Breast Conserving Therapy for The Treatment of Early Stage Breast Cancer Nicolas Ajkay, MD, FACS Assistant Professor of Surgery Hiram C. Polk Jr. MD, Department of Surgery University of Louisville School of Medicine Director, Breast Multidisciplinary Clinic James G Brown Cancer Center Louisville, Kentucky

Faculty Disclosure Nothing to disclose

Educational Need/Practice Gap Gap = Mastectomy rates are increasing while lumpectomy rates are decreasing. McGuire KP, et al. Ann Surg Oncol 2009 16:2682-2690

Objectives Upon completion of this educational activity, you will be able to: Discuss evidence supporting breast conservation therapy for the treatment of early stage breast cancer. Explain how to apply different surgical techniques to maximize the use of breast conservation therapy. Identify patient and surgeon related factors that increase mastectomy rates.

Expected Outcome Consider offering breast conserving therapy (BCT) for all early stage breast cancer patients.

1970 2016 Radical Mastectomy Nipple sparing mastectomy Breast Conservation therapy

EXTENT OF LOCOREGIONAL THEPARY FOR INVASIVE CARCINOMA WILLIAM STEWART HALSTED BERNARD FISHER, MD Extent of surgery appeared to influence outcome Breast cancer is a systemic disease from inception

No Systemic Adjuvant Therapy (1971-1974) NSABP B-04 Primary Operable Potentially Curable Breast Cancer Clinically Node Negative Clinically Node Positive Halsted Radical Mastectomy (includes axillary dissection) 389 Total Mastectomy + Radiation 386 Total Mastectomy (ALND if recurrence) 384 Halsted Radical Mastectomy (includes axillary dissection) 301 Total Mastectomy + Radiation 305 No Systemic Adjuvant Therapy (1971-1974) Fisher, et al. Cancer 1977;39:2827‐2839

NSABP B-04 No SS difference in distant disease free survival or overall survival for N- and N+ (25 year follow up). Fisher, et al. New Engl J Med 2002;347:567‐575

NSABP B-06 N+ : Melphalan and 5-FU (1976-1984) Clinical tumor size <4.0 cm, LN+/- (N=2163) Mastectomy + Axillary dissection (Radical Mastectomy) Lumpectomy + Axillary dissection Lumpectomy + Axillary dissection XRT N+ : Melphalan and 5-FU (1976-1984) Mastectomy if lumpectomy margins positive Negative margins = “no ink on tumor” Fisher, et al. New Engl J Med 2002;347:1233-41

NSABP B-06 Ipsilateral breast recurrence (at 20 years of FU): Lumpectomy alone: 39.2% Lumpectomy +XRT: 14.3% Mastectomy: 10.2% Cumulative incidence of 1st. ipsilateral rec. Fisher, et al. New Engl J Med 2002;347:1233-41

Fisher, et al. New Engl J Med 2002;347:1233-41 NSABP B-06 No significant differences in DFS, DDFS or OS between mastectomy and lumpectomy with or without XRT, despite differences local control. Fisher, et al. New Engl J Med 2002;347:1233-41

Breast Conserving Therapy BCT (lumpectomy and radiation) is the preferred local therapy for early stage breast cancer. Issues: Margins Localizing non palpable disease Poor breast to tumor ratio Adjuvant radiation

Mastectomy vs.. Breast Conservation Prospective, Randomized Trials Comparing Mastectomy and Axillary Dissection to Breast-Conservation Therapy

LUMPECTOMY MARGINS Margins meta-analysis: 33 studies (1965 – 2013) 28,162 patients (1,506 had local recurrence) Odds ratio for Local Recurrence: OR 1.96 for positive/close vs.. negative; (p < 0.001) Margin distance : >0 mm vs.. 1 mm (referent) vs.. 2 mm vs.. 5 mm (p = 0.12) Houssami, et al. Ann Surg Oncol. 2014 Mar;21(3):717-30

LUMPECTOMY MARGINS SSO-ASTRO CONSENSUS GUIDELINES “The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.”

“NO INK ON TUMOR” CONSENSUS Positive margins (ink on tumor) are associated with a two-fold increase in the risk of IBTR compared to negative margins. Increased risk is not mitigated by favorable biology, endocrine therapy or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR, specially for: Young patients Unfavorable biology Lobular cancers Extensive intra-ductal component.

EFFECT OF MARGINS CONSENSUS GUIDELINE ON RE-EXCISIONS Variable Pre consensus (n=124) Post consensus (n=42) p value Re-excisions, n (%) 40 (32%) 1 (2%) <0.0001 Lumpectomy, n 27 (22%)   Mastectomies, n 13 (10%) Heidrich et al, ASBS 2016

LOCALIZING NON-PALPABLE TUMORS Wire localized lumpectomy Radioactive seed localized lumpectomy

RADIOACTIVE SEED LOCALIZATION Radioactive I125 impregnated titanium seed Implanted1-5 days prior to surgery Detected with SLNB probe (I125) Less severe pain Increased convenience for patients No differences in volume of lumpectomy specimen or rate of positive margins Improves surgical scheduling Bloomquist, E et al. Breast J. 2016 Mar-Apr;22(2):151-7, ASBS 2014

INTRAOPERATIVE ULTRASOUND AND SPECIMEN RADIOGRAPHY

ONCOPLASTIC SURGERY

Neoadjuvant Chemotherapy and Endocrine Therapy MRI pre Neoadjuvant chemotherapy Clip MRI post Neoadjuvant chemotherapy

LUMPECTOMY WITH/WITHOUT XRT XRT decreases the risk of local recurrence after lumpectomy by 2/3

EFFECT OF RADIOTHERAPY ON BREAST CANCER SURVIVAL One breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, 1:4 EBCTCG, Lancet. 2005;366(9503):2087-2106 (meta-analysis)

Radiation therapy is time intensive: WBI = 6.5 weeks of daily treatment

ALTERNATIVES TO WHOLE BREAST IRRADIATION Hypofractionation: Canadian Protocol (6 vs.. 4 weeks) 50/25 vs.. 42.5/16 Gy, 1234 patients T1,T2,NO No difference in LR, OS,DFS or cosmetic outcome. Accelerated Partial Breast Irradiation: (1week BID) Whole breast vs.. APBI NSABP B-39 – ONGOING Whole breast 42.5/16 vs.. 3D-CRT APBI 38.5/10 BID RAPID No difference in local control with worse cosmetic outcome Intraoperative Radiation Therapy: (1 dose 21Gy) WBI vs.. IORT: TARGIT (1.3 vs.. 3.3%, p=0.042, 5 years FU) ELLIOT (0.4 vs.. 4.4%, p<0.001, 5 years FU) Higher local recurrence with IORT, no difference in survival.

CALGB 9343 – Avoidance of XRT >70 yo T1N0 ER(+) BCT (-) Margins N=636 1994-99 Tamoxifen + XRT 317 Tamoxifen 319 10 year FU 2% LRR, OS 67% 10% LRR, OS 66% 0% AxR (no ALND) 3% AxR (no ALND) Hughes et al, J Clin Onc 2013; 31:2382-87

BREAST MRI Sensitivity for invasive cancer 88-95%, specificity 37-97%.

Breast MRI for newly diagnosed BC Randomized controlled trials: COMICE: MRI vs.. no in breast cancer treated with lumpectomy. No difference in re-excision rates (19% for both groups). MONET: MRI vs.. no in non palpable breast cancer. Increased re-excision rate in MRI group (34 vs.. 12%). Meta-analysis of the effect of preoperative MRI vs. standard preoperative assessment MRI significantly increases mastectomy rates. No difference in re-excision rates (11% for both groups) Houssami et al, Ann Surg 2013

BREAST MRI FOR NEWLY DIAGNOSED BREAST CANCER Retrospective study of 756 women (30% had MRI). No difference in RFS (3% with MRI vs.. 4% without MRI) or OS (94% vs.. 95%) at 8 years. Solin et al, JCO 2008:26(3):386-91

Time Interval (TI) From Diagnosis to Surgery Median TI increased from 2011-2015 compared to 2006-2010 (35 vs.. 30 days, p <0.001). Independent predictors of TI >30 days included patients undergoing mastectomy (with or without reconstruction), MRI use, and age. Patient demographics, tumor biology and stage do not influence TI, while choice of surgery and MRI use are associated with longer TI. Mariella et al, SSO 2016

THANK YOU nicolas.ajkay@louisville.edu