2. 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

3. I have no conflicts of interest

4. 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….

5. 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

6. 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

7. 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

8. 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 (%)
>
No PMRT; “…more modern series show lower LRR with modern systemic therapy”
Recht A, JCO 1999; Katz A, JCO 2000

9. 10-Year Risk of LRR After MRM and Adjuvant CT (ECOG)
# + Nodes N LRR+/-D LRR
% 8%
% 19%
Initial surgery! Adj anthracycline, no PMRT
Recht A, JCO 1999

10. 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

11. 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

12. 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

13. 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% %
Stage III/IV + pCR 3% %
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

14. 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 % %
Stage III % % (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

15. 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

16. 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

17. 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 ??

18. 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)

19. 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

20. “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.

21. 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

22. 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

23. 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

24. 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
Zhang SpringerPlus 2015

25. 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

26. 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

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

28. 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

29. 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: /nrclinonc

30. 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: /nrclinonc

31. 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)

32. 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