Mauricio Camus Appuhn Associate Professor Chief, Department of Surgical Oncology, Pontificia Universidad Católica de Chile

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1 May 18-20, a 20 de Maio / 2017 Castro's Park Hotel Surgery for metastatic breast cancer: the controversy of local surgery for metastatic breast cancer Cirurgia em câncer de mama metastático: a controvérsia de cirurgia local para câncer de mama metastático Mauricio Camus Appuhn Associate Professor Chief, Department of Surgical Oncology, Pontificia Universidad Católica de Chile

2 THE SEED AND SOIL THEORIES ON THE NATURAL HISTORY OF CANCER Metastases resulted only when the appropriate seed was implanted in its suitable soil. Stephen Paget 1889

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6 THEORIES ON THE NATURAL HISTORY OF BREAST CANCER The Halsted Theory 1894: Spread from One Source and "contiguous" development of metastases Breast cancer is a disease that arose in one location (the breast) and, if left untreated, spread through the lymphatic system first to nearby lymph nodes and subsequently to other organs in the body.

7 THEORIES ON THE NATURAL HISTORY OF BREAST CANCER The Alternative Theory (Systemic DiseaseTheory) Bernard Fischer 1954: breast cancer is a systemic disease... and that variations in effective local regional treatment are unlikely to affect survival substantially.

8 THEORIES ON THE NATURAL HISTORY OF BREAST CANCER The Spectrum Theory, or Combined Theory Samuel Hellman 1994: breast cancer is a heterogeneous disease that can be thought of as a spectrum of proclivities extending from a disease that remains local throughout its course to one that is systemic when first detectable "This hypothesis suggests that metastases are a function of tumor growth and progression"

9 THEORIES ON THE NATURAL HISTORY OF BREAST CANCER The Spectrum Theory, Samuel Hellman breast cancer is a heterogeneous disease There are tumors 1.- that are destined to remain localized 2.- that metastasize as a function of size 3.- that possibly disseminate from persistent lymph node disease 4.- that have occultly disseminated by the time of diagnosis, since locoregional treatment is not universally effective in preventing metastases."

10 Stage IV breast cancer: Epidemiological facts Less than 10% of breast cancers, occur with metastasis at the time of diagnosis 20-30% of early breast cancers, will develop metastatic disease In metastatic breast cancer 1-10% could be considered "potentially curable" The use of best imaging techniques and personalized treatments have improved survival in stage IV

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12 Metastatic breast cancer Some assertions: Incurable disease, surgery does not play any role Palliative surgery may be useful for control of local symptoms such as ulceration Several retrospective studies indicate that patients with surgery, live longer

13 ... surgeons still think that surgery can cure it all

14 Palliative surgery may be useful for control of local symptoms such as ulceration

15 Surgical resection with free margins: mortality reduction 39% 3 years survival: Surgery with clear margins: 35% Surgery wuith involved margins (PM or TM): 26% No surgery: 17% Kahn, Surgery 2002, patients (p <.0001)

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18 patients with stage IV disease 52,8% underwent excision of the primary carcinoma 3 years survival: With surgery 40% No surgery 22%

19 Surgery for metastatic breast cancer, better survival? because It prevents future metastasis seeding, after removing the niche of stem cells? Lower levels of circulating tumor cells? Less tumor burden? Immunological mechanisms? Decrease in potential resistant cell lines? Selection bias?

20 Selection bias?: patients who are living longer, because they would have just lived more, even without surgery? They are: Younger patients with better performance status They receive systemic treatment, especially chemo or target therapies They have a smaller tumor burden They have asymptomatic metastases They have better response to systemic treatments

21 There are some theories that say that surgery could be detrimental... The primary tumor could be is a source of growth factors inhibitors and antiangiogenic factors and its resection could accelerate the metastatic seeding Release of growth factors related to healing Immunosuppression caused by anesthesia and surgery

22 Selection bias have tried to overcome with: Multivariate analysis Adjusting cases Excluding cases that cause bias... but what we need are prospective randomized studies

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24 Ongoing randomized trials testing local therapy in women with stage IV BC Country Accrual n Initial therapy US/Can Systemic therapy Japan Systemic therapy Radiotherapy Per standards for stage I-III Not addressed Austria Surgery Per standards for stage I-III Netherlands Surgery For (+) margins or palliation Primary endpoint Survival Survival Survival 2-year survival India CAF + T If indicated Time to progression Turkey Surgery For breast conservation Survival

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26 Tata Memorial Centre, Mumbay, India Feb 2005-Jan women presenting with de-novo metastatic BC Randomization: 350: 173 locoregional treatment 177 no locoregional treatment Median follow-up 23 months

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28 Baseline characteristic of the intention-to-treat population

29 Tata Memorial Hospital, Mumbai, India Median Overall survival: Results: No locoregional treatment = 20.5 months Locoregional treatment = 19.2 months Locoregional treatment resulted in a significant improvement in locoregional progression-free survival, but in contrast, resulted in a significant detriment in distant progression-free survival

30 Kaplan-Meier plot of overall survival

31 Overall survival subgroup analysis, unadjusted hazard ratios

32 Tata Memorial Hospital, Mumbai, India Conclusions: There is no evidence to suggest that locoregional treatment of the primary tumour, confers an overall survival advantage in patients with de-novo metastatic breast cancer This procedure should not be part of routine practice

33 Protocol MF07-01 Turkey The Breast Journal 2009

34 Turkish study MF07-01 Soran et al ASCO 2016 The MF07-01 trial is a multicenter phase III randomized trial of treatment naive stage IV BC patients comparing loco-regional surgery (LRS) followed by appropriate systemic therapy (ST) vs ST alone Patients: systemic therapy alone 138 Surgery + systemic therapy Surgery: PM + RT or TM + RT + SNB or AD

35 Turkish study MF07-01 Soran et al ASCO 2016 The groups were comparable regarding age, BMI, HER2 neu, tumor type and size, histologic grade, and bone and visceral metastasis (all p > 0.05) Most patients had grade 2 3 T2 or T3 invasive ductal carcinoma Approximately 30% of each arm had HER2-positive disease The surgery group had more hormone receptor positive disease (86%) than did the systemic therapy group (73%) and less triplenegative disease (7% vs 17%) Approximately 50% of patients had bone-only metastases.

36 Turkish Study MF07-01 Soran et al ASCO 2016 A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer At 3 years, overall survival was 68% with surgery and 51% with systemic therapy, which was not significantly different (P =.10) However, differences emerged by 5 years, where 41.6% of the surgery group was alive, compared with 24.4% of the systemic therapy group (hazard ratio [HR] = 0.66; P =.005) Median overall survival at that time was 46 months with surgery and 37 months without surgery

37 Turkish Study MF07-01 Soran et al ASCO 2016 A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer Surgery added an additional: 7 months for ER/PR (+) positive patients 12 months for HER2-negative patients 14 months for patients < 55 years old 10 months for patients with a solitary bone metastasis 14 months for patients with bone-only metastases Locoregional relapse was 11 times less with surgery, 1% vs 11%

38 Surgery and Survival in Stage IV Breast Cancer Turkish vs India Protocol Indian trial: locoregional treatment of the primary tumor did not affect overall survival. Median survival time (~20 months) Turkish trial: median overall survival at 5 years was 46 months with surgery and 37 months without surgery Indian Trial: Systemic therapies were not selected according to breast cancer subtypes Trastuzumab was not used for patients with HER2 positive tumors (28%) Less proportion of ER (+) tumors (60% vs 80%) More advanced disease with a very large tumor burden > 3 Mets sites 74% vs 40% There was uncertainty regarding the detection of metastases. Only bone scintigraphy was used to diagnose bone metastases

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40 To date, the removal of the primary tumor in patients with de novo stage IV breast cancer has not been associated with prolongation of survival, with the possible exception of the subset of patients with bone only disease However, it can be considered in selected patients, particularly to improve quality of life, always taking into account the patient s preferences 2B/Weak recommendation, moderate quality evidence

41 Surgery and Survival in Stage IV Breast Cancer CONCLUSIONS At present, whether primary tumor resection for Stage IV breast cancer provides any clinical benefit is unclear According to the results obtained in the trials, routine surgery for all Stage IV breast cancer patients is not warranty of better outcomes Some patients do obtain benefits from surgery but it is necessary to establish reliable means of identifying such patients Robust and definitive evidence supporting the use of surgery is lacking and we need to wait ongoing trials will resolve the controversy

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