M. R. C H R I S T I A E N S M D P H D M U L T I D I S C I P L I N A I R B O R S T C E N T R U M L E U V E N

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1 Metastatic Breast Cancer: A Surgical Challenge M. R. C H R I S T I A E N S M D P H D M U L T I D I S C I P L I N A I R B O R S T C E N T R U M L E U V E N

2 Traditional and new concepts MBC has a bad prognosis: survival of 1-2 years Palliative treatment: optimal choice Aggressive approaches: useless patient distress New treatments: improve survival Giordano et al; MD Anderson; Proc Am Soc Clin Oncol 2002 Median survival Months 3 y OS % 5 y OS %

3 Principles (1) 30% of patients with potential curable BC will eventually develop metastasis MBC remains incurable Limited understanding of the molecular mechanisms of metastasis Conventional model: primary tumor is heterogeneous Subpopulations of cells acquire stepwise genetic alterations, facilitating dissemination But: Evidence in human tumors is lacking! Clinical observations are challenging this model

4 Principles (2) New concepts Microarray studies: Metastatic potential is an inherent, genetically predetermined property that is expressed very early TC are programmed to metastasize to a certain site in the presence of a favorable microenvironment Escape cell Seed distant sites Self-seed to the primary tumor or other ongoing tumor growths Self-seed theory would support complete excision of the primary (Frank et al. Int. J. Radiation Oncology Biol. Phys. 2008)

5 Evolving insights in treatment of MBC Targeted therapy: tumor cells and microenvironment Today s stage IV is very different from that years ago: progress in imaging! Limited distant disease can be rendered clinically free of disease by local treatment : potential to achieve CR longer DFS Surgical treatments are improving: minimal invasive techniques Median survival is improving chronic disease

6 Challenge Metastasis restricted to one organ, resection combined with systemic therapy and/or RT may prolong survival In selected patients, resection of the primary tumor may improve progression free survival and mortality Literature Review: selection bias, publication bias, small series, retrospective nature

7 Urgent systemic recurrences May require regional RT or surgery or interventional procedures prior to, or along with systemic therapy Brain metastasis Cord compression Choroid disease Pleural effusion Pericardial effusion Pending/pathologic fracture Obstruction of Biliary tree Ureters Trachea Bowel Esophagus

8 Solitary lung metastasis 3% develop a solitary pulmonary lesion (2003) 8 retrospective studies: surgery +/- systemic treatment Median survival times: months 5 y actuarial survival: 35-89% 10 y actuarial survival: 8-60% Medical treatment only: median survival shorter Largest study (n=467) Fridel et al. Eur J Cardiothoracic Surgery 2002 DFI > 36 months and complete excision with or without chemotherapy: 5 year survival rate: 50% 15 year survival rate: 25% Conclusion: Pos. survival outcome after surgery (+/- chemo) is associated with 1. longer DFI after complete excision of the primary tumor and 2. receptor positive status

9 Liver metastasis (1) > 50% of MBC (2003) Late finding other metastasis 5% confined to the liver Median survival: 19 months ~ pre-taxane regimens months ~ taxane-containing regimens Isolated hepatic metastases treated with surgery 6 small, retrospective studies Median survival: months 5 y survival rates: 22-38%

10 Liver metastasis (2) Conclusions: (2003) Improved median survival Agreement on selection of patients? Normal performance status Normal liver function tests Size and number do not influence survival Complete excision (all M+ ; free margins) DFI????? Role of radiofrequency ablation? Studies ongoing promising

11 Bone and Brain metastasis Bone: (2003) Majority receptor positive tumors R/ endocrine treatment Symptoms: pain, fractures, spinal cord compression Indications for surgery: Reduce risk of fractures (Bifosfonates) Treat spinal cord compression (RT) Solitary sternum metastasis Brain: In 1/3 the only site 5 small studies WBRT + surgery: median survival: months Recommendation may be: Surgical excision where possible Stereotactic radio surgery for inaccessible sites

12 Recommendations - Surgery for metastasis Outcome related to Performance status Long DFI / response to systemic treatment Complete excision of the M+ Solitary M+ or multiple M+ at a single site E. Singletary et al. Oncologist 2003

13 Stage IV BC Loco-regional treatment? Conventional : Systemic treatment Surgery of the primary site: palliation or symptom control : Ulceration Infection Bleeding Quality of life Randomised clinical trials focus on stage 0-III Challenge: Which patients could benefit from surgery of the primary tumor? Timing of the surgery? Intend of the surgery? Possible benefit to be expected?

14 Khan et al. Surgery 2002 Surgery at primary site, with negative margins: survival advantage Rapiti et al. JCO : 300 MBC patients Complete excision with negative margins: 40% reduced risk of death Multi adjusted HR: 0.6 (95% CI, 0,4-1.0) In bone metastasis only: HR: 0.2 (95% CI 0,1 to 0,4) p=.001 Ruiterkamp et al. SABCS 2007 Retrospective : 288 of 728 patients underwent surgery Median survival: 2,55 vs. 1,17 years (p<0,0001) Surgery : independent prognostic factor HR: 0.69 (after correction) Multiple metastasis and co-morbidity: reduced effect but still significant Conclusion: 40% risk reduction of mortality Shien et al. ASCO-BCS 2008 Retrospective: 160 LRT vs. 184 No-LRT OS improved with surgery p= (but also with young age, bone or soft tissue metastasis) Barkley et al. SABCS 2007 Overall survival with adjustment for age, number of sites of metastasis, chemotherapy, endocrine therapy, trastuzumab and ER status Therapeutic resection: 5.34 years No therapeutic resection : 2.36 years (p=0.0004)

15 Barkley et al. SABCS 2007 Conclusions: Therapeutic surgery significantly improves survival in patients with Stage IV breast cancer Optimal timing to integrate surgery remains unclear Prospective trial is warranted to confirm these results

16 Loco-regional treatment Randomized trial Badwe et al. Randomized controlled trial OS Standard chemotherapy 93 women randomized: Complete LRT (surgery + RT) vs. No LRT 6 months post randomization : 33% PD Progression free survival: 61% vs. 72% (No LRT vs. LRT): p= ASCO BCS 2008 poster-abstract Cox prop. Hazard : LRT and receptor status determinants for PFS

17 Loco-regional treatment at presentation Timing of surgery Rao et al. Ann Surg Oncol 2008 M.D. Anderson : 224 patients 82 included ( ) Systemic treatment: Antracycline based regimen and/or HT (TAM/AI) HER2 positive: trastuzumab RECIST guidelines 3 groups: date of diagnosis day of surgery Group 1: months Group 2: months Group 3: > 9 months Study end points: death and metastatic progression Median OS predicted to be 54 months

18 Univariate analysis No. (%) OS: p-value (log-rank) MFS: p-value (log-rank) No. of metastatic sites 1 62 (83) or more 13 (17) Type of surgery Partial mastectomy 39 (52) Mastectomy 36 (48) Surgical margin status Positive 23 (31) Negative 44 (59) Unknown 8 (11) Type of axillary evaluation ALND 41 (55) SLNB or no surgery 34 (45) Factor p value Hazard ratio (95% confidence interval) Multivariate analysis of metastatic progressionfree survival Ethnicity: other versus Caucasian ( ) No. of sites: >1 vs ( ) Margins : + vs ( )

19 The effect of the timing on metastatic progression-free survival Rao et al. Ann Surg Oncol 2008

20 Conclusion: Rao et al. Ann Surg Oncol 2008 Improved metastatic progression free survival: One site of metastasis Resection of the intact primary tumor and lymph nodes Negative margins > 3 - <9 months after diagnosis of Stage IV

21 Expanding role of surgery in stage IV BC Take Home Message (1) Evolving concepts of cancer biology and treatment Emerging evidence of a potential survival benefit of loco-regional surgery > 3 and <9 months after diagnosis Good response to systemic treatment Single site M+ Young patients Provided: complete LRT : negative margins + axilla + radiotherapy

22 Expanding role of surgery in stage IV BC Take Home Message (2) Select patients for surgery of metastasis Good response to systemic treatment Long disease free interval Single site or multiple confined to one organ Provided: Complete excision of all M+ can be obtained Follow-up recommendations to be adapted Bone scintigraphy: symptomatic M+; most non-surgical treatment CT/MRI Brain: symptomatic M+ Chest X-ray and Liver US: cost effective analysis?

23 Expanding role of surgery in stage IV BC Take Home Message (3) Multidisciplinary treatment and patient counseling in all stages Guidelines to be developed? Prospective trial?

24 Blue Beauty by Astronaut Sunita Williams Thank you! Good night!