DIETARY FAT REDUCTION INPOSTMENOPAUSAL WOMEN WITH PRIMARY

BREAST CANCER: PHASE III WOMEN’SINTERVENTION NUTRITION STUDY (WINS)

R.T. Chlebowski, G.L. Blackburn, R.E. Elashoff, C. Thompson, M.T.Goodman, A. Shapiro, A.E. Giuliano, N. Karanja, M.K. Hoy, D.W. Nixon.

For the WINS Investigators

March 15, 2006

Dietary Fat and Breast Cancer Risk

Carroll Cancer Res 1975;35:3374-3383.

Dietary Fat and Breast Cancer Risk

WINS: BACKGROUND

Preclinical and observational studies suggest dietary fatintake may be related to breast cancer outcome (1982) 1

Feasibility of achieving dietary fat reduction in breastcancer patients demonstrated in randomized trials(1987, 1993) 2, 3

A randomized phase III clinical trial evaluating dietaryfat reduction influence on relapse-free survival in earlystage breast cancer patients receiving standard cancercare was initiated in 1994.

1 Wynder, Cohen Nutr Cancer 3:195-199, 19822 Chlebowski, Nixon, Blackburn, et al Breast Cancer Res Treat 10:21-29, 19873 Chlebowski, Blackburn, Buzzard et al J Clin Oncol 11:2072-2080, 1993

WINS: STUDY HYPOTHESIS

An intensive dietary intervention targetingfat intake reduction will prolong relapse-free survival as compared to a controlcondition with minimal dietary counselingin women receiving conventional therapyfor localized and resected breast cancer

WINS: TRIAL DESIGN

Women 48-79 yrs

Early breast cancer

Primary surgery +/- RTx

Systemic therapy*

Dietary fat intake> 20% of calories

Recruitment 1994-2001, Median follow-up 60 months

* Tamoxifen required, chemoRx optional for ER+; chemoRx required for ER-.Strata: Nodal status; Systemic Rx; Sentinel node Chlebowski, Blackburn, Elashoff, et al Proc Amer Soc Clin Oncol 24:10,2005

Dietary Intervention(n=975) to reducefat intakemaintainingnutritionaladequacy

Control (n=1462)

Randomization60:40 within 365days from 1o

surgery n=2437

WINS: STUDY DESIGN

Phase III, randomized prospective multi-centerclinical trial funded as peer-reviewed RO1.

Primary Endpoint: Relapse-free survival

Defined as time from randomization to:

breast cancer recurrence- local-regional- distant- ipsilateral breast

new contralateral breast cancer

Secondary Endpoint: Overall survival

WINS: INCLUSION CRITERIA

Women 48 to 79 years of age

Histologically confirmed, resected,unilateral invasive breast cancer

Lymph nodes examined

Acceptable adjuvant systemic therapy

Dietary fat intake > 20% of calories

Able to accept either randomization

Provide informed consent

WINS: EXCLUSION CRITERIA

Tumor < 1 cm with negative nodes

Tumor > 5 cm with positive nodes

> 10 nodes positive

Pre-operative chemotherapy

Previous neoplasm except skin cancer orin situ carcinoma of cervix

> 365 days from primary surgery

WINS: SYSTEMIC THERAPY

ER Positive (by local laboratory results):- Tamoxifen 20 mg/d x 5 yrs required- Approved chemotherapy optional

ER Negative- Approved chemotherapy required

Approved chemotherapy regimens: - (CMF, AC, CAF/FAC, AC → T)

WINS: DIETARY INTERVENTION

Goal: To reduce dietary fat intakemaintaining nutritional adequacy(target 15% calories from fat)

Weight loss not an interventiongoal; not counseled on weightreduction issues

WINS: DIETARY ASSESSEMENT

Unannounced dietary 24-hour telephonerecalls by trained interviewers 1, 2

Data entered in Nutrition Data System(NDS ®) software by NutritionCoordinating Center 1

3 recalls collected over two weeks foreligibility then two recalls annually whileon study

1 Buzzard, Faucett, Jeffery, et al J Amer Dietetic Assoc 96:574-9, 19962 Winters, Mitchell, Smicklers-Wright, et al J Amer Dietetic Assoc 104:551-9, 2004

WINS: DIETARY INTERVENTION

Diet Group: women given a fat gram goal bycentrally trained, registered dieticiansimplementing a low fat eating plan 1, 2

Eight bi-weekly individual counseling sessionsand subsequent contacts every 3 monthsMonthly group sessionsSelf-monitoring of fat gram intake

Control Group: women had dietician contactsevery three months

1 Chlebowski, Rose, Buzzard, et al Breast Cancer Res Treat 20:73-84, 19922 Winters, Mitchell, Smiciklas-Wright, et al J Am Diet Assoc, 104:551-9, 2004

WINS: STATISTICALCONSIDERATIONS

Sample size: calculation (n=2502) based on assumed7.5% ↑ in RFS with 0.10 drop-in and 0.30 drop-out, for84% power at 2-sided alpha of 0.05

Unbalanced randomization (60% control, 40% diet) toenhance resource allocation

Planned interim analyses on 2/2000; 10/2000; 11/2001;10/2002; and 11/2003

Primary efficacy analysis was a log rank testsupplemented by a Cox proportional hazards model

WINS: STRATIFICATION

Lymph node status negative positive

Systemic adjuvant therapy tamoxifen alone tamoxifen plus chemotherapy chemotherapy alone

Sentinel node evaluation yes no

WINS: STUDY POPULATION

2437 women from 37 U.S. clinicalsites, randomized 60:40 975 to dietary intervention group 1462 to control group

34 ineligible (most based on timefrom Dx, size, margins) but allare included in analyses as intent-to-treat

ENDPOINTS IN ADJUVANT HORMONETRIALS

XXXXXXNSABPDFS

XXXXXXWINSDFS

XXXXXXATACRFS*

OXXXXXIESDFS

OOXXXXMA-17DFS

OOXXXXWINSRFS

Newprimarycancer**

Deathwithoutrecurrence

Contrabreast

Ipsilateralbreast

DistantLocal-regional

TrialEndpoint

RFS – Relapse-free survival; DFS – Disease-free survival; * Recurrence – free survival** Other than breast cancer;

Goss et al N Engl J Med 349, 2003; Coombes et al N Engl J Med 350, 2004; ATAC Lancet 2003;Fisher et al J Natl Cancer Inst 93, 2001

WINS: STUDY TERMINATION

Following grant cycle completion, results from 5th interim analysiswere presented to an agency review panel for potential continuationof trial as recommended by the WINS External Advisory Committee(EAC)

Funding was not obtained and clinical center funding ended in May2004

The WINS External Advisory Committee reviewed results and statusof trial and supported submission for presentation as an interimefficacy report

Presented results reflect clinical events reported throughOctober 31, 2003

Additional non-intervention follow-up of participants is ongoing tomeet protocol requirements which may provide a more definitiveresult.

WINS: BASELINE CHARACTERISTICS

221 + 93227 + 96Time from 10 surgery toentry (SD), d

4.0%3.6% Other

8.6%10.1% Lobular

87.4%86.4% Ductal

Histologic Type

2.0 (1.6)2.0 (1.5) Mean No. + (SD)

72.9%73.1% Negative – (%)

Nodal Status

1.89 (0.9)1.93 (0.9) Mean (SD), cm

1462975Tumor Size, n

58.5 (7.61)58.6 (7.27)Age-yrs (SD)

ControlDiet

Differences between groups were not significant

WINS: BASELINE CHARACTERISTICS

7.5%6.3% AC → T

7.0%7.0% FAC/CAF

53.7%53.5% CMF

31.9%33.5% AC

763505ChemoRx Regimen, n

14.6%13.9% ChemoRx Alone

38.0%38.5% Tamoxifen + ChemoRx

47.4%47.7% Tamoxifen alone

1462975Systemic Rx, n

ControlDiet

Differences between groups were not significant

WINS: BASELINE CHARACTERISTICS

70.1%64.5% Breast Conserve

29.9%*35.5% Mastectomy

1452967Surgery, n

0.6%1.3% Borderline

29.0%28.4% Negative

67.3%67.8% Positive

1452967PgR Status, n

18.7%21.0% Negative

81.3%79.0% Positive

1462975ER Status, n

ControlDiet

* P = 0.004; other differences were not significant

Percent CAL from Fat Percent CAL from Fat

12 mo. Diet 20.3 + 7.8

p<0.0001

12 mo Control 29.2 + 8.2BaselineDiet 29.6 + 7.1

Baseline Control 29.2 + 6.7

WINS: PERCENT CALORIES FROM FAT

WINS: FAT GRAM INTAKEBY TREATMENT GROUP

56.3

57.3

51.3

33.3

53

33.4

53.7

33.9

52.2

34.8

53.9

34.8

0

30

60

Fa

t G

ram

s /

Da

y

BL 1 YR 2 YR 3 YR 4 YR 5 YR

Control

Diet

* Significantly different by T test from control and baseline, p<0.0001

* * * * *

BODY WEIGHT (POUNDS) ON STUDYBY TREATMENT GROUP

161.7 + 32.8155.6 + 32.1 *60

160.1 + 33.7157.0 + 32.9 *48

160.9 + 34.2157.1 + 32.9 *36

161.1 + 34.1157.1 + 34.1 *24

160.6 + 34.3155.6 + 33.6 *12

160.0 + 35.0 160.2 + 35.10

ControlDietMonths

All values mean + SD; a significantly different from baseline and from control, p<.0001

No. Diet = 975, 840, 781, 654, 530, 380, at O, 12, 24, 36, 48, 60, mos. respectively;No. Control = 1459, 1328, 1248, 1077, 852, 648, at 0, 12, 24, 36, 48, 60 mos, respectively.

WINS EFFICACY: RFS AND DFS EVENTS

n%n%

503.4 %282.9 %2nd Cancer1

191.3 %151.5 %Death2

25017.1 %13914.3 %DFS Events (389)

936.4 %525.3 % Distant

312.1 %111.1 %Ipsilateral Breast

372.5 %242.5 %Contra Breast

18112.4 %969.8 %RFS Events (277)

201.4 %90.9 % Local / Regional

Recurrence

Control (n=1462)Diet (n=975)

1 Other then breast cancer, 2 Without breast cancer recurrenceChlebowski, Blackburn, Elashoff, et al Proc Amer Soc Clin Oncol 24:10, 2005

Follow-up time (Years)

0 1 2 3 4 5 6 7 8

0

5

10

15

20

25

30

YEARS

ControlDiet

Absolutedifference:1%

3% 3% 3% 4% 7%

PA

TIE

NT

S (

%)

WINS: RELAPSE EVENTS

Source: Chlebowski RT et al. Presentation. ASCO 2005.

* From adjusted Cox proportional hazards model including: stratification factors, ER status,tumor size, and surgery (mastectomy/lumpectomy), p value = 0.067 by adjusted log rank test

Diet Control HR, 95% CI p-value*96/975 181/1462 0.76, 0.60-0.98 0.034

Diet 975 949 907 807 647 490 342 201 96Control 1462 1416 1352 1197 965 756 529 326 151

WINS: SUBGROUP ANALYSES

Three exploratory analyses examined dietaryeffect on relapse-free survival based on:

Body Mass Index (BMI)

Estrogen receptor status

Nodal status (positive/negative)

0 1 2 3 4 5 6 7 8

0

5

10

15

20

25

30

ControlDiet

Absolutedifference:1% 2% 1% 2% 2%

YEARS

PA

TIE

NT

S (

%)

Source: Chlebowski RT et al. Presentation. ASCO 2005.

Diet 770 753 725 641 512 385 265 156 71Control 1189 1165 1122 995 802 613 440 271 125

Diet Control HR, 95% CI68/770 122/1189 0.85, 0.63-1.14

WINS: Relapse Events in ER Positive

ControlDiet

Diet 205 196 182 166 135 105 77 45 25Control 273 205 230 203 163 133 88 55 26

0 1 2 3 4 5 6 7 8

0

5

10

15

20

25

30Diet Control HR, 95% CI28/205 59/273 0.58,0.37-0.91

Absolutedifference: 6% 8% 11% 11%6%

YEARS

PA

TIE

NT

S (

%)

Source: Chlebowski RT et al. Presentation. ASCO 2005.

P-value from adjusted Coxproportional hazard model

WINS: RELAPSE EVENTS IN ER NEGATIVE

ER and PgR RFS by Subgroups

0.85ER+, Any PgR

0.58ER-, Any PgR

0.54PgR- Any ER

0.83PgR+, Any ER

0.57ER-, PgR+

0.73ER+, PgR-

0.44ER-, PgR-

0.83ER+, PgR+

HRGroup

WINS: RFS BY BMI, NODE STATUSAND BY TREATMENT GROUP

0.83 (0.57-1.22) Positive

Node Status

0.66 (0.42-1.04) > 30

0.77 (0.56-1.07) Negative

BMI

0.77 (0.51-1.18) 25-30

0.83 (0.54-1.27) < 25

HR (95% CI)

P-value from adjusted Cox proportional hazard model

WINS: OVERALL SURVIVALBY TREATMENT GROUP

Deaths

0.4500.89, 0.65-1.2110764

P-valueHR, 95% CI

Controln=1462

Dietn=975

P-value by adjusted Cox proportional hazards modelChlebowski, Blackburn, Elashaff, et al. Proc Amer Soc Clin Oncol 24:10, 2005

No difference in overall survival

WINS: CONCLUSIONS

Dietary fat intake can be reduced in breast cancerpatients participating in a multi-center clinical trial.

A life-style intervention resulting in dietary fat reductionmay increase relapse-free survival in a population ofmostly postmenopausal breast cancer patients.

Exploratory analyses suggest a greater dietary effect inpatients with receptor negative disease

Further study of lifestyle interventions designed toimprove breast cancer outcome are warranted

Follow-up of WINS study participants continues

ACKNOWLEDGEMENTS

The women participants with breast cancer

The WINS Co-Investigators

The WINS Dieticians

The NCI for funding support

Back Up Slides

WINS: ENDPOINT ASSESSMENTPotential RFS and DFS events were identifiedat the clinical centers

Supporting medical records obtained and sentto the Statistical Coordinating Center (SCU)

The SCU removed group identifiers and sentrecords to the Clinical Director’s Officefor blinded adjudication

A final blinded adjudication was performed by WINSPathology Committee review of the records

WINS: SURGERY BY THERAPYGROUP

About 5.6% more women had mastectomy than lumpectomy in the diet comparedto control group

The surgical distribution favors the control group for local/regional recurrencesince local/regional recurrence was higher in NSABP trial in women withmastectomy compared to those with lumpectomy plus radiation 1 (14.8% versus8.1%, respectively), perhaps related to less common radiation use in themastectomy group. Since about 55 more women had mastectomy in the dietgroup, about 3 or 4 more local/regional recurrences would be anticipated in thediet group based on this imbalance (55 women x about 6.7% increased risk).

The surgical distribution slightly favors the diet group for ipsilateral recurrence.About 55 more women had lumpectomy in the control compared to diet group.Given 2.1 % ipsilateral breast recurrence in controls, about one less ipsilateralbreast recurrence would be expected in the diet group based in the imbalance.

Given these estimates, surgical imbalance does not explain the difference inbreast cancer events seen between the two treatment groups.

Fisher et al N Engl J Med 2002;347:1233