M.R. CHRISTIAENS MD PHD MULTIDISCIPLINAIR BORSTCENTRUM LEUVEN Metastatic Breast Cancer: A Surgical Challenge

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 %

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

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)

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”

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

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

Solitary lung metastasis 3% develop a solitary pulmonary lesion (2003) 8 retrospective studies: surgery +/- systemic treatment  Median survival times: months  5 y actuarial survival: %  10 y actuarial survival: %  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%

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: %

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

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

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

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?

Khan et al. Surgery 2002  Surgery at primary site, with negative margins: survival advantage Rapiti et al. JCO 2006  : 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)

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 Barkley et al. SABCS 2007

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=  Cox prop. Hazard : LRT and receptor status determinants for PFS

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

Multivariate analysis of metastatic progression- free survival

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

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

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

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?

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?

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