Dilemma in management of DCIS Julia Tchou, M.D., Ph.D. Abramson Cancer Center Rena Rowan Breast Center Department of Surgery University of Pennsylvania

96-98% of women with DCIS are cured with local therapy, yet … The Dilemma of DCIS 96-98% of women with DCIS are cured with local therapy, yet … Local recurrence rate after BCT of DCIS is ~ 2 fold higher than Invasive cancer. When I see patients in clinic, I often told my patients that it is counterintuitive to think of DCIS having a higher local recurrence rate than when we are treating invasive cancer. Local recurrence rate after BCT 3-4% in 5 years (Solin MRI paper in JCO) But the local recurrence rate is around 5 – 9 % in 5 years of DCIS Why? I think we should improve risk stratification

Standard Treatment in DCIS • Mastectomy • Excision + RT • Excision + Tamoxifen The need for adding RT after excision to maintain locla control in patients with DCIS has remained uncertain. (Harris J and Morrow 2009) Which Rx for which patient?

Key questions in management of DCIS Can we identify a subset of patient not benefiting from radiation therapy? What is an adequate margin? Leaving out other questions Is Sentinel node biopsy necessary When is mastectomy indicated Is partial breast radiation ready for prime time?

Survival in DCIS by Treatment L+RT B17 L+RT+TAM EORTC M B17; EORTC % Deaths Breast Ca Prognosis is extremely good whether the woman has undergone lumpectomy alone vs. lumpectomy with radiation (yellow lines). The NSABP B17 results are almost superimposable with the results of the european DCIS trial. Breast cancer death ranges from 0.5 to 3% not significantly different European Organixation for resarch and treatment of cancer EORTC EORTC 10853, Randomized controll trial 1986 -1996 1010 women 10 year follow up, LE local excisiom 503 vs LE + RT 507, no boost, , margins not free < = 1 mm 4.4 % death rate median FU 10 years 10 year LR for LE 26%, LE with RT 15%, B17 LE +/- RT, 8 year follow up, LE 403, LE + RT 411 B24 B24 Years

Effects of XRT on survival However, survival beniefit for radiation after excision in patients with invasive breast cancer has clearly established as It is hard not to extrapolate the survival benefit after excision of invasive cancerof XRT (Morrow M 2009 JCO) EBCTCG meta-analsyis, Lancet 2005

Key Management Concepts in DCIS Prevention of local recurrence (invasive and noninvasive) is a major goal of the treatment of DCIS The use of RT reduces LR in DCIS

Can we identify a subset of patient not benefiting from RT?

Can DCIS be treated by excision alone? Study LE alone LE + XRT Tamoxifen use Margins IBT rate NSABP B-17, 1998 403 411 no free 27% vs. 12% at 8 years UK Trial, 2003 508 522 yes 20 % vs. 10% at 5 years EORTC 10853, 2006 503 507 26% vs. 15% at 10 years Harvard, 2006 158 1 cm 12% at 5 years ECOG, 2009 565 3 mm 6.1% vs. 15% (5 year rate) 3 randomized control trials to look at whether DCIS can be treated by excision alone showed that local recurrence rate is significantly higher. NSABP Fisher F JCO 1998 UK trial: Lancet 2003 (estimate LR rate from Figure 4) European EORTC Bijker N 2006 2 subsequent and contemporary trials (prospective, single arm) looked at the local recurrence rate in low risk DCIS, less than 2.5 cm with good margins but Harvard: Wong JS JCO 2006, trial expected to accrue 200 patients but stopped early as the IBT recurrence rate has exceeded the stopping boundary 8 local recurrence in 200 patients. DCIS needs to be less than 2.5 cm with grade 1 or 2 DCIS. Necrosis is not a factor for exclusion. Patient may be undergoing first excision from another hospital and then re-excision – pathology assessment may not be as complete. ECOG: Hughes LL JCO 2006: median f/u of 6.2 years, ECOG only includes DCIS less than 2.5 cm stratified by low/intermediate grade vs. high grade 2 cohorts – low or intermdiate histologic grade DCIS 2.5 cm or smaller; the second consisted of high grade DCIS 1 cm or smaller. The surgical specimen were serially sectioned and completely embedded at the trating institution to determin size grade and margins. Central path review by david page.

Local recurrence risk stratification ECOG – < 2.5 cm Grade I & II DCIS EORTC – no subgroup does not benefit from radiation VNPI - Silverstein The EuropeanThere is not a subgroup that does not benefit from RT Bijker, N. JCO 2006;24:3381

Van Nuys Prognostic Index Silverstein, M 2003

Local recurrence free survival Silverstein M 2003

Outcome in DCIS Patients with Low VNPI Low VNPI (3 or 4) Silverstein de Mascarel # patients 101 195 Local recurrence 2% 9% Invasive 0 50% Br Ca Res Treat 2000 The very low recurrence rate seen by Silverstein is not duplicated in other study. Retrospective analysis of 195 cases of DCIS using the pathology assessment VNPI Median f/u in this French study (Bordeaux) 71 months. (1971-1995) the specimen was sectioned every 2 mm and embedded enirely

Is there a DCIS subgroup that does not benefit from XRT? Age Margins (uniform and meticulous assessment not done in randomized trials) VNPI score 4, 5 or 6 Low grade DCIS Biomarkers for risk stratification Utility of MRI in preoperative assessment (JNCI consensus statement, 2009) Morrow M 2008