the Anderson experience, the pattern of response to chemotherapy might influence the risk of LRR, and might explain why it is likely even more important to get clearly negative margins after neoadjuvant chemotherapy. While some tumors shrink concentrically, some shrink in a splotchy, or patchy pattern, with viable tumor cells interspersed with treated tumor. It is possible that a tumor can appear to be completely removed if the tumor is resected imbetween the areas of viable tumor.

BCT after NAC (Institut Curie) 1985 – 1994 Clinical T1-3 (84% T2) Tumors had to be < 3 cm after NAC Median FU: 93 months Margins: Positive 11% < 2 mm 17% > 2 mm 67% Indeterminate 4% We do not have much information on what specific margin width is optimal in this setting Rouzier J Clin Oncol 2001

BCT After NAC: Results LR at 10 yrs: 22% Predictive for LR on MVA: Age < 40 Margin < 2 mm (32% vs 17%) S-phase > 4% Clinical tumor size > 2 cm at time of surgery IBTR predicted for distant mets After IBTR, 60% developed mets at 5 yrs Older data/era likely less meticulous margin eval or limited techniques for margin eval Mean breast dose 53 Gy (44-64); 52% got a boost Rouzier J Clin Oncol 2001

Effect of Subtype on LRR (BCT) 2005 – 2012 Median follow up: 4.6 yrs N Path CR (%) (p<0.001) 5-yr LRR-free Survival (p = 0.44) HR+/HER2- 369 16.5 97% HR+/HER+ 105 46 96% HR-/HER2+ 58 72 94% HR-/HER2- 219 42 93% All HER2+ pts got Herceptin “Excellent 5 yr LC affected by subtype and response to chemo” Swisher Ann Surg Oncol 2016

Effect of Subtype on LRR (BCT) NACBCT N = 160, Med FU 28 mos 80% of HER2+ received trastuzumab LRR 8% overall On MVA, LRR higher in TNBC (p=0.04) N Path CR HR+/HER2- 75 5% HER2+ 46 26% TNBC 36 25% Short FU Higher LRR in TNBC (22%) among non-pCR group (HER+5.6%, HR+ 3%) In pCR broup, only 2 recurrences: 1 DM and 1 LR (both were TNBC) Years 1999-2012 Zhang SpringerPlus 2015

Effect of Subtype on LRR (NAC + PMRT) Stage II/III; med FU 62 mos pCR in 14%; 5 yr LRR 8% overall LRR 0% in pCR, 9% if no pCR (p=0.05) TNBC and path LN+ associated with LRR TNBC had higher LRR (20%) compared with HER2+ (6%) and HR+ (4%) MSKCC Years 2000 – 2009 Med 5040 cGy If no pCR, TNBC had higher LRR (26%) vs 7% for HER2+ and 4% for HER+ Yang TJ Ann Surg Oncol 2015

Predictors of LRR after NAC: NSABP Experience B-18 and B-27 NAC trials (AC, docetaxel) BCT or mastectomy (no PMRT) pCR = no residual invasive tumor 1988 – 1993 N = 3088; 10 yr follow up Clinical T1-3, N0-1 LRR 12% (mastectomy), 10% (BCT) Mamounas J Clin Oncol 2012

Predictors of LRR after NAC: Multivariate Analysis For the combined dataset (BCT + mastectomy) n=2961 Mamounas J Clin Oncol 2012

LRR after Neoadjuvant Chemotherapy Small patient numbers in some subgroups! Fig 2: BCT: Most LRRs were IBTRs; in age >50, IBTR similar regardless of path nodal status or path tumor response or initial clin nodal status. In age <50, trend toward more IBTR with decreasing path tumor response and +path nodes. RNF low if clin neg LNs and if clin+ but path neg. Path nodal status didn’t influence RNF rates in clin node-neg, but RNF higher if path node + Fig 3: Mastectomy: CW recurrence increased with decreasing path tumor response and + path nodal status; more so in tumore > 5 cm and in clin+ LNs. RNF low in clin node- in general regardless of tumor size, higher if clin node+ esp if remaining path + Not shown: LRR by #+LNs: >10% for anyone with 1-3+LNs (except clin node neg age>50 BCT) Mamounas, J Clin Oncol 2012

Figure 2 NSABP B‑51/RTOG 1304 (NRG 9353) trial schema King, T. A. & Morrow, M. (2015) Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.63

Figure 1 Alliance for Clinical Trials in Oncology A11202 trial schema King, T. A. & Morrow, M. (2015) Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.63

Summary Neoadjuvant chemotherapy provides advantages to adjuvant chemotherapy in selected clinical settings Local recurrence higher in earlier reports but now generally felt to be comparable to adjuvant setting In BCT, insufficient data for what margin width is adequate; clearly negative margins seems prudent (different patterns of tumor regression)

Summary Retrospective series suggest that there may be subgroups that can safely avoid RT or have more limited RT, without compromising local regional control The rules for when to use RT (or PMRT) are evolving; data from randomized trials critical pCR, subtypes