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

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

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

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

Wellings-Jensen model of breast cancer evolution

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

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

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

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

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

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

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

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

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

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

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.

ECOG 5194 Hughes L et al, JCO 2009

Hughes L et al, JCO 2009

Hughes L et al, JCO 2009

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

High grade DCIS Hughes L et al, JCO 2009

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

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

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

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

NSABP B24

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

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

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

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

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

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

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

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

Standard prognostic biomarkers in premalignant breast lesions

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).

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

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

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

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.

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