1. 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

2. 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?

3. 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:

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

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

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

7. 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

8. 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:

9. 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

10. 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

11. 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

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

13. 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

14. 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

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

16. DCIS: NSABP B-24 Role of Tamoxifen
Fisher, B, Lancet 353: , 1999

17. 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

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

19. 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:

20. 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

21. 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)

22. 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

23. 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

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

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

26. 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

27. 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

28. 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.

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