1. DL Wickerham MD Deputy Chairman NRG Oncology Oct 5, 2015
DCIS Update
DL Wickerham MD
Deputy Chairman
NRG Oncology
Oct 5, 2015

2. National Surgical Adjuvant Breast and Bowel Project

3. 2015 American Cancer Society Cancer Incidence
231,840 New Cases
40,290 Deaths
4% Melanoma of skin
6% Thyroid
29% Breast
13% 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
2% Brain
26% Lung and bronchus
15% Breast
7% 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
ASCO 06

4. Topic Outline What is DCIS? Treatment Options
Future Research Directions
Questions & Answers

5. What is DCIS? Ductal Carcinoma In-situ Cancer? Pre - cancer?
Risk factor for cancer?

6. Breast Carcinogenesis
Normal epithelium
Invasive breast
cancer
Atypical hyperplasia
Proliferative disease without atypia
DCIS

7. For training purposes only, not for use in detailing 2/1/08
Normal Duct
Atypical Hyperplasia
In Situ Cancer
Invasive Cancer
For training purposes only, not for use in detailing 2/1/08

8. Breast Cancer Pathologic Staging
Stage I
Stage II
Stage III
Stage IV

9. DCIS with Micro-calcification
STAGE 0
THE DEFINITION
Cells 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 OPTIONS
Patients whose lesions are tightly focused can be treated with lumpectomy and XRT. Some surgeons think surgery alone may be sufficient in certain cases.
The Outlook
Very good. Virtually no one does of breast cancer within 5 yrs of treatment for DCIS. No one knows what percentage of DCIS lesions eventually become invasive.
DCIS with Micro-calcification
TIME, Feb. 18, 2002

10. Treatment Options
Surgery
Radiation
Adjuvant therapy (hormonal)

11. Surgery

12. Radical Mastectomy

13. Lumpectomy

14. Clinical Tumor Size < 4.0 cm
NSABP B-06
Clinical Tumor Size < 4.0 cm
Stratification
Clinical Nodal Status
Clinical Tumor Size
Total
Mastectomy
+ Ax. Diss.
Lumpectomy
+ Ax. Diss
Lumpectomy
+ Ax. Diss
+ XRT

15. B-06 Cumulative Incidence of IBTR
L 570 pts., 220 IBTR’s
L+XRT 567 pts., IBTR’s
P < 0.001 % 39 14
Year

16. Mammography = Breast x-ray

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

18. B-17 No difference in survival (86% vs. 85% at 14 years)
In B-17, there have been few regional or distant events, and there are no statistically significant differences between study arms on these endpoints. Similarly, there is no difference in contralateral disease. At 14 years, survival on the observation arm is 86%, compared to 85% in patients receiving radiotherapy.

19. Radiation

20. B-17 Cumulative Incidence of Ipsilateral Breast Cancer
N # Events 12 Yr CI
L %
L+XRT %
RR=0.43
P<.0001
Not surprisingly, in-breast radiotherapy continues to result in a reduction in the occurrence of ipsilateral breast tumors. Cumulative incidence of IBTs at 12 years is now 32% in patients treated only by surgery, compared to 15% in those patients who received radiotherapy. This corresponds to a 57% reduction in the crude hazard of IBT as a first event, and is strongly statistically significant.

21. B-17 Ipsilateral Invasive Breast Cancer
N # Events 12 Yr CI
L %
L+XRT %
RR=0.39
P<.0001
Both invasive and noninvasive ipsilateral breast tumors are prevented or delayed by radiotherapy. In B-17, about ½ of all In-breast first events are invasive, and the crude hazard of these invasive tumors is reduced by 61% by radiotherapy.
Similarly, the hazard of noninvasive ipsilateral breast cancers is reduced by 52%. Reductions in the rates of both invasive and noninvasive ipsilateral events are both highly statistically significant.

22. Adjuvant Therapy (hormonal)

23. Chemical Structure of Tamoxifen
(CH3) 2 N (CH2) 2 O
Chemical Structure of Tamoxifen
C2 H5

24. NSABP B-24 Tamoxifen Placebo DCIS patients after lumpectomy +XRT
Stratification
Age ( 49,  50)
Tamoxifen
Placebo

25. B-24 Cumulative Incidence of All BC
N # Events 9 Yr CI
Placebo %
Tam %
RR=0.66
P=.0003
At 9 years, the use of tamoxifen has reduced the cumulative incidence of all breast cancers from 21% to 13%, corresponding to a 34% reduction in crude hazard. This reduction is highly statistically significant.

26. Sites of 1st Events by HR Status and Treatment Frequency (Percentage)
HR Positive
Placebo
N=282
Tam
N=292
All Breast Cancer
Events
IBT
Regional/Distant
Contralateral
68 (24%)
42 (15%)
4 (1%)
22 (8%)
40 (14%)
27 (9%)
0 (0%)
13 (4%)
This table shows the actual frequency of first events. Notice that the number of events in the HR-negative cohort is only 36, precluding the possibility of making any strong statements. In particular, the possibility of risk reduction for contralateral tumors in patients with hormone receptor negative DCIS cannot really be addressed by these data, since only 7 such first events were observed in this cohort. While there is little evidence of contralateral benefit in patients with HR-negative invasive primary breast cancers, this fact appears to be secondary to a strong correlation in receptor status of the primary invasive tumor and subsequent contralateral tumors. I am not aware of similar data correlating the receptor status of noninvasive primaries to subsequent

27. B-24 Increased frequency of endometrial cancer (11 vs. 4)
No difference in survival
(92% vs. 94% at 10 years)
Tamoxifen also appeared to reduce regional and distant disease, although the number of events was small and results were not statistically significant. There was the predictable increased rate of endometrial cancer, and there was no significant difference in survival. At 10 years, overall survival was 92% in the control arm, and 94% among patients treated with tamoxifen.

28. Chemical Structures Nonsteroidal Steroidal Letrozole AnastrozoleNC CN
CH3
CH3 CN CN
CH3 O
CH3
Steroidal
Exemestane O
CH2

29. Postmenopausal Women with ER or PR Positive DCIS, Treated with
NSABP DCIS Trial B-35
Postmenopausal Women with
ER or PR Positive DCIS, Treated with
Lumpectomy + XRT
Tamoxifen
Anastrozole

30. Time Since Randomization (months)
B-35: Overall Survival
92.5%
92.1%
Surviving %
At Risk by Year # of %
Treatment Events 10 yrs HR P-value
Tamoxifen
Anastrozole
Time Since Randomization (months)
NRG Oncology ASCO 2015

31. Time Since Randomization (months)
B-35: BCFI by Age Group
< 60 years
≥ 60 years
94.9%
92.2%
90.2%
88.2%
Event-Free %
Event-Free %
Treatment N Events HR P-value
Tamoxifen
Anastrozole
Treatment N Events HR P-value
Tamoxifen
Anastrozole
Time Since Randomization (months)
NRG Oncology ASCO 2015

32. B-35: Other Secondary Endpoints
Number of Events
Hazard Ratio
(HR)
P-value
Tamoxifen
(N=1,538)
n (%)
Anastrozole
(N=1,539)
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
0.66
Contralateral Breast Cancer
55 (3.5)
37 (2.4)
0.67
0.06
36 (2.3)
20 (1.3)
0.55
0.03
19 (1.2)
17 (1.1)
0.72
NRG Oncology ASCO 2015

33. Future Directions ≠ Over diagnosis Mis-diagnosis Molecular evaluation
The “switch”
HER2+ and ER–

34. Herceptin Mechanism

35. Dose 2: 6 mg/kg IV given 3 weeks after Dose 1
NSABP B-43 Schema
DCIS Resected by Lumpectomy Determined to be HER2-Positive by Central Testing
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 IV
Dose 2: 6 mg/kg IV given 3 weeks after Dose 1
* Patients with ER+ and/or PgR+ DCIS should receive a minimum of 5 years of hormonal therapy