Disclosures Nothing relevant to report. 1 Defining the Problem 5% - PDF document

CON: Removal of the Breast Primary in Patients with Metastatic Breast Cancer Amelia B. Zelnak, MD, MSc Assistant Professor of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Disclosures • Nothing relevant to report. 1

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 Rationale for Local Therapy PRO – 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 2

Proof of Principle: The kidney SWOG 8949 (N=241) EORTC 30947 (N=75) Nephrectomy + Nephrecto IFN ‐ Alfa2b IFN ‐ Alfa2b my + IFN ‐ (months) (months) IFN ‐ Alfa2b Alfa2b Median Survival 8.1 11.1 (months) (months) Performance Status 0 11.7 17.4 Median Survival 7 17 Performance Status 1 4.8 6.9 Lung only 10.3 14.3 Other 6.3 4.2 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 3

Khan et al. Mean Survival Surgical Therapy 3 Year Survival (months) Overall 24.9% 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? 4

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. No. Hazard Surgery Patients 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? 5

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 • (medain 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, used of Median Overall Survival 4.1 vs 2.4 chemotherapy, endocrine years, favoring surgery (P = 0.003) therapy, receptor status Bafford et al. Breast Cancer Res Treat 2009 6

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 7

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 8

Update on MDACC Series Lang et al. Ann Surg Oncol 2013 Update on MDACC Series Lang et al. Ann Surg Oncol 2013 9

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 10