1. Locoregional management and neoadjuvant systemic treatment Birgit Carly MD Breast Unit Isala Breast Cancer Prevention Center CHU Saint Pierre Brussels

2. Inoperable Breast Cancer (LABC and IBC) -Standard of care -Clinical downstaging T and N status - Makes surgery possible -Allows BCT -Complete Pathologic response of primary T and axillary N is a prognostic factor - Better overall survival Machiavelli MR, Cancer J Sci Am 1998 / Ferriere JP, Am J Clin Oncol 1998 / Cance WG, Ann Surg 2002 Neoadjuvant CT

3. Operable Breast Cancer Neoadjuvant CT vs adjuvant CT nchimioOSchir conserv(%) NSABP -B181523 60%T2, 13%T3 AC (4)id67 vs 60 EORTC 10902698FEC (4)id37 vs 21 ABCSG trial 7423CMF (3) + CMF or EC adj id Scholl390FAC (4)id82 vs 77 - BCT possible without compromising survival; - Pathologic Complete Response better outcome; - Can be used to study Breast Cancer Biology; - Same DFS and OS.

4. Questions NAC and Locoregional treatment Optimal Method for Staging at Diagnosis and Evaluation Clinical Response after NAC? Use Sentinel Node? How to mark the tumorbed? Which Surgery in the Breast and the Axilla? Which Chemotherapy Timing of Surgery?

5. Staging at diagnosis and after NAC: optimal method At diagnosis: Size, Unifocality, Type, Grading, Hormone Receptor status, Neu / HER2, Ki67, Contralateral breast, Nodal Status. Tools: - Breast: Physical Examination, Mammography, Ultrasound, Microbiopsy. MRI? - Axilla: Physical Examination, US, FNA, SN? After NAC: Clinical Response Tumor through Change Size, Change Nodal Status Tools: - Breast: Physical Examination, Mammography, Ultrasound, MRI - Axilla: Physical examination, US, SN? Correct cTNM to establish first treatment: surgery or systemic treatment Correct yTNM to establish surgery : Conservatice surgery vs mastectomy Which staging we use after NAC for completing treatment, cTNM and / or yTNM:implications in surgery and RT

6. Staging at diagnosis and after NAC: optimal Imaging method Breast? NAC: degeneration, necrosis, fibrosis, sclerosis, inflammation of the Tumor Chagpar AB, Ann Surg 2006 No NACAfter NAC

7. Staging Breast Tumor after NAC Peintinger F, Ann Surg Oncol 2006 Schott A, Breast Cancer Research and Treatment, 2005 Multidetector-row CT, PET, H MR spectroscopy 162 pat, retrosp.Accuracy Phys Ex53% Mx + US67% PE + Mx + US63% 43 pat, retrosp.Accuracy pCR Phys Ex75% Mx89% US82% MRI89% Good overall correlation between MRI and Overall response, but very bad correlation when pCR. Biopsy after NAC remains absolutely necessary to determine pCR Type of Tumor important in measurement of residual tumor: lobular underestimated, poorly differentiated overestimated.

8. How to mark the tumorbed? -Titanium clip in the center of the tumor before NAC - Tattoo with black coal in center or at 4 poles of tumor

9. Neoadjuvant CT for Early Breast Cancer B.C. nchimiocCR (%) pCR (%) BCR (%) NSAPB-B272411AC (4)409,861 AC (4), DOC (4)6518,763 GEPARDUO (GABG) 913A Pacl (4) / 2w32,57,765 AC (4), DOC (4)57,416,175 Penault-Llorca (France) 200AC645 A Pacl1556 Buzdar (Houston)174FAC (4)241835 Pacl (4)27646 Smith (Scottish)104CVAP (8)3315,448 CVAP (4), DOC (4) 5630,867

10. Operable Breast Cancer Neoadjuvant CT and BCT Breast conservation after NAC yields no higher incidence of positive margins than primary surgical treatment. Soucy G J Am Coll Surg 2007 NAC equivalent to adjuvant CT for survival and DFS. NAC increased risk of locoregional recurrence when RT without surgery was adopted. Mauri D J Natl Cancer Inst 2005

11. Operable Breast Cancer Neoadjuvant CT and BCT 340 patients NAC, Stage I 4%, Stage II 58%, Stage III 38% Medium FU 60 months 29 (95%)Local regional recurrence with 16 (91%) ipsilateral breast tumor recurrence Chen AM J Clin Oncol 2004 Variables positive correlation: - Clinical N2 or N3 - Pathological residual tumor larger then 2 cm - Multifocal pattern - Lymphovascular space invasion

12. Role of type of surgery on LR, risk factors 1772 women, breast cancer stade I-II, randomised (EORTC et DBCG), retrospective Voogd A, J Clin Oncol 2001 BCT: Age < 35 yrs Extended DCIS Local recurrence 10% at 10 yrs 9% at 10 yrs Tumor size Nodal Status High histological grade Vascular Invasion BCT + MRM Vascular Invasion Distant metastasis BCT + MRM

13. Axilla: Staging at diagnosis. Khan A Surg Oncol 2005; Kilbride KE Ann Surg Oncol 2008; Grube BJ Arch Surg 2008;

14. Which Surgery to the Axilla. Optimal integration of SNB into neoadjuvant chemotherapy program Kilbride KE Ann Surg Oncol 2008; Khan A Ann Surg Oncol 2005; Grube BJ Arch Surg 2008;

15. Which Surgery to the Axilla. SN as definitive treatment before NAC when SN negative? Schrenk P Am J Surg 2008 Feasibility of SN mapping before NAC in cN0? Feasibility of FU lymphatic mapping after NAC? Can patients be spared Axillary Clearance post NAC?

16. Which Surgery to the Axilla. SN as definitive treatment before NAC when SN negative? Schrenk P Am J Surg 2008 45 cT2T3N0 (PE, US) Pre NAC: SN IR 100%; 19 SN0, 26 SN+ ( 6/26 micromet) After NAC all axillary cleareance: SN IR 64%: - 80% SN0 or micromet pre NAC - 45% SN+ pre NAC FNR 0% N0 pre NAC 50% N+ pre NAC

17. Which Surgery to the Axilla. SN as definitive treatment before NAC when SN negative? Grube BJ Arch Surg 2008

18. Optimal integration of SNB into neoadjuvant chemotherapy program. SN Post NAC Grube BJ Arch Surg 2008

19. NSABP B-27 Neoadjuvant CT for Early Breast Cancer AC +/- docetaxel SN after NAC 2411women 2411women, T1c-3, operable, palpable, N0-1 428 lymphatic mapping after NAC was attempted Primary enpoint: Identification Rate, False Neg. Rate Mamounas E, J Clin Oncol 2005 - Succes rate 84.8% - 98.9% SN in axilla - 36.4% N+ - False Neg Rate 10.7% Only to offer when pCR in breast

20. Optimal integration of SNB into neoadjuvant chemotherapy program 33/104 patients Lymphoscintigraphy before and after NAC: same image on lymphoscintigraphy Kinoshita T, Breast Cancer 2007 Questions: Does tumour response to NAC causes lymphatic scarring that could affect drainage pattern? Does NAC has the same effect on involved SN as it does on non-involved SN

21. SNB after NAC in N + patients at diagnosis. Can downstaging prevent Axillary dissection? Retrospective, 69patients, N+ at diagnosis by US FNA, mean T 4 cm IR 92.8%, FN 25% Shen J, Cancer 2007 Retrospective, 54 patients, N+ at diagnosis by US FNS or SNB, mean T 3 cm; IR 98%, FN 8.6% Newman E, Annals of Surgical Oncology 2006

22. Optimal integration of SNB into neoadjuvant chemotherapy program It is prognostically valuable to differentiate patients who presented as node negative from those who were downstaged by chemotherapy

23. Which systemic neoadjuvant treatment ? Chemotherapy or Endocrine treatment. Same treatment that reflects state of the art in adjuvant regimens.

24. Timing of Surgery All CT upfront or Split CT by Surgery? - The ideal timing of surgery, when NAC is given, is not known. - Treatment plan should be devised at the start and should not be altered until there is clear evidence of disease progression. - Patients with disease progression during initial course of treatment should be switched to alternate regimen or offered local therapy. - Use of additional CT after standard course of CT with residual tumour has no proven benefit.

25. Questions NAC and Locoregional treatment Optimal Method for Staging at Diagnosis and Evaluation Clinical Response after NAC? Use Sentinel Node? How to mark the tumorbed? Which Surgery in the Breast and the Axilla? Which Chemotherapy Timing of Surgery?