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 nonaggressive 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
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
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 DCIS
IBTR
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
0.53
0.63
P value
0.02
0.01
NS
0.01
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
Alessi, Janet S
00168971
10/11/1942
66 YEAR
F
RCC
Alessi, Janet S
00168971
10/11/1942
66 YEAR
F
Screen Save
SAS
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GE MEDICAL SYSTEMS
Senograph 2000D ADS_17.5
PM392_03
9/24/2009, 10:08:20 AM
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GE MEDICAL SYSTEMS
Senograph 2000D ADS_17.5
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Z: 0.45
C: 2383
W: 900
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W : 900
Study:CAD not performed
Study:CAD not performed
TUCSON BREAST CENTER RM # 4
2028 E PRINCE ROAD
TUCSON, AZ 85719
TUCSON BREAST CENTER RM # 4
2028 E PRINCE ROAD
TUCSON, AZ 85719
Page: 1 of 1
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IM: 1 SE: 8089
IM: 4117 SE: 18089
Alessi, Janet S
00168971
10/11/1942
66 YEAR
F
RCC
346
BIOPTICS
Bioptics Inc
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--9/24/2009, 2:01:34 PM
Z: 0.33
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Study:CAD not performed
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UMC
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IM: 1 SE: 1
Case
Alessi, Janet S
00168971
10/11/1942
67 YEAR
F
RCC
• Oncoplastic radially
oriented segmental
mastectomy with
sentinel node
• Sentinel node positive
on frozen section,
immediate ALND
performed
TLP
aws4
GE MEDICAL SYSTEMS
Senographe Essential ADS_43.10.1
PL102_05
7/15/2010, 11:36:09 AM
Z: 0.33
C: 2917
W: 900
Study:CAD not performed
Page: 1 of 1
cm
Tucson Breast Center #12
2028 E Prince Road
Tucson,
AZ 85719
IM: 1 SE: -25694
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
Modern Day Pathology Only Estimates
The Surgical Margin
•Carter et al
estimated needed
3,000 sections
through a 2cm
tumor to accurately
assess the margins
•Pathology
assesses ~ 1/1000 of
the margin
Carter D. Margins of “lumpectomy” for breast
cancer. Human Pathology 1986;17:330-333.
Courtesy of Dr.
Suzanne Klimberg
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
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