1. Ductal Carcinoma In Situ: Where Are We Now?
Julie Lang, MD, FACS
Assistant Professor of Surgery and BIO5
Director of Breast Surgical Oncology
University of Arizona

2. What is ductal carcinoma in-situ (DCIS)?
Non-obligate precursor lesion of invasive ductal carcinoma
Stage 0 breast cancer
No invasive through basement membrane
Molecular distinctions from invasive ductal carcinoma surprisingly difficult to identify
The problem: science and medicine cannot reliably distinguish aggressive DCIS from non-aggressive DCIS
Allegra JNCI 2010
Kuerer et al, JCO 2008

3. What is ductal carcinoma in-situ (DCIS)?
Non-invasive Breast Cancer
Pre-invasive Breast Cancer
Intraductal Carcinoma
Pre-cancer
Allegra JNCI 2010
Kuerer et al, JCO 2008

4. Epidemiology Incidence of ~ 50,000 new cases per year in United States
More than ½ million patients alive with diagnosis of DCIS in United States
Long term distant disease free survival for DCIS is 96-98%
Not immediately life threatening but associated with increased risk of invasive breast cancer
Allegra JNCI 2010
Kuerer et al, JCO 2008

5. Wellings-Jensen model of breast cancer evolution

6. Sontag and Axelrod model of progression of DCIS and IDC
Parallel model of progression of DCIS and IDC
DCIS is not a progenitor of IDC, but rather both diverge from a common progenitor
Results of computer simulation and mathematical modelling compared to clinical observations
Kuerer et al, JCO 2008
Sontag and Axelrod, J Theor Biol 2005

7. Diagnosis 20 years ago +: frequently palpable
Modern era: frequently calcifications on mammogram
Rarely may be etiology of nipple discharge
May be associated with Paget’s disease of nipple
Often associated with concurrent invasive component (11-25%)
20% of newly diagnosed cancers are DCIS
Marker for development of invasive breast cancer
Allegra JNCI 2010
Kuerer et al, JCO 2008

9. Screening Mammography
Screening mammography detected a four-millimeter, nonpalpable invasive ductal carcinoma, identified by the white arrow on the left (it is enlarged with a coned view in the small box). On the screening mammogram on the right, obviously malignant calcifications can be seen.
Invasive cancer (4 mm)
Malignant microcalcifications

10. Diagnosis Mammography often underestimates the extent of disease
High grade lesions are generally contiguous, however, more than 50% of low to intermediate grade lesions are multifocal
While breast MRI has high sensitivity for DCIS, it lacks specificity because of poor discrimination between benign proliferative disease and DCIS.
Kuerer et al, JCO 2008

11. Diagnosis
DCIS is usually diagnosed as mammographically suspicious pleomorphic microcalcifications
Tissue diagnosis is usually obtained by stereotactic core needle biopsy
Rarely, DCIS may be palpable, which is associated with more aggressive biology – ultrasound guided or stereotactic core biopsy

12. Do all DCIS patients treated by lumpectomy need radiation therapy?
Treatment
BCS is the most common surgical treatment for DCIS in the United States (30% mastectomy, 30% BCS alone, 40% BCS with radiation therapy)
Do all DCIS patients treated by lumpectomy need radiation therapy?
Baxter et al, JNCI 2004

13. Prospective randomized trials testing excision followed by radiation for DCIS
Study N
Median follow up (months)
IBTR Excison, %
IBTR Excision + Radiation, %
NSABP B17
813
128 32 16
Eortc 10853
1010
126 26 15
UK Trial
1030 53 14 6
SweDCIS
1046 96 27 12

14. Radiation following Excision for DCIS
RT reduces ipsilateral breast tumor recurrence 50-60% - persists with long term follow-up
Approximately 50% of recurrences after excision alone are invasive and 50% are DCIS
RT reduces both invasive and DCIS recurrences by approximately 50-60%
With RT, annual rate of an invasive recurrence is 0.5%-1% per year
No subgroup failed to benefit from RT

15. Early Breast Cancer Trialists’ Collaborative Group
Meta-analysis of all 4 RCTs of DCIS
N=3729 women
Radiotherapy reduced absolute 10 year risk of any ipsilateral breast event by 15.2%
Effective regardless of age, extent of BCS, use of tamoxifen, method of detection, margin status, focality, grade, comedonecrosis, archtecture or size
Proportional reduction in IBE greater in women >=50 years of age
EBCTCG, JNCI 2010

16. ECOG 5194: Local Excision Alone Without Irradiation for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Cooperative Oncology Group
Hughes L et al, JCO 2009

17. Eligibility: non-palpable DCIS 3mm or larger treated with BCS with margins of at least 3mm
Cohort 1: low or intermediate grade DCIS 2.5 cm or smaller
Nuclear grade 1 or 2 with limited or no foci of necrosis
Cohort 2: high grade DCIS 1 cm or smaller
Nuclear grade 3 atypia and comedo-type necrosis that was zonal
● Post-operative mammography required for patients presenting with suspicious microcalcifications; patients with residual suspicious calcifications were ineligible.
● Central pathology review performed for 97% of cases with sequential sectioning of complete specimen for margin assessment and lesion size assessment.

18. ECOG 5194
Hughes L et al, JCO 2009

19. Hughes L et al, JCO 2009

20. Hughes L et al, JCO 2009

21. Low-intermediate grade DCIS
Hughes L et al, JCO 2009

22. High grade DCIS
Hughes L et al, JCO 2009

23. Conclusions
IBE rate of 6% for low-intermediate grade DCIS is acceptable (Note careful selection criteria)
Although 4 RCTs demonstrated advantage of Excision +RT over Excision alone for DCIS, none found difference in overall survival, distant metastasis or breast cancer specific survival – in contrast to invasive breast cancer
Substantially longer follow-up time is warranted to evaluate outcomes of DCIS treated by excision without RT
Hughes L et al, JCO 2009

24. APBI and DCIS ASBS Mammosite Registry
194 patients with pure DCIS treated with Mammosite
Median follow-up 54.4 months
IBTR 3.1%
92% favorable cosmetic results
Pure DCIS <= 3cm is in ASTRO APBI “cautionary” group
Smith et al, Int J. Rad Onc Biol. Phys. 2009
Jeruss et al, Annals of Surgical Oncology 2011

25. Role of Tamoxifen in DCIS NSABP B24
All patients treated with lumpectomy (E) + RT
Patients randomized to Tamoxifen vs Placebo
Assessed breast cancer events (ipsilateral (IBTR), contralateral; DCIS vs invasive)
Only 25% of DCIS is ER negative
Fisher et al, Lancet 1999

26. Role of Tamoxifen in DCIS
NSABP-B24 evaluated addition of tamoxifen to lumpectomy plus radiation therapy (median follow up 82 months)
IBTR
Invasive IBTR
DCIS IBTR
Contra
Lateral events
All events
E + RT (n=899)
18.4 9
9.4
8.3
28.2
E +RT + T (n=899)
12.8
4.8 8
4.4
17.7 RR
0.69
0.53
0.85
0.63
P value
0.02
0.01 NS
0.0003

27. NSABP B24

28. Treatment
Mastectomy is curative in 98-99% of patients with DCIS but without IDC
Segmental mastectomy (lumpectomy) plus radiation is reasonable for small fields of DCIS
No prospective randomized trial has compared treatment of DCIS by mastectomy with treatment by breast conserving surgery
Necessary to do sentinel node dissection if planning mastectomy for DCIS

29. Case
68 year old female found to have 6cm span of suspicious microcalcifications on screening mammogram
Multiple co-morbidities including DM and morbid obesity; very frail
Stereotactic core biopsy upper outer quadrant: DCIS, solid type, ER 90%, PR 80%, Ki67 <5%.
Subareolar core biopsy also shows DCIS
Strongly motivated to have BCS

32. Case
Oncoplastic radially oriented segmental mastectomy with sentinel node
Sentinel node positive on frozen section, immediate ALND performed

33. Case
1cm IDC, ER Greater than 95% cells, PR greater than 85%, HER2 0+, Ki-67 index: 20%
DCIS high grade, multifocal (largest foci 8 mm), margins negative
3/18 lymph nodes positive
Recurrence Score 19 (intermediate range)
Treated with radiation therapy and aromatase inhibitor

34. Predictors of Invasive Component – Indicating Need for SLN Dissection
DCIS patients to be treated by mastectomy
Large lesion size (>5 cm)
Palpable mass lesion
High Grade
Cancerization of lobules
Yi et al, Am J. Surgery 2008
Huo et al, Cancer 2006

35. Margin Assessment Margin Assessment in DCIS notoriously problematic
Rates of re-operation for margin control 21-70% for BCS, largely due to DCIS
Most centers agree that a 2mm or greater negative margin Is adequate but no universal agreement

37. Margin Assessment with photodynamic detection in cell lines
Fluorescence confocal microscope imaging of the four cell lines treated with 250µg/ml ALA and 0µg/ml ALA
Conley et al, Lang laboratory

38. Margin assessment with photodynamic detection in cell lines
Conley et al, Lang laboratory

39. Standard prognostic biomarkers in premalignant breast lesions

40. Nearly 50% of cases show 2 or more areas with different nuclear grades, which is probably an underestimate since <1% of the tumor was analyzed in this study by Allred et al (n=120).

41. Pure DCIS shows a broad distribution of histological differentiation
Pure DCIS shows a broad distribution of histological differentiation. Nearly all well differentiated DCIS is ER positive and PR positive. Receptor positive cases decline to about 20% in the most poorly differentiated. DCIS shows a similar distribution of intrinsic subtypes luminal, basal and ERB2 subtypes as IDC

42. Diversity of histological nuclear grades, biomarkers and intrinsic subtypes within individual cases of DCIS (n=120). Allred et al, 2008 Cancer Research. Nearly 50% of cases showed 2 or more areas with different nuclear grades, nearly 1/3 showed internal diversity of biomarkers when comparing areas with different nuclear grades. All of this diversity shows there is considerable placticity during tumor progression, presumably different areas would compete for dominance and eventually the most aggressive would prevail

43. Biomarkers and Risk of Subsequent Breast Cancer in DCIS
DCIS patients with high breast density treated with BCS followed by radiation had a 3 fold increased risk of contralateral invasive disease, compared with those with low density.
Risk of invasive recurrence was highest among those with palpable DCIS or with positive expression of the immunohistochemical biomarkers p16, cyclooxygenase 2 (COX2) and Ki67
Hwang et al, Cancer Epidemiology, Biomarkers and Prevention 2007
Kerlilowske et al, JNCI 2010

44. Conclusions
We cannot reliably distinguish aggressive DCIS from non-aggressive DCIS – this is an area of active investigation
RT reduces both invasive and DCIS recurrences by approximately 50-60% after lumpectomy
Substantially longer follow-up time is warranted to evaluate outcomes of DCIS treated by excision without RT
Variable nuclear grades, ER/PR/HER2 phenotypes and intrinsic subtypes often existed within the same lesion.

45. Conclusions
Risk factors for local recurrence include: high grade lesions, comedonecrosis, age, palpable disease, tumor size and positive surgical margins
Tamoxifen is only FDA approved adjuvant systemic agent for preventing recurrence in DCIS – NSABP B-35 evaluating AI in DCIS