dcis update dl wickerham md deputy chairman nrg oncology oct 5, 2015

DCIS Update

DL Wickerham MDDeputy Chairman

NRG OncologyOct 5, 2015

National Surgical Adjuvant

Breast and Bowel Project

231,840 New Cases 40,290 Deaths

4% Melanoma of skin

6% Thyroid

29% Breast13% Lung and bronchus

3% Kidney & renal pelvis

8% Colon and rectum

3% Leukemia

7% Uterus

3% Pancreas

4% Non-Hodgkin lymphoma

20% All other sites

2015 American Cancer SocietyCancer Incidence

2% Brain

26% Lung and bronchus

15% Breast7% Pancreas

9% Colon and rectum

5% Ovary

4% Uterus

3% Non-Hodgkin lymphoma

4% Leukemia

3% Liver & intrahepatic bile duct

22% All other sites

2015, American Cancer Society, Inc., SEER; Siegel RL, et al. CA Cancer J Clin. 2015 http://onlinelibrary.wiley.com/enhanced/doi/10.3322/caac.21254/

Topic Outline

• What is DCIS?

• Treatment Options

• Future Research Directions

• Questions & Answers

What is DCIS?

• Ductal Carcinoma In-situ

• Cancer?

• Pre - cancer?

• Risk factor for cancer?

Breast Carcinogenesis

Normal epitheliumNormal

epithelium

Invasivebreastcancer

Invasivebreastcancer

Atypicalhyperplasia

Atypicalhyperplasia

Proliferativedisease

without atypia

Proliferativedisease

without atypiaDCISDCIS

Normal Duct

In Situ Cancer

Invasive Cancer

Atypical Hyperplasia

For training purposes only, not for use in detailing 2/1/08

Breast Cancer Pathologic Staging

Stage I Stage II

Stage III Stage IV

STAGE 0 THE DEFINITIONCells that look like cancer but have not invaded surrounding tissue are called ductal carcinoma in situ (cancer confined to the duct). The lesions may be tiny as pinpoints and may pop up throughout the breast.

THE OPTIONSPatients whose lesions are tightly focused can be treated with lumpectomy and XRT. Some surgeons think surgery alone may be sufficient in certain cases.

DCIS with Micro-

calcificationTIME, Feb. 18, 2002

Treatment Options

• Surgery

• Radiation

• Adjuvant therapy (hormonal)

Surgery

Radical Mastectomy

Lumpectomy

Clinical Tumor Size < 4.0 cm

NSABP B-06

Stratification• Clinical Nodal Status• Clinical Tumor Size

TotalMastectomy+ Ax. Diss.

Lumpectomy+ Ax. Diss

Lumpectomy+ Ax. Diss

+ XRT

B-06 Cumulative Incidence of IBTR

0

10

20

30

40

50

60

70

0 2 4 6 8 10 12 14 16 18 20Year

L 570 pts., 220 IBTR’sL+XRT 567 pts., 78 IBTR’s

P < 0.00139

14

%

Mammography =Breast x-ray

Breast XRT

No Further Therapy

Stratification

• Age• Method of Detection

• Pathologic Characteristics

• Axillary Dissection

NSABP B-17

DCIS Treated by Lumpectomy

B-17

• No difference in survival(86% vs. 85% at 14 years)

Radiation

B-17 Cumulative Incidence ofIpsilateral Breast Cancer

RR=0.43P<.0001

N # Events 12 Yr CIL 403 131 32%L+XRT 410 65 15%

B-17 Ipsilateral Invasive Breast Cancer

N # Events 12 Yr CIL 403 72 18%L+XRT 410 32 7%

RR=0.39P<.0001

Adjuvant Therapy (hormonal)

Chemical Structure of Tamoxifen

Chemical Structure of Tamoxifen

(CH3) 2 N (CH2) 2 O

C2 H5

Tamoxifen

DCIS patients afterlumpectomy +XRT

Stratification• Age ( 49, 50)

NSABP B-24

Placebo

B-24 Cumulative Incidence of All BC

N # Events 9 Yr CIPlacebo 899 183 21%Tam 899 126 13%

RR=0.66P=.0003

Sites of 1st Events by HR Status and Treatment

Frequency (Percentage)

All Breast CancerEvents

IBT

Regional/Distant

Contralateral

68 (24%)

42 (15%)

4 (1%)

22 (8%)

40 (14%)

27 (9%)

0 (0%)

13 (4%)

HR Positive

PlaceboN=282

TamN=292

B-24

• Increased frequency of endometrial cancer (11 vs. 4)

• No difference in survival(92% vs. 94% at 10 years)

ExemestaneO

CH2

O

Nonsteroidal

Steroidal

Chemical Structures

Anastrozole

N

N

NC CN

NN

LetrozoleN

N

N

CH3

CN

CH3

CN

CH3CH3

Postmenopausal Women withER or PR Positive DCIS, Treated with

Lumpectomy + XRT

AnastrozoleTamoxifen

NSABP DCIS Trial B-35

0 12 24 36 48 60 72 84 96 108 1200

20

40

60

80

100

Time Since Randomization (months)

B-35: Overall SurvivalS

urv

ivin

g %

At Risk by Year # of %Treatment 0 6 10 Events 10 yrs HR P-value

Tamoxifen 1543 1388 368 88 92.1

Anastrozole 1540 1390 396 98 92.5 1.110.48

92.1%

92.5%

NRG Oncology ASCO 2015

0 12 24 36 48 60 72 84 96 108 1200

20

40

60

80

100

Time Since Randomization (months)

B-35: BCFI by Age GroupE

ven

t-F

ree

%

Treatment N Events HR P-value

Tamoxifen 722 58

Anastrozole 725 31 0.52

0.003

0 12 24 36 48 60 72 84 96 108 1200

20

40

60

80

100

Ev

ent-

Fre

e %

Treatment N Events HR P-value

Tamoxifen 816 56

Anastrozole 814 53 0.95 0.77

≥ 60 years< 60 years

88.2%

94.9%

90.2%

92.2%

NRG Oncology ASCO 2015

B-35: Other Secondary Endpoints

Number of EventsHazard Ratio(HR)

P-value

Tamoxifen(N=1,538)

n (%)

Anastrozole(N=1,539)

n (%)

Ipsilateral Recurrence

53 (3.4) 43 (2.8) 0.80 0.27

Invasive 21 (1.4) 14 (0.9) 0.65 0.22 DCIS 32 (2.0) 29 (1.9) 0.89 0.66Contralateral Breast Cancer

55 (3.5) 37 (2.4) 0.67 0.06

Invasive 36 (2.3) 20 (1.3) 0.55 0.03 DCIS 19 (1.2) 17 (1.1) 0.89 0.72

NRG Oncology ASCO 2015

Future Directions

• Over diagnosis Mis-diagnosis

• Molecular evaluation

• The “switch”

• HER2+ and ER–

≠

Herceptin Mechanism

NSABP B-43 Schema

* Patients with ER+ and/or PgR+ DCIS should receive a minimum of 5 years of hormonal therapy

STRATIFICATION· Menopausal Status (premenopausal; postmenopausal)· Plan for Hormonal Therapy (yes; no)· Nuclear Grade (low or intermediate; high)

RANDOMIZATION

Group 1*

Radiation Therapy

Group 2*

Radiation Therapy+

Trastuzumab x 2 doses

Dose 1: 8 mg/kg IVDose 2: 6 mg/kg IV

given 3 weeks after Dose 1

DCIS Resected by Lumpectomy Determined to be HER2-Positive by Central Testing