Ductal Carcinoma In Situ (DCIS) JoAnne Zujewski, MD Head, Breast Cancer Therapeutics Clinical Investigations Branch Cancer Therapy Evaluation Program Division of Cancer Diagnostics and Treatment May 2011

Questions How DCIS differs from Stage 1 breast cancer Types of DCIS that affect prognosis of DCIS/development of breast cancer Standard of Care: surgery, radiation risks of under-treatment and overtreatment Can we improve diagnosis through MRI and sentinel lymph node biopsy?

Pathobiologic Events Associated with DCIS Figure 1. Pathobiologic Events Associated with Ductal Carcinoma in Situ. The molecular, cellular, and pathological processes that occur in the transformation from healthy tissue to preinvasive lesions, such as ductal carcinoma in situ, to breast cancer are shown. The majority of the changes that give rise to cancer, including the accumulation of genetic changes, oncogene expression, and the loss of normal cell-cycle regulation, appear to have occurred by the time ductal carcinoma in situ is present. Most of the clinical features of a subsequent invasive breast cancer are already determined at this stage, although additional events, including tissue invasion and changes in the surrounding stroma, characterize the invasive tumor. Burstein H et al. N Engl J Med 2004;350:1430-1441

Rosen’s Breast Pathology, 1997 DCIS: Pathology Comedo Cribiform, High grade Solid, Low grade Rosen’s Breast Pathology, 1997

DCIS: actin Stain of Myoepithelium Rosen’s Breast Pathology, 1997

SEER Breast Carcinoma in situ 5-year Survival : 1992-1999 All < 50 50+ 100.0 99.9 White Black 99.5

Survival DCIS: RCT NSABP B17 EORTC UKANZ CTG NSABPB24 N 813 1002 1694 1798 Mets 17 (2.1%) 24 (2.4%) 11 (0.6%) Breast Deaths 27 (3.3%) 15 (1.5%) 23 (1.4%) 15 (0.8%) Years F/up 10.8 4.3 4.4 6.9

Natural History 25 cases untreated with 16 yrs follow up 28% developed invasive cancer 11 fold increase in relative risk to controls Contralateral relative risk 2-3 Page et al Cancer 1985;55:2698-708

Role of Total Mastectomy Year No. cases % mortality Ashikari 1971 182 0.9 Rosner 1980 2.0 Farrow 1970 181 Silverstein 1996 228 Bradley 1990 588 1.7

Surgery Mastectomy has not been compared to BCT in randomized trials of DCIS Breast cancer deaths within 10 years after the diagnosis of DCIS occurs in 1-2% of all patients, irrespective of surgery type

RATIONALE FOR RADIATION TREATMENT AFTER LUMPECTOMY FOR DCIS All reported randomized trials show that radiation reduces the rate of local recurrence after lumpectomy by about half “[P]atients who may avoid radiation therapy have not been reproducibly and reliably identified by any clinical trials.” (1999 DCIS Consensus Conference Statement, Cancer, 2000) Slide courtesy of L. Solin

Oxford Overview of Randomized Trials of BCS±RT for DCIS Presented NIH DCIS Conference, 2009 Darby, JNCI Monograph, 2010

ECOG STUDY E5194 (n = 670) Registration of small DCIS after wide excision alone Negative margin width > 3 mm Tamoxifen optional Two arms (not randomized) Grade 1-2, non-comedo, size < 2.5 cm Grade 3, comedo, size < 1.0 cm

ECOG E5194: EXCISION WITHOUT RADIATION (+/-TAM) High grade Low or intermediate grade 2 4 6 8 0.0 0.05 0.15 Ipsilateral (43 events/ 572 cases) Contralateral (18 events/ 572 cases) 6% 4% 15% Low/intermediate grade stratum breast events Ipsilateral breast events 52% invasive +/- DCIS, 49% DCIS only Contralateral breast events 61% invasive +/- DCIS, 39% DCIS only No SS difference in univariate analysis wrt intention to take TAM, margin >=10mm vs. <10mm by inst. Or CPR Size? Age? Year Hughes, JCO, 2009

LOCAL FAILURE ACCORDING TO PATHOLOGY Lumpectomy plus radiation Lumpectomy alone Solin, JCO, 1996 Slide courtesy of L. Solin Balleine, Clin Cancer Res, 2008

DCIS: NSABP B-24 Role of Tamoxifen Fisher, B, Lancet 353:1993-2000, 1999

DCIS: NSABP B-24 Median follow-up 7 years placebo tamoxifen P-value All breast cancer 145 16% 84 9.3% ipsilateral 100 11.1% 72 7.7% 0.02 Contra-lateral 45 4.9% 25 2.3% 0.01 survival 95% 5.2% absolute risk reduction in all breast cancer on tamoxifen 40% relative risk reduction 16% had SM+ Fisher, B et al, Semin Oncol 28:400-18, 2001

NSABP B-24: Conclusions Tamoxifen decreases risk of breast cancer events by 40% No difference in overall survival

The Risk of Ipsilateral or Contralateral Breast Tumor for Patients with DCIS Treated with Excision Alone; Excision and Radiotherapy; Excision, Radiotherapy, and Tamoxifen; or Excision, Radiotherapy, and Placebo Figure 3. The Risk of Ipsilateral or Contralateral Breast Tumor after Surgical Excision among Patients with Ductal Carcinoma in Situ Who Were Treated with Excision Alone; Excision and Radiotherapy; Excision, Radiotherapy, and Tamoxifen; or Excision, Radiotherapy, and Placebo. The overall risk, the risk of invasive cancer, and the risk of noninvasive cancer are shown. Data are from combined analyses of the National Surgical Adjuvant Breast and Bowel Project B-17 and B-24 trials. Adapted from Fisher et al.43 with the permission of the publisher. Burstein H et al. N Engl J Med 2004;350:1430-1441

DCIS: Conclusions Local therapy Systemic therapy: Tamoxifen Mastectomy Breast Conserving Surgery plus radiotherapy Consider omission if Short lifespan Sever co-morbidities Systemic therapy: Tamoxifen “Prevention” intervention Consider individual risk/benefits

What about lymph nodes? Axillary lymph node involvement is <1% therefore axillary lymph node dissection is not recommended Sentinel lymph node biopsy? Not recommended due to low risk of disease unless performing a mastectomy (in the chance that invasive disease is found) Consider: extensive high grade DCIS or palpable mass (increased chance of invasive disease being found)

Potential Benefits SLNB at time of definitive surgery avoids 2nd operation in 2-21 % of patients who have IDC at definitive surgery May identify subset of patients who would benefit from systemic therapy

Risks of SLNB in DCIS Increase anxiety: curable prognosis to one that is life-threatening SLNB risks infection, bleeding, seroma, paresthesias, anaphylaxis, lymphedema (3%) Risks of full ALND in up to 13% Risks of systemic chemotherapy ? Public health costs

Mammography is the current standard for detection of DCIS, MRI could help improve the ability to diagnose DCIS, especially in high-grade DCIS

DCIS: Calcifications Cannot be diagnosed as non-invasive with cytology Irregular clusters Branching (comedo)

Mass, heterogeneous and rim enhancement, spiculated margins MRI: Contrast required…..spatial resolution improves morphologic assessment Mass, heterogeneous and rim enhancement, spiculated margins DCIS consensus conference. C. Lehman

DCIS diagnosed in high risk patient on screening MRI with negative screening mammogram Fine linear, branching NMLE in ductal distribution DCIS consensus conference. C. Lehman

ACR-ASS-CAP-SSO 2006 practice guideline The role of other image modalities, especially MRI, has yet to be established in DCIS. Berg found that MRI was more sensitive than mammography and sonography in detecting DCIS; however, disease extent was overestimated in 50% of involved breasts. The impact of MRI on clinical outcomes such as local recurrence in the preserved breast remains to be demonstrated.

KEY QUESTIONS FOR THE MANAGEMENT OF DCIS Courtesy of L. Solin 2010