Ductal Carcinoma In Situ - AHN · Ductal Carcinoma In Situ A.A. Sahin, M.D. ... R Breast Biopsy ....

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Ductal Carcinoma In Situ

A.A. Sahin, M.D.

Professor of Pathology and Translation Molecular Pathology

Section Chief of Breast Pathology

23rdAnnual Seminar in Pathology

Outline

• Incidence and natural history of DCIS

• Morphologic features and differential

diagnosis

• Treatment of DCIS based on biologic

factors

• Ongoing clinical trials

Outline

• Morphologic features of spindle cells

lesions

• Differential diagnosis

• Case presentations

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Ductal Carcinoma In Situ

• Incidence: ≈ 62,000 new cases US

2015 • 25% screen detected carcinomas • 20% of our practice

Diagnosis and Management of Ductal Carcinoma in Situ

Virnig BA, Shamliyan T, Tuttle TM, et al. 2009, 1-549



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DCIS is Heterogeneous

Diverse:

–Presentation

–Clinical Features

–Biology (Behavior)

Risk of invasive cancer after biopsy alone

N Ca %

Farrow 1970 (25) 5 20

Haagensen 1971 (11) 8 73

Millis 1975 (8) 2 25

Rosen 1980 (15) 8 53

Eusebi 1994 (80) 11 14

Page 1995 (28) 9 32

Mean = 28%

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Natural history of low grade DCIS

• 28 patients with low grade identified

from 1950-1968

• 30 yrs follow up

• 11 (39%) invasive cancer

• 5 (18%) breast cancer deaths

• 4 of the 5 breast cancer deaths occurred within 15 years

M Sanders D Page et al Cancer 2005

Nurses' Health Study DCIS

• Review of 1877 breast bx specimens

• 13 bx specimens with DCIS

• Received no treatment beyond the diagnostic bx

Collins et al Cancer 2005;103:1778-84


Result:

compared with nonproliferative lesions

13.5 OR for DCIS for development of invasive breast carcinoma (n=6)

20.1 OR for the development of any subsequent invasive or in situ breast ca event (n = 10)


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4 - low nuclear grade

6 - intermediate nuclear grade

3 - high nuclear grade

0 - comedo-type necrosis

Invasive carcinomas developed among women with DCIS of all nuclear grades

All 10 breast carcinoma events (100%) were in the ipsilateral breast



Conclusion:

These results provided further evidence that patients with DCIS who received no treatment beyond a diagnostic biopsy were at substantially increased risk for developing ipsilateral invasive breast carcinoma, and that the increased risk in this setting was seen in DCIS of low, intermediate, and high nuclear grades


Sequential and Parallel Models of Breast Carcinogenesis

N Inv DCIS P

N

P

Inv

DCIS

Alternative model

Inv DCIS

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Differential Diagnosis

• Atypical ductal hyperplasia

• Lobular carcinoma in situ

• Intravascular tumor

• Invasive ductal carcinoma

ATYPICAL DUCTAL HYPERPLASIA

Intraductal epithelial proliferation

with some, but not all features of

low grade intraductal carcinoma

Definition


Intraductal epithelial proliferation

with cytologic features identical to

low grade intraductal carcinoma but

lacks architectural features or

quantitatively too small

Revised Definition

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FEATURES OF DCIS

•Uniform population of cells

•Smooth geographic spaces with even cellular placement

•Hyperchromatic nuclei


• Monotonous, uniform rounded cell

population

• Organized nuclear distribution

• Subtle increase in N/C ratio

Cytologic Features


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• Incompletely involved the

duct space

• Completely involved duct

space is too small

Epithelial Proliferation


What is too small?

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• Two membrane bound spaces

• 2 mm in aggregate cross-sectional

diameter

Quantitative Criteria

A D H

1mm 1mm

1mm 1mm

D C I S

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2mm

0.3 mm 0.3 mm

0.3 mm

A D H vs D C I S


• Definition

• Application of histologic criteria

• Clinical significance

Controversies


• Clinically silent lesion

• Either mammographic finding or

incidental finding in biopsies done for

clinically evident lesions

• Median age: 50 yrs (range: 15 - 78)

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• Usually less than 3-4 mm

• Confined to an individual TDLU

• Commonly associated with

microcalcifications


•Is ADH merely a small example of non-comedo DCIS?

•Is ADH a biologically distinct

lesions?

ATYPICAL DUCT HYPERPLASIA

The definition includes:

• Cytologic features

• Histologic pattern

• Some indication of size (extent)

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Atypical Ductal Hyperplasia

vs

Intraductal Carcinoma

Benign

vs

Malignant

ADH vs low grade DCIS

Are they distinct entities?

Intraductal Epithelial Proliferations of Breast

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Yes • Magnitude of risk

varies

• Laterality of risk different

• Type of subsequent ca. histology different

No

• Histologic criteria poorly defined difficult to have standard criteria

• Molecular/geneticfeatures are similar

• ADH appears to be a neoplastic, clonal proliferation of cells identical to those of low grade DCIS

• Less completely developed

ADH vs DCIS

• AH are “markers” of generalized increase in risk and not precursor lesions

• Family history more than doubles breast cancer risk among women with AH

• Among women with AH, risk highest in first 10 years after bx.

Changing Views of AH

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A D H / D C I S

A D H / D C I S

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Challenges:

- Understanding molecular genetic pathogenesis

- Identification of clinical relevance

- Effective strategies for management

- Development of reproducible criteria for

classification

Classification of In situ Epithelial Proliferations the Breast


Usual hyperplasia

Hyperplastic Neoplastic

“Malignant” “Benign”

“Well-informed” DCIS ? Some forms

of LCIS

ADH / low grade DCIS ? Lob Neoplasia ? Columnar alteration

carcinoma in situ adenoma /

neoplasia /low grade

DCIS

Allelic imbalance analysis suggests

that low grade & high grade

carcinomas follow different genetic

pathways

Roylance et al. J Pathol 2002; 196:32-36


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Genetic alterations

LOH Studies

UDH Approx 10% (0-30%) usually one locus only

ADH Approx 50% Similar loci to low grade DCIS and similar Alterations found in subsequent inv ca of same breast

50 – 80% numerous sites (similar to inv ca)

DCIS

Bocker et al Virchow Arch A Pathol Anat 421 315 & 323, 1992 Shoker et al J Pathol 188; 237, 1999 put on an excel spreadsheet

Hyperplasia Neoplasia

CK 5, 6, 14 + -

ER Heterogeneous Homogeneous

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Breast Carcinogenesis Model

Moulis & Sgroi, 2008

LOH 16q

Her-2 and p53

Lobular Carcinoma

High Grade Carcinoma

Low Grade Carcinoma

16q

High Grade Pathway

E Cadherin

17q

?Common Precursor

Low Grade Pathway

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Sorlie, et al.

PNAS 2001

ER neg ER pos

The molecular diversity of invasive breast cancers is also seen in DCIS

Vincent-Salomon et al. Clin Cancer Res 2008

Molecular Features of DCIS

• Gene expression patterns in DCIS & invasive & metastatic tumors with serial analysis of gene expression (SAGE) (8 DCIS cases grouped)

• 16,430 transcripts analyzed

• mRNA ISH to examine gene expression (18 tumors) & IHC on TMAs (769 cases)

No universal "in situ" or "invasive" signature

Porter D. Mol Cancer Res 2003;1:362

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DCIS Heterogeneity

• Morphologic and biologic diversity has important implications with regard to mammographic evaluation, distribution in the breast and patient management

Clinical Behavior

Clinical Factors

Young age

Genetic background

Treatment Factors Extent of excision Use of XRT

Use of hormonal therapy

Tumor Factors

Size/extent of lesion

Nuclear grade/necrosis

Volume of DCIS at margin

D C I S

Determination of Size

• Frequently underestimated

• Accurate assessment requires

careful evaluation of specimens

by multidisciplinary approach

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D C I S

• 50 yr old presented with

suspicious microcalcifications on

a screening mammogram

• She underwent a core biopsy

showing DCIS and had segmental

mastectomy

D C I S Pathology Report

Gross: 5 X 4 X 3 cm specimen is cross

sectioned and representative sections

are submitted in 20 cassettes

Final: DCIS measuring 0.8 cm

Margins free, closest margin 1.0 cm

Previous biopsy changes

D C I S

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XX XX

DCIS measures 0.8 cm and is 1.0 cm from the nearest margin

. . . . . . . . . .

. . . . . . .

. . . .

. . . .

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. .

. . . . . . .

. . . . . . . . .

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. . . . . . . . . .

. . . . . . .

. . . .

. . . .

.

. . . . . . . . .

. . . . . . . . . .

DCIS measures 5 cm and extends to multiple surgical margins

superior

lateral

R Breast Biopsy

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Segmental Resection

R Breast Biopsy

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Segmental Resection

1 3 2

4 5 6

7 8 9

10 11

12 13 14

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B18

B19 B20 B21

B22

B23

1 8

2 9

3 10

4 11

5 12

6 13

7 14

X

X

X

X

X

X

X

1 3 2

4 5 6

7 8 9

10 11

12 13 14

5 12

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S

M L X

X X X

X

X

X

I

Sup / inf = 3 x 5 = 15 mm

Med / lat = 5 + 5 + 2 = 12 mm

Sup / deep = 5 mm

D

B18 B19 B20 B21 B22 B23

B18

B19 B20 B21

B22

B23

DCIS

When is it appropriate

to obtain specimen

x-ray ?

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DCIS Whenever preoperative

mammographic findings suggest

that extent of the disease may not

be appreciated by gross

evaluation

DCIS

DCIS

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DCIS

DCIS

•Clinically relevant

•Reproducibly applicable by different observers

DCIS

• Histologic grading should include:

• nuclear grade

• architectural pattern

• presence of necrosis

2012 Consensus Conference of the Classification of DCIS

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+

-

-

Low

low

near diploid

1q+, 16q-

No; 8p11.2-p12 (rare)

Luminal A > B

ER/PR

Her2/neu

p53

Proliferation

Number of changes

Ploidy

Recurrent changes

Amplifications

Molecular subtype

+/-

-/+

-/+

Variable

intermediate

aneuploid (50%)

1q+, 8p-, 11q-, 16q-,

8p11.2-p12, 11q13

Luminal A, B

-/+

+/-

+/-

High

High

frequently aneuploid

1q+, 3q+, 17q+, 8q+, 5q-, 11q-,

14q-, 8p-, 13q-

17q12, 6q22, 8q22,11q13, 20q13

Luminal B, Her2, Basal

DCIS Heterogeneity

LG IG HG

DCIS

Most important factor in

successful treatment

Margin Status

DCIS

• Negative

• Positive

?

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DCIS

Positive Margin

DCIS extends inked

surface of tissue section

Margin Status

DCIS

DCIS

Negative Margin

DCIS does not extend

to inked surface

Margin Status

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DCIS

DCIS

DCIS

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DCIS

DCIS

DCIS

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Margin Evaluation

• For DCIS 50 %

• For inv. ca 5-20 %

Residual disease with < 1 mm clearance

Mathias Worni et al. JNCI J Natl Cancer Inst 2015;107:djv263

Time trends of treatment and survival among Ductal Carcinoma in Situ

Total Mastectomy for DCIS

N Recurrence

Follow-up (yrs)

Farrow et al’70 181 1 5-20

Sunshine et al’85 68 3 >10

Schuh et al’86 52 1 5.5

Fisher et al ’86 28 1 3.2

Arneson et al’89 28 0 6.4

Silverstein et al’95

167 2 6.5

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Grade of Invasive Ca Developing within DCIS

Histological grade of invasive ca DCIS grade I II III Total

Low 13

81%

3

19%

0 16

Intermediate 22

24%

63

70%

5

6%

90

High 3

1%

90

42%

119

56%

212

318 Cadman et al. The Breast (1997) 6, 132-137; Olubunmi et al (1994) Seminar in Diag Path 11, 215-222

% Local Recurrence after WLE alone

N All Invasive

NSABP 403 4.7 2.4

EORTC 500 4.2 2.0

Milan 74 4.4 2.7

Florence 106 1.9 1.0

Manchester 127 4.5 1.0

Edinburgh 67 3.5 1.2

Nottingham 97 1.9 1.0

Philadelphia 233 4.4 1.3

Mean = 3.9 1.7

Van Nuys Prognostic Index

Score 1 2 3

Size <16mm 16-40mm >40mm

Margin width >9mm 1-9mm <1mm

Pathology Not high Not high High

No necrosis +/- Necrosis Necrosis

Age >60yr 40-60yr <40yr

Van Nuys Score

4- 6 7 – 9 10 – 12

10-yr LR free 96% 73% 37%

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DCIS

• 1804 women randomized

Tamoxifen vs. Placebo

• Ipsilateral cancer events

were evaluated

NSABP B - 24

Lumpectomy/XRT +/- Tamoxifen

DCIS

• Tamoxifen reduced the risk of developing subsequent events (invasive carcinoma or DCIS)

• 37% reduction in the event incidence

NSABP B – 24

DCIS

• ER status was determined

retrospectively in 628 patients

• 77% (428 tumors) were

ER positive

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DCIS

DCIS

IBCR ER+ ER-

7% 17%

P = <001

DCIS

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DCIS

Breast Cancer Develops Over Time

Breast cancer cells progress through changes over a period of years

Normal Duct

Ductal Hyperplasia

Ductal Hyperplasia with Atypia

Ductal Carcinoma In situ

Invasive Ductal Carcinoma

Reversible with Tamoxifen Reversible ?

Endocrine Therapy for DCIS

• All patients: Lumpectomy + XRT

• 1804 women randomized: Tamoxifen vs.

Placebo

• Breast cancer events (Ipsilateral,

Contralateral, DCIS, invasive)

NSABP B-24

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NSABP B-24 (UPDATED 12 year follow up)

Placebo Tamoxifen p

DCIS 7.6% 6.7% NS

Invasive Cancer

9% 6.6% <0.05

Placebo Tamoxifen p

8.1% 4.9% <0.05

Ipsilateral Breast Events

Contralateral Breast Events

↓ 2.4%

↓ 3.2%

JNCI Monograph, 2010

NSABP B-24 Stratification Based on ER Status

• ER determined in 732 cases – Median f/u 14.5 years

• No benefit in ER negative • HR 0.49 for all breast cancer events among ER+

DCIS • 10-year IBTR

– ER negative = 20% – ER+ placebo= 16% – ER+ tam= 10%

Allred et al, JCO, 2012

UCSF Preoperative Endocrine Treatment for ER-positive DCIS

3-month

MMG MRI

core bx

MMG MRI

Surgery

Letrozole 2.5 mg PO QD Tamoxifen 20 mg PO QD

Exclusion criteria: • palpable disease • microinvasion • not visible on MRI

N= 62

Chen et al, BMC Cancer, 2009

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Alteration of biomarker expression is associated with endocrine treatment for DCIS

Ki67 CD68

baseline

treated


Biomarker changes associated with endocrine treatment

0

10

20

30

40

50

60

Baseline Treated0

10

20

30

40

50

60

Baseline Treated

Ki67, premenopausal Ki67, postmenopausal

0

50

100

150

200

250

Baseline Treated

0

50

100

150

200

250

Baseline Treated

CD68, premenopausal CD68, postmenopausal

p=0.04

p=0.001 p=0.002

p=0.0.01


Three-Month Pre-op Endocrine Therapy in DCIS

• Preoperative endocrine therapy of ER-positive DCIS – Safe – Histologic and radiologic changes are evident

• No long term data on efficacy and the question remains in what proportion of women might this therapy actually prevent the occurrence of invasive breast cancer

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HER-2/Neu Gene Amplification in DCIS

• High grade- 56% • Low grade- 19% • This also parallels

IDC with DCIS

Hoque et al, Cancer Epi & Prev 2002

Trastuzumab for Treatment of DCIS?

HER2 3+

Kuerer et al. CANCER, 2011

Can we selectively eradicate or prevent HER-2 + invasive breast cancer ?

ER Neg HER2 +

DCIS

ER Neg HER2 + Invasive

Trastuzumab

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MDACC Preoperative Trastuzumab Schema for DCIS

DCIS

by Core Biopsy Her 2 +

C O N S E N T

Trastuzumab 8 mg/kg

X One-dose

SURGERY at 3 weeks

Segmental or

Mastectomy

•Blood •Ki67 •cCaspase-3

•Ki67

•cCaspase-3

•Pathologic & Immune Response

Trastuzumab for DCIS Trial

Clinical Pathologic Factors

• Median age: 53 yrs

• Mean Mammographic Size: 5.1 cm

• Overall ER+: 80%

• Overall HER2+: 35%

• Total eligible: 24 patients HER2 Pos

– 12 patient samples not receiving drug used as control experiments


HER2 Correlated With Grade Grade Total Percent Percent HER2+

I 6% 0%

II 38% 27%

III 56% 44%

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Relationship ER and HER2 ER Status Number

(Percent) Percent HER2+

Positive 54 (81%) 28%

Negative 13 (19%) 62%

Immune Response Studies

Patient’s PBMC and Serum obtained

– Before and after Trastuzumab therapy

– Evaluated for ADCC

– Development of HER2 Specific CD4 response

Proliferation and Apoptotic Markers Ki67 and Cleaved Caspace-3

Patient’s NK Cells Actively Kill HER2 Target Cells

• Patient’s CD56+ NK cells are functional in presence of HER2+ target cells and trastuzumab

• CD107a+= degranulating NK cells

CD107a Assay with autologous serum

0

4.5

9

Pre-Herceptin Post-Herceptin

% C

D1

07

a+

am

on

g C

D5

6+

NK

ce

lls

HD001

HD002

HD003

HD004

HD005

HD006

HD007

HD008

HD010

HD011

HD012

P = 0.00012

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Trastuzumab for DCIS

• Trastuzumab can induce specific immunity in pts w HER2+ DCIS after 3 weeks of treatment

• Future studies-

– PRE-surgical

– What kind of histologic response should we be looking for?

– Which biomarkers to measure?

DCIS ‘Pre-Cancer’ But Treated Like Cancer

• DCIS is a marker for development of invasive breast cancer

• Diagnosis and treatment critical

– Rule out concurrent presence of invasive carcinoma (11-25%)

– Prevent development of invasive ca

– Much like LCIS or ADH

NIH Recommendations

• Develop risk-stratification models to identify subsets of women who have DCIS who are candidates for:

– active surveillance only

– local excision only

– local excision with radiotherapy

– Mastectomy

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Treatment of DCIS =

Prevention of Invasive Cancer

Which patients will go on to develop invasive disease?

Addressing overtreatment of Screen detected DCIS; the LORIS Trial

Francis, A. et al European Journal of Cancer 51 (2015) 2296-2303

LORIS Trial in UK 2014 Watch and Wait: Active Surveillance

• Screen detected low/intermediate grade DCIS, > 46 years

• Randomize surgery versus no surgery

– Non-inferiority trial 932 patients

– Primary endpoint: invasive disease at 5 year

– Secondary: Mastectomy rate, quality of life, biomarkers

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NEW Trial Alliance-CALGB 40903: Phase II Single-Arm Study of Neoadjuvant letrozole for

ER(+) postmenopausal DCIS

3 months Letrozole

MMG MRI

core bx

MMG MRI

Surgery MRI

Clinical exam

stable or responding

progression

3 months Letrozole

regi

stra

tio

n

Measure change Ki67, Imaging-

path correlation PI: Shelley Hwang

N=96

8/1/14: 54

Women with DCIS on BX

Endpoints Primary: 1. Proliferation (Ki67 IHC) in DCIS 2. Toxicity Secondary: 1. DCIS Incidence on excision 2. Modulation of tissue markers

Pre- or post Menopausal EGFR+ or Her2+ DCIS

RANDOMIZE

SURGERY

2-6 weeks

Lapatinib (1000mg) (N=30)

Tissue used for marker analysis (“Pre-treatment”)

Tissue used for marker analysis (“Post-treatment”)

LAPIS Trial (LAPatinib for In Situ Breast Cancer) PI: Powel Brown

Being conducted at BCM, DFCI, WRAMC, Georgetown University, M.D. Anderson, Mayo Clinic Supported by the SPORE Grant and a grant from the Breast Cancer Research Foundation

Placebo (N=30)

Rationale for using Trastuzumab in combination w/ RT in DCIS

• Trastuzumab is a radiosensitizer in HER2

overexpressing cancer cells

• Trastuzumab does not radiosensitize cells which do not overexpress HER2

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Summary & Conclusions

• Preoperative therapy paradigm has moved into DCIS

• May allow for more rapid identification of useful alternative pharmacologic interventions

• Sets stage for potential for observation in select patients without further local therapy

The Oncotype DX® Breast Cancer Assay for DCIS Report: A Tool for Shared

Treatment Decisions

PR Ki-67 STK15

Survivin Cyclin B1

MYBL2

GSTM1

Beta-actin GAPDH RPLPO

GUS TFRC

Hormone Receptor Group Proliferation Reference

The DCIS Score result: • Is a continuous variable • Is a quantitative risk assessment (number between 0 – 100) • Reflects each individual patient’s tumor biology

Solin et al. J Natl. Cancer Inst. 2013.

DCIS Score™ Result: Gene Selection

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Solin et al. J Natl Cancer Inst. 2013.

The ECOG 5194 study validated the DCIS Score result as a predictor of any LR or an invasive LR

• The DCIS Score result provides greater visibility into the risk of LR based on the underlying tumor biology and separates patients with a lower risk from patients with a higher risk of LR

DCIS Score™ Result: 10-Year Local Recurrence by Risk Group in E5194

Any Local Recurrence Invasive Local Recurrence

Solin et al. J Natl Cancer Inst. 2013.

The ECOG E5194 study validated the DCIS Score result as a predictor of LR (increasing DCIS Score corresponds to increasing risk) • Any DCIS or invasive LR • An invasive LR

DCIS Score™ Result: 10-Year Local Recurrence in E5194

Any Local Recurrence Invasive Local Recurrence

DCIS Score™ Result: 10-Year Invasive or DCIS Local Recurrence by Risk Group in the Ontario

Provincial DCIS Cohort

Rakovitch et al. SABCS 2014.

• As in the E5194 study, this study showed that the DCIS Score result stratifies patients for risk of an invasive LR

• Further, the DCIS Score result was able to stratify patients for risk of a DCIS LR

Invasive Local Recurrence DCIS Local Recurrence

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Summary: DCIS

• Novel clinical trial designs

– New emerging targets for DCIS

– Multigene RTPCR Biologic Assays

• DCIS may be ideal opportunity to study promising agents for prevention

• VISION:

– Selective approach for surgery and radiation

Ductal Carcinoma In Situ - AHN · Ductal Carcinoma In Situ A.A. Sahin, M.D. ... R Breast Biopsy ....

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