the role of surgery in metastatic breast cancer (mbc)
TRANSCRIPT
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Faina NakhlisDivision of Surgical OncologyDana Farber Cancer Institute
September 24, 2016
The Role of Surgery in Metastatic Breast Cancer (MBC)
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Outline
•Palliative surgery for MBC• Symptomatic intact primary site• Local and/or regional recurrence
•Surgery in the asymptomatic patient with MBC
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Incidence of De Novo Stage IV Breast Cancer in the US (SEER)
De Meglio et al, Breast Cancer Res Treatment, 2016
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What is the Role of Palliative Surgery?
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Complex Resections of Advanced Primary or Recurrent Disease
Feasible* but what are the endpoints?
*Veronesi et al, The Breast 2007
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Goals of Palliative Surgery (Overview of Published Literature – 1990-1994)
Pain Control (12%)
Quality of Life (17%)
Morbidity and Mortality (61%)
Survival (64%)
“Prophylactic” Palliation (59%)
Cost Effectiveness (2%)
Physiologic Response (69%)
Miner et al, Am J Surg 1999
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Surgical Palliation for Symptom Control or Quality of Life Improvement
Miner et al, Ann Surgery, 2004
Palliative procedures (N=823)
Improved symptoms (N=659, 80%)
Symptom free (N=303, 46%),
median 135 days
Additional symptoms (N=191, 29%)
median 58 days
Recurrent symptoms (N=165, 25%)
Median 52 days
No improvement (N=164, 20%)
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How Symptomatic is Local Disease?
MSKCC Experience* - June 2001 – July 2003
Median follow-up after intervention – 75 months
Symptom relief:•30 days – 91%•100 days – 81 %
Stage IV breast cancer, N=91 (de novo – N=20, 22%)
Palliative procedures, N=109 (Mastectomies, N=3, 3%)
Additional procedures, N=60, 60%
*Morrough et al, Cancer 2010
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Primary Local Therapy (PLT) for Stage IV LABC (SEER Medicare, N=5111, 2005-2010)
Fairweather et al, SABCS 2015
Total Cohort (N=5111)
Asymptomatic (N=4645, 91%)
PLT (N=1294, 28%)
Asymptomatic(N=998, 81%)
New symptoms(N=246, 19%)
No PLT (N=3351, 72%)
Asymptomatic(N=3003, 90%)
New symptoms (N=348, 10%)
Symptomatic(N=466, 9%)
PLT (N=118, 25%)
Asymptomatic(N=57, 48%)
New/recurrent symptoms(N=61, 52%)
No PLT (N=348, 75%)
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Is Palliative Surgery Justified in the Setting of Stage IV Breast Cancer?
Pain Control - Yes
Quality of Life - Yes
Morbidity and Mortality - ?
Survival - ?
“Prophylactic” Palliation - ?
Cost Effectiveness - ?
Physiologic Response - ?
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Patients with Stage IV Breast Cancer and Asymptomatic Intact Primary Site
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Do Patients with Stage IV Breast Cancer Live Longer with Their Disease?
*Chia et al, Cancer 2007
Kaplan-Meier Overall Survival Curves• British Columbia Registry*
• N=2150 patients with stage IV breast cancer
• Diagnosis years – 1991-2001
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Systemic Therapy Utilization
Chia et al, Cancer 2007
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Cox Regression Analysis for Survival in Stage IV Breast Cancer
Chia et al, Cancer 2007
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Improved Disease Specific SurvivalSEER, 1973-2010*
*Park et al, JCO 2015A <3 years from diagnosisB >5 years from diagnosis
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Does Surgery in Stage IV Breast Cancer Improve Survival?
Meta-analysis of Retrospective Data*Overall Mortality – Surgery vs. No Surgery
*Headon et al, Molecular and Clinical Oncology, 2016
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How can Surgery Impact Survival in Stage IV Breast Cancer:“Theories”
Control of seeding from primary tumor site1
Decrease in formation of tumor stem cells within the primary
tumor stroma2
Decrease in tumor-induced
immunosuppression by the intact primary site3,
4
1Norton, Massague, Nat Med 20062Kamoub et al, Nature 20073Campbell et al, Breast Cancer Res Treat 20054Danna et al, Cancer Res 2004
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*King et al, ASCO 2016
A Prospective Analysis of Surgery and Survival in Stage IV Breast Cancer (TBCRC 013)*
Cohort A (N=112)Median Age 51 years (21-77)
Median Follow-up 54 months (34-78)
Median Tumor Size 3.2 cm (0.8-15 cm)
ER+/HER2- 71 (63%)
ER+/HER2+ 24 (21%)
ER-/HER2+ 9 (8%)
ER-/HER2- 8 (7%)
Responders 94 (85%)
3 year OS 70% (95% CI, 63-79%)
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*King et al, ASCO 2016
A Prospective Analysis of Surgery and Survival in Stage IV Breast Cancer (TBCRC 013)*
Responders (N=94)
Surgery (N=39, 41%)
No Surgery (n=55, 59%) P
Median Tumor Size 3.8 cm 3.2 cm 0.01
Single Metastatic Site 77% 41% 0.001
1st Line Chemotherapy 39% 17% 0.002
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*King et al, ASCO 2016
A Prospective Analysis of Surgery and Survival in Stage IV Breast Cancer (TBCRC 013)*
Responders Surgery N Median Survival, mos (95%CI) 3yr OS (95%CI) P
OverallN 51 71 (56-NR) 76 (66-89)
0.85Y 39 77 (52-NR) 77 (65-91)
ER positiveN 46 71 (56-NR) 78 (67-91)
0.47Y 34 77 (53-NR) 79 (67-94)
HER2 positiveN 12 NR (NR-NR) 83 (65-100)
0.39Y 15 77 (77-NR) 100 (100-100)
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TBCRC 013Prognostic Impact of 21-Gene Recurrence Score in Patients
With Stage IV Breast Cancer*
*King et al, JCO 2016
• Prospective registry to evaluate approach to local therapy for stage IV breast cancer (N=127)
• Cohort A – Patients diagnosed with de novo metastatic disease (N=112)
• Cohort B – Patients found to have distant metastases within 3 months of breast cancer diagnosis (N=15)
• Median patient age - 52 years
• Median follow-up – 29 months
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TBCRC 013Clinical Characteristics and the 21-Gene Recurrence Score in Patients With
Stage IV Breast Cancer*
*King et al, JCO 2016
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TBCRC 01321-Gene RS vs. Time to First Progression and 2 Year Overall Survival*
*King et al, JCO 2016
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TBCRC 013Median Time to Progression and 2 Year Overall Survival in Patients with De
Novo Stage IV Breast Cancer*
*King et al, JCO 2016
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Prospective Randomized Trials
Country Accrual Period N Initial Therapy Radiotherapy Status
India 2005-2012 350 Chemotherapy If indicated Closed, mature follow-up
Japan 2011-2016 410 Systemic therapy Not addressed Enrolling
USA, Canada 2011-2015 368 Systemic therapy
As for stage I-III disease Closed, July 2015
Turkey 2008-2012 271 Surgery For breast conservation
Closed, mature follow-up
Netherlands 2011-2016 516 SurgeryFor positive margins and
palliationClosed due to lack of accrual
Austria 2010-2019 254 Surgery As for stage I-III disease
Closed, now allows pre-operative
systemic therapy
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Locoregional Treatment versus No Treatment of the Primary Tumour in Metastatic Breast Cancer: an Open-Label Randomized Controlled Trial*
*Badwe et al, Lancet Oncology 2015
• 350 patients with de novo stage IV breast cancer (February 2005 – January 2013) who had an objective response to 6 cycles of anthracycline-based chemotherapy
• Randomization• Loco-regional treatment (LRT) (N=173)• No LRT (N=177)
• LRT – Surgery (breast conservation or mastectomy , plus ALND), followed by radiation therapy, “as per standard adjuvant guidelines”
• Stratification (balanced by all criteria)• ER Status• Number of metastatic lesions (<3 vs. >3)• Metastatic sites:
• Bone• Visceral• Both
• Median Follow-up – 17 months• Total deaths N=218 (LRT – N=111 (64%), no LRT – N=107 (60%))
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Locoregional Treatment versus No Treatment of the Primary Tumour in Metastatic Breast Cancer: an Open-Label Randomized Controlled Trial*
*Badwe et al, Lancet Oncology 2015
LRT (N=173)
No LRT (N=177) Hazard Ratio P
Median OS (months) 18.8 20.5 1.07 (95% CI 0.82-1.4) 0.6
2 year OS 40.8% 43.3% 1.00 (95% CI 0.76-1.33) 0.98
Problem – lack of HER2 directed therapy
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Locoregional Treatment versus No Treatment of the Primary Tumour in Metastatic Breast Cancer: an Open-Label Randomized Controlled Trial*
*Badwe et al, Lancet Oncology 2015
Locoregional Progression
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Locoregional Treatment versus No Treatment of the Primary Tumour in Metastatic Breast Cancer: an Open-Label Randomized Controlled Trial*
*Badwe et al, Lancet Oncology 2015
Distant Progression
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A Randomized Controlled Trial Evaluating Resection of the Primary Breast Tumor in Women Presenting with De Novo Stage IV Breast
Cancer: Turkish Study (Protocol MF07-01)*
*Soran et al, ASCO 2016
• 274 patients with de novo stage IV breast cancer• Randomization• Loco-regional surgery (LRS) group (N=138)• Systemic therapy (ST) only group (N=136)
• Balanced for age, BMI, HER2 status, tumor histology, tumor size, tumor grade, bone and visceral metastases
• Median follow-up – 40 months• Total deaths – N=187 (LRS – N=76 (55%), ST – N=101 (74%))• 36-month survival – no difference (60% for LRS, 51% for ST, p=0.5)• Median OS - 34 months longer with LRS than with ST
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Median Overall SurvivalTurkish Study (Protocol MF07-01)*
*Soran et al, ASCO 2016
Hazard Ratio P
LRS vs. ST 0.66 (95% CI 0.49-0.88) 0.005
ER+/PR+ vs. not 0.64 (95% CI 0.46-0.91) 0.01
HER2 negative vs. not 0.64 (95% CI 0.45-0.91) 0.01
Age <55 years 0.57 (95% CI 0.38-0.86) 0.006
Solitary bone metastasis only 0.47 (95% CI 0.23-0.98) 0.04
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Is Definitive Local Therapy Justified in the Asymptomatic Stage IV Breast Cancer Patient?
•Possibly for those with a dramatic and durable response to systemic therapy - more data are needed
•Systemic therapy and advances in the development of future targeted therapies remain a top priority for these patients