Metastatic Breast Cancer: A Surgical Challenge

1. Metastatic Breast Cancer: A Surgical Challenge M.R. Christiaens MD Phd MultidisciplinairBorstcentrum Leuven

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

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 15-20 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: 42 - 79 months • 5 y actuarial survival: 35 - 89% • 10 y actuarial survival: 8 - 60% • Medical treatment only: median survival shorter 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 • 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%

9. Liver metastasis (1) • > 50% of MBC (2003) • Late finding – other metastasis • 5% confined to the liver • Median survival: • 19 months ~ pre-taxane regimens • 22-26 months ~ taxane-containing regimens • Isolated hepatic metastases treated with surgery • 6 small, retrospective studies • Median survival: 22 - 44 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: 15-37 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 2006 • 1977-1996: 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= 0.049 (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 survivalin 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. ASCO BCS 2008 –poster-abstract • 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= 0.194 • Cox prop. Hazard : LRT and receptor status determinants for PFS

17. Loco-regional treatment at presentationTiming of surgery Rao et al. Ann SurgOncol2008 • M.D. Anderson : 224 patients – 82 included (1997-2002) • 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: 0- 2.9 months • Group 2: 3-8.9 months • Group 3: > 9 months Study end points: death and metastatic progression Median OS predicted to be 54 months

18. Multivariate analysis of metastatic progression-free survival

19. The effect of the timing on metastatic progression-free survivalRao et al. Ann SurgOncol 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 BCTake Home Message (3) • Multidisciplinary treatment and patient counseling in all stages • Guidelines to be developed? • Prospective trial?

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