Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project p-1 study

Tamoxifen for Prevention of Breast Cancer:
Report of the National Surgical Adjuvant Breast and
Bowel Project P-1 Study
Bernard Fisher, Joseph P. Costantino, D. Lawrence Wickerham, Carol K.
Redmond, Maureen Kavanah, Walter M. Cronin, Victor Vogel, Andre´Robidoux, Nikolay Dimitrov, James Atkins, Mary Daly, Samuel Wieand,Elizabeth Tan-Chiu, Leslie Ford, Norman Wolmark, and other NationalSurgical Adjuvant Breast and Bowel Project Investigators from administration of tamoxifen, its use as a breast cancer
Background: The finding of a decrease in contralateral
preventive agent is appropriate in many women at increased
breast cancer incidence following tamoxifen administration
risk for the disease. [J Natl Cancer Inst 1998;90:1371–88]
for adjuvant therapy led to the concept that the drug might
play a role in breast cancer prevention. To test this hypoth-
On June 1, 1992, the National Surgical Adjuvant Breast and esis, the National Surgical Adjuvant Breast and Bowel Proj-
Bowel Project (NSABP) implemented a randomized clinical ect initiated the Breast Cancer Prevention Trial (P-1) in
trial to evaluate the worth of tamoxifen for the prevention of 1992. Methods: Women (N = 13 388) at increased risk for
breast cancer in women considered to be at increased risk for the breast cancer because they 1) were 60 years of age or older,
disease. (The term ‘‘prevention,'' as used in this article, indi- 2) were 35–59 years of age with a 5-year predicted risk for
cates a reduction in the incidence [risk] of invasive breast cancer breast cancer of at least 1.66%, or 3) had a history of lobular
over the period of the study. Although tamoxifen prevented the carcinoma in situ were randomly assigned to receive placebo
appearance of a substantial number of breast cancers over the (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years.
duration of this study, the term ‘‘prevention'' does not neces- Gail's algorithm, based on a multivariate logistic regression
sarily imply that the initiation of breast cancers has been pre- model using combinations of risk factors, was used to esti-
vented or that the tumors have been permanently eliminated.) mate the probability (risk) of occurrence of breast cancer
The primary aim of the NSABP Breast Cancer Prevention Trial over time. Results: Tamoxifen reduced the risk of invasive
(BCPT; P-1) was to determine whether tamoxifen administered breast cancer by 49% (two-sided P<.00001), with cumulative
for at least 5 years prevented invasive breast cancer in women at incidence through 69 months of follow-up of 43.4 versus 22.0
increased risk. Secondary aims were to determine whether per 1000 women in the placebo and tamoxifen groups, re-
tamoxifen administration would lower the incidence of fatal and spectively. The decreased risk occurred in women aged 49
nonfatal myocardial infarctions and reduce the incidence of bone years or younger (44%), 50–59 years (51%), and 60 years or
fractures. Additional objectives were to evaluate breast cancer older (55%); risk was also reduced in women with a history
mortality and tamoxifen's adverse effects in order to assess the of lobular carcinoma in situ (56%) or atypical hyperplasia
benefits and risks from the drug and, in keeping with recent (86%) and in those with any category of predicted 5-year
advances, to obtain information with regard to breast cancer risk. Tamoxifen reduced the risk of noninvasive breast can-
cer by 50% (two-sided P<.002). Tamoxifen reduced the oc-
Tamoxifen was chosen as the agent to be evaluated because currence of estrogen receptor-positive tumors by 69%, but
of its demonstrated benefit when used alone as well as in com- no difference in the occurrence of estrogen receptor-negative
bination with chemotherapy to treat advanced breast cancer (1– tumors was seen. Tamoxifen administration did not alter the
5) and because of its proven efficacy in reducing tumor re- average annual rate of ischemic heart disease; however, a
reduction in hip, radius (Colles'), and spine fractures was
observed. The rate of endometrial cancer was increased in
Affiliations of authors: B. Fisher, National Surgical Adjuvant Breast and the tamoxifen group (risk ratio = 2.53; 95% confidence in-
Bowel Project (NSABP) and Allegheny University of the Health Sciences, Pitts- terval = 1.35–4.97); this increased risk occurred predomi-
burgh, PA; J. P. Costantino, C. K. Redmond, W. M. Cronin, V. Vogel, Univer-sity of Pittsburgh; D. L. Wickerham, N. Wolmark, NSABP and Allegheny nantly in women aged 50 years or older. All endometrial
General Hospital; M. Kavanah, Boston Medical Center, MA; A. Robidoux, Hotel- cancers in the tamoxifen group were stage I (localized dis-
Dieu de Montreal, Quebec, Canada; N. Dimitrov, Michigan State University, East ease); no endometrial cancer deaths have occurred in this
Lansing; J. Atkins, Southeast Cancer Control Consortium, Winston-Salem, NC; M.
group. No liver cancers or increase in colon, rectal, ovarian,
Daly, Fox Chase Cancer Center, Cheltenham, PA; S. Wieand, NSABP Biostatistical or other tumors was observed in the tamoxifen group. The
Center, University of Pittsburgh; E. Tan-Chiu, Allegheny University of the HealthSciences; L. Ford, National Cancer Institute, Bethesda, MD.
rates of stroke, pulmonary embolism, and deep-vein throm-
Correspondence to: Bernard Fisher, M.D., Scientific Director, Allegheny Uni- bosis were elevated in the tamoxifen group; these events
versity of the Health Sciences, Four Allegheny Center, Suite 602, Pittsburgh, PA occurred more frequently in women aged 50 years or older.
15212-5234 (e-mail: [email protected]).
Conclusions: Tamoxifen decreases the incidence of invasive
See ‘‘Notes'' following ‘‘References.'' and noninvasive breast cancer. Despite side effects resulting
Oxford University Press Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 currence and prolonging survival when administered as mately 11 100 women had either been randomly assigned or had agreed to postoperative adjuvant therapy in stages I and II disease (6–10). participate in the study. At that time, accrual was interrupted and was notresumed until March 1995. Randomization was completed on September 30, Findings indicating that tamoxifen-treated patients had a statis- 1997. More detailed information regarding participant accrual has been pub- tically significantly lower incidence of contralateral breast can- lished (29). cer (9–13) and that most patients used tamoxifen safely with Conditions for Participant Eligibility
good compliance and minimal side effects also provided justi-fication for its evaluation as a preventive agent (14). Equally Women were deemed acceptable for the P-1 study if they met certain eligi- compelling was the extensive information related to the drug's bility criteria defined in the protocol and were enrolled at one of the NSABPinstitutions that had been selected as contributors to the study. To be eligible for pharmacokinetics, metabolism, and antitumor effects that had the trial, the participants had to have 1) signed a consent document that had been been observed in experimental animals and humans (15–18). In witnessed and dated before randomization; 2) been either 60 years of age or older addition, there was evidence to indicate that tamoxifen interfered or between the ages of 35 and 59 years with a 5-year predicted risk for breast with the initiation and promotion of tumors in experimental cancer of at least 1.66% or had a history of lobular carcinoma in situ (LCIS); 3) systems and inhibited the growth of malignant cells by a variety had a life expectancy of at least 10 years; 4) had a breast examination thatdemonstrated no clinical evidence of cancer; 5) had a mammogram within 180 of mechanisms (19–21). days before randomization that showed no evidence of breast cancer; 6) had Because tamoxifen had been shown to alter lipid and lipo- normal white blood cell and platelet counts and normal hepatic and renal func- protein metabolism (22–26), which could reduce the risk of tion tests; 7) not been pregnant upon entry into the study or planned not to coronary artery disease, it seemed appropriate that the incidence become pregnant while on protocol therapy; 8) been accessible for follow-up; 9) of and mortality from ischemic heart disease also be assessed. In undergone an endometrial sampling before randomization if they had a uterusand were randomly assigned after July 8, 1994 (Endometrial sampling upon addition, there was evidence to indicate that, perhaps because of study entry was optional for participants randomly assigned before that date.); its estrogen agonist activity (27,28), tamoxifen might have a 10) taken no estrogen or progesterone replacement therapy, oral contraceptives, beneficial effect on osteoporosis. Consequently, the decision or androgens for at least 3 months before randomization; and 11) had no history was made to determine whether tamoxifen reduced the incidence of deep vein thrombosis or pulmonary embolism.
of bone fractures at selected sites.
Breast Cancer Risk Assessment
By September 30, 1997, 13 388 women aged 35 years and The algorithm for estimating breast cancer risk was based on the work of Gail older had been randomly assigned in the P-1 trial. Because this et al. (30), who developed a multivariate logistic regression model in which number was considered adequate to meet the study objectives as combinations of risk factors were used to estimate the probability of occurrence they related to breast cancer, participant entry was terminated.
of breast cancer over time. The variables included in the model were age, number On March 24, 1998, an independent data-monitoring committee, of first-degree relatives with breast cancer, nulliparity or age at first live birth, which had provided oversight for the study since its inception, number of breast biopsies, pathologic diagnosis of atypical hyperplasia, and ageat menarche. In its original form, the model predicted the combined risk of determined that, in accordance with prespecified rules for stop- invasive and noninvasive breast cancers for white women. Making appropriate ping the study, the findings indicating a reduction in breast can- modifications to account for a different attributable risk, we applied the risk ratio cer risk were sufficiently strong to justify disclosure of the re- (RR) for each of the parameters used in the Gail model to the expected rates of sults. This article is the first published report of the findings invasive breast cancer only. Modifications to allow for race-specific determina- obtained from the P-1 study.
tions of breast cancer risk were also incorporated into the model. The 1984–1988Surveillance, Epidemiology, and End Results (SEER)1 rates of invasive breast cancer were used as the expected rates. The total U.S. mortality rates for the year 1988 were used to adjust for the age-specific competing risk of death from Planning and Initiation of the Trial
causes other than breast cancer.
Risk Benefit
In June 1990, the National Cancer Institute (NCI) invited proposals from clinical cooperative groups for a feasibility (pilot) study that, if approved, would Each woman screened was provided with a risk profile that identified her permit the design and conduct of a protocol for a breast cancer prevention trial.
breast cancer risk and displayed a plot of projected risk over her lifetime (Fig. 1).
These proposals were to be reviewed by the Cancer Control Protocol Review To enable the women to make a more informed decision about their participation Committee in the NCI Division of Cancer Prevention and Control, by the Cancer in the trial, each of them received information about the potential number of Therapy Evaluation Program Review Committee, by representatives of the Na- breast cancer and coronary artery cases that might be prevented from the use of tional Heart, Lung, and Blood Institute, and by other NCI/National Institutes of tamoxifen, as well as the number of cases of endometrial cancer and pulmonary Health staff. In addition, external peer review was to be conducted by an ad hoc embolism that might be caused by the drug.
Special Review Committee convened by the Division of Extramural Activities of the NCI. In February 1991, the NCI and the National Cancer Advisory Boardapproved the application submitted by the NSABP; on July 3, 1991, the NSABP Randomization of participants in a double-blind fashion was performed cen- received approval from the Food and Drug Administration. Investigators from trally by the NSABP Biostatistical Center, and participants were stratified by age 131 clinical centers throughout the United States and Canada (see ‘‘Appendix (35–49 years, 50–59 years, ù60 years), race (black, white, other), history of A'') were selected by a peer-review process to be contributors to the trial. All LCIS (yes, no), and breast cancer RR (<2.5, 2.5–3.9, ù4.0). To avoid imbalances investigations conducted were approved by review boards at each institution and in treatment assignment within a clinical center, an adaptive randomization were in accord with an assurance filed with and approved by the U.S. Depart- scheme using the biased-coin method of Efron (31) was used.
ment of Health and Human Services. Each of the 131 clinical centers had on-site The trial was monitored by an independent data-monitoring committee known as auditing to monitor and assess data quality. Screening for breast cancer risk the Endpoint Review, Safety Monitoring and Advisory Committee eligibility was initiated on April 22, 1992, and randomization was begun on June (ERSMAC), which was composed of representatives with expertise in clinical trial methodology from a variety of disciplines, including oncology, gynecology, cardi- During the first year of accrual, i.e., from June 1, 1992, through May 31, 1993, ology, biostatistics, epidemiology, and research ethics. The design of the study nearly half (48%) of the 16 000 women—the number originally projected as included formal interim monitoring for early stopping based on the primary end being necessary to accomplish the study goal—were accrued to the study. Dur- point of the trial, i.e., the incidence of invasive breast cancer. The stopping rule of ing the last 7 months of 1993 and the first 3 months of 1994, nearly 3300 Fleming et al. (32) was employed by the use of bounds that used additional participants were enrolled. Thus, by the end of March 1994, approxi- less than 1% of alpha. In addition, as an informal tool to facilitate the monitoring Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 May 20, 1997, risk assessments were per-formed for 98 018 women (Table 1); 57 641(58.8%) of these women were deemed eligible,on the basis of their risk, for participation in thetrial. Of this group, 14 453 women agreed tobe medically evaluated for complete eligibil-ity. A total of 13 954 women met all eligibilityrequirements. Of those, 13 388 (95.9%) wererandomly assigned to receive, in a double-blind fashion, 20 mg per day of eithertamoxifen or placebo for 5 years; 6707 were toreceive placebo, and 6681 were to receivetamoxifen (Table 1). Both tamoxifen and pla-cebo were supplied by Zeneca Pharmaceuti-cals, Wilmington, DE. After one of the par-ticipants had been randomly assigned, it wasdiscovered that she had invasive breast cancerrather than a noninvasive lesion (LCIS), ashad originally been reported following mam-mographic and pathologic examination.
Therefore, she was not at risk for development Fig. 1. Example of a breast cancer risk profile. NSABP 4 National Surgical Adjuvant Breast and
of breast cancer and was not included in the Bowel Project; UNK 4 unknown. (Reproduced from Cancer Control 1997;4:78–86 with permission analyses. At the time of analysis, there were from the copyright holder.) 212 participants with no follow-up, 108 in theplacebo group and 104 in the tamoxifen group.
of multiple potential beneficial and detrimental outcomes, the ERSMAC adopted All of the 13 175 women at risk and with follow-up were in- a form of global monitoring using a global index modeled after the one proposed cluded in the analyses. In each study group, 7.2% of the partici- by Freedman et al. (33) for the Women's Health Initiative trial. The use of this pants withdrew their consent but were followed until consent supplemental monitoring tool was not included in the protocol design but was withdrawal. When the treatment groups were combined, 21.6% adopted by the ERSMAC before the time of the first formal interim analysis.
All analyses were based on assigned treatment at the time of randomization, of the participants discontinued their assigned therapy for rea- regardless of treatment status at the time of analysis. All randomly assigned sons not specified in the protocol. The proportion of women who participants with follow-up were included in the analyses. Average annual event stopped their therapy was greater in the tamoxifen group, i.e., rates for the study end points were calculated for each treatment group by means 19.7% in the placebo group versus 23.7% in the tamoxifen of a procedure in which the number of observed events was divided by the group. Also, 1.6% of the participants in each study group were number of observed event-specific person-years of follow-up. P values (two-sided) for tests of differences between the treatment groups for the rates of lost to follow-up. When the consent withdrawals were excluded, invasive breast cancer, noninvasive breast cancer, and invasive endometrial can-cer were determined by use of the exact method, assuming that the events camefrom a Poisson distribution and conditioning on the total number of events andthe person-years at risk (34). Under these conditions, the expected proportion of Table 1. Summary of screening, accrual, and follow-up information for
events in the tamoxifen group (p) has a binomial distribution and was defined as the number of person-years in the tamoxifen group (PY ) divided by the total number of person-years in both groups (PY ). The observed propor- Screening, accrual, tion of events (p ) was defined as the number of events in the tamoxifen group ) divided by the total number of events in both groups (n value for testing a difference in the event rates between the groups was then Breast cancer risk assessments computed as an exact binomial test of the hypothesis that p 4 p . Event rates in the two treatment groups were also compared by use of the RR and 95% con- Women meeting risk eligibility fidence intervals (CIs), in which the rate in the tamoxifen group was contrastedwith that in the placebo group. CIs for RRs were also determined assuming that Medical eligibility assessments the events followed a Poisson distribution, conditioning on the total number of Women meeting both risk and events and person-years at risk. Under this circumstance, the CI for an RR was medical eligibility requirements determined by first finding the upper (p ) and lower (p ) limits of the CI for p , Women randomly assigned where p 4 [(RR) (PY )]/[ (RR) (PY )] and RR 4 1. Then the CI Not at risk for breast cancer* for the RR was determined by solving the equation RR 4 [(p) (PY )]/[(1 – p) Without follow-up )], where p and p were substituted as the value of p, respectively.
Included in analysis Cumulative incidence rates by follow-up time were determined, accounting for Average follow-up time, mo competing risk due to death (35). Median follow-up time, mo % followed for >36 mo % followed for >48 mo % followed for >60 mo Study Screening, Accrual, and Follow-up Information
Person-years of follow-up† Breast cancer risk assessments were used to determine the *See text for details.
eligibility of women for the study. From April 22, 1992, through †Based on time at risk for death.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 the percent of participants with complete follow-up was 92.4% Table 2. Participant characteristics at time of randomization for women
in the placebo group and 92.3% in the tamoxifen group. The included in the analyses study was designed to maintain statistical power even if the rate of noncompliance, defined as permanently discontinuingtamoxifen therapy, was as high as 10% per year of follow-up.
While the cumulative rate of noncompliance was below the planned level, the interruption of accrual in 1994 resulted in a substantial increase in the rates of noncompliance and of consent withdrawal. In the 6-month interval following the interruption, the proportion of women who became noncompliant or who withdrew their consent was two to three times higher than before or after that interval.
The mean time on the study for the 13 175 participants who were included in the analysis was 47.7 months; 73.9% had a No. of first-degree relatives follow-up exceeding 36 months, 67.0% were followed for more with breast cancer than 48 months, and 36.8% had follow-up exceeding 60 months.
The median follow-up time was 54.6 months. All data included in this article are based on information received as of July 31, 1998, concerning follow-up through March 31, 1998. This was Prior hysterectomy the cutoff point selected because it was the day before the trial was unblinded. On April 1, 1998, investigators were provided History of lobular carcinoma in situ with lists identifying the treatment assignment for each partici- History of atypical hyperplasia Of the 13 175 participants included in the analysis, 39.3% 5-y predicted breast cancer risk, % were 35–49 years old at randomization, 30.7% were 50–59 years old, and 30.0% were 60 years of age or older (Table 2). Only 2.6% of the participants were 35–39 years of age, and 6.0% were 70 years of age or older. Almost all participants were white (96.4%), more than one-third (37.1%) had had a hysterectomy,6.3% had a history of LCIS, and 9.1% had a history of atypicalhyperplasia. The distribution of participants among the placeboand tamoxifen groups relative to these characteristics was simi- those receiving tamoxifen (P<.002). Through 69 months, the cumulative incidence of noninvasive breast cancer among the Almost one fourth (23.8%) of the participants had no first- placebo group was 15.9 per 1000 women versus 7.7 per 1000 degree relatives with breast cancer. More than one half (56.8%) women in the tamoxifen group. The average annual rate of non- had one first-degree relative with breast cancer, 16.4% had two, invasive breast cancer per 1000 women was 2.68 in the placebo and 3.0% had three or more. About one quarter of the women group compared with 1.35 in the tamoxifen group, yielding an had a 5-year predicted breast cancer risk that was 2.00% or less.
RR of 0.50 (95% CI 4 0.33–0.77). The reduction in noninva- Almost three fifths (57.6%) had a 5-year risk between 2.01% and sive cancers related to a decrease in the incidence of both ductal 5.00%, and 17.4% had a risk of more than 5.00%.
carcinoma in situ (DCIS) and LCIS. No survival differenceswere observed. Nine deaths were attributed to breast cancer, i.e., Breast Cancer Events
six in the group that received placebo and three in the tamoxifengroup.
A total of 368 invasive and noninvasive breast cancers oc- To assess the consistency of the effect of tamoxifen across the curred among the 13 175 participants; 244 of these occurred in population, rates of invasive breast cancer were calculated for the placebo group and 124 in the tamoxifen group (Fig. 2). There several subgroups of women. When age, history of LCIS, history was a highly significant reduction in the incidence of breast of atypical hyperplasia, and levels of predicted risk of breast cancer as a result of tamoxifen administration; that decrease was cancer were taken into consideration, tamoxifen was found to be observed for both invasive and noninvasive disease. For invasive effective in preventing breast cancer in all subgroups (Table 3).
breast cancer, there was a 49% reduction in the overall risk.
The reduction in the incidence of invasive breast cancer associ- There were 175 cases of invasive breast cancer in the placebo ated with tamoxifen ranged from 44% among women who were group, as compared with 89 in the tamoxifen group (P<.00001).
49 years of age or younger at the time of randomization to 55% The cumulative incidence through 69 months was 43.4 per 1000 among those who were 60 years of age or older at randomiza- women and 22.0 per 1000 women in the two groups, respec- tion. Among women with a history of LCIS, the reduction in risk tively. For noninvasive breast cancer, the reduction in risk was was 56%. The reduction was particularly noteworthy among 50%; there were 69 cases in women receiving placebo and 35 in those with a history of atypical hyperplasia—there were 23 cases Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 tamoxifen group, there was a substantial reduction in riskfor each year of follow-up in the latter group. The ob-served rates of reduction by year were 33%, 55%, 39%,49%, 69%, and 55%.
Rates of invasive breast cancer by selected tumor characteristics are compared in Fig. 4. The annual rate ofestrogen receptor (ER)-positive breast cancers was 69%less in women in the tamoxifen group. The rates were5.02 per 1000 women in the placebo group comparedwith 1.58 per 1000 women in the tamoxifen group (RR4 0.31; 95% CI 4 0.22–0.45). There was no evidenceof a significant difference in the rates of tumors present-ing as ER-negative (1.20 per 1000 women in the placebogroup and 1.46 per 1000 women in the tamoxifen group;RR 4 1.22; 95% CI 4 0.74–2.03). Of the seven inva- Fig. 2. Cumulative rates of invasive and noninvasive breast cancers occurring in partici-
sive breast cancers that occurred among black women, pants receiving placebo or tamoxifen. The P values are two-sided.
four were ER negative and three were ER positive. Ofthose that were ER positive, two were in the placebo of invasive breast cancer in the placebo group and three in the group and one was in the tamoxifen group.
tamoxifen group. When related to the level of predicted risk The rate of invasive breast cancer among women in the among participants, the reduction of cancer risk ranged from tamoxifen group was less than that among women in the placebo 32% to 66%. Because the proportion of nonwhite women ran- group in all tumor-size categories. The greatest difference be- domly assigned in the trial was small (3.6%), only nine invasive tween treatment groups was evident in the occurrence of tumors breast cancer events were observed in this population. Seven that were 2.0 cm or less in size at the time of diagnosis. The events occurred in black women and two in women of other observed rates of occurrence of tumors of 1.0 cm or smaller were races. Of the seven tumors that occurred among blacks, two were 2.43 per 1000 women in the placebo group and 1.43 per 1000 in the placebo group and five were in the tamoxifen group.
women in the tamoxifen group. The rates of occurrence of tu- The effectiveness of tamoxifen in preventing invasive breast mors 1.1–2.0 cm were 2.63 and 1.04 per 1000 women, respec- cancer was assessed by means of a comparison of the rates of the tively. The rates of occurrence of tumors of 2.1–3.0 cm were occurrence of that disease during each of the first 6 yearly in- 0.85 per 1000 women in the placebo group and 0.54 per 1000 tervals of follow-up (Fig. 3). When the average annual rate per women in the tamoxifen group; for tumors 3.1 cm or larger, the 1000 women in the placebo group was compared with that in the rates were 0.73 and 0.42 per 1000 women, respectively.
Table 3. Average annual rates for invasive breast cancer by age, history of lobular carcinoma in situ (LCIS), history of atypical hyperplasia, 5-year predicted
breast cancer risk, and number of first-degree relatives with breast cancer Rate per 1000 women Patient characteristic History of atypical hyperplasia 5-y predicted breast cancer risk, % No. of first-degree relatives with breast cancer Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 fen group. The rates of breast cancers presenting without nodalinvolvement were 4.48 and 2.31 per 1000 women in the placeboand tamoxifen groups, respectively. The rates of occurrence oftumors presenting with one to three involved nodes were 1.39and 0.54 per 1000 women, respectively. The rates for cancerspresenting with four or more positive axillary nodes were thesame in both study groups.
Participants who received tamoxifen had a 2.53 times greater risk of developing an invasive endometrial cancer (95% CI 41.35–4.97) than did women who received placebo, an averageannual rate per 1000 participants of 2.30 in the former group and0.91 in the latter group (Table 4). The increased risk was pre-dominantly in women 50 years of age or older. The RR of Fig. 3. Rates of invasive breast cancer occurring in participants receiving pla-
women aged 49 years or younger was 1.21 (95% CI 4 0.41– cebo or tamoxifen, by yearly interval of follow-up. Numbers above the bars 3.60), whereas it was 4.01 (95% CI 4 1.70–10.90) in women indicate numbers of events.
aged 50 years or older. The increase in incidence after tamoxifenadministration was observed early in the follow-up period (Fig.
The rate of invasive breast cancer by nodal status at the time 5). Through 66 months of follow-up, the cumulative incidence of diagnosis differed in the two treatment groups. Because ax- was 5.4 per 1000 women and 13.0 per 1000 women in the illary dissection was not performed for all cases of invasive placebo and tamoxifen groups, respectively. Fourteen (93%) of breast cancer, pathologic nodal status was not available for 12 the 15 invasive endometrial cancers that occurred in the placebo women in the placebo group and for three women in the tamoxi- group were International Federation of Gynecology and Obstet-rics (FIGO) stage I, and one (7%) was FIGO stage IV. All 36invasive endometrial cancers that occurred in the group receiv-ing tamoxifen were FIGO stage I. Four in situ endometrial can-cers were reported; three of these occurred in the placebo groupand one in the tamoxifen group.
Invasive Cancers Other Than Cancer of the Breast and
Uterus (Endometrium)
Invasive cancers at sites other than the breast and endome- trium were equally distributed, with 97 cases in each group (RR4 1.00; 95% CI 4 0.75–1.35) (Table 5). At no site was thereevidence of a disproportionate number of events. Of particularimportance were the observations that no liver cancers occurredin either group and that there was no increase in the incidence ofcolon, rectal, ovarian, or other genitourinary tumors. The great-est incidence of tumors occurred in the lung, trachea, and bron-chus (17 in the placebo group and 20 in the tamoxifen group).
Ischemic Heart Disease
Women who experienced more than one ischemic heart dis- ease event were categorized according to the most severe eventin decreasing order from fatal myocardial infarction to acuteischemic syndrome. The number of participants who had a myo-cardial infarction in the placebo and tamoxifen groups was 28and 31, respectively. Eight (29%) of the 28 events that occurredin the placebo group were fatal, as compared with seven (23%)of the 31 events in the group that received tamoxifen (Table 6).
Likewise, the number of participants who had angina requiringa coronary artery bypass graft or angioplasty was 14 in theplacebo group and 13 in the tamoxifen group. The number ofwomen reported as having acute ischemic syndrome was 20 inthe placebo group and 27 in the tamoxifen group (RR 4 1.36;95% CI 4 0.73–2.55). Of the total number of events related to Fig. 4. Rates of invasive breast cancer occurring in participants receiving pla-
ischemic heart disease, 62 occurred in the placebo group (five in cebo or tamoxifen, by tumor size, lymph node status, and estrogen receptor status. Numbers above the bars indicate numbers of events. UNK. 4 unknown; ø49 years and 57 in women aged ù50 years); 71 Path. 4 pathologic; Neg. 4 negative; Pos. 4 positive.
events occurred in the tamoxifen group (10 and 61 in the two age Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Table 4. Average annual rates of invasive and in situ endometrial cancer
Rate per 1000 women* In situ cancer *Women at risk; nonhysterectomized.
groups, respectively). Overall, the average annual rate of isch-emic heart disease was 2.37 per 1000 women in the placebogroup and 2.73 per 1000 women in the tamoxifen group.
Fractures of the hip and radius (Colles') were defined in the protocol as the primary fracture events to be evaluated in thetrial. Soon after initiation of the study, fractures of the spine Fig. 5. Cumulative rates
were also included. These three fracture sites were selected a of invasive endometrialcancer occurring in par- priori as those that would most likely be associated with osteo- ticipants receiving pla- porosis. Also, when the radiology reports were reviewed to iden- cebo or tamoxifen. The P tify fractures of the radius that were Colles' fractures, it became value is two-sided.
evident that, without the actual x-ray films, it was difficult todetermine whether some of the lower radial fractures were Col-les' or not. Thus, to ensure that reporting was complete, a fourthcategory of fractures, i.e., fractures of the lower radius other thanColles', was included. A total of 955 women experienced bonefractures, 483 and 472 in the placebo and tamoxifen groups,respectively. Fewer osteoporotic fracture events (combined hip,spine, and lower radius) occurred in women who receivedtamoxifen than in those who received placebo. Overall, 111women in the tamoxifen group experienced fractures at one ormore of these sites, as compared with 137 women in the placebo Table 5. Distribution of invasive cancers other than breast and uterine
(endometrial) cancer group; this represents a 19% reduction in the incidence of frac-tures, a reduction that almost reached statistical significance (RR 4 0.81; 95% CI 4 0.63–1.05) (Table 7). There was a 45% Primary cancer site* reduction in fractures of the hip (RR 4 0.55; 95% CI 4 0.25–1.15), a 39% reduction in Colles' fractures (RR 4 0.61; 95% CI Mouth, pharynx, larynx 4 0.29–1.23), no reduction in other lower radial fractures (RR 4 1.05; 95% CI 4 0.73–1.51), and a 26% reduction in fractures of the spine (RR 4 0.74; 95% CI 4 0.41–1.32). The overall reduction was greater in the older age group ( ù50 years at entry) (RR 4 0.79; 95% CI 4 0.60–1.05).
Lung, trachea, bronchus Lymphatic, hematopoietic systems Ovary/fallopian tube Women who experienced both a stroke and a transient isch- emic attack or both a pulmonary embolism and a deep vein thrombosis were categorized according to the most severe event, Connective tissue i.e., stroke or pulmonary embolism, respectively. While not sta- tistically significant at the traditional level (95% CI), the inci- dence of stroke increased from 24 events in the placebo group to 38 events in the tamoxifen group, i.e., from 0.92 per 1000 par- ticipants per year in the former group to 1.45 per 1000 partici- Average annual rate per 1000 women Risk ratio (95% confidence interval) 1.00 (0.75–1.35) pants per year in the latter group (Table 8). The RR was 1.59,and the 95% CI was 0.93–2.77. Fourteen of the 24 strokes that *International Classification of Diseases code 9 (68).
occurred in the placebo group were reported as being the resultof vascular occlusion, and six were considered to be hemor- Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Table 6. Average annual rates of ischemic heart disease
Rate per 1000 women 95% confidence interval Myocardial infarction* Acute ischemic syndrome‡ *International Classification of Diseases codes 410–414 (68).
†Requiring angioplasty or coronary artery bypass graft.
‡New Q-wave on electrocardiogram without angina or elevation of serum enzymes or angina requiring hospitalization without surgery.
Table 7. Annual rates for fracture events among participants
Rate per 1000 women 95% confidence interval Other lower radius* ø49 y of age at entry ù50 y of age at entry *Excludes women who had a Colles' fracture.
†One woman had a hip fracture and a Colles' fracture, and one woman had a hip fracture and another lower radial fracture.
‡One woman had a hip fracture and a Colles' fracture, one woman had a hip fracture and a spine fracture, and two women had hip fractures and other lower radial Table 8. Average annual rates of vascular-related events by age at study entry
Rate per 1000 women Type of event by age at entry 95% confidence interval Transient ischemic attack Pulmonary embolism† Deep vein thrombosis‡ *Seven cases were fatal (three in the placebo group and four in the tamoxifen group).
†Three cases in the tamoxifen group were fatal.
‡All but three cases in each group required hospitalization.
rhagic in origin. The etiology of four was unknown. Two deaths deaths that occurred in the placebo group and four that occurred occurred in women who had the occlusive type, and one death in the tamoxifen group were related to stroke. When the distri- occurred in a woman who had a stroke that was hemorrhagic in bution of strokes was examined according to age, the number of origin. Of the 38 strokes that occurred in the group receiving events in women aged 49 years or younger was similar, i.e., four tamoxifen, 21 were occlusive, 10 were hemorrhagic in origin, in the placebo group and three in the tamoxifen group. Among and seven were of unknown etiology. Three of the hemorrhagic women aged 50 years or older, 20 strokes occurred in those who strokes were fatal. One death occurred among the seven women received placebo and 35 in those who received tamoxifen. In that who experienced stroke of unknown etiology. Thus, three of the age group, the RR was 1.75, and the 95% CI was 0.98–3.20.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Twenty-five transient ischemic attacks occurred in the placebo 4 1.57; 95% CI 4 1.16–2.14). A total of 943 women reported group and 19 in the tamoxifen group (Table 8).
having cataracts at entry into the study. The RR of cataract Pulmonary emboli were observed in almost three times as surgery in these women was similar to that experienced by many women in the tamoxifen group as in the placebo group (18 women who developed cataracts after randomization. This ex- versus six; RR 4 3.01; 95% CI 4 1.15–9.27) (Table 8). When cess risk was observed primarily among women in the older age the incidence of pulmonary embolism was related to the age of participants, there was an increase in those events in postmeno- Quality of Life
pausal women who received tamoxifen. In women aged 49 yearsor younger, one event occurred in the placebo group and two At each follow-up visit, participants were evaluated relative events occurred in the tamoxifen group (RR 4 2.03; 95% CI 4 to tamoxifen-related, non-life-threatening side effects that could 0.11–119.62); in contrast, in those aged 50 years or older, five affect their quality of life. Information was collected with regard events occurred in the former group and 16 in the latter group to the occurrence of hot flashes, vaginal discharge, irregular (RR 4 3.19; 95% CI 4 1.12–11.15).
menses, fluid retention, nausea, skin changes, diarrhea, and More women who received tamoxifen developed deep vein weight gain or loss. A self-administered depression scale devel- thrombosis than did women who received placebo (35 versus 22 oped by the Center for Epidemiological Studies (CES-D) (36) cases, respectively) (Table 8). The average annual rates per 1000 was used to estimate the relation of tamoxifen to the occurrence women were 1.34 versus 0.84 (RR 4 1.60; 95% CI 4 0.91– of mental depression. Also self-reported at each visit were data 2.86). The excess risk appeared to be greater among women from the Medical Outcomes Study Short Form 36 (MOSSF-36) aged 50 years or older. For women aged 49 years or younger, the and the Medical Outcomes Study (MOS) Sexual Functioning number of cases was eight in the placebo group versus 11 in the Scale (37). tamoxifen group (RR 4 1.39; 95% CI 4 0.51–3.99). In women The only symptomatic differences noted between the placebo 50 years of age or older, the number of cases was 14 versus 24, and tamoxifen groups were related to hot flashes and vaginal with an RR of 1.71 (95% CI 4 0.85–3.58).
discharge, both of which occurred more often in the latter group(Table 10). The proportion of women who reported hot flashes as being quite a bit or extremely bothersome was 45.7% in the More than 1.5 years before the trial was stopped and the tamoxifen group, as compared with 28.7% in the placebo group.
treatment assignments were unblinded (October 1996), the The proportion reporting vaginal discharge that was moderately ERSMAC released information to the NSABP leadership with bothersome or worse was 29.0% in the tamoxifen group, as regard to an excess risk of cataracts and cataract surgery ob- compared with 13.0% in the placebo group. There were no no- served among women in the tamoxifen group. The NSABP lead- table differences between the two groups relative to any of the ership then informed officials of the NCI, the Office for Protec- findings obtained from the various self-reporting instruments. Of tion From Research Risks, and the principal investigators and particular note are the findings for depression scores determined participants in the trial. It was also provided (by the NCI) to from the CES-D scale. The distribution of participants in the two chairpersons of the local Institutional Review Boards respon- groups according to the various levels of clinical depression was sible for oversight of all breast cancer treatment trials in which almost identical. The highest depression score observed was less tamoxifen was administered. The status regarding these out- than or equal to 15 for 65.4% of the women in each group, and comes at the time of this analysis is summarized in Table 9.
the proportion of women with a score that was greater than or Information on the development of cataracts was based on un- equal to 30 was 9.0% in the placebo group and 8.8% in the confirmed self-reporting. However, information regarding cata- tamoxifen group. The findings regarding quality of life will be ract surgery was verified and documented by examination of presented in a subsequent publication.
medical records. The rate of cataract development among Causes and Demographics of Deaths
women who were cataract-free at the time of randomization was21.72 per 1000 women in the placebo group and 24.82 per 1000 Seventy-one deaths occurred among participants in the pla- women in the tamoxifen group. This represents an RR of 1.14, cebo group and 57 occurred among women in the tamoxifen with CIs that indicate marginal statistical significance (95% CI group (RR 4 0.81; 95% CI 4 0.56–1.16) (Table 11). Forty-two 4 1.01–1.29). There was also a difference by treatment group deaths in the placebo group and 23 deaths in the tamoxifen groupwith respect to cataract surgery. In the placebo and tamoxifen were due to cancer. Aside from the breast, uterus, ovary, and groups, the rates of developing cataracts and undergoing cataract lung, a small number of deaths were related to cancer occurring surgery were 3.00 and 4.72 per 1000 women, respectively (RR at a variety of other sites, such as the brain, colon, pancreas, Table 9. Average annual rates of cataracts and cataract surgery among participants
Rate per 1000 women Status of participants 95% confidence interval Without cataracts at randomization Developed cataracts Developed cataracts and underwent cataract surgery Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Table 10. Distribution of participants in the placebo and tamoxifen groups by
thyroid gland, and kidney. Fifteen deaths in the placebo group highest level of hot flashes, vaginal discharge, and depression reported* and 22 deaths in the tamoxifen group were from causes relatedto the vascular system. Four women died of stroke in the tamoxi- % of participants fen group, whereas three women died of stroke in the placebo group. Two women in the tamoxifen group and none in the placebo group died of arterial disease other than stroke. Three Hot flashes, bothersome women in the tamoxifen group and none in the placebo group died as a result of pulmonary embolism.
Vaginal discharge, bothersome Although, in the past, consideration had been given to pri- mary prevention, the aim of which was to prevent cancer by identifying and eliminating cancer-causing agents, and to sec- ondary prevention, which involved screening individuals at in- creased risk for cancer in the hope that early detection and Depression (CES-D)† treatment would affect survival, it was not until the mid-1980s that serious attention was given to chemoprevention, an ap- proach aimed at reducing cancer risk by the administration of natural or synthetic clinical compounds that prevent, reverse, or suppress carcinogenesis in individuals at increased risk for the *The quality-of-life questionnaire that was used was a self-reporting instru- disease (38). Although biologic and clinical considerations re- ment. Some participants opted not to complete the questionnaires. Thus, infor- lated to chemoprevention have received much attention (39–41), mation is not available for 101 women in the placebo group and 110 in thetamoxifen group.
almost no studies have been directed toward evaluating the con- †CES-D refers to a self-administered depression scale developed by the Cen- cept as it relates to breast cancer. Although information obtained ter for Epidemiological Studies (36).
in the l980s provided support for the theory that dietary fat mightbe associated with the occurrence of breast cancer and that re-stricting fat intake could perhaps reduce the incidence of thedisease (42), a trial to test that hypothesis has only recently been Table 11. Distribution of causes of death
implemented. The use of retinoids for the prevention of breast cancer began to receive attention in 1987, when a study wasinitiated to evaluate the effectiveness of fenretinide (4-HPR) (43). To date, as far as we are aware, no information with regard to breast cancer end points has been reported from that trial.
The findings in this article provide the first information from a randomized clinical trial to support the hypothesis that breast Uterus (endometrium) cancer can be prevented in a population of women at increased risk for the disease. They show that tamoxifen administration reduced the risk of invasive and noninvasive breast cancers by almost 50% in all age groups. Of particular importance is the Extrahepatic bile duct finding that a benefit from tamoxifen was identified among women at various levels of risk within the spectrum of risks associated with participants in the P-1 study.
Primary site unknown Because of the importance of knowing whether or not the Cardiac and vascular disease finding that tamoxifen reduces the incidence of tumors can be Heart disease (ischemic and other) generalized to all women, extensive effort was directed toward Pulmonary embolus recruiting nonwhite participants. Despite great effort, the num- ber of nonwhite participants was small, and there were few events among those women. For these reasons, the size of the Amyotrophic lateral sclerosis treatment effect estimated from the total population (49% reduc- Automobile accident Miscellaneous (11 different causes) tion of breast cancer risk) may not be a reliable estimate for nonwhite women.
Also of importance are the findings obtained in women who Average annual rate per 1000 women had a history of LCIS or atypical hyperplasia, pathologic entities Risk ratio (95% confidence interval) 0.81 (0.56–1.16) thought to increase the risk of invasive breast cancer. Althoughthe present study was not designed to address these issues, itprovides the only quantitative information available from a clini-cal trial about the magnitude of the risk of invasive cancer inwomen with a reported history of LCIS or atypical hyperplasia Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 and presents the only information to demonstrate that tamoxifen employing the drug for the treatment of breast cancer was in- can reduce the magnitude of that risk. When compared with women conclusive. The P-1 study findings that failed to demonstrate who had no history of LCIS or atypical hyperplasia, the finding of that tamoxifen reduced the risk of and mortality from ischemic a 100% increase in the average annual rate of invasive cancer heart disease differ from those obtained in the Stockholm (48) among women in the placebo group who had a history of LCIS and and the Scottish (49) studies, in which it was reported that of a nearly 57% increase in this rate among women with a history tamoxifen reduced cardiac morbidity in breast cancer patients.
of atypical hyperplasia clearly indicates that these pathologic enti- These findings are similar, however, to those observed in the ties are associated with a substantial increase in a woman's risk for NSABP B-14 trial. In that study (50), although there was a trend invasive breast cancer. Even more important is the finding that that suggested the possibility of such an effect, statistically sig- tamoxifen administration dramatically reduced the risk of invasive nificant differences in cardiovascular mortality were not ob- cancer in women with a history of LCIS or atypical hyperplasia.
served in tamoxifen-treated patients. Thus, although tamoxifen Although the findings indicating the extent to which the in- can improve lipid profiles, its effect on the reduction of cardio- vasive cancer risk was reduced are compelling, the occurrence of vascular disease in women taking the drug remains uncertain.
a 50% reduction in the risk of noninvasive breast cancer is While the current findings suggest that tamoxifen does not play equally important for the following reasons. The expanded use a role in preventing ischemic heart disease, they do show that, at of mammography has resulted in the more frequent detection of least during the duration of the P-1 study, the drug did not have DCIS. In view of the cost involved and the effort required to a detrimental effect on the heart.
diagnose these tumors and in light of the debate about both the One of the original aims of the P-1 study was to determine initial and subsequent treatment of patients with DCIS and the whether tamoxifen reduced the risk of fractures of the hip, radius(Colles'), and spine. The current findings indicating a 45%, putative relationship between DCIS and the subsequent occur- 39%, and 26% reduction in fractures at those sites cannot be rence of invasive breast cancer, a reduction in the risk of DCIS viewed as inconsequential. When considered in light of the es- must be viewed as an important finding, since prevention of that timate made in 1990 that 24 million American women suffer disease would obviate the above considerations. Moreover, the from osteoporosis, that 1.3 million fractures per year occur sec- reduction in the incidence of DCIS provokes consideration of ondary to that disease, and that the estimate of the cost of treating the biologic significance of that finding. Cells comprising most such patients is $6.1 billion per year, the prevention of fractures is DCIS lesions have been demonstrated to be ER positive (44,45). important for women at increased risk for breast cancer who are Consequently, if DCIS is, indeed, a precursor of invasive cancer, also at risk for osteoporosis as they age (51). Because the findings at least some of the invasive tumors that were prevented by with regard to fractures are based on a relatively small number of tamoxifen in the P-1 study could be the result of the elimination events, definitive conclusions relative to the effect of tamoxifen on of occult DCIS by the drug. In that regard, the findings regarding the rate of fractures must await additional information.
the characteristics of the invasive breast cancers that occurred Whether the benefit achieved from tamoxifen in the P-1 study among the participants in the P-1 study are of importance. When was due to the drug's interference with the initiation and pro- the findings from tumors that occurred in the two groups were motion of tumors or to hindrance of the growth of occult tumors compared, it was observed that, in the tamoxifen group, there is unknown. Because it is likely that a broad spectrum of mo- was a decreased rate of invasive cancers that were ER positive, lecular–biologic and pathologic changes in breast tissue existed that were 2.0 cm or less in size, or that were associated with among participants at the time of their entry into the trial, it negative lymph nodes. These observations provide insight rela- might be assumed that both mechanisms were responsible for tive to the biologic nature of the tumors that were prevented.
the finding. Nonetheless, the absence of specific information to These findings are consistent with the thesis that the benefit from resolve the issue does not detract from the evidence indicating tamoxifen results from its inhibition of the growth and progres- that tamoxifen did, in fact, prevent the clinical expression of sion of tumors that are ER positive, i.e., those that are more tumors, i.e., the goal of primary disease prevention.
likely to exhibit slower growth and less likely to be associated The length of tamoxifen administration is another concern. It with axillary nodal involvement. It is also of interest that LCIS has been speculated that tamoxifen administration for only 5 and atypical hyperplasia are, most often, ER positive (46,47) and years may merely delay tumor growth for a short time and that, that there was a marked reduction in tumors that occurred in if the drug fails to affect the process of tumor initiation and women with a history of those lesions. In view of these findings, promotion, tumors will subsequently appear. In view of the time a question to be answered relates to when cells in the biologic required for a tumor to become clinically evident, another con- cascade of events leading from tumor initiation to the pheno- cern that has been raised is that the administration of tamoxifen typic expression of invasive tumors express their ER status and, for only 5 years may be inadequate. Information from NSABP thus, may be affected by tamoxifen.
B-14, which indicated that the benefit from 5 years of tamoxifen Although the P-1 study was not designed to have the power administered to women with stage I ER-positive tumors re- to evaluate specifically the hypothesis that tamoxifen reduced mained through 10 years of follow-up, fails to support that con- the rate of heart disease, a secondary goal was to obtain infor- cern (52). Since the findings in that study also demonstrated that mation regarding the incidence of fatal and nonfatal myocardial more than 5 years of tamoxifen did not enhance the drug's infarctions. When the study was being designed, there was evi- effect, in the P-1 study the drug was administered for only 5 dence that tamoxifen altered lipid and lipoprotein metabolism years. However, additional studies with more prolonged tamoxi- (22–26). However, information about tamoxifen's effect on the fen administration and follow-up time are necessary before a cardiovascular system that had been obtained from clinical trials hypothetical issue such as this one can be resolved.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Another question that has been raised by the study results ment of cataracts among women who were cataract free at the relates to the timing of tamoxifen administration. In women at time of randomization. An increase in the rate of cataracts was sufficient risk for receiving the drug, the issue of timing should found in the tamoxifen group. We do not consider the ophthal- not be considered critical. On the other hand, it is likely that the mic toxicities from tamoxifen administration sufficiently great biologic changes that occurred in breast cells were present when to warrant withholding the drug from women such as those who participants who subsequently developed tumors were enrolled in participated in the P-1 trial.
the trial. Consequently, it is not unexpected that such tumors began Finally, as we (10,62) and others (63,64) have noted in pre- to be diagnosed early in the follow-up period. Thus, it does not vious investigations, certain vascular-related events reported in seem justified to delay administration of the drug to women such as the P-1 study were more frequent in older women who received those in the P-1 study who were at increased risk for breast cancer.
tamoxifen than in those who received placebo. While there was It is appropriate to consider whether the benefit from tamoxi- an overall increase in the average annual rate of stroke in women fen in reducing the incidence of breast cancer is sufficiently 50 years of age or older, uncertainty exists regarding the mecha- great to justify its use as a chemopreventive agent despite the nism responsible for these results. There is also uncertainty re- risk of undesirable side effects. From the onset of the P-1 study, garding the cause of death in women who had a pulmonary there has been considerable emphasis on the adverse effects of embolism. Although three deaths were reported as being due to tamoxifen, particularly with regard to endometrial cancer and pulmonary embolism, all were associated with comorbid condi- vascular-related toxic effects, which predominate in postmeno- tions that could have accounted for those deaths.
pausal women. Recent reviews and individual studies of the rela- On the basis of the P-1 findings and this commentary, it is tionship between tamoxifen and endometrial cancer indicate that necessary to consider the question of who should receive the concern with regard to the level of excess risk of endometrial tamoxifen to decrease their risk of breast cancer. The findings in cancer may have been exaggerated and that, when endometrial this article indicate that women 50 years of age or younger who cancers do occur in women who receive tamoxifen, they have as would have been eligible for the P-1 study are candidates for the favorable a prognosis as those in women who do not receive the drug. Similarly, women with a history of LCIS or atypical hy- drug or who receive estrogen replacement therapy (53–57). perplasia and postmenopausal women at high risk for breast In the P-1 trial, the average annual rate of invasive endometrial cancer who have had a hysterectomy should be considered eli- cancer in women 50 years of age or older who received tamoxifen gible for tamoxifen.
was similar to what we had noted in the B-14 trial, i.e., about 2 per Women who have a history of DCIS may also be appropriate 1000 women per year. Of particular importance are the observa- candidates for tamoxifen. Findings from other NSABP trials tions in this study that refute the claim that endometrial cancers (B-17 and B-24) have demonstrated that the risk for an invasive occurring in tamoxifen-treated women are more aggressive, are less breast cancer in women with localized DCIS is at least as high, easily manageable, and cause more deaths than endometrial cancersthat occur in non-tamoxifen-treated women or in those who have if not higher, than that for women with a history of LCIS. In the received hormone replacement therapy (58). There is no evidence, current study, women in the placebo group who had a history of either from this study or from any other NSABP trial (59,60), to LCIS had an annual rate per thousand for breast cancer of 12.98.
support those contentions. To date, all of the invasive endometrial The annual rate of invasive cancer among women who under- cancers noted in the P-1 study in women who received tamoxifen went lumpectomy for DCIS was 23.7 (B-17) and, among those were FIGO stage I, i.e., localized tumors. Thus, our findings fail to treated with lumpectomy and radiation therapy, it was 14.4 (B- show that such tumors carry an unfavorable prognosis. Nonethe- 24). In both of those studies, the risk of developing an invasive less, because of the increased risk of endometrial cancer, women cancer was considerable. That risk could be substantially re- receiving tamoxifen should have regular gynecologic examinations duced by tamoxifen administration.
and should see their physicians if they experience abnormal vaginal Another group of women who might also be candidates for tamoxifen are those at high risk for breast cancer because they Reports have appeared about the dangers of liver damage, carry BRCA1 or BRCA2 genetic mutations. In the P-1 study, hepatoma, colon cancer, and retinal toxicity resulting from blood that was obtained from participants for the conduct of tamoxifen administration. As the findings in this article and in future scientific investigations is now being used to determine reports from other NSABP studies attest, such concerns have not how many of them had these mutations and whether tamoxifen been substantiated. To date, no primary liver cancers have been decreased their breast cancer risk. While that information is, as reported in the P-1 trial and no increase in the incidence of either yet, unavailable, offering women who carry these mutations the colon or any other second cancer, other than cancer of the uterus, option of taking tamoxifen may be considered, since doing so has been observed. Also, no differences in the self-reporting of provides an alternative to bilateral mastectomy.
macular degeneration were observed (59 cases in the placebo Many women 50 years of age or older who have stopped group and 60 cases in the tamoxifen group). Reports suggesting menstruating, have not had a hysterectomy, and have no history that tamoxifen administration might be associated with ocular of LCIS, DCIS, or atypical hyperplasia may also be eligible for changes led to the conduct of a Tamoxifen Ophthalmic Evalu- tamoxifen. The decision relative to which of these women ation Study in NSABP B-14. A recent report (61) from that should or should not receive tamoxifen for breast cancer pre- study indicated that no cases of vision-threatening toxicity oc- vention is complex. The primary determinant for making such a curred among tamoxifen-treated women, although posterior sub- decision relates to each woman's projected risk for breast can- capsular opacities were more frequently observed in that group.
cer. The higher the risk, the more likely that tamoxifen would In this article, information is presented relative to the develop- confer a benefit. Women whose breast cancer risk is sufficiently Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 high to offset the potential detrimental effects of tamoxifen It is likely that the paucity of events in the European studies was would be candidates for the drug. However, women whose due to the relatively small number of participants and to the fact breast cancer risk is not as high should evaluate their individual that the risk of breast cancer occurring among women in these benefits and risks with their physicians in order to make an trials was lower than that among participants in the P-1 trial. Be- informed decision with regard to the use of tamoxifen.
cause the criteria used for selecting participants in the Italian and One way in which the benefit from tamoxifen can be estimated the British studies were different from those used in the P-1 trial, is to subtract the overall number of unfavorable events from the women in those studies had a different risk for breast cancer than overall number of cancers prevented. Whether such a risk–benefit did P-1 trial participants, in that the expected proportion of ER- analysis is appropriate in deciding if tamoxifen should be used in negative tumors could have been higher in them. This difference is the prevention setting is questionable. It seems inappropriate to important because tamoxifen is unlikely to prevent the occurrence view an endometrial cancer as being ‘‘equivalent'' to a breast can- of ER-negative tumors. The true statistical power of a study to cer, since, when endometrial cancers occur in women who receive detect an effect of tamoxifen would be a function of the number of tamoxifen, they are most often curable by hysterectomy and the tumors that are ER positive rather than a function of the total mortality rate is minimal. Consequently, in the P-1 study, the breast number of breast cancer events. Thus, if the expected proportion of cancers that would have occurred had tamoxifen not been used ER-negative tumors is high, then the ability to show an effect of would have resulted in an estimated mortality rate that would likely tamoxifen would be substantially reduced, since the statistical have been higher than that observed from the undesirable effects of power that is based on the total number of events would be dimin- the drug. Moreover, the morbidity after hysterectomy would likely ished. The fewer the number of events, the more likely it is that this have been less than that resulting from the surgery, radiation, che- reduction in statistical power is a critical factor affecting the ability motherapy, and tamoxifen used to treat the unprevented breast can- to detect a difference between the study groups.
cer. Tools that can be used for determining a woman's breast can- Noncompliance is another factor that affects the ability to cer risk and the net effect from tamoxifen when used to prevent detect differences, since it will result in a decrease of the antic- breast cancer are currently being developed.
ipated effect of a drug. The rates of noncompliance were appre- As has been observed with the successive use of newer che- ciable in the European trials. With small numbers of participants motherapeutic agents for the treatment of breast cancer, it is and relatively small numbers of events, as occurred in those likely that new prevention agents will improve upon the benefits trials, a high level of noncompliance will result in a substantial achieved with tamoxifen. The new NSABP chemoprevention reduction in the likelihood of identifying a treatment effect. In trial P-2 represents such an effort. That trial will compare the the P-1 study, a high rate of noncompliance was used for sample- toxicity, risks, and benefits of the selective ER modulator size estimates (10% per year of follow-up). Thus, the sample size (SERM) raloxifene with those of tamoxifen. Raloxifene, which was planned to be sufficiently large to preserve adequate power has been shown to prevent osteoporosis, will be evaluated in post- even in the presence of a high rate of noncompliance.
menopausal women to determine its value in preventing breast Perhaps the most important reason for the failure of the Eu- cancer without increasing the risk of endometrial cancer (65). ropean studies to provide an adequate test of tamoxifen's effect The uncertainty of the clinical application of the current find- could be due to the fact that 41% of the women in the British ings is analogous to uncertainties related to the use of systemic trial and 14% in the Italian study received hormone replacement adjuvant therapy for breast cancer. With each demonstration of therapy. This introduced a potential confounding factor that the worth of such therapy, questions continue to arise as to who could have interfered with testing of the hypothesis that gave rise should receive the treatment, i.e., who will benefit and who will to the conduct of both trials. The use of hormone replacement not, who will not need the therapy because they will never therapy was considered to be a protocol violation in the P-1 trial.
demonstrate a treatment failure, how much of a benefit is worth- Until a clinical trial evaluating the efficacy of using tamoxifen while, and whether or not the toxicity and mortality encountered with hormone replacement therapy is conducted, it is difficult to justify its administration. Despite these uncertainties, the use of assess the relevance of findings from trials using that regimen.
adjuvant therapy was considered to be a major advance in the The issue has been raised that the P-1 trial was stopped pre- treatment of early stage breast cancer. The use of a chemopre- maturely and that the findings were reported too early. The trial ventive agent denotes a similar advance in that it is being employed was stopped only when the independent monitoring committee at an even earlier stage, i.e., during the origin and development of for that study (ERSMAC), on the basis of stopping rules estab- a phenotypically expressed cancer before its diagnosis.
lished before the onset of the trial, concluded that the primary Before submission of this article for publication, the results of study hypothesis had been confirmed beyond a reasonable two European studies were published (66,67) that failed to con- doubt, i.e., that tamoxifen decreased the incidence rate of inva- firm the P-1 study findings. None of the information presented in sive breast cancer (P<.00001). It was concluded that additional them alters our conclusion that tamoxifen significantly reduces follow-up would not have resulted in improved estimates of the probability of breast cancer in women at increased risk for treatment effects that would have justified withholding from the the disease. The three studies are too dissimilar in design, popu- participants on placebo the knowledge that tamoxifen was an lation enrolled, and numerous other aspects to permit making effective prophylactic agent. This allows those women on pla- valid comparisons among them. For a variety of reasons, it is cebo to consider taking tamoxifen. While additional studies are unlikely that the European studies provided an adequate test of needed to address the issues that have arisen as a result of our tamoxifen's effectiveness as a preventive agent. There were rela- findings, we consider it highly inappropriate to not offer tamoxi- tively few breast cancer events (70 in the British trial and 49 in fen to women who are similar to those in the P-1 study and who the Italian study, as compared with 368 events in the P-1 study).
may benefit from its use as a breast cancer preventive agent.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Appendix A. Clinical centers participating*
Principal investigator Program coordinator Albert Einstein Cancer Center, Philadelphia, PA Allegheny Cancer Center Network, Pittsburgh, PA Alliant Health System, Louisville, KY Arizona Cancer Center, Tucson Arrington Cancer Research and Treatment Center, Lubbock, TX C. Geyer, Jr.
Atlanta Breast Cancer Prevention Program Atlanta Community Women's Health Project, GA Atlanta Regional CCOP Baltimore Clinical Center, MD Baptist Cancer Institute CCOP, Memphis, TN Baptist Health System, Birmingham, AL Baptist Regional Cancer Institute, Jacksonville Bassett Hospital, Cooperstown, NY Bay Area Cancer Control Consortium, CA M. Milian-Menendez Baylor-Sammons Cancer Center, Dallas, TX Boston University Medical Center, MA Breast Health Center, New England Medical Center, Boston, MA British Columbia Cancer Agency, Vancouver Carle Cancer Center CCOP, Urbana, IL Cedar Rapids Oncology Project CCOP, IA Central Illinois CCOP, Springfield Central New York Group, Syracuse Charleston/Morgantown Groups, WV City of Hope, Duarte, CA Colorado Cancer Research Program CCOP, Denver Columbia River CCOP, Portland, OR Columbus CCOP, OH Connecticut Task Force, Hartford Credit Valley Hospital, Mississauga, ON Creighton Cancer Center, Omaha, NE Cross Cancer Institute, Edmonton, AB Dana-Farber Consortium, Boston, MA Dartmouth-Hitchcock Medical Center, Lebanon, NH Dayton Clinical Oncology CCOP, OH Duke University Medical Center, Durham, NC E. Carolina University, Greenville, NC E. Maine Medical Center, Bangor Ellis Fischel Cancer Center, University of Missouri, Columbia Fairfax Hospital, Falls Church, VA Fox Chase Cancer Center, Philadelphia, PA Geisinger Breast Clinic of Danville, PA Georgetown University Lombardi Cancer Center, Washington, DC Glens Falls Hospital Cancer Program, NY Greater Phoenix CCOP, AZ Greenville CCOP, SC Hamilton Regional Cancer Center, ON Harbor-UCLA, Torrance, CA Hennepin County Medical Center, Minneapolis, MN Hoosier Oncology Group, Indianapolis, IN Huntsman Cancer Institute, Salt Lake City, UT Illinois Cancer Center, Chicago, IL Illinois Masonic Cancer Center, Chicago Jewish General/St. Mary's Montreal, PQ Kaiser Permanente CCOP, San Diego, CA Lehigh Valley Hospital, Allentown, PA Long Beach Memorial Cancer Institute, CA Los Angeles Oncologic Institute, CA M. D. Anderson Cancer Center, Houston, TX M. D. Anderson Cancer Network, Ft. Worth, TX Main Line Health System CCOP, Wynnewood, PA Manitoba Cancer Foundation, Winnipeg, MB Marshfield Clinic CCOP, WI Mayo Clinic CCOP, Scottsdale, AZ Medical Center of Delaware CCOP, Wilmington Medical College of Virginia MBCCOP, Richmond Memorial Sloan-Kettering Cancer Center, New York, NY Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Appendix A (continued). Clinical centers participating*
Principal investigator Program coordinator Mercy Hospital CCOP, Scranton, PA Metro-Minnesota Center, St. Louis Park Midwest BCPT, Kansas City, MO Milwaukee Group, WI Montana Group, Billings Michigan State University, East Lansing, MI N.E. Ohio BCPT Group, Cleveland New York Consortium: St. Vincent's Hospital/Guttman N. New Jersey CCOP, Hackensack N. Shore University Hospital CCOP, Manhasset, NY N.W./Virginia Mason CCOP, Tacoma, WA Ochsner CCOP, New Orleans, LA Ohio State/James Cancer Hospital, Columbus Oklahoma City Consortium, OK Project for Prevention of Cancer, Sein, PQ Puget Sound Oncology Consortium, Seattle, WA Roswell Park Cancer Institute, Buffalo, NY Royal Victoria Hospital, Montreal, PQ Rush-Presbyterian-St. Luke Medical Center, Chicago, IL S. Florida Group, Miami Beach S. Nevada CCOP, Las Vegas San Joaquin Valley CGOP, Fresno, CA San Juan MBCCOP, Puerto Rico Scott & White Texas A&M, Temple, TX Sioux Community Cancer Consortium CCOP, Sioux Falls, SD Southeast Cancer Control Consortium CCOP, Winston-Salem, NC St. Francis Program CCOP, Tulsa, OK St. Louis-Cape Girardeau CCOP, MO A. Greco, Jr.
St. Luke's Hospitals, CCOP, Fargo, ND St. Mary/Long Beach Community, CA Stanford University, Palo Alto, CA Strang Cancer Prevention Center, New York, NY Sutter/California Healthcare System Center, Sacramento, CA Texas Tech. University Health Sciences Center, Southwest Cancer Center, Lubbock Thompson Cancer Center, Knoxville, TN Tom Baker Cancer Centre, Calgary, AB Toronto Hospital Breast Group, ON University of Alabama at Birmingham J. Carpenter, Jr.
University of Arkansas for Medical Science, Little Rock University of California–Davis Cancer Center, Sacramento J. Goodnight, Jr.
University of California–Los Angeles Center for Health Sciences University of Chicago, IL University of Cincinnati Medical Center, OH University of Hawaii, Honolulu University of Iowa, Iowa City University of Kansas, Kansas City University of Kentucky Consortium, Lexington Clinic University of Michigan, Ann Arbor University of Montreal, PQ University of North Carolina, Chapel Hill University of New Mexico Cancer Center, Albuquerque University of Pennsylvania Cancer Center, Philadelphia University of South Alabama MBCCOP, Mobile University of Texas Health Science Center, San Antonio University of Wisconsin Comprehensive Cancer Center, Madison Upstate Carolina CCOP, Spartanburg, SC USC/Norris Comprehensive Cancer Center, Los Angeles, CA Vermont Cancer Center/University of Vermont, Burlington W. Pennsylvania Project, Pittsburgh, PA Wayne State University, Detroit, MI Wilford Hall Medical Center, TX Women's College Hospital, Toronto, ON *CCOP 4 Community Clinical Oncology Program; MBCCOP 4 Minority-Based Community Clinical Oncology Program; CGOP 4 Cooperative Group Outreach Program.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 Appendix B. The following key personnel were involved in the planning, implementation, conduct, and analysis of the National Surgical Adjuvant Breast and
Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) BCPT Steering Committee
Nikolay V. Dimitrov Charles Geyer, Jr.
Richard Margolese D. Lawrence Wickerham C. Conrad Johnston, Jr.
Endpoint Review, Safety Monitoring, and Advisory Committee (ERSMAC)
Laurence Freedman Lawrence Friedman Participant Advisory Board
Mary Ellen Gorman Romenza Kaye Thomas BCPT Coordinator Committee
Connie Szczepanek Sidney Shonkwiler C. Conrad Johnston, Jr.
Quality of Life Committee
Elizabeth Maunsell A. H. G. Paterson Jean-Clause Lasry John Ware, Jr.
Joseph Costantino Charles Geyer, Jr.
D. Lawrence Wickerham George Lewis, Jr.
Recruitment, Promotion, and Compliance Committee
Erwin Bettinghaus Paul Engstrom, Jr.
Rose Mary Padberg Antronette Yancey Joseph Costantino Joseph Costantino Santica Marcovina D. Lawrence Wickerham Northwest Lipid Research Laboratories
Santica Marcovina Katherine Rosecrans Farida Rautaharju Pentti Rautaharju Pat Halpin Murphy National Cancer Institute (NCI)
Sunita Kallarakal Rose Mary Padberg Alfred Fallavollita Barnett S. Kramer NSABP Biostatistical Center
Joseph Costantino Deborah Darnbrough Janet Famiglietti NSABP Operations Center
D. Lawrence Wickerham Donna Szczepankowski Elizabeth Tan-Chiu Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998 (24) Bruning PF, Bonfrer JM, Hart AA, de Jong-Bakker M, Linders D, van Loon J, et al. Tamoxifen, serum lipoproteins and cardiovascular risk. Br J (1) Heuson JC. Current overview of EORTC clinical trials with tamoxifen.
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This investigation was supported by Public Health Service grants U10-CA- (60) Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin 37377 and U10-CA-69974 from the National Cancer Institute, National Insti- WM. Endometrial cancer in tamoxifen-treated breast cancer patients: find- tutes of Health, Department of Health and Human Services.
ings from the National Surgical Adjuvant Breast and Bowel Project We thank Tanya Spewock for editorial assistance, Mary Hof for preparation (NSABP) B-14. J Natl Cancer Inst 1994;86:527–37.
of the manuscript, and Lynne Anderson and Gordon Bass for assistance with the (61) Gorin MB, Day R, Costantino JP, Fisher B, Redmond CK, Wickerham L, analysis. We gratefully acknowledge the courage and commitment of the 13 388 et al. Long-term tamoxifen citrate use and potential ocular toxicity. Am J women who agreed to participate in this trial. Without their support and efforts, the results of the study would not have been possible. Acknowledgement of (62) Fisher B, Redmond C. Systemic therapy in node-negative patients: updated additional contributions is presented in Appendix B.
findings from NSABP clinical trials. National Surgical Adjuvant Breast and Manuscript received July 29, 1998; revised August 27, 1998; accepted August Bowel Project. J Natl Cancer Inst Monogr 1992;11:105–16.
Journal of the National Cancer Institute, Vol. 90, No. 18, September 16, 1998

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