risk of recurrence after ductal carcinoma in situ of the breast’ · ease codes for carcinoma in...

Vol. 7, 689-6%, August 1998 Cancer Epidemiology, Biomarkers & Prevention 689

Risk of Recurrence after Ductal Carcinoma in Situ of the Breast’

Laurel A. Habel,2 Janet R. Daling, Polly A. Newcomb,Steven G. Self, Peggy L. Porter, Janet L. Stanford,Kritsy Seidel, and Noel S. Weiss

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center,

Seattle. Washington 98109 IL. A. H.. J. R. D., P. A. N., S. G. S., P. L. P.,

J. L. S., K. S.. N. S. WI, and Departments of Epidemiology [L. A. H., J. R. D.,

P. A. N.. J. L. S., N. S. W.] and Biostatistics [S. G. S.], University ofWashington. Seattle, Washington 98195

Abstract

A cohort study was conducted to estimate the risk of

breast cancer recurrence among women diagnosed withductal carcinoma in situ (DCIS) and to identify tumor orpatient characteristics that influence that risk. Apopulation�based cancer registry was used to identify a

cohort of 709 female residents of western Washingtonwho were diagnosed with DCIS between January 1980and June 1992 and were treated with breast.conservingsurgery. Information about breast cancer recurrences,treatment, and several patient characteristics andexposures was obtained from postal questionnaires.Recurrences were confirmed using information from thecancer registry or hospital pathology reports.Approximately 15% of women experienced a recurrencewithin the first S years after diagnosis [95% confidenceinterval (CI), 12-18%]; 31% had a recurrence within 10years (95% CI, 24-38%). There was a suggestion thatrisk was slightly elevated for women with larger tumors(�1.5 cm) and tumors of comedo subtype. Relative risks

(RRs) were elevated for women who were premenopausal

at diagnosis of DCIS (RR 2.3; 95% CI, 1.1-5.0).

Women in the upper decile of body mass index were attwice the risk of a recurrence as those women in thelower four deciles (RR 2.3; 95% CI, 1.1-4.8). Therewas also a suggestion that women who used menopausalhormones for at least 2 years after their diagnosis ofDCIS were at increased risk of recurrence compared tononusers of menopausal hormones (RR = 1.8; 95% CI,0.7-5.0). Our results suggest that the risk of recurrencemay be related to some tumor characteristics as well as

Received 12/15/97: revised 4/28/98: accepted 5/22/98.

The costs of publication of this article were defrayed in part by the payment of

page charges. This article must therefore be hereby marked advertisement in

accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

I Supported in part by the CSS of the Fred Hutchinson Cancer Research Center,

which is funded by Contract NO1-CN-05230 from the Surveillance, Epidemiol-

ogy. and End Results Program of the National Cancer Institute with additional

support from the Fred Hutchinson Cancer Research Center, and by Grants

5-T32-CA09168 and R35-CA39779 from the National Cancer Institute and Grant

DAMD17-94-J-4l48 from the United States Army Medical Research Acquisition

Activity, Breast Cancer Research Program.

2 To whom requests for reprints should be addressed. Present address: Division of

Research, Kaiser Permanente Medical Care Program. Northem Califomia Re-

gion. 3505 Broadway, Oakland, CA 9461 1. Phone: (510) 450-2328: Fax: (510)

450-2070; E-mail: [email protected].

the hormonal milieu of the patient at or after herdiagnosis of DCIS. However, larger studies are needed tomore clearly document predictors of disease recurrenceafter DCIS.

Introduction

In the United States, the reported incidence of DCIS3 hasincreased 300-400% during the last decade, due mainly to the

increased use of and improvement in mammographic screeningprocedures (1, 2). DCIS currently accounts for 10-15% of thebreast cancers diagnosed in the United States.

DCIS is considered to be a preinvasive breast cancer. Theterm refers to a heterogeneous group of lesions that rangewidely in size, histological growth pattern, cellular differenti-ation, and behavior ( 1 , 3, 4). Subsequent breast cancer after

DCIS is usually ipsilateral ( 1 ), although women with DCIS arealso at increased risk for new primary disease in the contralat-

eral breast (5, 6). Most subsequent ipsilateral breast cancers arelocated near the site of the initial tumor and are thought to result

from the persistence and growth of occult cells left behind afterexcision of the primary tumor. Approximately 40% of womenwhose DCIS tumors have been removed with clear surgical

margins have been found to have residual disease in the samequadrant upon mastectomy or reexcision (7, 8). Unfortunately,it is difficult to differentiate ipsilateral cancers that result fromthe growth of tumor cells left behind after excision from thosethat are new independent tumors; hence, any subsequent in situ

or invasive cancer in the ipsilateral breast has usually been

referred to as a local recurrence (3-5, 7-10).The clinical management of DCIS is one of the most

controversial issues in breast cancer treatment (4, 8, 1 1 ). Untilthe early l980s, virtually all breast cancer, invasive as well asin situ, was treated by mastectomy. In the mid-l980s, clinical

trials demonstrated that breast-conserving therapy is an appro-priate treatment strategy for most early invasive breast cancer.

Consequently, breast-conserving therapy has also been consid-

ered for the treatment of DCIS. However, there is no consensusas to which women diagnosed with DCIS can be appropriatelytreated with breast-conserving therapy, and over 40% ofwomen continue to be treated by mastectomy (2). Althoughdata suggest that only a portion of women diagnosed with DCISand left untreated would develop subsequent invasive breast

cancer (9), information has not been available to accuratelyidentify the women at greatest risk for subsequent disease

recurrence who should be treated and followed most aggres-

sively.

The results of several studies suggest that recurrenceamong women diagnosed with DCIS and treated with breastconservation may be reduced by adjuvant radiotherapy (12-14)

3 The abbreviations used are: DCIS, ductal carcinoma in situ: RR, relative risk:

CI, confidence interval: BMI, body mass index: CSS, Cancer Surveillance Sys-

tem: OC, oral contraceptive: HRT, hormone replacement therapy: NSABP. Na-

tional Surgical Adjuvant Breast Project.

Association for Cancer Research. by guest on August 27, 2020. Copyright 1998 Americanhttps://bloodcancerdiscov.aacrjournals.orgDownloaded from

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690 Risk of Recurrence after DCIS

and by clear surgical margins (15). Although not entirely con-sistent, the results of some studies also suggest that features ofthe initial DCIS tumor, such as histological subtype and tumorsize, may be related to local recurrence rates (10, 15, 16).However, data are unavailable on whether the risk of recurrenceis associated with patient characteristics or exposures.

We conducted a population-based cohort study to estimate

the risk of breast cancer recurrence among women diagnosedwith DCIS and to identify tumor or patient characteristics that

influence that risk.

Materials and Methods

Study Population. Women diagnosed with a first primary

unilateral DCIS between January 1980 and June 1992 wereidentified through the CSS. This population-based cancer reg-istry serves I 3 counties of western Washington and is part ofthe National Cancer Institute’s Surveillance, Epidemiology,

and End Results Program. The study cohort included all womenages 20-74 years who were residents of the 13 counties in-cluded in the registry’s catchment area at the time of diagnosis.

Initial diagnoses of DCIS were restricted to those confirmed bypathology and included all International Classification of Dis-ease codes for carcinoma in situ of the breast except 8520

(lobular carcinoma in situ). Women whose initial treatment forDCIS included mastectomy or who had previously been diag-nosed with in situ or invasive breast cancer were considered

ineligible for the study. Women were also required to have atleast 6 months of follow-up time to be eligible.

Patient contact began in December 1993 and ended in

January 1996. Several data sources were used to locate women.

The CSS collects information on personal identifiers includingname, address at diagnosis, date of birth, reporting institution,

and treating physician. Women whose address had changedsince their initial diagnosis were traced using a variety oftechniques including surveys of regional telephone directories

and Cole’s city-wide directories, cross-matching names andbirth dates with data on Department of Motor Vehicle tapes,address corrections from the United States Postal Service, andfollow-up through treating physicians recorded by the CSS.

A total of 709 eligible study subjects were identified, and

480 (67.7%) completed a postal questionnaire. Approximately20.5% of the cohort declined to participate (36 of these womenprovided information on recurrence only), 5.3% could not belocated, and 6.5% had died.

Ascertainment of Recurrence Information. A recurrencewas considered any subsequent breast cancer, DCIS or invasivedisease, in the ipsilateral breast or metastasis outside the breastsat least 6 months after the initial DCIS diagnosis. Cancer

identified during the 6 months after the initial DCIS was con-sidered to be part of the initial disease episode. Five women had

ipsilateral breast cancer diagnosed within 6 months of theirinitial DCIS; in three women, the disease was invasive, and

they were excluded from the study cohort.To obtain complete information on recurrences, data were

collected from several sources. Women in the cohort wereasked about the diagnosis, method of detection, and treatment

of all episodes of primary and recurrent breast disease requiringa biopsy or surgery. In addition, the CSS medical record ab-

straction forms were reviewed for pathology information onsubsequent ipsilateral breast cancer and metastatic disease. His-torically, the CSS has collected data on all primary cancers

diagnosed among residents of its catchment area. Before 1991,all cancer in the ipsilateral breast after an initial diagnosis ofbreast cancer (invasive or in situ) was considered to be recur-

rent disease unless otherwise specified by a physician. Whereas

data on recurrent disease was not systematically collected orentered into the CSS database, information about recurrences

was frequently available in notes recorded on the registry’s

medical record abstraction forms. In January 1991, the CSS

began systematically collecting and coding information onbreast cancer recurrences. Death certificates were sought for allsubjects who were known to have expired. A form requestingrecurrence information was also sent to the physician listed on

the death certificate. Deaths were considered to be due to arecurrence of DCIS if the death certificate listed breast cancer

as a cause of death, and the patient was not known to have in

situ or invasive breast cancer diagnosed in the contralateral

breast (based on CSS information). Deaths listed as due tometastatic cancer of unknown origin were also considered to be

due to a recurrence of DCIS if the patient’s CSS abstract orpathology report listed the probable origin of the metastasis as

the breast. Recurrence information was obtained on 28 patients

who had died. Pathology reports were requested for all reportedrecurrences of breast cancer.

Recurrences were considered confirmed if they were ver-ified by pathology information from the pathology report or the

CSS abstract form, even if they were not reported by the

patient. The date of the recurrence was considered to be the date

that a tissue specimen was obtained for pathological examina-tion, as listed on the CSS registry abstract form or the pathology

report. Of the 103 confirmed recurrences, 77 were reported by

the patient (74 of these were among women who completed thefull questionnaire; 3 were among women who provided recur-

rence information only). There were 26 recurrences that were

identified solely from information available from the cancerregistry or death certificate; 2 women had a confirmed recur-rence but did not report it on their questionnaire, I 2 were

among the subjects who were nonresponders to the question-

naire, and I 2 were among the subjects who had died.

Ascertainment of Exposure Information. In addition to

breast cancer recurrences, the questionnaire collected informa-tion on a number of patient characteristics and exposures in-

cluding several demographic factors, reproductive history, andfamily history of breast cancer. Women were asked to provide

the type and beginning and ending dates of each episode ofhormone use. In addition, information was collected on height

and weight for each year between 1980 and the questionnaire

date and alcohol consumption beginning at age 15 through theage at the questionnaire date.

Information on initial DCIS diagnosis date, age at diag-nosis, ethnicity, tumor characteristics (size and histological

subtype), and treatment (surgery and radiotherapy) was ob-tamed from the CSS. The CSS routinely collects information on

the initial treatment regimen (treatment within or documented

as planned within 4 months after the initiation of treatment) for

patients with primary breast cancer.

Analysis. The Quetelet’s index (weight in kilograms dividedby height in square meters) was used to calculate BMI at initial

DCIS. Menopausal status was classified similar to that de-scribed by Voigt et a!. (17). Women were classified as prem-

enopausal at initial DCIS if they reported having menstrualperiods within 12 months of DCIS diagnosis. Women were

considered to be postmenopausal if both ovaries had beenremoved or if their last period was 12 or more months beforethe diagnosis date. Women who had had a hysterectomy but

retained at least one ovary (n = 68) were considered to bepostmenopausal if they were older than 50 years (the median

age of natural menopause in our cohort) at initial DCIS diag-



36 7.5 27 11.8

191 39.8 105 45.9

253 52.7 97 42.4

297 61.9 153 66.8

112 23.3 42 18.3

71 14.8 34 14.8

314 65.4 141 61.6

40 8.3 27 11.8

126 26.3 61 26.6

201 41.9 145 63.3

266 55.4 81 35.4

13 2.7 3 1.3

89 18.5 45 19.6

148 30.8 55 23.9

142 29.6 50 21.7

101 21.0 79 34.8

27

335

93

25

447

9

19

62

35.5

5.6 23

69.8 143

19.4 55

5.2 8

93.1 208

1.0 7

1.9 10

4.0 4

62

52.0

I0.0

62.4

24.0

3.5

90.8

3.1

4.4

1.7

41 53.9 7 25.9

35 46.1 20 74.1

Cancer Epidemiology, Biomarkers & Prevention 69/

nosis; those who were 50 years or younger at initial DCIS wereclassified as premenopausal. Any women who had started usingmenopausal hormones more than 12 months before their initialDCIS were considered to be postmenopausal; all but one of

these women had also stopped menstruating more than 12months before diagnosis. Information on date of the last period

was not available on six women; all were 60 years or older atDCIS and were classified as postmenopausal. The risk of re-

currence associated with tumors of unspecified histologicalsubtype was similar to that for the noncomedo subtypes, andthese were grouped together in the analysis.

Entry into the cohort began 6 months after the initial

diagnosis of DCIS. The end of follow-up was considered to bethe patient’s recurrence date, questionnaire date, or, if thepatient was a non.responder, the last follow-up date availablefrom the CSS, whichever occurred first. Women whose first

event was a cancer in the contralateral breast continued to beconsidered at risk until the time of an ipsilateral recurrence,mastectomy of the ipsilateral breast, or the questionnaire date,whichever occurred first. The median follow-up time for both

responders and nonresponders was 62 months.

Cumulative incidence estimators (1 8, 19) were used tocalculate the simple probability of recurrence at 5 and 10 years

after DCIS. These estimators compute the cumulative incidence

of an event of interest in the presence of competing risks amongpatients with varying follow-up times. Probability curves werealso generated to describe the pattern of recurrence over time.

Only subjects with recurrence information available were in-eluded in these analyses (n = 556).

Cox regression modeling, with the number of months afterthe diagnosis of DCIS as the time axis, was used to estimateRRs and 95% CIs (20). Women were censored at the time oftheir in situ recurrence when estimating RRs of invasive dis-

ease. The following variables were examined as risk factorsand, when appropriate, as potential confounders: (a) tumor sizeand histology of the initial DCIS lesion; (b) radiotherapy for

initial disease; (c) age; (d) marital status; (e) education level; (f)height; (g) weight; (h) BMI; (i) average alcohol use at diagno-sis; (j) age at menarche; (k) menopausal status; (1) parity; (m)age at first birth; (n) breast cancer in first-degree relatives; and

(o) exogenous hormone use. Postmenopausal hormone use after

diagnosis was treated as a time-dependent variable.

Results

Selected characteristics of the study population, stratified byresponse to the questionnaire, are presented in Table 1 . Re-

sponders to the questionnaire were similar to nonresponders

with respect to tumor histology and size. Compared withwomen completing the questionnaire, women without question-

naire data were more likely to be younger than 35 years of age

or older than 65 years, to be single, to be non-white, to havebeen treated by excision without radiotherapy, and to have aninvasive recurrence.

A total of 103 recurrences (55 cases of invasive diseaseand 48 cases of DCIS) were identified, 76 of which were amongwomen who had completed the questionnaire. No women hadan invasive recurrence after a recurrence of in situ cancer

during the follow-up period. There were 1 1 women who died asa result of an invasive recurrence. An additional 35 women died

of other causes. The cumulative probability of a recurrenceincreased steadily during the 10 years after a diagnosis of DCIS

(Fig. 1); there was no indication that risk waned over time. AtS years, there was a 15% probability (95% CI, 12-18%) of

having a recurrence of some type, an 8% (95% CI, 5-10%)

Table I Characteristics of subjects, stratified by completion of questionnaire

Questionnaire No questionnaire

n480 % n�229 %

Diagnosis year

I980-1984

1985-1988

1989-1992

Histological subtype

DCIS, not specified

DCIS, comedo

DCIS, other

Tumor size (cm)

<1.5

1.5 +

Unknown size

Radiation therapy

No

Yes

Unknown

Age at DCIS diagnosis (yr)

20-44

45-54

55-64

65-74

Marital status at DCIS diagnosis

Single, never married

Married

Formerly married

Unknown

Race/ethnicity

White

Black

Asian

Other

Median follow-up time (ma)

Median time to recurrence (mo)

Stage of recurrence

In situ

Invasive

probability of having an invasive recurrence, and a 0.6% (95%

CI, 0-1%) probability of dying of an invasive recurrence; at 10years, the probabilities were 3 1 (95% CI, 24-38%), 1 8 (95%CI, 12-24%), and 6% (95% CI, 1-10%), respectively.

RRs of recurrence associated with tumor and patient char-acteristics are presented in Tables 2-4. Months since diagnosiswas the time variable used for the Cox regression model;

therefore, all RR estimates in these tables were adjusted for

follow-up time. Each factor (other than age itself) was alsoadjusted for age (as a continuous variable). Adjustment forradiotherapy or other variables did not materially change theRR estimates.

There was a suggestion that larger tumors and tumors ofthe comedo subtype were associated with a slight increase inthe risk of recurrence (Table 2). Women who were treated fortheir initial DCIS with excision plus radiotherapy were at

decreased risk ofrecurrence compared with women treated withexcision alone; the reduction seemed to be more pronounced forthe recurrence of invasive disease (RR for invasive disease =

0.4; RR for in situ disease = 0.7). Recurrence was not related

to whether the initial DCIS was or was not detected by ascreening mammogram.

Women who were single at the time of their initial DCIS

seemed to be at an increased risk for any recurrence; however,

the pattern disappeared when recurrence was restricted to in-



0 20-

0.00 -

692 Risk of Recurrence after I)CIS

1.00 -

0 80 -

0.60-

Probability

0 40 -

any recurrence

e to recurrence

Fig. 1. Cumulative incidence of recurrence.

�t � � � 4 � � � e oYears After Diagnosis

Table 2 RR of recurr ence associat ed with tumor factors ,treatment, and detection”

All subjectsAll recurrences Invasive only

n RR5 95% Cl n RR5 95% Cl

Histology

Noncomedo or unspecified 428 76 1.0 42 1.0

Comedo 128 27 1.7 (1.1-2.7) 13 1.6 (0.9-3.0)

Tumor size (cm)

< I .5 363 59 1 .0 35 1.0

1.5+ 50 14 1.6 (0.9-2.9) 8 1.6 (0.7-3.5)

Radiation therapy

No 248 63 1.0 37 1.0

Yes 293 40 0.5 (0.3-0.7) 18 0.4 (0.2-0.6)

Detection of initial DCIS’

Screening mammogram 328 45 1.0 22 1.0

Lump or symptom 142 24 1.0 (0.6-1.6) 8 0.7 (0.3-1.5)

“Restricted to women with information on recurrence.

I, All RRs were adjusted for age (continuous) at diagnosis and follow-up time.‘ Restricted to subjects who completed the questionnaire.

vasive disease (Table 3). Risk was not associated with educa-

tion level. The number of non-white subjects in our studypopulation was so small that comparisons by race/ethnicitywere not informative. The risk of recurrence did not seem to berelated to age at menarche, parity, or age at first birth. Seven

women reported having a pregnancy after their diagnosis of

DCIS; two of these women had a recurrence. Women who werepremenopausal at initial DCIS seemed to be at greater risk of a

recurrence. There was a suggestion that risk of recurrence wasweakly associated with a family history of breast cancer, butonly when the first-degree relative was diagnosed with breast

cancer before age 50. In addition, when women were stratifiedon age at DCIS, it seemed that an increase in risk was associ-ated with having a family member with early-onset breastcancer only among women diagnosed with early-onset DCIS.The RR for women ages < 50 years at DCIS diagnosis was 2.4

(95% CI, 0.8-7.0); the RR for women ages > 50 at DCISdiagnosis was 1.2 (95% CI, 0.4-3.4). Risk of recurrence in-creased modestly with increasing BMI; obese women (those in

the highest decile of BMI) were twice as likely to have arecurrence as women of below average body size (those in thebottom four deciles of BMI). The association seemed to be

stronger when recurrences were restricted to invasive disease.Risks of recurrence associated with body size measures were

fairly similar among women who were either premenopausal or

postmenopausal at diagnosis (data not shown).

Only a small percentage of women who were postmeno-pausal at diagnosis had a history of using OCs, and the RRs ofrecurrence associated with OC use are presented for premeno-

pausal women only (Table 4). There was a suggestion thatwomen with a history of OC use before their initial diagnosis of

DCIS were less likely to be diagnosed with a recurrence. It alsoseemed that the risk of recurrence might be decreased with

increasing duration of OC use.Approximately 60% of women who were postmenopausal

at diagnosis had a history of prior HRT. There was no clearpattern of risk of recurrence associated with the use of meno-pausal hormones before diagnosis of DCIS (Table 4). Over20% of women who were postmenopausal at diagnosis used

HRT for some period after their DCIS. All but five of thesewomen had also used HRT before their DCIS. Although esti-mates are imprecise, there is a suggestion that women who hadused either estrogen alone or estrogen with a progestin after

their DCIS were at increased risk of recurrence compared withwomen who had not used any menopausal hormones during this

period. RRs of recurrence (in situ and invasive combined)associated with HRT use of 2 or more years were elevated forboth the use ofestrogen alone (RR = 2.1; 95% CI, 0.7-6.1) and



Cancer Epidemiology, Biomarkers & Prevention 693

Table 3 RRs of recurrence associa ted with sd ected patient charac teristics and exposures”

All subjectsAll recurrences -

n

Invasive only�- -� -RR” 95� CIn RR5 95% CI

Age at DCIS diagnosis (yr)

20-44 89 19 1.0 8 1.0

45-54 148 22 0.8 (0.4-1.4) 1 1 0.9 (0.4-2.3)

55-74 243 35 0.8 (0.4-1.4) 16 0.8 (0.3-1.9)

Marital status at DCIS diagnosis

Married 335 50 1 .0 24 1.0

Formerly married 93 17 1.4 (0.8-2.5) 8 1.4 (0.6-3.2)

Single, never married 27 7 2.2 (1.0-4.9) 2 1.4 (0.3-5.9)

Highest grade level attained

No college I 76 28 1 .0 1 1 1 .0

Some college 301 48 0.9 (0.6-1.5) 24 1.2 (0.6-2.5)

Age at menarche (yr)�rrl2 222 37 1.0 17 1.0

13 141 23 1.0 (0.6-1.6) 10 0.9 (0.4-2.O

14 58 8 0.8 (0.4-1.8) 3 0.6 (0.2-221

15+ 48 7 0.8 (0.4-1.8) 4 0.9 (0.3-2.8)

Parity

Parous 398 63 1.0 33 1.0

Nulliparous 82 13 1.0 (0.5-1.8) 2 0.3 (0.1-1.2)

Age at first birth (yr)’

<20 78 9 1.0 4 1.0

20-29 272 50 1 .7 (0.9-3.6) 27 2. 1 (0.7-6.1)

30+ 48 4 0.7 (0.2-2.3) 2 0.7 (0.1-4.0)

Menopausal status at DCIS diagnosis

Postmenopausal 296 38 1 .0 15 1.0

Premenopausal 183 38 2.3 (1.1-5.0) 20 5.9 (1.8-19.3)

First-degree family history of breast cancer

No 356 56 1.0 26 1.0

Yes, relative 50+ yr at diagnosis 82 1 1 0.9 (0.5-1.7) 4 0.7 (0.2-1.91

Yes, relative <50 yr at diagnosis 35 8 1.6 (0.7-3.3) 4 I .7 (0.6-5.0)

Alcohol use at DCIS diagnosis

Neveruse 105 19 1.0 10 1.0

1-2 drinks/wk 242 36 0.7 (0.4-1.3) 14 0.6 (0.3-1.3)

3-7 drinks/wk 90 16 0.9 (0.4-1.7) 8 0.8 (0.3-2.0)

8+ drinks/wk 42 5 0.5 (0.2-1.3) 3 0.5 (0.1-1.9)

BMI at DCIS diagnosis”

<22.9 (deciles 1-4) 189 26 1.0 9 1.0

22.9-27.7 (deciles 5-8) 188 30 1.2 (0.7-2.1) 14 1.6 (0.7-3.8)

27.8-30.7 (decile 9) 48 9 1 .4 (0.7-3. 1 ) 6 2.8 ( I .0-8. 1)

30.8+ (decile 10) 47 10 2.3 (1.1-4.8) 5 3.5 (1.1-10.8)

‘�Restricted to women who completed the questionnaire.b All RRs were adjusted for age (continuous) at diagnosis and follow-up time.

� Excludes nulliparous women.‘I BMI was computed using Quetelet’s index lweight (in kilograms)/height (square meters)l.

for the use of estrogen plus progestin (RR = 2.6; 95% CI,

0.3-20.3). Additional adjustment for radiation therapy, BMI, orother variables did not materially change RR estimates. Therisk associated with HRT use after diagnosis remained elevatedwhen recurrence was restricted to invasive disease only. Anincrease in risk associated with estrogen alone or estrogen with

a progestin was also observed when recurrent tumors wererestricted to those diagnosed because of symptoms (data notshown).

Discussion

In this large population-based cohort study of women withDCIS, we identified several tumor or patient factors that may berelated to breast cancer recurrence. However, some limitationsshould be considered when interpreting the results of this study.The small number of recurrences resulted in risk estimates thatwere unstable. Recurrence information was only available on a

small percentage of the nonrespondents, and it is likely that thisinformation was more often available when nonrespondents

had a recurrence. Therefore, our cumulative recurrence esti-

mates may be slightly inflated. Questionnaire information was

not obtained for approximately 32% of the study cohort. RR

estimates based on questionnaire data might be biased to the

extent that participation was related to both disease outcome

and the exposure of interest. There is also a possibility that the

validity of exposure information based solely on self-report,

such as hormone use, depended on disease recurrence. How-

ever, all of the women in the study had initially been diagnosedwith breast carcinoma in situ, and it seems unlikely that women

with recurrences would have more accurately reported infor-

mation requested by the questionnaire. Agreement between the

questionnaire and medical record or pharmacy data has been

found to be quite good for most reproductive variables as well

as for the use of exogenous hormones (2 1-25). Information was

not available on the status of surgical margins. In some studies,recurrences were found to be more common when surgical

margins were not clear of the tumor ( 15, 26). Lack of control

for this factor may have resulted in the attenuation of some RR

estimates, such as that for adjuvant radiotherapy. It seems that

approximately 4% of women will be diagnosed with a new




Table 4 RRs of recu rrence assoc iated with exogenou s hormone use”

All subjectsAll recurrences Invasive only

n RRh 95% CIn RR” 95% CI

Use of OCs’

OC use before DCIS diagnosis

Never 55 16 1.0 9 1.0

Ever 128 22 0.6 (0.3-1.3) 1 1 0.6 (0.2-1.4)

Duration of OC use

Never 55 16 1.0 9 1.0

<5 yr 65 1 1 0.7 (0.3-1.4) 6 0.6 (0.2-1.8)

5+ yr 63 1 1 0.6 (0.3-1.4) 5 0.5 (0.2-1.6)

Use of HRT”

HRT use before DCIS

Nonuser 115 14 1.0 6 1.0

Estrogen alone 136 19 1.2 (0.6-2.4) 7 0.9 (0.3-2.8)

Estrogen + progestin 39 3 0.7 (0.2-2.6) 2 1 .4 (0.3-7.2)

Duration of HRT use before DCIS

Nonuser 115 14 1.0 6 1.0

<10 yr 109 13 1.1 (0.5-2.4) 6 1.3 (0.4-4.0)

10+ yr 66 9 1.1 (0.5-2.6) 3 0.7 (0.2-2.9)

HRT use after DCIS

Nonuser 222 27 1.0 9 1.0

Estrogen ± progestin

<2 yr 32 5 1.2 (0.4-3.0) 2 1.7 (0.4-8.2)

2+ yr 32 5 1.8 (0.7-5.0) 3 2.4 (0.6-9.6)

“Restricted to women who completed the questionnaire.b � were adjusted for age (continuous) at diagnosis and follow-up time.‘Restricted to women who were premenopausal at initial DCIS.d Restricted to women who were postmenopausal at initial DCIS: HRT use excludes vaginal regimens.

primary cancer in the contralateral breast within 5 years of their

initial DCIS (6). Therefore, a number of subsequent cancers inthe ipsilateral breast may be new primary disease. If risk factorsfor recurrence differ from those associated with second primarybreast cancer, our RR estimates may be attenuated.

A wide range of recurrence estimates has been reported forwomen diagnosed with DCIS and treated with breast-conserv-

ing therapy (12, 14, 26). Most reports have been based on small,selected groups of patients and have not provided actuarialestimates that account for varying follow-up time. The women

in our study were identified from a population-based cancerregistry. All women between 20 and 74 years of age diagnosedwith a first primary DCIS and treated with breast-conserving

therapy were eligible. Our results are very similar to thosereported by the NSABP B-l7 clinical trial, the only treatmenttrial of DCIS with published results (12). This trial included

790 women diagnosed with a first primary DCIS and random-ized to excision alone or excision plus radiotherapy. Afterdefinitive surgery, women were followed every 6 months todetermine disease status. After a mean follow-up time of 43

months, 97 (14%) women were identified as having recur-rences. There were 92 ipsilateral recurrences and 5 regional or

distant recurrences; 2 women were reported to have died ofmetastatic disease. The NSABP B-17 trial had fairly strict entrycriteria, and it is believed that only a minority of DCIS cases

were eligible (27). Women were ineligible for the trial if theyhad radiological evidence of diffuse microcalcifications suchthat excision would be inadequate to resect all foci, or if theyhad microscopic evidence of involved surgical margins. These

may well be the primary criteria that physicians in westernWashington use when advising women diagnosed with DCISabout the appropriateness of mastectomy.

Past observational studies of DCIS patients treated by

excision plus radiotherapy or excision alone have observedsubstantial differences in ipsilateral recurrence rates, with es-

timates ranging from 2-1 2 and 2-54%, respectively ( 13, 14).

The NSABP B-l7 trial found that radiotherapy reduced the

5-year cumulative incidence of ipsilateral recurrence from20.9% to 10.4% (12). In our study, the 5-year cumulativeincidence of any recurrence was 22% among women treated

with excision alone and 10% among women treated with ex-cision plus radiotherapy. As with the NSABP B-17 trial, ourdata also suggest that radiotherapy reduces the risk of invasive

recurrence to a greater extent than it reduces the risk of in situ

recurrence.

Some but not all case series have observed an increased

frequency of recurrence among women whose DCIS tumorswere classified as the comedo subtype compared with womenwith tumors were classified as the noncomedo subtype ( 10, 13,

28). The comedo subtype has several features associated withtumor aggressiveness (large pleomorphic nuclei, often withmitotic figures, and necrotic cellular debris in the center of theducts) and has been reported to be more likely than the othersubtypes to have evidence of microinvasion (29-31). TheNSABP B-17 trial found that women with tumors with comedo

necrosis were 1 .9 times more likely to have a recurrence aswomen with tumors without comedo necrosis. We observed aRR of recurrence of 1 .7 among women whose initial DCIS

tumors were classified as comedo subtype, compared withwomen whose tumors were of noncomedo or unspecified sub-type (15). Histological subtype in our study was obtained from

the CSS, which bases subtype characterization on diagnosesmade by community pathologists. Some misclassification of

subtype is likely to have occurred, because the diagnosticcriteria for histological subtypes are not well defined, andlesions may exhibit a mixture of growth patterns (1 1). Inaddition, a large proportion of tumors in our study had nosubtype specified. Such misclassification may have attenuatedour RR estimates.

In our study, almost 70% of DCIS tumors were detectedby screening mammography, and only approximately 13% ofwomen with known tumor size had tumors that were 1 .5 cm or



Cancer Epidemiology, Biomarkers & Prevention 695

larger. Women with tumors 1 .5 cm or larger had slightly more

recurrences than women with smaller tumors, although thisassociation may have occurred by chance. No association be-tween tumor size and recurrence was observed among women

in the NSABP B-17 trial (15) or among 268 women with DCISfollowed by Solin et al. (26). However, studies by Arnesson et

a!. (16) and Lagios et a!. (10) observed fewer recurrencesamong women with small DCIS tumors. In addition, it has beenreported that larger tumors are more likely to have evidence of

microinvasive foci (29). The size of DCIS tumors is determined

by mammography, macroscopic examination of the specimen,or pathological examination of histological sections (1 1). Eachof these methods may be inaccurate, making the true relation-ship between tumor size and risk of recurrence difficult to

establish.Only a small number of follow-up studies of women with

DCIS have reported on the presence or absence of an associa-tion between patient characteristics and recurrence. As in our

study, Bornstein et al. (32) and Solin et a!. (33) reported noclear association between recurrence and age at diagnosis. A

follow-up study of 54 women diagnosed with DCIS conductedby McCormick et a!. (34) observed twice as many recurrences

among premenopausal women as among postmenopausalwomen. A second study of 38 women with DCIS found noassociation between recurrence and menopausal status (32). In

our study, approximately 38% of women were premenopausal

at their initial diagnosis of DCIS. Premenopausal women wereobserved to be at over twice the risk of a recurrence comparedwith women who were postmenopausal at initial diagnosis of

DCIS.We did not observe any clear pattern of risk associated

with age at menarche, gravidity, parity, age at first pregnancy,or history of oophorectomy. There was a suggestion that risk ofrecurrence was increased among women with a family history

of breast cancer, but only when the first-degree relative wasdiagnosed with breast cancer before age 50. Furthermore, thisrelationship was only observed among women diagnosed with

DCIS at an early age (<50 years). This suggests that there may

be an increased risk of recurrence after DCIS for women withhereditary breast cancer. Women with invasive breast cancerwho have a family history of breast cancer have not consistently

been found to have a worse prognosis (35, 36). However, theydo seem to be at higher risk than other women with breastcancer for developing a new primary breast cancer (37). It is

possible that a large proportion of the apparent recurrences weobserved among women with a young family member with

breast cancer were actually new primary disease.In our study, 60% of the women who were postmeno-

pausal at the time of their initial diagnosis of DCIS had ahistory of prior HRT use. Slightly over 20% of postmenopausal

patients used HRT for some period after their diagnosis. We didnot observe an association between HRT use before diagnosis

and risk of recurrence. However, our data suggest that postm-enopausal patients who used HRT after their diagnosis were atincreased risk of recurrence compared with women who werenonusers of menopausal hormones. Because of small numbers,

our estimates were quite unstable and should be interpretedwith caution. Furthermore, it is possible that women with DCIS

who used HRT were followed more closely by their physiciansand were therefore more likely to have recurrent disease de-tected. However, the increase in risk was observed for invasiveas well as in situ recurrences, and we continued to see an

increase in risk even after restricting recurrences to those de-tected because of a lump or symptom.

Little is known about the safety of HRT after either in situ

or invasive breast cancer. Two small case series of women with

prior invasive breast cancer who received HRT reported veryfew recurrences during 2 years of follow-up (38, 39). In addi-tion, a recent case-control study observed a reduced risk of

recurrence among users of estrogen therapy (a median of 1.5

years of use) after breast cancer relative to the risk observed

among women who had not used estrogen after breast cancer(RR = 0.4; 95% CI, 0.2-0.9; Ref. 40). Although this is reas-

suring, there is also indirect evidence for a possible adverse

effect of HRT in at least some women with breast cancer. Invitro studies suggest that estrogen stimulates the proliferation of

some breast cancer cell lines (41). Frequently, estrogen recep-tor-positive (and, to a lesser extent, estrogen receptor-negative)

breast cancers are responsive to adjuvant hormonal therapies.These therapies are thought to be effective primarily because

they are antiestrogenic in breast tissue. In addition, it has been

suggested that the positive association of obesity with recur-rence after invasive breast cancer may be due to the increased

levels of circulating estrogen and decreased levels of sex hor-mone-binding globulin observed in obese women (42).

We observed a modest increase in risk of recurrence after

DCIS associated with increasing BMI. An adverse effect ofobesity on disease prognosis has been observed in several

studies of women with invasive breast cancer (42-44). The

association has been seen in both premenopausal and postm-enopausal women. Although most of these studies adjusted for

the stage of breast cancer at initial diagnosis, there has been aconcern that inadequate staging (and more advanced disease) inobese women may, at least in part, account for these results.

There should be less potential for a bias of this type in a study

of DCIS. Furthermore, we did not observe an association be-tween weight or obesity (BMI) and tumor size or histologicaltype among study subjects, and results remained virtually un-

changed after adjusting for the size or histology of the initial

tumor.

In summary, our results suggest that women diagnosedwith DCIS and treated with breast-conserving therapy are at

considerable risk of a subsequent recurrence. Our study popu-

lation had a 8% probability ofbeing diagnosed with an invasiverecurrence within S years after their initial DCIS diagnosis andan 18% probability within 10 years after their initial DCIS

diagnosis. This is severalfold higher than what has been re-cently estimated for women in the general population: women

between the ages of 40 and 60 years have been estimated tohave a 1.6-3.6% chance of being diagnosed with invasive

breast cancer in the next 10 years (45). Our results lend addi-

tional support to the findings of others that the risk of recur-rence after DCIS is influenced by tumor subtype and treatment

with radiotherapy. Our results also suggest that the risk of

recurrence may be related to the hormonal milieu of the patientat or after her diagnosis of DCIS. Women likely to have higher

levels of either endogenous or exogenous estrogen (premeno-

pausal women, women with higher BMI, and women takingHRT) seemed to be at somewhat higher risk for a recurrence of

breast cancer after their diagnosis of DCIS. Both BMI and the

use of menopausal hormones are modifiable risk factors, butlarger studies are needed to further examine their possiblerelationship with disease recurrence among women diagnosedwith DCIS.

Acknowledgments

We are grateful to Kay Byron and Ken Scholes for assistance in programming and

data management and to Marge Blunt and Sheila Fan for assistance in data

collection.




References

I . Frykberg. E. R.. and Bland, K. I. In situ breast carcinoma. Adv. Surg.. 26:

29-72, 1993.

2. Emster, V. L., Barclay, J.. Kerlikowske, K., Grady, D., and Henderson, C.

Incidence of and treatment for ductal carcinoma in situ of the breast. J. Am. Med.

Assoc., 275: 913-918, 1996.

3. Page. D. L., and Jensen, R. A. Ductal carcinoma in situ of the breast.

Understanding the misunderstood stepchild. J. Am. Med. Assoc., 275: 948-949,

1996.

4. Schnitt, S. J., Harris, J. R., and Smith, B. L. Developing a prognostic index for

ductal carcinoma in situ of the breast. Cancer (Phila.), 77: 2189-2192, 1996.

5. Webber, B. L., Heise, H., Neifeld, J. P., and Costa, J. Risk of subsequent

contralateral breast carcinoma in a population of patients with in situ breast

carcinoma. Cancer (Phila.), 47: 2928-2932, 1981.

6. Habel, L. A., Moe, R. E., Daling, J. R., Holte, S., Rossing, M. A., and Weiss,N. S. Risk of contralateral breast cancer among women with carcinoma in situ of

the breast. Ann. Surg.. 225: 69-75, 1997.

7. Fisher, E. R., Sass, R., Fisher, B., Wickerhan, L., Paik, S. M., and Collabo-

rating NSABP Investigators. Pathologic findings from the National SurgicalAdjuvant Breast Project (Protocol 6) 1. Intraductal carcinoma (DCIS). Cancer

(Phila.), 57: 197-208, 1986.

8. Silverstein, M. J. Noninvasive breast cancer. The dilemma of the l990s.

Obstet. Gynecol. Clin. N. Am., 21: 639-658, 1994.

9. Harris, J. R., Lippman, M. E., Veronesi, U., and Willett, W. Breast cancer

(second of three parts). N. EngI. J. Med.. 327: 390-398, 1992.

10. Lagios, M. D., Margolin, F. R., Westdahl, P. R., and Rose, M. R. Mammo-

graphically detected carcinoma in situ: frequency of local recurrence following

tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer

(Phila.), 63: 618-624, 1989.

I I . Fisher. B. A biological perspective of breast cancer: contributions of the

National Surgical Adjuvant Breast and Bowel Project clinical trials. CA Cancer

J.Clin.,4/:97-Ill, 1991.

12. Fisher, B., Costantino, J., Redmond, C., Fisher, E., Margolese, R., Dimitrov,N., Wolmark, N., Wickerhan, D. L., Deutsch, M., Ore, L., Mamounas, E., Poller,

W_, and Kavanah, M. Lumpectomy compared with lumpectomy and radiation

therapy for the treatment of intraductal breast cancer. N. Engl. J. Med., 328:

1581-1586. 1993.

13. Silverstein, M. J., Cohlan, B. F., Gierson, E. D., Furmanski, M., Gamagami.

P., Colburn, W. J., Lewinsky, B. S., and Waisman, J. R. Duct carcinoma in situ:

227 cases without microinvasion. Eur. J. Cancer, 28: 630-634, 1992.

14. Recht, A., Connolly, J. L., Schniu, S. J., and Harris, J. R. Therapy of in situ

cancer. Hematol. Oncol. Clin. N. Am., 3: 691-708, 1989.

15. Fisher, E. R., Costantino, J., Fisher, B., Palekar, A. S., Redmond, C., and

Mamounas, E. Pathologic findings from the National Surgical Adjuvant BreastProject (NSABP) Protocol B-17. Cancer (Phila.), 75: 1310-1319, 1995.

16. Amesson, L. G., Smeds, S., Fagerberg, G., and Grontoft, 0. Follow-up of two

treatment modalities for ductal cancer in situ of the breast. Br. J. Surg., 76:

672-675, 989.

17. Voigt, L. F., Koepsell. T. D., Nelson, J. L., Dugowson, C. E., and Daling,

J_ R. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis.

Epidemiology. 5: 525-532, 1994.

18. Kalbfleisch, J. D., and Prentice, R. L. The Statistical Analysis ofFailure Time

Data, pp. 167-168. New York: Wiley, 1980.

19. Pepe. M. S., Longton, G., Pettinger, M., Mori, M., Fisher, L. D., and Storb,

R. Summarizing data on survival, relapse, and chronic graft-versus-host disease

after bone marrow transplantation: motivation for and description of new meth-

ods. Br. J. Haematol., 83: 602-607, 1993.

20. Kahn, H. A., and Sempos, C. T. Statistical methods in epidemiology. In: B.MacMahan (ed), Monographs in Epidemiology and Biostatistics, pp. 193-198.

New York: Oxford University Press, 1989.

21. Bean, J. A., Leeper. J. D., Wallace, R. B., Sherman, B. M. and Jagger, H.

Variations in the reporting of menstrual histories. Am. J. Epidemiol.. /09:

181-185, 1979.

22. Colditz, G. A., Stampfer, M. J., Willen, W. C., Stason, W. B., Rosner, B.,

Hennekens, C. H., and Speizer. F. E. Reproducibility and validity of self-reported

menopausal status in a prospective cohort study. Am. J. Epidemiol., 126: 319-

325, 1987.

23. Harlow, S. D., and Linet, M. S. Agreement between questionnaire and

medical records. The evidence for accuracy of recall. Am. J. Epidemiol., 129:

233-248, 1989.

24. Persson, I., Bergkvist. L., and Adami, H-O. Reliability of women’s histories

of climacteric oestrogen treatment assessed by prescription forms. Int. J. Epide-

miol., 16: 222-228, 1987.

25. Stadel, B. V., and Weiss, N. Characteristics of menopausal women: a survey

of King and Pierce counties in Washington. 1973-1974. Am. J. Epidemiol.. /02:

209-216, 1975.

26. Solin, L. J., Kurtz, J., Fourquet, A., Amalric, R., Recht, A., Bornstein, B. A.,

Kuske, R., Taylor, M., Barrett, W., Fowble, B., Haifty, B., Schultz, D. J., Yeh,

I-T., McCormick, B., and McNeese, M. Fifteen-year results of breast-conserving

surgery and definitive breast irradiation for the treatment of ductal carcinoma in

situ of the breast. J. Clin. Oncol., 14: 754-763, 1996.

27. National Surgical Adjuvant Breast and Bowel Project. A clinical trial to

evaluate the worth of tamoxifen in conjunction with lumpectomy and breast

irradiation for the treatment of noninvasive intraductal carcinoma (DCIS) of the

breast. NSABP Protocol No. B-24, 1991.

28. Solin, L. J., Yeh, I. T., Kurtz, J., Fourquet, A., Recht, A., Kuske, R.,

McCormick, B., Cross, M. A., Schultz, D. J., Amalric, R., LiVolsi, V. A.,Kowalyshyn, M. J., Torhorst, J., Jacquemier, J., Westermann, C. D., Mazon-

jian, G., Zafrani, B., Rosen, P. P., Goodman, R. L., and Fowble, B. L. Ductal

carcinoma in situ (intraductal carcinoma) of the breast treated with breast-

conserving surgery and definitive irradiation: correlation of pathologic pa-rameters with outcome of treatment. Cancer (Phila.), 7/: 2532-2542,

1993.

29. Silverstein, M. J., Waisman, J. R., Gamagami, P., Gierson, E. D., Colbum,

W. J., Rosser, R. J., Gordon, P. S., Lewinsky, B. S., and Fingerhut, A. Intraductal

carcinoma of the breast (208 cases). Clinical factors influencing treatment choice.

Cancer (Phila.), 66: 102-108, 1990.

30. Patchefsky, A. S., Schwartz, G. F., Finkelstein, S. D., Prestipino, A., Sohn,

S. E., Singer, J. S., and Feig, S. A. Heterogeneity of intraductal carcinoma of the

breast. Cancer (Phila.), 63: 731-741, 1989.

31 . Schwartz, G. F., Patchefsky, A. S., Finklestein, S. D., Sohn, S. H., Prestipino,

A., Feig, S. A., and Singer. J. S. Nonpalpable in situ ductal carcinoma of the

breast. Arch. Surg., 124: 29-32, 1989.

32. Bomstein, B. A., Recht, A., Connolly, J. L., Schnitt, S. J., Cady, B.,

Koufman, C., Love, S., Osteen, R. T., and Harris, J. R. Results of treating ductal

carcinoma in situ of the breast with conservative surgery and radiation therapy.

Cancer (Phila.), 67: 7-13, 1991.

33. Solin, L. J., Recht, A., Fourquet, A., Kurtz, J., Kuske, R., McNeese, M.,

McCormick, B., Cross, M. A., Schultz, D. J., Bornstein, B. A., Spitalier, J-M.,

Vilcoq, J. R., Fowble, B. L., Harris, J. R., and Goodman, R. L. Ten-year

results of breast-conserving surgery and definitive irradiation for intraductal

carcinoma (ductal carcinoma in situ) of the breast. Cancer (Phila.), 68:2337-2344, 1991.

34. McCormick, B., Rosen, P. P., Kinne, D., Cox, L., and Yahalom, J. Duct

carcinoma in situ of the breast: an analysis of local control after conservation

surgery and radiotherapy. Int. J. Radiat. Oncol. Biol. Phys., 2/: 289-292, 1991.

35. Malone, K. E., Daling. J. R., Weiss, N. S.. McKnight, B., White, E., andVoigt, L. F. Family history and survival of young women with invasive breast

cancer. Cancer (Phila.), 78: 1417-1425, 1996.

36. Schouten, L. J., Hupperets, P. S., Jager, J. J., Volovics, L., Wils, J. A.,Verbeek, A. L., and Blijham, 0. H. Prognostic significance of etiological risk

factors in early breast cancer. Breast Cancer Res. Treat., 43: 217-223, 1997.

37. Hom-Ross, P. L. Multiple primary cancers involving the brea.st. Epidemiol.

Rev., /5: 169-176, 1993.

38. DiSaia, P. J. Estrogen replacement therapy in breast cancer survivors. ln: F.

Calvo, M. Crepin, and H. Magdelenat (mis.), Breast Cancer: Advances in Biologyand Therapeutics. pp. 347-350. London: John Libbey Eurotext, 1996.

39. Wile, A. G., Opfell, R. W., and Margileth, D. A. Hormone replacement

therapy in previously treated breast cancer patients. Am. J. Surg., /65: 372-375,

1993.

40. Eden, J. A., Bush, T., Nand, S., and Wren, B. G. A case-control study of

combined continuous estrogen-progestin replacement therapy among women with

a personal history of breast cancer. Menopause, 2: 67-72, 1995.

41 . Isaacs, C. J. D., and Swain, S. M. Hormone replacement therapy in women

with a history of breast carcinoma. Hematol. Oncol. Clin. N. Am., 8: 179-195,

I 994.

42. Spicer, D., Pike, M. C., and Hendersen, B. E. The question of estrogen

replacement therapy in patients with a prior diagnosis of breast cancer. Oncology(Basel), 4: 49-54. 1990.

43. Kyogoku, S., Hirohata, T., Takeshita, S., Nomura, Y., Shigematsu, T., andHorie, A. Survival of breast-cancer patients and body size indicators. Int. J.

Cancer, 46: 824-831, 1990.

44. Senie, R. T., Rosen, P. P., Rhodes, P., Lesser, M. L., and Kinne, D. W.

Obesity at diagnosis of breast carcinoma influences duration of disease-free

survival. Ann. Int. Med., 116: 26-32, 1992.

45. Feuer, E. J., Wun, L-M., Boring, C. C., Flanders, W. D., Timmel, M. J., and

Tong, T. The lifetime risk of developing breast cancer. J. NatI. Cancer Inst., 85:892-897, 1993.



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