CON: Removal of the Breast Primary in Patients with Metastatic Breast Cancer Amelia B. Zelnak, M.D., M.Sc. Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine
Defining the Problem 5% of women with breast cancer present with metastatic disease Staging scans often performed after initial surgery Current approach: treat with systemic therapy and offer surgery if needed for palliation Does local therapy improve survival? What constitutes adequate local therapy? Breast-conserving surgery vs. mastectomy Role of radiation When is the optimal time for local therapy
PRO Rationale for Local Therapy Primary tumor is source of reseeding distant sites and therefore should be removed CON Once patient develops distant metastases, local therapy offers no survival advantage
Proof of Principle: the kidney SWOG 8949 (N=241) EORTC 30947 (N=75) Nephrectomy + IFN-Alfa2b (months) IFN-Alfa2b (months) Median Survival 8.1 11.1 Performance Status 0 11.7 17.4 Performance Status 1 4.8 6.9 Lung only 10.3 14.3 Other 6.3 4.2 Nephrecto my + IFN- IFN-Alfa2b (months) Alfa2b (months) Median Survival 7 17 Flanigan et al, N Engl J Med 2001 Mickisch et al, Lancet 2001
Retrospective Study: Khan et al. National Cancer Database: 16,023 patients presented with metastatic breast cancer between 1990-1993 6861 (42.8%) did not have surgery 9162 (57.2%) underwent either partial or total mastectomy 10,160 with complete information included in the analysis 5806 (36.2%) received radiation therapy, unknown if this was local or to metastatic site Khan et al, Surgery 2002
Surgical Therapy Khan et al. 3 Year Survival Overall 24.9% Mean Survival (months) None 17.3% 19.3 Partial Mastectomy 27.7% 26.9 Total Mastectomy 31.8% 31.9 No. Patients Hazard Ratio 95% CI No operation 4735 Negative Margins 3099 0.612 0.581-0.646 Positive Margins 2326 0.751 0.710-0.793 Metastatic Burden 1 site 6490 2 sites 2352 1.25 1.185-1.319 3 sites 1318 1.523 1.424-1.629 Type of Metastasis Visceral 3944 Soft tissue 6216 0.747 0.713-0.782
Limitations: Khan et al. Patients with 1 metastatic site were more likely to undergo surgical resection Patients with bone/soft-tissue metastases (61.7%) were more likely to undergo surgery vs. patients with visceral metastases (52.7%) Data regarding receptor status is unknown. Unknown whether patients were diagnosed with metastatic disease after surgery or before Does local therapy really make a difference or are we simply identifying metastatic breast cancer patients with better prognosis?
Retrospective Study: Rapiti et al. Geneva Cancer Registry: 300 metastatic breast cancer patients diagnosed between 1977-1996 76% presented with symptoms of primary tumor or metastatic sites Potential Bias among Surgery Patients Mean age of women of patients undergoing surgery was younger (61.8 vs. 71.6 years) lower T and N stage Only 1 metastatic site (61% vs. 41%) Visceral metastases were less common (43% vs. 58%) Rapiti et al., J Clin Oncol 2006
Rapiti et al. Surgery No. Patients Hazard Ratio 95% CI No operation 173 Negative Margins 61 0.5 0.3-0.7 Positive Margins 33 0.8 0.5-1.1 Unknown Margins 33 0.8 0.6-1.3 Is local therapy responsible for the difference? Were patients with positive margins too sick for additional surgery? Did their tumors have poor prognostic features?
Retrospective Study of SEER Database Population-based cohort study using SEER database from 1988-2003 of 9734 patients with Stage IV breast cancer 4578 (47%) underwent breast surgery 1844 (40.3%) had partial mastectomies 2485 (54.3%) had mastectomies 5156 (53%) did not have breast surgery Surgery group was younger (median age of 62 vs 66), smaller tumors, ER/PR-positive Median Overall Survival 36 vs 21 months (P < 0.001) Gnerlich et al., Ann Surg Oncol 2007
Impact of Staging and Patient Selection Retrospective Analysis of 147 patients who presented with stage IV breast cancer at Dana- Farber between 1998 and 2005 61 (41%) underwent breast surgery Adjusted for age, number of metastatic sites, use of chemotherapy, endocrine therapy, receptor status Median Overall Survival 4.1 vs 2.4 years, favoring surgery (P = 0.003) Bafford et al. Breast Cancer Res Treat 2009
Impact of Staging and Patient Selection 61 (41%) underwent breast surgery 25 had surgery after diagnosis of stage IV disease 31 had surgery before diagnosis of stage IV disease Median Survival varied significantly based on timing of stage IV diagnosis Post surgery: 4.05 years Pre surgery: 2.4 years No difference seen in survival between presurgery and no surgery groups Bafford et al. Breast Cancer Res Treat 2009
Retrospective Study: Babiero et al. MDACC: 224 patients presented with stage IV disease and intact primary tumor between 1997 and 2002. Median age 52 142 (63%) did not have surgery 82 (37%) underwent surgery 39 (48%) had breast-conserving surgery 43 (52%) had mastectomy Surgery group was younger, had fewer sites of metastatic disease, less nodal involvement; more likely Her2-positive Babiero et al., Ann Surg Oncol 2006
Babiero et al. Overall Survival Progression-Free Survival Babiero et al., Ann Surg Oncol 2006
Update on MDACC Series Longer follow-up (74.2 vs. 32.1 months) Excluded 16 patients from prior analysis N=208 74 (35.5%) underwent breast surgery 33 Breast-conserving surgery; 41 mastectomy 32% received local RT: 9 after BCS, 15 after mastectomy 44 (59.5%) had proven metastatic disease presurgery; 30 diagnosed within 3 months of surgery Lang et al. Ann Surg Oncol 2013
Update on MDACC Series Lang et al. Ann Surg Oncol 2013
Update on MDACC Series Lang et al. Ann Surg Oncol 2013
ECOG-ACRIN 2108 Planned Accrual = 368 Registration may occur at time of diagnosis up to 30 th week of treatment Randomization must occur between week 16 to 32