TOPICS IN BREAST CANCER
| ESTROGEN AND BREAST CANCER: IS THERE A LINK ?—William T. Creasman, MD, J. Marion Sims Professor, Department
of Obstetrics and Gynecology, Medical University of South Carolina, Charleston
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| Introduction: introduction of mammography as standard of care in mid to late 1980s led to significant increase in breast
cancer diagnoses in United States; decrease in incidence of breast cancer and mortality from breast cancer since 1998;
>50,000 cases of ductal carcinoma in situ (DCIS) diagnosed annually in United States (80%-85% diagnosed using mammography)
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| Study data: results of studies estimating risk for breast cancer with estrogen replacement therapy/hormone replacement
therapy (ERT/HRT; 1975-2000 [Bush TL et al])—concluded no benefit or risk, suggesting no adverse effect; six meta-
analyses (1988-1991)—showed no adverse effect; reanalysis of world data in 1997—showed 14% increased risk of developing
breast cancer in ever-users of HRT (statistically significant, but questionable whether clinically relevant); 24%
increased risk for current users; women using HRT for >5 yr had 35% increased risk; risk slightly elevated, but not statistically
significant for past users; clinically speaking, woman 65 yr of age using estrogen for 10 yr has 0.5% increased risk
of developing breast cancer, compared to nonuser; important to distinguish relative risk from attributable risk; attributable
risk for breast cancer from ERT—takes into consideration overall incidence of cancer; study looked at Surveillance
Epidemiology and End Results (SEER) data; woman 50 yr of age has 2.5% risk of developing breast cancer over 10 yr;
absolute risk for 10 yr, 3.1%; risk attributable to ERT over 10 yr, slightly >0.5%; death from breast cancer attributed to
ERT (factoring in 20% mortality), ≈0.1%; majority of breast cancer diagnosed at stage 1; long-term survival for stage 1,
97%; risk of not developing breast cancer over 10-yr period for woman 50 yr of age not using HRT, 97.5%; for same
woman using ERT, 96.8%; speaker notes study design factors affect study results
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| Closer look at Women’s Health Initiative (WHI): prospective double-blind randomized study; possible eligibility bias—
participants described as healthy postmenopausal women (“healthy” in title), even though those with history of heart attack,
stroke, pulmonary embolism or coronary bypass included; women with moderate vasomotor symptoms or history of
hip fracture ineligible for study; intent-to-treat analysis controversial—subjects may not adhere to protocol to which
they were randomized, but when evaluated, included as member of original group; preliminary report—not intended for
publication, yet had significant impact on prescribing of HRT; prospective double-blind randomized study gold standard
only for population studied and item or drug evaluated—study data should not be extrapolated from one patient population
to another (as done with WHI data); average age of WHI participant, 63 yr; HRT normally initiated in those ≈50 yr
of age; 10% of WHI participants 54 yr of age; approximately one-third of participants 70 to 79 yr of age; why study
stopped—investigators cited excess number of breast cancers; 1.26 hazard ratio (HR); confidence interval not statistically
significant; difference of 8 per 10,000 women-years between participants on ERT and those on placebo; annualized
death rates equal; no difference between placebo and ERT groups in in-situ cancers; speaker believes lack of significant
increase in DCIS suggests lack of cause-effect relationship between HRT and breast cancer; follow-up data from 2002
article—additional 17% incidence of breast cancer; HR decreased from 1.26 to 1.24; statistically significant at nominal
level, but not at adjusted level (speaker notes this is over-time analysis, not true multivariate analysis)
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| Review of 2002 report (2003 article): provided more details; breast cancer characteristics—tumors in HRT group 2 mm
larger than those in placebo group (statistically significant, but speaker questions whether clinically significant); breast
cancers diagnosed in various centers (variability in pathologists’ expertise and methods); greater number of positive
lymph nodes in estrogen-plus-progestin group than in placebo group (changes in surgical management and histopathology
may have played role); estrogen receptor (ER) positivity ≈90% in both groups (may not be representative of women
in United States; estrogen receptor positivity in United States, 65%) mammography—more abnormal mammograms reported
among women in study; 9.5% of participants in HRT group had abnormal mammogram in first year of study;
however, abnormal mammogram rate in United States, 11% (speaker questioning whether study results representative of
women in United States); data review—medical records and pathology reports reviewed locally; no pathology adjudication
(pathology centrally adjudicated using SEER coding system); mammography performed at >3000 locations (speaker
concerned about difference in interpretation among radiologists); “abnormal” not defined before study initiated
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| Estrogen-only trial: >50% of participants dropped out; almost 6% of participants in estrogen group desired more estrogen
(which they received from local physicians); data showed 23% decrease in breast cancer in women on estrogen only, and
28% reduction in women 50 to 59 yr of age (speaker believes would have been statistically significant if more participants
in study); statistically significant decrease in risk of developing breast cancer and in risk for ductal cancers in
women with no previous estrogen use; also, statistically significant decreased risk of developing breast cancer in those
taking estrogen only; total deaths—decreased (not statistically significant) among younger patients; lower among
women 50 to 59 yr of age
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| Observational arm of WHI (≈80,000 participants): exercise—data show exercise decreased risk for breast cancer by
14% in women 35 yr of age who exercised 1.25 to 2.5 hr per week; similar exercise at 18 or 50 yr of age did not decrease
risk; effective in women with body mass index (BMI) of 24, with increased benefit (risk decreased 30%) as exercise increases;
women with BMI of 24 to 28 decreased risk, but with only 1.25 to 2.5 hr per week of exercise; no benefit from exercise
if BMI >28.5; exercise benefit seen even if woman on HRT; anthropometric factors—increased weight increases
risk for breast cancer (likely second most important factor after age); data show anthropometric factors not associated with
breast cancer among women who ever used HRT; never-users with BMIs >31 had 2.5-fold greater risk of developing
breast cancer than lean women; speaker believes generalized obesity increases risk for breast cancer, but only in women
who have never taken HRT; HRT not risk factor for woman of average size or less who exercises; exercise does not decrease
risk in heavy woman, but risk not increased if woman on HRT; length of exposure to HRT—data suggest effect of
HRT dissipates quickly after discontinuation; mortality—mortality from breast cancer lower among women who developed
breast cancer while using estrogen; data looking at women with family history of breast cancer showed no increased
risk in women using HRT for >5 yr; other cancers—HRT associated with statistically significant decreased risk of developing
colon cancer; also associated with decreased risk for endometrial cancer
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| ASSESSING RISK AND SCREENING FOR BREAST CANCER —Marie E. Wood, MD, Professor of Medicine, University
of Vermont College of Medicine, and Director, Familial Cancer Program, Fletcher Allen Health Center, Burlington, VT
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| Risk factors: hormonal—increased endogenous hormone production with early menarche and late menopause (relative
risk ≤3); slight increased risk among women taking estrogen and progesterone (≈50% above baseline); diet—role unclear;
alcohol—risk greatest for women having 3 to 5 drinks per day; breast pathology—increased risk with breast biopsy
showing atypia; family history—confers greatest risk, but applies to smallest percentage of population
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| Assessment models: Gail model—takes into account age, first-degree family history, age at menarche, age at first childbirth,
and biopsy history; validated in clinical trials; not valid for women <35 yr of age or those not in active screening
program; can underestimate risk when there is strong family history or paternal transmission; Claus model—uses 2 first-
or second-degree relatives affected with cancer and age at cancer onset; calculates risk based on current age and lifetime
risk; estimates based on family history of 5000 women (cases and controls); does not incorporate other factors, eg, biopsy
or hormonal history; not used for those with >2 affected relatives
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| Hereditary breast cancer and genetic testing: accounts for 5% to 10% of cases; genes and environment account for another
15% to 20%; ≈75% of breast cancers sporadic; BRCA1 and BRCA2, account for 60% to 70%; Li-Fraumeni syndrome
(TP53 gene) and Cowden disease (PTEN gene) rare mutations; genetic testing may not provide conclusive
answers; BRCA1 mutation carriers —lifetime risk 50% to 85% (new information may lower risk estimate); median age
at onset of breast cancer in BRCA1 carrier, 43 yr; >50% chance of developing second primary breast cancer; risk for ovarian
cancer, 10% to 45%; increased risk for prostate cancer (not associated with early development of prostate cancer);
BRCA2 mutation carriers— median age at onset of breast cancer, 45 yr; risk for ovarian cancer ≈50% of risk associated
with BRCA1, with median age at onset similar to that of general population (sixth decade of life); men with BRCA2 mutation
have 6% risk of developing breast cancer; increased risk for prostate, head and neck, gastrointestinal, and pancreatic
cancers and melanoma; screening recommendations for those at high risk for breast cancer—monthly breast self-
examination (BSE), beginning at 15 to 20 yr of age; semiannual clinical breast examination, starting at 20 to 25 yr of age;
annual mammography; family testing initiated at age 5 to 10 yr younger than youngest case of cancer in family, but not
<25 yr of age; American Cancer Society (ACS) recommendations for individuals at average risk—BSE starting at 20 yr
of age; clinical breast examination every 3 yr between 20 and 40 yr of age, and annually after 40 yr of age; annual mammography
at >40 yr of age; studies looking at women between 39 and 70 yr of age show 28% reduction in breast cancer
mortality because of mammographic screening
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 | Mammography: women >50 yr of age—20% to 30% improvement in breast cancer survival; false-negative rate, 10% to
15%; women 40 to 50 yr of age—16% improvement in breast cancer survival; higher false-negative and false-positive
rates (≤25% and 30%, respectively); women <40 yr of age—untested efficacy; false-negative rate higher (>25%) because
of breast density; consider breast density when reviewing mammography report
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| Breast ultrasonography (US): time intensive; quality dependent on technician; best for evaluating abnormal physical examination
or mammography; can distinguish between solid and cystic mass; data suggest increased detection of small
cancers when US added to mammography
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| Breast magnetic resonance imaging (MRI): interpretation not sensitive to breast density; no radiation exposure; must be
done at specific time in menstrual cycle (in pre- and perimenopausal women); interpretation dependent on volume; expensive
and associated with reimbursement issues; high false-positive rate leads to high biopsy rate (contributes to increased
anxiety); data looking at usefulness in high-risk population—effective in detecting breast cancer in high-risk
population (SBE and mammography lack efficacy in this population); ACS endorses MRI screening for high-risk
women (defined as someone who, based on family history, has 20% risk of developing breast cancer); studies show
MRI more efficacious than mammography in detecting in situ and invasive cancer in high-risk population of women;
sensitivity—depends on several factors, eg, definition of sensitivity, inclusion of invasive and in situ cancer, breast
density; recent study showed MRI sensitivity equal in women wth low or high breast density; MRI recommended for
all women at increased risk; ACS does not recommend for women with lobular carcinoma in situ (LCIS) or atypical
ductal hyperplasia (ADH); specificity—fibroadenoma, proliferative and nonproliferative fibrocystic changes, and normal
parenchyma enhanced on MRI; interpreter must be able to identify normal changes and distinguish benign lesion
from malignant lesion; lower specificity rate; biopsy capability—facility with MRI-directed biopsy recommended;
cost—bilateral mammography, $300 to $500; bilateral US, $300; bilateral MRI, $1400 per breast (based on figures
from several years ago)
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| Prevention options for high-risk populations: mastectomy—decreases risk for breast cancer by 90%; prophylactic
oophorectomy—decreases risk for ovarian cancer by 90%; decreases risk for breast cancer by 50%; tamoxifen—
approved for prevention; 2 large studies show 50% reduction in incidence of breast cancer in women taking tamoxifen
for 5 yr, compared to placebo (2 smaller European studies did not show same effect); raloxifene—approved for prevention
of osteoporosis; study showed more DCIS in women on raloxifene than in women on tamoxifen; speaker not convinced
that prophylactic efficacy equivalent for tamoxifen and raloxifene; aromatase inhibitors—letrozole (Femara);
exemestane (Aromasin); anastrozole (Arimidex); block peripheral conversion of androstenedione and testosterone to estrone
and estradiol in postmenopausal women (cannot block estrogens produced by ovaries); 85% to 99% decrease in estrogen;
not associated with uterine cancer or thrombosis (as is tamoxifen); increased risk for bone fractures, osteoporosis,
and arthralgias
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| Statins for chemoprevention: may prevent ER-positive and ER-negative breast cancer (tamoxifen, raloxifene, and aromatase
inhibitors prevent only ER-positive disease; more ER-negative disease in BRCA1 mutation carriers and younger
women); mechanism of action unclear (lowering of serum cholesterol or inhibition of inflammation hypothesized); desirable
side effect and toxicity profiles; ongoing study at University of Vermont looking at effect of statins on breast cancer
biomarkers
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| Energy balance: diet and exercise play role in breast cancer, but specifics unknown; Women’s Intervention Nutrition
Study—evaluated effect of fat reduction on breast cancer outcome; women ages 48 to 80 yr, with early breast cancer
(stages 1-3), treated with surgery; anyone whose diet already good (<20% of calories from fat) ineligible for study; participants
in intervention arm significantly lowered dietary fat intake (grams/day), decreased calories consumed, increased
fiber intake, lowered BMI, and reduced weight by ≈6%; in women with ER-positive disease, no difference in relapse-free
survival between women in intervention arm and those in control group; however, significantly lower risk for recurrence
of ER-negative disease seen in intervention group, suggesting diet may have impact on ER-negative disease; Nurse’s
Health Study cohort—showed exercise lowered mortality from breast cancer; 9 metabolic-hours (met-hr) equivalent to 3
hr of walking; 10-yr follow-up showed significant difference between women exercising 3 met-hr/wk and those exercising
9 met-hr/wk; study of housework and cancer—showed lowering of premenopausal and postmenopausal breast cancer
(greatest effect seen in premenopausal breast cancer); speaker’s conclusion—“the more exercise and the more you
move, the more you are going to prevent breast cancer”
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Suggested Reading
Bush TL et al: Hormone replacement therapy and breast cancer: a qualitative review. Obstet Gynecol 98:498, 2001; Chlebowski
RT et al: Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention
Nutrition Study. J Natl Cancer Inst 98:1767, 2006; Chlebowski RT et al: Influence of estrogen plus progestin on breast cancer
and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA
289:3243, 2003; Creasman WT: WHI: Now that the dust has settled: a commentary. Am J Obstet Gynecol 189:621, 2003;
Garbe E et al: Variability of breast cancer risk in observational studies of hormone replacement therapy: a meta-regression
analysis. Maturitas 47:175, 2004; McTiernan A et al: Recreational physical activity and the risk of breast cancer in postmenopausal
women: the Women’s Health Initiative Cohort Study. JAMA 290:1331, 2003; Pierce JP et al: Influence of a diet
very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s
Healthy Eating and Living (WHEL) randomized trial. JAMA 298:289, 2007; Santen RJ, Petroni GR: Relative versus attributable
risk of breast cancer from estrogen replacement therapy. J Clin Endocrinol Metab 84:1875, 1999; Sprague JR, Wood
ME: Statins and breast cancer prevention: time for randomized controlled trials. J Clin Oncol 24:2129, 2006.
Educational Objectives
| The goal of this program is to improve management of breast cancer (through an enhanced understanding of the Women’s
Health Initiative [WHI]) and improve breast cancer screening. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Counsel patients about the use of estrogen and the risk of developing breast cancer.
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| 2. Analyze data from the WHI about the association between estrogen and breast cancer risk.
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| 3. Discuss the data on exercise and hormone replacement therapy in the prevention of breast cancer.
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| 4. Identify women at risk for breast cancer and formulate an assessment plan.
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| 5. Discuss prevention options for women at high risk for breast cancer.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose relevant
financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified
conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business
or commercial interest. For this program, the following has been disclosed: Dr. Creasman is on the Speaker’s Bureau of
Wyeth.
Acknowledgments
Dr. Creasman was recorded at the 38th Annual Ob/Gyn Spring Symposium, sponsored by the Medical University of
South Carolina, and held March 26-28, 2007, in Charleston, SC. Dr. Wood was recorded at Women’s Health Issues for
Primary Care Providers, sponsored by the University of Vermont College of Medicine, and held May 9-11, 2007, in
Burlington, VT. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production
of this program.
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