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Clinical Practice Guidelines in Oncology–v.1.2003
Breast Cancer
Risk Reduction
Version 1.2003
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NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
NCCN Breast Cancer Risk Reduction Panel Members
* Robert W. Carlson, MD/Chair
Stanford Hospital and Clinics
* Mary Gemignani, MD
Memorial Sloan-Kettering Cancer Center
Therese B. Bevers, MD
University of Texas M.D. Anderson
Cancer Center
William J. Gradishar, MD
Robert H. Lurie Comprehensive Cancer Center
of Northwestern University
Kimberly L. Blackwell, MD
Duke Comprehensive Cancer Center
Tom Lawton, MD
University of Washington Medical Center
Kenneth H. Cowan, MD, PhD
UNMC Eppley Cancer Center at
the University of Nebraska
Mary B. Daly, MD, PhD
Fox Chase Cancer Center
Stephen B. Edge, MD
Roswell Park Cancer Institute
Judy E. Garber, MD, MPH
Dana-Farber Cancer Institute
Deborah J. MacDonald, RN, MS
City of Hope Cancer Center
Martin C. Mahoney, MD, PhD
Roswell Park Cancer Institute
Sofia D. Merajver, MD
University of Michigan Comprehensive Cancer
Center
Susan Minton, DO
H. Lee Moffitt Cancer Center & Research
Institute at the University of South Florida
Rena V. Sellin, MD
University of Texas M.D. Anderson
Cancer Center
Charles L. Shapiro, MD
Arthur G. James Cancer Hospital &
Richard J. Solove Research
Institute at The Ohio State University
Eva Singletary, MD
University of Texas M.D. Anderson
Cancer Center
Richard Theriault, DO, MBA
University of Texas M.D. Anderson
Cancer Center
John H. Ward, MD
Huntsman Cancer Institute
at the University of Utah
Alice Whittemore, PhD
Stanford Hospital and Clinics
Eric P. Winer, MD
Dana-Farber Cancer Institute
Continue
* Writing Committee member
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
Table of Contents
NCCN Breast Cancer Risk Reduction Panel Members
Risk Assessment, Risk Status (BRISK-1)
Preventive Counseling For Patients Who Do Not Elect Risk Reduction
Therapy (BRISK-2)
For help using these
documents, please click here
Manuscript
References
Baseline Exam, Risk-Reduction Therapy, Monitoring on Tamoxifen,
Monitoring, Findings, and Management (BRISK-3)
Components of Risk/Benefit Assessment and Counseling (BRISK-A)
Breast Cancer Risk-Reduction Agents (BRISK-B)
Guidelines Index
Print the Breast Cancer Risk Reduction Guideline
Clinical Trials: The NCCN
believes that the best management
for any cancer patient is in a clinical
trial. Participation in clinical trials is
especially encouraged.
To find clinical trials online at NCCN
member institutions, click here:
nccn.org/clinical_trials/physician.html
NCCN Categories of Consensus:
All recommendations are Category
2A unless otherwise specified.
See NCCN Categories of Consensus
These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician
seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to
determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kind
whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are
copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in
any form without the express written permission of NCCN. ©2003.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
RISK ASSESSMENT
Qualitative Risk Assessment:
· Age a
· Ethnicity/race b
· Family history c
· Age at menarche
· Parity
· Age at first live birth
· Age at menopause
· Prior breast biopsiesd
· Atypical hyperplasia or LCIS
· Prior thoracic irradiation (e.g.,
Hodgkin’s disease)
· Known or suspected BRCA1,
BRCA2, p53, PTEN, or other gene
mutation associated with breast
cancer riske
aUtility
Guidelines Index
Breast Risk Reduction TOC
MS, References
RISK STATUS
Quantitative Risk Assessment:
· Known or suspected BRCA1,
BRCA2, p53, PTEN or other
gene mutation associated with
breast cancer risk e
· Close relatives with breast
and/or ovarian cancer
· Prior thoracic irradiation
· History of lobular carcinoma
in situ f
· Breast cancer risk
assessment g
(modified Gail Model
for women > 35 y of age)
Woman does not
desire risk reduction
therapy
(See BRISK-2)
Risk-reduction therapy counselingh,i
5 y breast cancer risk ³ 1.7% j
and
Life expectancy ³ 10 y k
and
No contraindication to tamoxifen h
5 y breast cancer risk < 1.7% j
or
Life expectancy < 10 y k
or
Contraindication to tamoxifenh
Woman desires risk
reduction therapy
(See BRISK-3)
See NCCN Breast
Cancer Screening and
Diagnosis Guidelines
of tamoxifen for breast cancer risk reduction in women under 35 years of
age is unknown.
bFor example there is an increased incidence of BRCA1 or BRCA2 mutations in
hSee Components of Risk/Benefit Assessment and Counseling (BRISK-A).
Ashkenazi Jewish individuals.
i The clinical utility and role of ductal lavage in assessment of risk and monitoring of
cShould include 3 generations, (including proband, offspring, paternal and
patients at increased risk of breast cancer remains an area of active
maternal generations) and include age diagnosed with cancer.
dProcedure done with the intent to diagnose cancer, multiple biopsies of the same investigation. The Panel awaits the results of further trials of ductal lavage before
definitive statements can be made regarding the routine use of ductal lavage.
lesion are scored as one biopsy.
j The definition of risk as defined by the National Surgical Adjuvant Breast and
eSee the NCCN Genetic/Familial High Risk Assessment Guidelines.
Bowel Project Breast Cancer Prevention Trial (NSABP BCPT).
fSee the NCCN Breast Cancer Screening and Diagnosis and Breast Cancer
kAs a reference point, the life expectancy of the average 78 y old woman in the US
Treatment Guidelines.
is 10.2 years.
gThe NCI Breast Cancer Risk Assessment Tool is a computer-based version of the
modified Gail model and may be obtained through the NCI Web site. There are
circumstances in which the Gail model underestimates risk for development of
breast cancer-for instance, BRCA1 and BRCA2 carriers and those with a strong
family history of breast cancer. The Claus model may be particularly helpful in
determining risk for breast cancer in woman with strong family history of breast
cancer.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-1
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
PREVENTIVE COUNSELING/SCREENING
Known or suspected BRCA1, BRCA2,
p53, PTEN or other gene mutation
associated with breast cancer risk e
or
Close relatives with breast and/or
ovarian cancer
History of lobular carcinoma in situ
See NCCN Genetics/Familial High
Risk Assessment Guidelines and
Breast Cancer Screening and
Diagnosis Guidelines
See NCCN Breast Cancer Screening
and Diagnosis Guidelines
Woman does not desire
risk-reduction therapy
Prior thoracic irradiation
5 y breast cancer risk ³ 1.7% j
and
life expectancy ³ 10 y k
and no contraindication to tamoxifen h
See NCCN Breast Cancer Screening
and Diagnosis Guidelines
eSee
the NCCN Genetics/Familial High Risk Assessment Guidelines.
Components of Risk/Benefit Assessment and Counseling (BRISK-A).
j The definition of risk as defined by the National Surgical Adjuvant Breast and Bowel Project Breast Cancer
Prevention Trial (NSABP BCPT).
kAs a reference point, the life expectancy of the average 78 y old woman in the US is 10.2 years.
hSee
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Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-2
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Normal
Woman desires
risk-reduction
therapy
MONITORING FINDINGS AND
MANAGEMENT
RISK REDUCTION
THERAPYm
BASELINE EXAM
· Clinical breast
exam
· Bilateral
mammogram if
not done in
prior 6 mo
Risk reduction
mastectomy
desired n
Bilateral mastectomy
± reconstruction
Routine follow-up
as clinically
indicated
Risk reduction bilateral
salpingo-oophorectomy
desired (Limited to those
with known or strongly
suspected BRCA1 and
BRCA2 mutations)
Bilateral salpingo-oophorectomy
and with peritoneal washings.
Pathologic assessment should
include fine sectioning of ovaries
and fallopian tubes
Routine follow-up
as clinically
indicated
Nonsurgical
risk reduction
desired
Abnormal
Guidelines Index
Breast Risk Reduction TOC
MS, References
Clinical triall
or
Tamoxifena,m
· Pelvic exam
· Consider ophthalmology
exam if cataracts or poor
vision
· Consider monitoring for
bone mineral density loss
if premenopausal
(category 2B)
See Non-surgical
risk reduction
therapy (BRISK-4)
See NCCN Breast Cancer Screening and
Diagnosis Guidelines
a Utility
of tamoxifen for breast cancer risk reduction in women under 35 years of age is unknown.
clinical trial should have baseline exam, follow-up, and monitoring as per protocol.
m See Breast Cancer Risk Reduction Agents (BRISK-B).
n Risk reduction mastectomy should generally be considered only in women with very high risk, such as
BRCA1 or BRCA2 mutations, or women with LCIS. Evaluation should include consultation with surgery
and reconstructive surgery. Psychological consultation may also be considered.
l Women in
Return to Breast Cancer Risk Reduction
Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-3
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
NON-SURGICAL RISK
REDUCTION THERAPYm
Tamoxifena,m
20 mg/day for 5 y
(category 1)
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
MONITORING ON
TAMOXIFEN
· H&P every 6 months or for symptoms
· Annual mammography
· Annual pelvic exam including age-appropriate Pap
smear (optional if post-hysterectomy)
· Ophthalmology exam if cataracts or vision problems
· Consider monitoring for bone mineral density loss if
premenopausal (category 2B)
· Monthly breast self-exam (category 2B) o
See Monitoring, Findings
and Management (BRISK-5)
aUtility
of tamoxifen for breast cancer risk reduction in women under 35 years of age is
unknown.
mSee Breast Cancer Risk Reduction Agents (BRISK-B).
oProspective trials of breast self examination in high-risk populations have not been
performed. However, the use of breast self-examination is generally encouraged.
Return to Breast Cancer Risk Reduction
Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-4
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
MONITORING FINDINGS AND MANAGEMENT
Asymptomatic
Abnormal vaginal
bleeding
Continue tamoxifen
Prompt evaluation for
endometrial cancer if
uterus intact
If endometrial cancer found, reinitiation of
tamoxifen may be considered after hysterectomy
if early stage disease
See NCCN Endometrial Cancer Treatment
Guidelines for management
Continue follow-up
If no endometrial cancer found, continue
tamoxifen and reevaluate if symptoms persist
or reccur
Hot flashes or
other symptoms
Deep vein thrombosis,
pulmonary embolism,
cerebrovascular accident
Symptomatic treatment.
If persists, reevaluate
role of tamoxifen
Continue tamoxifen
Discontinue tamoxifen, treat
underlying condition
Return to Breast Cancer Risk Reduction
Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-5
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
COMPONENTS OF RISK/BENEFIT ASSESSMENT AND COUNSELING
Options for risk reduction should be discussed in a non-directive counseling environment. For breast cancer risk reduction,
elements of this discussion include:
· Discussion of overall health status, including health risks/benefits of estrogen or hormone replacement therapy vs. risk reduction
options.
· If a woman is at high-risk secondary to a strong family history or very early onset of breast or ovarian cancer, special genetic
counseling should be offered. See NCCN Genetic/Familial High Risk Assessment Guidelines.
· Tamoxifen:
= Use of tamoxifen in combination with hormone replacement therapy (HRT) is not recommended outside a clinical trial, given the
uncertainty regarding long-term side effects of the combination and the association of HRT with increased breast cancer risk.
(Estring is permitted, category 3)
= Discussion of relative and absolute risk reduction with tamoxifen.
= Contraindications to tamoxifen: history of deep vein thrombosis, pulmonary embolus, thrombotic stroke, transient ischemic
attack, pregnancy or pregnancy potential without effective method of contraception.
= Common and serious adverse effects of tamoxifen, with emphasis on age-dependent risks. See Table 2 (MS-10)
= Prior hysterectomy.
· Risk reduction surgery
= Discussion of risk reduction mastectomy in high-risk women. Risk reduction mastectomy should generally be considered only
in women with very high risk, such as BRCA1, BRCA2 carriers, or women with LCIS. Evaluation should include consultation with
surgery and reconstructive surgery. Psychological consultation may also be considered.
= Discussion regarding the risk of breast or ovarian cancer and the option of risk reduction bilateral salpingo-oophorectomy.
· Option of participation in clinical research for screening or risk assessment (e.g., screening MRI and ductal lavage studies) or
chemoprevention (e.g. NSABP Study of Tamoxifen and Raloxifene or other studies).
Return to Breast Cancer Risk Reduction
Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-A
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
BREAST CANCER RISK-REDUCTION AGENTS
· Insufficient data are currently available regarding tamoxifen risk reduction in women who are carriers of BRCA1 or
BRCA2 mutations or who have had prior thoracic irradiation.
· Data regarding tamoxifen risk reduction is limited to women 35 y of age or older.
· For high-risk premenopausal women, data regarding the risk/benefit ratio for tamoxifen appears relatively favorable
(category 1)
· For high-risk postmenopausal women, data regarding the risk/benefit ratio for tamoxifen appears less favorable than
that for premenopausal women and is influenced by age, race, and presence of uterus (category 1).
· Raloxifene for breast cancer risk reduction is inappropriate unless as part of a clinical trial.
Return to Breast Cancer Risk Reduction
Table of Contents
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
BRISK-B
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Guidelines Index
Breast Risk Reduction TOC
MS, References
· personal history of proliferative benign breast disease
Manuscript
· history of radiation exposure
NCCN Categories of Consensus
Category 1: There is uniform NCCN consensus, based on high-level
evidence, that the recommendation is appropriate.
Category 2A: There is uniform NCCN consensus, based on lowerlevel evidence including clinical experience, that the
recommendation is appropriate.
Category 2B: There is nonuniform NCCN consensus (but no major
disagreement), based on lower-level evidence including clinical
experience, that the recommendation is appropriate.
Category 3: There is major NCCN disagreement that the
recommendation is appropriate.
All recommendations are category 2A unless otherwise noted.
Overview
Breast cancer is the most commonly diagnosed cancer in American
women, with 203,500 cases and 39,600 deaths estimated in 2002 in
1
the United States alone. Major risk factors for the development of
breast cancer have been identified and include:
· female gender
· increasing age
· early menarche
· late menopause
· BRCA1, BRCA2, p53, or PTEN mutations.
Estimating risk for the individual woman is difficult, and most breast
cancers are not attributable to risk factors other than female gender
and increased age. The modified Gail model is a computer-based
multivariate logistic regression model that uses age, race, age at
menarche, age at first live birth, number of first-degree relatives with
breast cancer, number of previous breast biopsies, and histology of
the breast biopsies to produce actuarial estimates of future breast
cancer risk.2-4
In women with a strong family history of breast cancer, women who
are known carriers of BRCA1, BRCA2, p53, or PTEN mutations, or
women who have had previous exposure to therapeutic doses of
thoracic radiation, the modified Gail model may underestimate
future risk for breast cancer. Models for risk estimation based on
family history of breast cancer exist, including the Klaus model,
which is especially effective in estimating risk of breast cancer in
5
women with a positive family history of breast cancer. The
development of effective strategies for the reduction of breast
cancer incidence has been difficult, because few of the existing risk
factors are modifiable and many of the potentially modifiable risk
factors have social implications extending beyond concerns for
breast cancer (e.g., age at first live birth).
· nulliparity
Tamoxifen for Risk Reduction
· older age at first live birth
The benefits of tamoxifen in the treatment of breast cancer in the
adjuvant and metastatic settings are well documented.
· family history of breast cancer
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Retrospective analysis of randomized, controlled clinical trials
comparing tamoxifen with no tamoxifen in the adjuvant treatment of
breast cancer has shown a reduction in the incidence of
6-9
contralateral second primary breast cancer. The Early Breast
Cancer Trialists' meta-analysis confirms that 5 years of tamoxifen
therapy reduces the risk of contralateral second primary breast
cancers by 47%.
10
The effectiveness of tamoxifen in this setting gave rise to the
National Surgical Adjuvant Breast and Bowel Project (NSABP)
Breast Cancer Prevention Trial, a randomized clinical trial of healthy
women aged 35 or older with a 1.7% or greater cumulative 5-year
risk for developing breast cancer. Women enrolled in the trial were
randomized in a double-blinded fashion to treatment with tamoxifen,
20 mg daily for 5 years, or placebo. Breast cancer incidence and
mortality were the primary end points of the study; high-priority
secondary end points included the occurrence of thromboembolic
disease, cardiovascular disease, bone fracture, and endometrial
cancer. The breast cancer risk reductions demonstrated in the
NSABP Breast Cancer Prevention Trial are presented in Table 1.
The results show that treatment with tamoxifen decreases the shortterm risk for future development of breast cancer by 49% in healthy
women over the age of 35 who have an increased risk for
developing breast cancer (Table 1). The median follow-up in the
NSABP Breast Cancer Prevention Trial was 54.6 months; thus, no
definite conclusions regarding long-term risk reduction can yet be
drawn. The benefits in terms of risk reduction exist across all age
groups (Table 1). The risk reduction in participants with atypical
hyperplasia was particularly striking (risk ratio, 0.14; 95%
confidence interval [CI], 0.03-0.47). However, as was anticipated
from the experience in women taking tamoxifen for breast cancer,
Guidelines Index
Breast Risk Reduction TOC
MS, References
the drug was associated with toxicities, including hot flashes,
increased risk of thromboembolic disease, an increased risk of
invasive endometrial cancer in postmenopausal women, and an
increased risk of cataracts (Table 2). An additional benefit of
tamoxifen was a decrease in bony fractures (Table 2 ). Average
annual mortality from all causes in tamoxifen-treated women was
2.17 per 1,000 women compared with 2.71 per 1,000 women in
placebo-treated women, for a risk ratio of 0.81 (95% CI, 0.56-1.16).
Based on the results of the NSABP Breast Cancer Prevention Trial,
the U.S. Food and Drug Administration approved tamoxifen for use
in the reduction of breast cancer incidence in October 1998.
European Studies of Tamoxifen
Three reported European studies comparing tamoxifen with placebo
for the reduction of breast cancer risk have also been reported. The
Royal Marsden Hospital is performing an 8-year extended pilot trial
of tamoxifen versus placebo in women ages 30 to 70 who are at
increased risk for breast cancer based largely on their family
11
history. Women in the trial are allowed to continue or to initiate
postmenopausal hormone replacement therapy. With 2,471
participants available for analysis, no difference between the 2 study
groups in the frequency of breast cancer has been observed.
Moreover, the toxicity experience between the 2 groups is not
significantly different statistically.
The Italian Tamoxifen Prevention Study randomized 5,408 women
ages 35 to 70 without breast cancer, who had undergone a previous
12
hysterectomy, to receive tamoxifen or placebo for 5 years. Women
in the trial were allowed to receive hormone replacement therapy.
With a median follow-up of 30.5 months, no difference in the
occurrence of breast cancer has been identified. Thromboembolic
Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-2
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
events, predominantly superficial thrombophlebitis, increased in the
tamoxifen-treated women.
The reason that the Royal Marsden Trial and the Italian Tamoxifen
Prevention Study failed to show the risk reduction shown in the
NSABP Breast Cancer Prevention Trial is not clear. However, the
European trials are smaller, allow for the concurrent use of hormone
replacement therapy, and enroll different study populations. At the
time of the interim report, only 149 women had completed 5 years of
treatment in the Italian Tamoxifen Prevention Trial.
The first International Breast Cancer Intervention Study (IBIS-I)
randomized 7,152 women at increased risk for breast cancer and
ages 35 to 70 to receive either tamoxifen or placebo for 5 years
(International Breast Cancer Intervention Study, 2002). Tamoxifen
provided a risk reduction for breast cancer (invasive or in situ) of
32% (95% CI 8-50; P = .013). Thromboembolic events increased
with tamoxifen (odds ratio 2.5 [95% CI 1.5 -4.4], P = .001), and
endometrial cancer increased nonsignificantly (P=.2). An excess of
deaths from all causes was seen in the tamoxifen treated women (P
= .028).
Raloxifene for Risk Reduction
Raloxifene is another selective estrogen receptor modulator that is
chemically different from tamoxifen. Like tamoxifen, it binds to the
estrogen receptor and blocks estrogen-mediated DNA transcription.
Unlike tamoxifen, experience with raloxifene in patients with
documented breast cancer has been very limited, and this agent
currently has no established role in the treatment of women with
breast cancer.
Guidelines Index
Breast Risk Reduction TOC
MS, References
The MORE Trial
The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was
designed to determine whether 3 years of raloxifene treatment
reduced the risk of fracture in postmenopausal women with
13
osteoporosis. A total of 7,705 postmenopausal women younger
than age 80 were randomized to receive placebo, 60 mg/d of
raloxifene, or 120 mg/d of raloxifene for 3 years. At study entry,
participants were required to have osteoporosis (defined as a bone
density at least 2.5 standard deviations below the mean for young
women) or a history of osteoporotic fracture. The study showed a
reduction in the vertebral fracture risk and an increase in bone
mineral density in the femoral neck and spine for the raloxifenetreated women, compared with those who received placebo.
After a median follow-up of 40 months in the MORE trial, breast
cancer was reported in 40 patients: 27 cases in 2,576 women on
14
placebo and 13 cases in 5,129 women on raloxifene. The relative
risk of developing invasive breast cancer on raloxifene, compared
with placebo, was 0.24; (95% CI, 0.13-0.44). Raloxifene markedly
decreased the risk of estrogen receptor-positive cancers (relative
risk, 0.10; 95% CI, 0.04-0.24) but did not appear to influence the risk
of developing an estrogen receptor-negative cancer (relative risk,
0.88; 95% CI, 0.26-3.00).
Side effects associated with the use of raloxifene included hot
flashes, influenza-like syndromes, endometrial cavity fluid,
peripheral edema, and leg cramps. In addition, there were more
deep vein thromboses (0.7% for raloxifene vs 0.2% for placebo) and
pulmonary emboli (0.3% for raloxifene vs 0.1% for placebo)
associated with raloxifene treatment. However, there was no
increase in the risk of endometrial cancer associated with raloxifene.
The results from this trial led to the initiation of the NSABP Study of
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MS-3
NCCN
®
Practice Guidelines
in Oncology – v.1.2003
Breast Cancer Risk Reduction
Tamoxifen and Raloxifene (STAR) trial, which is comparing the 2
drugs in postmenopausal women who are at increased risk of
developing breast cancer.
Prophylactic Mastectomy for Risk Reduction
The use of bilateral prophylactic mastectomy has not been
subjected to prospective, randomized study as a means of
decreasing breast cancer risk. However, bilateral prophylactic
mastectomy has been estimated in a retrospective analysis to
decrease the risk of developing breast cancer by approximately 90%
15
in moderate- and high-risk women. The psychosocial effect of
prophylactic bilateral mastectomy on women has not been
adequately studied. Such surgery would be expected to negatively
impact perceptions of body image, ease of forming new
relationships, and the quality of existing relationships. Moreover, the
procedure also eliminates the breast as a sexual organ. Bilateral
prophylactic mastectomy should be limited to those at very high risk,
such as patients with lobular carcinoma in situ (LCIS) or those who
are known carriers of BRCA1 or BRCA2 mutations.
Women and their physicians who are considering tamoxifen or
prophylactic mastectomy to reduce the risk of breast cancer must
balance the demonstrated benefits with the morbidity of the
interventions. Furthermore, the monitoring of patients undergoing
tamoxifen therapy is complex, because several organ systems are
at risk for adverse events. To assist patients and their physicians
with risk reduction strategies, the NCCN has developed these
guidelines for breast cancer risk reduction.
Guidelines Index
Breast Risk Reduction TOC
MS, References
Risk Assessment
Qualitative risk assessment includes the assessment of known risk
factors for the development of breast cancer. Based on the
qualitative risk assessment, women with known risk factors, such as
BRCA1, BRCA2, p53, or PTEN mutations, or more than 2 firstdegree relatives with breast cancer or ovarian cancer, may be
identified. Patients with BRCA1 or BRCA2 mutations or with a strong
family history of breast cancer should be evaluated and managed
according to the NCCN Genetic/Familial High-Risk Screening
Guidelines. These women may also be appropriate candidates for
risk reduction therapy.
Women with a history of thoracic irradiation, especially if it was
administered at a young age, are also at greatly increased risk for
16-18
the future development of breast cancer,
and are appropriate
candidates for risk reduction strategies. Women with a history of
LCIS are also known to be at substantially increased risk for the
future development of invasive breast cancer in both the ipsilateral
and contralateral breast,
risk reduction therapy.
19,20
and are thus appropriate candidates for
Women without BRCA1, BRCA2, p53, or PTEN mutations, a strong
family history of breast cancer, LCIS, or a history of thoracic
radiation should have their risk for future breast cancer estimated
2,4
according to the modified Gail model. As estimated by the modified
Gail model, the threshold risk required for a woman to consider the
use of risk reduction strategies must depend on an evaluation of the
efficacy, morbidity, and expense of the proposed intervention. As a
reasonable discriminating risk threshold, the panel has adopted the
estimated 1.7% or greater 5-year actuarial risk of breast cancer
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used to identify women eligible for the NSABP Breast Cancer
4
Prevention Trial. The Claus model provides estimation of risk for
future breast cancer in women with a strong family history of breast
cancer.5
The Gail model, modified by the NSABP investigators, is available
on a computer disk from the National Cancer Institute and may be
ordered through the NCI website at www.cancer.gov.
Risk Reduction Counseling
After determining qualitative and quantitative risk of future breast
cancer, women at relatively low risk (namely, women with less than
a 1.7% risk of invasive breast cancer within 5 years) should be
monitored according to the NCCN Breast Cancer Screening and
Diagnosis Guidelines. Women with a risk of greater than 1.7% may
be followed according to the NCCN screening guidelines if they (1)
decline consideration of risk reduction interventions, (2) have a
contraindication to risk reduction intervention (see BRISK-A), or (3)
have an overall health status that predicts a life expectancy of less
than 10 years. As a guideline, the life expectancy of the average 78year-old woman in the United States is 10.2 years. 21
Women who are appropriate candidates for risk reduction
intervention should undergo counseling that provides an estimate of
the future risk of breast cancer and the available strategies to
decrease that risk. Options for risk reduction should be discussed in
a nondirective counseling environment. The counseling should
include a discussion and consideration of (1) the individual's overall
health status; (2) the relative and absolute breast cancer risk
reduction achieved with tamoxifen; (3) the contraindications to
tamoxifen therapy; (4) the common and serious side effects of
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tamoxifen, with an emphasis on age-dependent risks; and (5) the
presence or absence of the patient's uterus.
Data from the NSABP Breast Cancer Prevention Trial show that the
toxicity experienced with tamoxifen is much more favorable in
younger than in older women, and the benefits in relative risk
reduction are similar across all age groups and risk groups. Thus,
the tamoxifen treatment risk/benefit ratio is especially favorable in
women between the ages of 35 and 50. Although the ratio is less
favorable in older women, it still generally favors the use of
tamoxifen. Unfortunately, individualized data regarding the
risk/benefit ratio for tamoxifen are not generally available except for
the broad age categories of 50 and younger versus older than 50.
Postmenopausal women without a contraindication to tamoxifen
may be eligible for the STAR trial. Women who submit a risk
assessment form for the STAR trial receive a computer-generated
estimate of their future risk of breast cancer using the modified Gail
model, which is age, race, and breast cancer risk-factor specific and
also projects risks (age and race specific) for the known, potentially
serious complications of treatment with a selective estrogenreceptor modulator. Completion of this form (or a similar
assessment) is encouraged. It provides an accurate estimate of an
individual's risks and benefits and further encourages women to
participate in ongoing breast cancer risk reduction clinical trials.
The risk reduction discussion should also cover the risks and
benefits of bilateral prophylactic mastectomy in women at very high
risk, such as those who are known carriers of BRCA1, BRCA2, p53,
or PTEN mutations or LCIS (rare instances). If bilateral prophylactic
mastectomy is considered, the evaluation and counseling should
include input from surgery, reconstructive surgery, and psychiatry.
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Discussion regarding the risk of ovarian cancer and the option of
prophylactic oophorectomy should also be included. For women
considered at increased risk because of genetic traits or very early
onset of breast or ovarian cancer in their families, the evaluation
should also include special genetic counseling, according to the
NCCN Genetic/Familial High-Risk Screening Guidelines.
considerably lower than the risk of breast cancer in BRCA1 or
BRCA2 mutation carriers, the absence of reliable methods of early
detection and the poor prognosis associated with advanced ovarian
cancer have supported the recommendation of bilateral prophylactic
oophorectomy after completion of childbearing in these women. The
risk of primary peritoneal cancer (cancer of the lining of the
peritoneal cavity) may still persist after bilateral salpingo-
Risk Reduction Therapy
oophorectomy in this setting.
Bilateral Mastectomy
Breast cancer risk reduction in patients undergoing bilateral
prophylactic oophorectomy has been reported. Retrospective
reports have indicated that in BRCA1 mutation carriers, a bilateral
salpingo-oophorectomy may offer breast cancer risk reduction as
Carefully selected women at increased risk (ie, with LCIS or BRCA1,
BRCA2, p53, or PTEN mutations) who have had appropriate
multidisciplinary consultations and who desire risk reduction therapy
should first undergo a clinical breast examination and bilateral
mammogram if not performed within the past 6 months. If results are
normal, patients who choose bilateral prophylactic mastectomy
should undergo the procedure with or without immediate breast
reconstruction. Women undergoing prophylactic mastectomy do not
require an axillary lymph node dissection unless breast cancer is
identified on pathologic evaluation of the mastectomy specimen.
After prophylactic mastectomy, women who are carriers of BRCA1
or BRCA2 mutations should be monitored according to the NCCN
Genetic/Familial High-Risk Screening Guidelines. Patients with
LCIS who undergo bilateral mastectomy should be followed up with
routine health maintenance. Patients found to have invasive breast
cancer or ductal carcinoma in situ at the time of prophylactic
mastectomy should be treated according to the NCCN Breast
Cancer Treatment Guidelines.
Bilateral Salpingo-oophorectomy
Women with BRCA1 or BRCA2 mutations are at risk for developing
breast and ovarian cancer. Although the risk of ovarian cancer is
22-24
25
well. Decreases in ovarian hormone exposure after surgical
removal of the ovaries may alter breast cancer risk. This may reach
50% risk reduction, depending on the age of surgical menopause.
Two recent studies reported on bilateral salpingo-oophorectomy in
carriers of BRCA1 or BRCA2 mutations.
In both studies, the
effectiveness of prophylactic oophorectomy in preventing ovarian
cancer was noted. The persistent risk of peritoneal tumors was
approximately 1% in both studies after bilateral oophorectomy. The
mean age of diagnosis of ovarian cancer was 50.8 years, thus
supporting the recommendation for delaying oophorectomy until
after the completion of childbearing. Risk reduction for breast cancer
was noted to be of the magnitude of 25% to 50% in the patients
undergoing bilateral salpingo-oophorectomy.
26,27
The removal of the ovaries results in premature menopause with an
associated increased risk of osteoporosis and cardiovascular
disease. Vasomotor symptoms and cognitive changes associated
with menopause may also substantially affect quality of life. The
surgery itself may have some associated complications. Hormone
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replacement in women undergoing bilateral salpingo-oophorectomy
did not adversely affect risk reduction in breast cancer noted and is
generally not recommended past the age of 50 years of age in
BRCA carriers.
It is unlikely that a prospective randomized study on the use of
bilateral salpingo-oophorectomy for breast cancer risk reduction will
be performed. Therefore, discussion of the risk reduction offered by
bilateral salpingo-oophorectomy is appropriate. Whether the
resulting reduction in the risk of breast cancer from this procedure is
preferable to a risk reducing bilateral mastectomy is likely to remain
a personal decision.
28
Nonsurgical Risk Reduction
Women without a known contraindication to tamoxifen who desire
nonsurgical breast cancer risk reduction therapy should be treated
with 20 mg/d of tamoxifen or enrolled in a clinical trial for breast
cancer risk reduction. Women receiving tamoxifen as a risk
reduction agent should undergo a pelvic examination with cervical
cytology (Papanicolaou smear) if the uterus is intact and an
ophthalmologic evaluation if they have had cataracts or poor vision.
Because evidence regarding the effect of tamoxifen on bone mineral
density in premenopausal women is contradictory, a baseline bone
mineral density determination may be considered (category 2B).
The optimal duration of tamoxifen therapy for risk reduction is not
known. In the Early Breast Cancer Trialists' most recent overview
analysis, continuing tamoxifen therapy for up to 5 years resulted in
an increasingly reduced risk for development of contralateral
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4
profile. Thus, 5 years appears to be a reasonable period for
tamoxifen treatment when this agent is used to reduce the risk of
breast cancer.
Patients who have abnormal results from their clinical breast
examination or bilateral mammogram should be treated according to
the NCCN Breast Screening and Diagnosis Guidelines or, if results
indicate malignancy, the NCCN Breast Cancer Treatment
Guidelines.
Raloxifene and Breast Cancer Risk Reduction
Despite the encouraging results from the MORE trial, raloxifene
cannot be recommended for breast cancer risk reduction outside of
a clinical trial. The number of breast cancer events in the MORE trial
was relatively small, and the median follow-up was only 40 months.
More importantly, the patient population included in the MORE trial
was not at elevated risk of developing breast cancer (as confirmed
by the small number of breast cancer events). It remains unknown
whether raloxifene treatment would produce similar results in a
group of women at elevated risk such as those included in the
NSABP Breast Cancer Prevention Trial.
For these reasons, the panel does not endorse the routine use of
raloxifene for breast cancer risk reduction in women who have an
elevated risk of developing breast cancer. The NCCN panel's
recommendation is similar to the conclusion drawn in the American
Society of Clinical Oncology Technology Assessment.
29,30
Monitoring Patients on Tamoxifen
10
primary breast cancer. In addition, the NSABP Breast Cancer
Prevention Trial, in which women received either placebo or
tamoxifen for 5 years, demonstrated a favorable benefit/toxicity
Follow-up of women treated with tamoxifen for breast cancer risk
reduction should focus on the early detection of breast cancer and
the management of adverse symptoms or complications.
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Appropriate monitoring for breast cancer and the evaluation of
breast abnormalities should be performed according to the NCCN
Breast Cancer Screening and Diagnosis Guidelines. The population
of women eligible for tamoxifen risk reduction therapy is at
sufficiently high risk to warrant, at a minimum, yearly bilateral
mammography, a clinical breast examination every 6 months, and
monthly breast self examination.
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were diagnosed with MMMT (carcinosarcoma). Overall, the rate of
sarcoma in women taking tamoxifen was 0.17 per 1,000 womenyears. This translates to less than one-tenth of 1%. AstraZeneca
reviewed all available global data on tamoxifen through July 2001
for the occurrence of uterine malignancy. These data included
worldwide literature reports. This study identified 942 uterine
malignancies, of which 140 (15%) were uterine sarcomas. Seventy38
three percent were the MMMT variant. Because of the malignant
epithelial component noted in MMMT (carcinosarcoma), these are
generally treated and staged as epithelial endometrial cancers.
Compared with endometrial cancers, they present at a more
advanced stage and thus may carry a worse prognosis in terms of
disease free and overall survival.
Endometrial Cancer
The increased risk for endometrial cancer in postmenopausal women
treated with tamoxifen requires monitoring. Early reports that
tamoxifen-associated endometrial cancer may be more aggressive
than other endometrial cancers have not been confirmed on further
study.
31-36
In the NSABP Breast Cancer Prevention Trial, the only
death from endometrial cancer occurred in a placebo-treated subject.
4
Recent analysis from the NSABP data has noted a small number of
uterine sarcomas among the number of patients taking tamoxifen with
an intact uterus. These patients have already been included in the
reported number of patients diagnosed with endometrial cancer.
Uterine sarcoma is a rare form of uterine malignancy occurring in 2% to
4% of all patients with uterine malignancy. It has an annual worldwide
37
incidence of between 0.5 and 3.3 cases per 100,000 women. Uterine
sarcomas arise from the stromal elements of the uterus and are
classified on the basis of whether they are pure, containing only a
malignant stomal element (i.e., leiomyosarcoma, stromal cell sarcoma),
or mixed, containing an epithelial and stromal element (e.g., MMMT
[malignant mixed Mullerian tumor] or carcinosarcoma).
In the NSABP trials (B-09, B-14, B-21, B-23, B-24, and P-1), a small
number of uterine sarcomas (12) were noted among the number of
patients diagnosed with endometrial cancer. Nine of the 12 patients
Because patients with uterine sarcomas have been included in the
estimation of risk for endometrial cancer, the detailed risk benefits
statistics previously published do not need to be changed. These
can be used to determine which women may benefit from tamoxifen
for reduction of breast cancer risk. However, a new “black box” Food
and Drug Administration warning on tamoxifen has been added to
highlight the uterine cancer risk (both endometrial and uterine
sarcoma) and will also include pulmonary embolism and stroke
risks.
Annual pelvic examination should include an age- appropriate
Papanicolaou smear if the woman has an intact uterus. The vast
majority of women with tamoxifen-associated endometrial cancer
present with vaginal spotting as an early symptom of cancer.
Therefore, prompt evaluation of vaginal spotting in the
postmenopausal woman is essential.
At present, there is insufficient evidence to recommend the
performance of uterine ultrasonography or endometrial biopsy for
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39-41
routine screening in asymptomatic women.
In women diagnosed
with endometrial cancer while taking tamoxifen, the drug should be
discontinued until the endometrial cancer has been fully treated.
The panel believes that it is safe and reasonable to resume
tamoxifen therapy after completion of treatment for early stage
endometrial carcinoma.
Retinopathy and Cataract Formation
Tamoxifen is associated with the rare occurrence of retinopathy and
with a 1.14 relative risk of cataract formation (95% CI, 1.01-1.29),
4
compared with placebo. Individuals developing cataracts while on
tamoxifen have a relative risk for cataract surgery of 1.57 (95% CI,
1.16-2.14), compared with placebo. Thus, in patients experiencing
visual symptoms, prompt ophthalmologic evaluation is appropriate.
Bone Mineral Density
Although tamoxifen is associated with an increase in bone mineral
density in postmenopausal women, there is concern that it may be
associated with a decrease in bone mineral density in
premenopausal women. Thus, monitoring bone mineral density in
premenopausal women may be considered.
Thromboembolic Disease
The prospective intermittent screening of women for
thromboembolic disease is unlikely to be of value. However, women
taking tamoxifen should be educated regarding the symptoms
associated with deep vein thrombosis and pulmonary emboli. They
should also be instructed to contact their physicians immediately if
they develop symptoms of deep vein thrombosis or pulmonary
emboli. Women with documented thromboembolic disease should
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be treated appropriately for the thromboembolic process and should
discontinue tamoxifen permanently.
Duration of Treatment
The optimal duration of tamoxifen therapy for the reduction of breast
cancer incidence has yet to be determined. Until further information
is available, a treatment period of 5 years appears to be appropriate.
After completing 5 years of therapy, women should continue to be
monitored according to the NCCN Breast Cancer Screening and
Diagnosis Guidelines and should continue to undergo monitoring for
late toxicity, especially for endometrial carcinoma and cataracts.
Management of Toxicity
Hot flashes are a common complaint among older women. In the
NSABP Breast Cancer Prevention Trial, hot flashes occurred in
approximately 81% of tamoxifen-treated women and 69% of
placebo-treated women. In women whose quality of life is
diminished by the experience of hot flashes, an intervention to
eliminate or minimize hot flashes should be undertaken. Although
estrogen and/or progestins are effective in eliminating hot flashes in
women taking tamoxifen, the safety of these agents is uncertain in
women at increased risk for breast cancer, and there is a potential
for interaction with tamoxifen that might affect its efficacy.
Anecdotal evidence suggests that vitamin E may decrease the
frequency and severity of hot flashes, but a randomized clinical trial
of this agent documents only a very modest improvement in hot
42
flashes when compared with placebo. Both the oral and
transdermal formulations of clonidine reduce hot flashes in a dosedependent manner.
43-45
Toxicities associated with clonidine include
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dry mouth, constipation, and drowsiness. Recently, a
nonrandomized pilot study suggested that low-dose venlafaxine was
successful in decreasing hot flashes.
46
However, not all women who experience hot flashes require medical
intervention, and the decision to intervene requires consideration of
the efficacy and toxicity of the intervention. Anecdotal evidence also
suggests that the use of a number of different herbal or food
supplements may alleviate hot flashes. Most of these herbal or food
supplements contain active estrogenic compounds, the activity and
safety of which are unknown. The panel, therefore, discourages the
use of herbal or food supplements in the symptomatic treatment of
hot flashes.
Summary
Breast cancer risk factor analysis allows the identification of women
at very high risk for the future development of breast cancer. Many
of the known risk factors are either not modifiable or are not
reasonably modifiable because of social implications or other
potential health benefits (e.g., those associated with hormone
replacement therapy). Thus, effective strategies to decrease the risk
of breast cancer are needed.
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The recent demonstration that the use of tamoxifen for 5 years
decreases the future risk of breast cancer by approximately 49%
provides the opportunity for a risk reduction intervention. Women
taking tamoxifen must be monitored for the occurrence of welldefined toxicities, including hot flashes and, more rarely,
endometrial carcinoma, thromboembolic disease, and cataract
formation. Strategies are available for the management of tamoxifen
toxicity.
In special circumstances, such as in carriers of BRCA1 or BRCA2
mutations, the risk of future breast cancer is very high, and the
performance of a bilateral prophylactic mastectomy may be
considered. Women considering bilateral prophylactic mastectomy
should undergo multidisciplinary consultation so that they may make
a fully informed decision.
The panel strongly encourages patients and health care providers to
participate in clinical trials to test new strategies for decreasing the
risk of breast cancer. Only through the accumulated experience
gained from well-designed, prospective clinical trials will additional
advances in the reduction of breast cancer risk be realized.
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Table 1
Breast Cancer Risk Reduction in the NSABP Breast Cancer Prevention Trial
Patient
Characteristic
Risk Ratio
(tamoxifen vs placebo)
95% Confidence
Interval
All women
Age
0.51
0.39–0.66
£ 49 yr
50-59 yr
0.56
0.49
0.37–0.85
0.29–0.81
³ 60 yr
Atypical hyperplasia
0.45
0.14
0.27–0.74
0.03–0.47
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast
cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J
Natl Cancer Inst 1998;90:1371-1388, by permission of Oxford University Press.
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Table 2
Toxicity Experience in Women Enrolled in the NSABP Breast Cancer Prevention Trial
Toxicity
Annual Rate Per 1,000 Subjects
Placebo
Tamoxifen
Invasive endometrial cancer
£ 49 yr
³ 50 yr
Deep-vein thrombosis
£ 49 yr
³ 50 yr
Stroke
£ 49 yr
³ 50 yr
Pulmonary embolism
£ 49 yr
³ 50 yr
Bone fracture
£ 49 yr
³ 50 yr
Ischemic heart disease
Cataracts
developed
Cataracts developed
and underwent surgery
Risk Ratio
95% Confidence
Interval
1.09
0.76
1.32
3.05
1.21
4.01
0.41–3.60
1.70–10.90
0.78
0.88
1.08
1.51
1.39
1.71
0.51–3.99
0.85–3.58
0.39
1.26
0.30
2.20
0.76
1.75
0.11–4.49
0.98–3.20
0.10
0.31
0.20
1.00
2.03
3.19
0.11–119.62
1.12–11.15
2.24
7.27
2.37
1.98
5.76
2.73
0.88
0.79
1.15
0.46–1.68
0.60–1.05
0.81–1.64
21.72
24.82
1.14
1.01–1.29
3.00
4.72
1.57
1.16–2.14
Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for the prevention of breast cancer:
Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer
Inst 1998;90:1371-1388, by permission of Oxford University Press.
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Version 1.2003, 11/05/02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.