Radiation and DCIS The 16 th Annual Conference on A Multidisciplinary Approach to Comprehensive Breast Care and Imaging Einsley-Marie Janowski, MD, PhD Assistant Professor Department of Radiation Oncology University of Virginia Health System
Disclosures none
Objectives Participants will understand the etiology behind development of DCIS Participants will understand data regarding the role of radiation in DCIS treatment Participants will learn about multidisciplinary management of DCIS
DCIS Natural History DCIS falls between atypical ductal hyperplasia and invasive ductal carcinoma within the spectrum of breast proliferative abnormalities Low(er) grade: Papillary, Micropapillary, Cribiform High(er) grade: Solid, Comedo DCIS is heterogeneous 70-90% are ER positive If untreated, 30% of DCIS will progress to invasive disease by 10 years High-grade or extensive DCIS progresses to invasive carcinoma at higher rates Factors most important in defining local failure risk Palpable mass, tumor size, histopathologic subtype, nuclear grade, central necrosis, margin status, age <50 years
DCIS Epidemiology In the United States, DCIS incidence markedly increased from 5.8 per 100,000 women in the 1970s to 32.5 per 100,000 women in 2004; it then reached a plateau. This is largely due to the widespread adoption of mammographic screening. DCIS is less common than invasive cancer. The risk of DCIS increases with age. The risk of development of metastases and/or death in a patient with DCIS is very low (<1%). However, invasive breast cancer has been found in 8-43% of resection specimens from patients who were primarily diagnosed with DCIS based on preoperative biopsy. Groen, et al. The Breast 2017; 31: 274-283.
DCIS management
BCT +/- RT for DCIS Trial No. patients Follow-up (years) IBTR (%) (DCIS + invasive) BCS BCS + RT NSABP B-17 818 12 17.2 EORTC 10853 1010 10.5 15.8 UK/ANZ 1030 4.4 12.7 Swedish 1067 5.2 8 32 35 26 30 14 19 23 27 16 20 15 17 6 7 8 12 All showed a reduction in noninvasive and invasive IBTR with 50Gy RT None showed OS benefit Fisher, B, et al. Semin Oncol 2001; 28 (4): 400-418. EBCCG. J Clin Oncol 2006; 24 (21): 3381-3387. Houghton, J, et al. Lancet 2003; 362 (9378): 95-102. Holmberg, L, et al. J Clin Oncol 2008; 26 (8):1247-1252.
DCIS Meta-analysis EBCTCG meta-analysis confirmed RT decreases IBTR by ~50% (HR 0.49) RT lowers 10-yr LR from 28% to 13% (~50% reduction) Benefit in all subgroups, regardless of age, surgery, Tamoxifen, surgical margin, nuclear grade, size, architecture, focality, or method of detection EBCTCG, J Natl Cancer Inst 2010; 41: 162-177.
Survival benefit for XRT and DCIS? SEER analysis of patients with DCIS diagnosed between 1988 and 2007 treated with BCS with or without XRT. There were significant improvements in survival in the XRT group compared with the non-xrt group. These improvements were only observed in patients with higher nuclear grade, younger age, and larger tumor size. The magnitude of the survival difference was significantly correlated with the prognostic score. Sagara, Y. J Clin Oncol, 2016; 34 (11): 1190-1196.
Hypofractionation for DCIS MDACC: women 40 or older with stage 0-2 cancer receiving breast only XRT randomized to: 50 Gy/25 fx + 10-14 Gy/7 fx (n=149) 42.56 Gy/16 fx + 10-12.5 Gy/4/5 fx (n=138) Shaitelman et al. JAMA Oncol. 2015; 1 (7):931-941.
APBI DCIS RAPID Trial San Antonio Breast Cancer Symposium 2018
APBI DCIS B-39 Rapid 24% DCIS 10 year recurrence was 6.5% for WBI and 6% for PBI (NS) 18% DCIS Results from DCIS alone not reported San Antonio Breast Cancer Symposium 2018
Guideline Update Correa, et al., Practical Radiation Oncology, 2017; 7, 73-79
Omitting RT for DCIS? Wong et al: Prospective study (n=158) of grade 1-2 patients with < 2.5 cm tumors treated with WLE w/margins > 1cm; median follow-up 40 months Projected recurrence rate at 5 years = 12% - study closed early (2.4% per patient year). 8 year IBTR 14.4% ECOG 5194: 606 pts w/ low- or intermediate- nuclear grade < 2.5 cm (no necrosis) or high nuclear grade < 1cm w/>3mm margins (50% had >1cm margins). Tamoxifen was allowed mid-way through the trial (30%). Median tumor sizes 6 and 5mm IBTR low/intermediate-grade stratum: 6.1% (5y), 12.4 (12y) IBTR high-grade stratum 15.3% (5y), 24.6 (12y) Hughes, L, et al J Clin Oncol 2009; 27 (32): 5319-5324. Wong, JS, et al. J Clin Oncol 2006; 24 (7): 1031-1036.
RTOG 9804 RCT of 636 women with DCIS s/p BCS +/- RT Inclusion criteria: low/intermediate nuclear grade DCIS 2.5 cm, margins 3mm. Exclusion criteria: palpable disease 5 year IBTR 3.5% in observation arm vs. 0.4% in RT arm (p=0.0023); 7 year 6.7 obs and 0.9 XRT Grade 1-2 toxicities 76% in RT arm vs. 30% in observation arm, Grade 3 toxicities 4% in both arms McCormick B, J Clin Oncol 2015; 33 (7): 709-715.
Oncotype
Oncotype
Tamoxifen: DCIS Trial N F/U LR (%) DCIS + Invasive -Tam +Tam p value NSABP B-24 1,804 5-yr 13.4 8.2.0009 UKCCCR 1,576 4.38-yr median 18 14.0.13 NSABP B-24: small benefit (absolute reduction ~3%) Randomized women wt DCIS s/p surgery + RT to ± tamoxifen Reduction of ipsilateral invasive recurrences, reduction of contralateral in situ recurrences UKCCCR: no benefit when radiation given Randomized women with DCIS 2 X 2 to surgery ± RT ± tamoxifen Breast events: OBS 22% vs TAM 18% vs RT 8% vs TAM + RT 6% Small reduction in DCIS events in NO RT group Fisher, B, et al. Lancet 1999; 353 (9169): 1993-2000. Houghton, J, et al. Lancet 2003; 362 (9378): 95-102.
Aromatase Inhibitors: DCIS Trial N F/U NSABP B-35 3104 5-yr 10-yr LR (%) DCIS + Invasive -AI tamoxifen +AI p value 3.7 10.9 NSABP B-35: benefit in post menopausal women under age 60 to receiving anastrozole compared to tamoxifen Postmenopausal women with hormone positive DCIS s/p R0 lumpectomy and XRT randomized to tamoxifen or anastrozole Reduction of ipsilateral recurrences with anastrozole compared to tamoxifen with longer follow up. There was only a significant interaction between treatment and age for women less than 60. IBIS-II: benefit in postmenopausal women at high risk with AI Postmenopausal women at risk of breast cancer (mostly family history and hormone replacement therapy but 8% had h/o DCIS) randomized to placebo or anastrozole Reduction in both DCIS (mostly high grade) and invasive events with anastrozole 3.7 6.9 0.02 IBIS-II 1920 5-yr 4% 2% 0.0001 Margolese, R, et al. Lancet. 2016; 387: 849-856. Cuzick, J, et al. Lancet. 2014; 383: 1041-48.
On-line tools
Active Surveillance ASCO post
Active Surveillance Groen, et al. The Breast 31 (2017) 274-283.
Active Surveillance The Comet Study
Conclusions If untreated, 30% of DCIS will progress to invasive disease by 10 years. Standard of care treatment is either mastectomy or lumpectomy followed by radiation. High-grade or extensive DCIS progresses to invasive carcinoma at higher rates. There are many tools that may help identify lower risk DCIS. Radiation decreases the risk of local recurrence of both DCIS and invasive cancers by approximately 50%. Hormonal therapy may benefit women at high risk for DCIS and may reduce recurrence risk as a part of DCIS treatment. There is some evidence that low risk DCIS has an acceptably low rate of recurrence so that observation and/or endocrine therapy may also be appropriate treatments. Ongoing randomized trials are looking into active surveillance.
References Correa, et al., Accelerated Partial Breast Irradiation: Executive summary for the update of an ASTRO Evidence-Based Consensus Statement. Practical Radiation Oncology, 2017; 7, 73-79 Cuzick, J, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2014; 383: 1041-48. EBCTCG, Overview of the Randomized Trials of Radiotherapy in Ductal Carcinoma in Situ of the Breast, 2010; 41: 162-177. EORTC Breast Cancer Cooperative Group. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853 a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol 2006; 24 (21): 3381-3387 Fisher, B, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol 2001: 28 (4): 400-418. Fisher, B, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999; 353 (9169): 1993-2000. Groen, et al. Finding the balance between over and under treatment of ductal carcinoma in situ, The Breast 31 (2017) 274-283. Holmberg, L, et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast. J Clin Oncol 2008; 26 (8):1247-1252. Houghton, J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet 2003; 362 (9378): 95-102. Hughes, L, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009; 27 (32): 5319-5324. Margolese, R, et al. Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double blind, phase 3 clinical trial. Lancet 2016; 387: 849-856. McCormick, B, et al. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. Journal of Clinical Oncology 2015; 33 (7): 709-715. Sagara, Y, et al. Patient Prognostic Score and Associations with Survival Improvement Offered by Radiotherapy After Breast- Conserving Surgery for Ductal Carcinoma in Situ: A Population-Based Longitudinal Cohort Study. J Clin Oncol, 2016; 34 (11): 1190-1196. Shaitelman et al. Acute and Short-term Toxic Effects of Conventionally Fractionated vs Hypofractionated Whole-Breast Irradiation: A Randomized Clinical Trial. JAMA Oncol. 2015; 1 (7):931-941. Solin, LJ, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. Journal of National Cancer Institute 2013; 105 (10): 701-710. Wong, JS, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 2006; 24 (7): 1031-1036.