Ductal Carcinoma In Situ - Stanford Hospital & Clinics

Evolving Standards for
In Situ Cancer
Treatment, Outcomes and Innovation in DCIS
Irene Wapnir MD
Chief of Breast Surgery
Associate Professor for Surgery

Outline
• Changing epidemiology
• Mammographic screening and other breast
imaging modalities
– The utility of MRI
• Surgical treatment
• Retrospective analyses are usually perceived as
“exploratory” or “hypothesis-generating” studies
• Evidence-based outcomes with breast
conserving approaches
• Innovations in Mastectomy treatment

Innovations in Surgery for DCIS
• Ductoscopy : a surgical tool
– In patients with nipple discharge/detection of
DCIS
– To delineate nipple-side extent of DCIS
• Central Lumpectomy
• Skin-sparing mastectomies
– Nipple-sparing
– Intraoperative evaluation of skin perfusion
• Partial Breast Irradiation
– Intraoperative or post-operative approaches

Pathological definitions remained unclear
until 1970s
Not an obligate
precursor of
invasive DCIScancer
Benign Malignant

September 22-24, 2009
… a risk factor for
invasive breast cancer

NIH DCIS Consensus Conference 2009
…the diagnosis and management of DCIS is
highly complex with many unanswered
questions, including the fundamental natural
history of untreated disease.
Because of the noninvasive nature of DCIS,
coupled with its favorable prognosis, strong
consideration should be given to elimination of
the anxiety-producing term “carcinoma”…

Synonyms
• Intraductal carcinoma
• Non-invasive, or non-infiltrating
• Comedocarcinoma
• Pre-invasive carcinoma
• Ductal carcinoma in situ

TYPES OF DCIS
Comedo /high grade Low grade/ cribriform Low grade/ solid
Micropapillary low gr
Low gr papillary
X
Microinvasion in
DCIS
Allred C, 2009 NIH-DCIS Consensus Conference

DNA Microarray Subtypes in Pure DCIS
Similar to IDC
Allred D C et al. Clin Cancer Res 2008;14:370-378

Magnitude of Problem
• ~ 20-25% new BCs
2009______
• 62,280 DCIS
• 192,370 IBC
• By 2020 1 million
survivors

35% increase
500% increase

Age-adjusted incidence rates of different histological types of in situ
breast carcinoma among women ages >=30 years, 1980 to 2001
Li, C. I. et al. Cancer Epidemiol Biomarkers Prev 2005;14:1008-1011
Copyright ©2005 American Association for Cancer Research
SEER Registry Data
All
noncomedo
Comedo DCIS
LCIS

The goal of treating DCIS remains
Prevention of Invasive Breast
Overtreatment
Lumpectomy
Cancer
DCIS
Overdiagnosis
Mastectomy
Definitive
Cure

Risk Associations
• Not as strong as invasive breast cancer
– Family history
– Previous biopsies
– Nulliparity and age at 1 st birth
– BMI
– Post-menopausal HRT
• None or conflicting association
– OCP, alcohol, smoking
• Race-ethnicity
– Unlike invasive BC, rates are the same across
races

Hereditary Breast Cancer and DCIS
• Hwang S et al 2007
– Higher grade DCIS in mutation carriers
• Frank et al 2002
– BRCA1/2 mutations were less prevalent in
women< age 50 with
• DCIS 13%
• Invasive 24%

Diagnosis
• Detection by palpation is
uncommon
• Widespread use of
mammography increased
detection rates
– Microcalcifications
• Shortcoming : underestimate
extent of disease
• Overdetection ? finding
clinically irrelevant lesions ?

MRI in DCIS
Final path ~ 5.7 cm high grade DCIS
MRI sensitivity for DCIS 38%-100%

• Not all lesions enhance
• MRI can overestimate tumor size
• Increases MX conversion rate
(Morrow et al 2008 )
• 47 yr old palpable mass
• Mammography:
• 4 cm spiculated mass
w/microcalcifications
• MRI 6 cm x 4.7 cm
• Pathology : 3.5 cm DCIS

Surgery For DCIS
• MASTECTOMY was the principal treatment for
all BC into 1980s
• Survival nearly 98%-99%
• Chest wall / local recurrences : RARE
• Axillary lymph node dissection was largely
abandoned in 1980s

1985 Invasive Breast Cancer
(NSABP B-06)
Lumpectomy+ ALND = MRM

1985-1990
NSABP B-17 B 17
DCIS Treated by Lumpectomy
No Further
Therapy
Negative Margins
Stratification
• Age
• Method of Detection
• Pathologic Characteristics
• Axillary Dissection
Breast
XRT

NSABP B17 – Five year Results: Lumpectomy (open circle)
vs Lumpectomy plus Radiation Therapy
60% lower risk of IBTR with RT

Study No. Follow-
up
NSABP B17
Wapnir et al
1985-1991
Swedish
Holmberg et al
1987-1999
EORTC 108
Bijker et al
1986-1996
UK/ANZ
Houghton et al
1990-1998
Randomized DCIS Trials
Lumpectomy + RT
813 12 y
median
Outcomes RT Decrease
IBTR w/RT
P
value
Cum Inc 12y 15.8% 52%

SEER : Breast Cancer-Specific Survival
Breast Conservation + RT versus Total Mastectomy
Disease Specific Survival
Probability
1
0.8
0.6
0.4
0.2
0
Logrank p < 0.0001
Ibrahim et al ASCO 2007
0 12 24 36 48 60 72 84 96 108 120
Time (Months)
BCS + RTX Total Mastectomy

DCIS and Nodal Staging
• Not needed for most noninvasive
carcinomas
• EXCEPTION: large
tumors > 5cm
• Maybe high gr/ ? invasion
• SNBX for clinically
node negative pts
• Consideration of
SNBx procedure
exacerbated by use of
core biopsy def Sx

Sentinel Node Biopsy
• Core biopsy --> definitive Sx
• Possibility of upstaging DCIS to microinvasive
or invasive disease 10-38%
• “avoiding a second trip to OR”
• Hypothetical impossibility of performing SNB
after Mx
• Rates reported in single institution series 1.8
to 12% on high grade DCIS

Opinions
• Philadelphia Consensus Conference SNB
2002
• ASCO Guidelines SNB 2005
• City of Hope Cancer Center series:
No nodal recurrence at 14-year 14 year FU
• NCCN Guidelines 2009
• NIH DCIS Consensus 2009
Do not favor SNB routinely in DCIS

Evaluation of XRT
• Data from non-randomized non randomized cohorts
– USC/Van Nuys Experience
• Single arm Prospective Trials (premature closures)
– ECOG 5194
– Dana Farber
– RTOG 98-04 98 04

ECOG 5194 : Omission of Radiation
Two arm prospective study
• Low or intermediate grade 2.5 cm or smaller
(~ X 6 mm)
• High grade 1.0 cm or smaller (~X 5mm)
TAM allowed after 2000
DCIS grade Local Recurrence
5 yr rate 7 yr rate
Low 6.1% 10.5%
High 15.3% 18.0%
Hughes, L. L. et al. J Clin Oncol 2009; 27:5319-5324

ECOG 5194 : Ipsilateral (IBEs) and contralateral breast
events (CBEs) in patients with high-grade DCIS (N=105)
Copyright © American Society of Clinical Oncology
Hughes, L. L. et al. J Clin Oncol; 27:5319-5324 2009

Metanalysis of Local Recurrence
According to Margin S tatus in
DCIS
4,660 Patients BCS+XRT
• Neg vs Pos Margin OR = 0.36
• Neg vs Close Margin OR = 0.59
• Close vs Pos Margin OR = 0.43
• 2 mm vs < 2 mm OR = 0.53
• No difference when margin 2mm or >5mm
Dunne et al J Clin Oncol 2009

Completed NSABP Randomized DCIS Trials
Lumpectomy
Negative Margins
No Further
Therapy
1985-1990
Breast
XRT
1991-1994
Lumpectomy +XRT + XRT
75% Negative Margins
Placebo Tamoxifen

IBTR
• 2,612 randomized women with follow-up
• 490 IBTR (1st failures)
– 227 noninvasive (DCIS) 46.3%
– 263 invasive 53.7%

IBTR Events by Trial
B-17* & B-24 ALL IBTR Noninvasive Invasive
LO
N= 403
LRT B17
N= 410
LRT B24
N=900
LRT+TAM
N= 899
35.0% 15.4% 19.6%
19.8% 9.0% 10.7%
16.6% 7.6% 9.0%
13.2% 6.7% 6.6%
* % on B-17 will be higher irrespective of rates, due to longer follow-up

DCIS-IBTR : Cumulative Incidence
15 year
LO 15.7%
LRT B-17 8.7%
LRT B-24 8.5%
LRT+TAM 7.5%
Wapnir, Dignam, et al 2010

Invasive-IBTR : Cumulative Incidence
15 year
LO 19.4%
LRT B-24 10.0%
LRT B-17 8.9%
LRT+TAM 8.5%
Wapnir, Dignam, et al 2010

All Contralateral Cancers
Wapnir, Dignam, et al 2010

Cumulative Incidence of I-IBTR by
Margin Status in NSABP B-24
LRT inv marg 17.4%
LRT+TAM inv marg
11.5%
LRT+TAM free mar
7.5%
LRT free marg 7.4%
Wapnir, Dignam et al 2010

Mortality Risk after DCIS-IBTR
• Increased mortality for patients who
experience invasive-IBTR:
– HR = 2.07 (95% CI 1.45 - 2.96)
• No increase in mortality for patients
who experience DCIS-IBTR:
– HR= 0.77 (95% CI 0.46-1.28)

Proportion of Patients Experiencing
Other (non-IBTR) First Failure Events
B17 & B24
LO
N= 403
LRT
N= 1310
LRT+TAM
N= 899
Second
Primaries
Distant
Recurrences
5.7% 1.0%
7.3% 0.8%
7.5% 0.4%

NSABP B-24: Cumulative Incidence of
All Breast Cancer Events
% All Breast Cancers
40
35
30
25
20
15
10
5
0
Trt
L+XRT Plac
L+XRT TAM
N
900
899
Evts
232
170
HR
0.69
p‐value
0.0002
0 2 4 6 8 10 12
Years after Surgery
24.5
18.0

Cumulative incidence of deaths attributable
to breast cancer
Wapnir, Dignam et al 2010

Mortality after BCT for DCIS
Non-breast CA
related deaths
313
Randomized
2612
Total Deaths 385
Breast CA-
specific deaths
72*
* Encompasses ALL BC related deaths

Outcomes after I-IBTR
• Median follow-up post I-IBTR ~ 84 months
• 39 deaths (14.8%) among 263 I-IBTR cases
22 BC-related
8.4 %
All Patients
0.84%

Innovations in Surgery for
DCIS

Ductoscopic Appearance of DICS
Solid and
cribriform

Central Areolar-sparing Lumpectomy

Alternatives to Post-lumpectomy
Whole Breast Radiation Therapy
Whole breast
Partial breast

Resurgence of Mastectomy
Freedom from Recurrence and from Continuous Surveillance
Myocutaneous flap
Implant reconstruction

Nipple-sparing Mastectomy
24 hours postsurgery

Tumor Involvement of Nipple-areola
Complex
• Fisher E et al (B-04) 1975 : 11%
• Lagios et al 1979 : 30%
• Morimoto et al 1985 : 31%
• Santini et al 1989 : 12%
• Laronga et al MD Anderson 1999 : 5.6%
– Areolar involvement on Mx ~0.9%

Nipple-sparing Mastectomy
• Alternative
• Historically 0% - 58% of
nipple involved with tumor
• 21% of 232 Mx
specimens had nipple
involvement (IC, DCSI,
LVI)
• 10% DCIS cases had
nipple involvement
Brachtel, E. F. et al. J Clin Oncol; 27:4948-4954 2009
PROCEDURE : Subcutaneous dissection
and coring out of nipple ducts

Complications of Total Skin-sparing
Mastectomy
• Nipple necrosis 5%
• Skin flap necrosis 11%
• Significant infection 9%
• Implant loss 10%
• Contracture (implants only) 16%
Garwood et al Ann Surg 249: 26; 2009

DCIS
7.5 cm suspicious
enhancement
Ultrasound : 2.4 cm
Pathology : 3.6 cm x 1.8 cm
micropapillary intermed gr

Pre Nipple sparing mastectomy

Post op TE -240cc Post op TE -180cc

Contralateral Prophylactic Mastectomy
Rates in DCIS
Tuttle, T. M. et al. J Clin Oncol; 27:1362-1367 2009
ALL Mastectomy Patients with CPM (DCIS-SEER)

Three weeks post operative after second expansion (total 400 ml)
PLAN: Complete expansion, right chest wall irradiation and
delayed permanent implant exchange

Current and Future Directions
• Genomic analysis of DCIS subtypes
• Improving prognostic molecular tools
• Expanding the repertoire of targeted
therapies
– ER+ (tamoxifen and AI)
– HER2neu (trastuzumab)

Outcomes and QOL Issues in DCIS
• Human costs of overdiagnosis
– Toxicity, time, money
• “Generalized fear of breast cancer and the
marketing of early diagnosis for a disease
that kills very few…”
Ganz P. NIH DCIS Consensus 2009