Kaplan Medical Center

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1 Local lth Therapy Following Primary Systemic Therapy (PST) In LABC Noa Ben Baruch, MD Kaplan Medical Center

2 Which LABC Are We Talking About Advanced primary tumors o T3 Advanced regional lymph nodes o N2 or N3 NOT o Inflammatory breast cancer o Fixation to chest wall, skin ulceration o Multicentric disease o Diffuse extensive DCIS In these cases breast conservation is rarely an option NOT o Operable breast cancer T 2 N 1 In these cases breast conservation is the goal

3 How do we define response to PST Clinically Physical examination Imaging o US o Mammography o MRI Pathological response o No unified method o AJCC added d a y notation ti to denote a pathological l response o Is PCR classified as no tumor in the breast? Breast and nodes?

4 Definitions of Pathologic Response Chevallier 4 tier: 1. tumor disappearance 2. residual DCIS 3. sclerosis inbreast4. no change Chollet NSABP MDACC Modified NPI. Residual tumor size, modified breast grading index No residual invasive cancer in breast No residual invasive cancer in breast or nodes Miller/Payne Reduction of cellularity: no change, <30%, 30-60%, >90%, 100% Sataloff Bonadonna Smith Symmans Response in breast and nodes. Breast total or near effect, >50%, <50%, no effect Reduction in cellularity: none, mild loss, moderate to 90%, marked, no residual tumor Same as Bonadonna plus nodal effect Residual Cancer Burden

5 Reduction in Tumor Cellularity: Miller and Payne Histopathology scoring system to assess response Compares cancer cellularity of the core biopsy (before treatment) with the resected tumor (after treatment) Grade 1: No reduction Grade 2: Minor loss ( 30%) Grade 3: Some loss (30% - 90%) Grade 4: Marked loss (> 90%) Grade 5: No residual invasive cancer 170 patients Tumor 4cm Rx: CVAP 4-6 cycles Grade 1: Grade 2: Grade 3: Grade 4: Grade 5: 15% 24% 27% 20% 14% Ogston et al The Breast :320-7

6 Pathological Response and Survival (Miller and Payne grading system) p= p=0.003* months Ogston et al, 2003

7 What Can We Achieve With PST in HER2 negative e Tumors Most large randomized studies are on operable breast cancer not true LABC as defined Study Therapy Response Rate CR+PR *pcr NSABP B 18 AC X4 79% 13% NSABP B 27 AC X4 TXT X4 91% 26% NSABP B 40 AC X4 TXT X4 + Avastin 87% 33.7% * pcr in breast only DCIS +no tumor

8 What Can We Achieve With PST in HER2 positive Tumors Much smaller studies, some still in abstract form More advanced tumors, some IBC Study Therapy Response Rate CR+PR *pcr NOAH AT T CMF H 89% 43% NeoSphere Taxotere H T 46% NeoALTO Taxol H Lap 80% 51% * pcr in breast

9 The largest benefit by. NST in patients who have high likelihood for pcr pcr Higher likelihood: Age: < 40 years Tumor size: < 2 cm Histology: ductal Grade: high (G3) Proliferation: high Ki67 ER: negative Intrinsic subtype: Basallike or HER2 positive pcr Lower likelihood: Age: over 60 years Tumor size: > 4 cm Histology: lobular Grade: low (G1) Proliferation: low Ki67 ER: positive Intrinsic subtype: luminal A

10 What can we achieve with PST Excellent response rate to multiple chemotherapy regimens No invasive tumor in breast in 30-50% of patients depending on biological properties of the tumor o Best responses seen in HER2+ tumors treated with chemotherapy and dual HER2 blockade o Excellent responses seen in triple negative tumors

11 RISK OF LOCAL RECURRENCE

12 The Questions In patients who achieve an excellent response, should we conserve the breast regardless of initial tumor size? o Does the tumor shrink centrally or piecemeal o Is there a difference in local recurrence rate depending on initial/post treatment size of the tumor? Does initial/post therapy nodal status contribute local recurrence risk? Does local control influence survival? o Can we predict local recurrence rate in LABC post PST?

13 Tumor Response to Chemotherapy The biggest barrier to the use of BCT after PST remains the inability to determine the extent of viable residual tumor Post-Chemotherapy Tumor MRI might be instrumental in determining the type of response

14 Local-regional recurrence (LRR) -free survival rates according to the morphology of the residual primary tumor. Chen A M et al. JCO 2004;22: by American Society of Clinical Oncology

15 NSABP B-18 Should We Conserve The Breast Regardless Of Initial Tumor Size Initial Surgery proposed Surgery done Local recurrence Survival Mastectomy Lumpectomy 16% No difference Lumpectomy Lumpectomy 10% EORTC Initial Surgery proposed Surgery done Local Recurrence Survival Mastectomy Lumpectomy Not reported HR 2.35 Lumpectomy Lumpectomy Not reported HR 1.0

16 EORTC Survival by surgery planned vs. performed van der Hage J A et al. JCO 2001;19: by American Society of Clinical Oncology

17 Ipsilateral breast tumor recurrence (IBTR) -free survival rates according to clinical tumor stage. Clinical T stage did not correlate with breast recurrence when T3/T4 tumors responded to chemotherapy by breaking up and leaving a multifocal pattern of residual disease, the breast recurrence rate was 20% 2004 by American Society of Clinical Oncology Chen A M et al. JCO 2004;22:

18 Local-regional recurrence (LRR) -free survival rates according to the size of the residual primary tumor. Chen A M et al. JCO 2004;22: by American Society of Clinical Oncology

19 Does initial/post therapy nodal status contribute to local recurrence risk? Local-regional recurrence (LRR) -free survival rates according to clinical nodal stage by American Society of Clinical Oncology Chen A M et al. JCO 2004;22:

20 Neoadjuvant chemotherapy Results from EBCTCG 2006 Does local control influence survival? Preliminary results Not for citation or publication

21 The trials 11 trials, start dates women,1300 deaths Woman years: median follow up: 6.5 yrs period 0 9: yrs period d10+: yrs Older trials generally used CMF, later trials anthracyclines Mix of eligibility criteria Preliminary results Not for citation or publication

22 Analysis plan Any death Extent of surgery Isolated local recurrence Any recurrence Breast cancer mortality Prognostic factors*: age / tumour size / ER status / PR status ( no data on tumour grade / pcr / HER2) * must be measured before randomisation for comparability between treatment arms

23 Extent of surgery Surgery Treatment arm Neoadj. Standard BCS/None* 62 % 46 % Mast./? 38 % 54 % Total 100% 100% * if no surgery, generally given radiotherapy

24 Preliminary results Not for citation or publication

25 ANY Preliminary results Not for citation or publication

26 Summary Based on 4700 women in 11 trials: 18 % of women in the neoadjuvant arm had a less extensive surgical procedure 3% (SE 0.9) loss in absolute local recurrence risk by year 5 no significant difference in any recurrence, breast cancer mortality, or death by year 10. Preliminary results Not for citation or publication

27 Does local control influence survival? Local recurrence and breast cancer mortality women, 51% with node positive disease EBCTCG Lancet 2005; 366:

28 Interpretation Differences in local treatment can substantially affect local recurrence rates This would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided. This could reduce 15-year overall mortality. EBCTCG Lancet 2005; 366:

29 Can we predict local recurrence rate in LABC Post PST? Can we integrate multiple factors? Poorly defined and not well validated Will be discussed in the next presentation Prediction of local recurrence risk is the one of the most important elements in the decision making process of suitable candidates for BCS

30 The Institute Curie experience of IBTR after NAC Probability of local control was decreased by the following independent factors: Age < 40 yrs Excision margins <2 mm S-phase fraction >4% Clinical i l tumor size >2 cm at the time of surgery Pts who developed d IBTR after NAC had significantly ifi worse distant metastases free survival Rouzier, JCO, 2001

31 The MD Anderson Prognostic Index (MDAPI) prognostic index for clinical decision making on BCS after NAC 340 pts treated with BCS after NAC 4 statistically significant predictors of IBTR and LRR: 1. Clinical i l N2 or N3 disease 2. Residual pathological tumor size >2 cm 3. A multifocal pattern of residual disease 4. Lympho-vascular space invasion in the specimen Scores of 0 (favorable) or 1 (unfavorable) -> overall MDAPI score 0-4 Chen, Cancer 2005

32 The MD Anderson Prognostic Index (MDAPI) Low Score 0 1 N= 276 Intermediate Score 2 N=43 High Score 3 4 N=12 5 yrs IBTR free survival rate 5yrs LRR free survival rate 97% 94% 88% 83% 82% 58% P< P< Patients with an MDAPI of 0 1 1, which made up 81% of the study population, had very low rates of IBTR (3%) and LRR (6%). The MDAPI enabled the identification of a small group (4%) of pts at high risk for IBTR and LRR, who may benefit from alternative locoregional treatment strategies. Nearly all pts (96%) had Stage II or Stage III disease. Chen, Cancer

33 Prognostic Index (MDAPI) critics Some of the criteria in the MDAPI correlate with LRR even after mastectomy (N2-N3), and some correlate with the risk of developing distant metastasis. Some of the criteria are not available at the time of surgical decision making (residual T, pathological response pattern). A prediction tool for IBTR and LRR. Age and histological subtypes which definitely correlate with pcr were not included. Single institute experience

34 Take Home Message Excellent response rates and down-staging can be achieved with PST in LABC. The integration of targeted biological therapy improves pcr rates. Local control remains a key issue in patients initially unsuitable for breast conservation. The risk of local failure following BCS is dependent on multiple factors and is poorly defined BCS can be considered in patients with a significant breast and nodal response to PST. o Caution in very large tumors with unclear response pattern

35 Thank you