Management of Women at Increased Risk for Breast Cancer
Carol J. Fabian
University of Kansas Medical Center
Kansas City, KS
Breast cancer is a common disease with 211,300 cases of invasive cancer and 55,700 cases of DCIS
expected in 20031. Although the chance of dying from invasive breast cancer once detected has
been reduced to approximately 25% by early detection and treatment, the majority of women who survive
endure significant morbidity from local and systemic therapy. Hence, the interest in risk assessment and
prevention. Fewer than 20% of affected women will be identified as having major risk factors such as a
positive family history or precancerous biopsy prior to their breast cancer diagnosis. Thus, healthy
lifestyle behaviors known to reduce risk of breast cancer should be employed by all women include
childbirth as early as feasible2, adequate intake of calcium, Vitamin D and other
nutrients3, exercise4, maintenance of normal weight5, avoidance of
prolonged or high dose hormone replacement therapy6, and avoidance of smoking and excessive
Standard Pharmacologic and Surgical Risk Reduction Interventions for High Risk Women
Pharmacologic and surgical risk reduction measures are associated with expense and side effects and
are thus reserved for women at increased risk for breast cancer. Tamoxifen is currently the only FDA
approved drug for breast cancer risk reduction. FDA approval was based on results from the NSABP P-1
trial in which women over 35 with a five year risk estimated by the Gail model to be 1.66% or greater
were randomized to tamoxifen or placebo for five years. Women randomized to tamoxifen were noted to have
a 49% decrease in the incidence of invasive cancer at a median follow-up time of four years from
randomization.7 The incidence of benign breast biopsies, including those exhibiting atypical
hyperplasia, was also reduced by about one-third in women randomized to tamoxifen8. The
minimum Gail risk requirement for entry in the NSABP-P1 trial was approximately equal to the average risk
for a 60 year old, double that for the average 40 year old, and eight times that for the average 30 year
old (SEER Data)9. Relative risk reduction in the NSABP P-1 trial was highest for those with
prior diagnosis of LCIS or atypical hyperplasia, and women over 607. The incidence of ER+
breast cancer was reduced by 69%, but there was no decrease in the incidence of estrogen receptor
negative breast cancers7. Estrogen receptor negative cancers tend to be more common in
premenopausal women, women harboring a deleterious BRCA1 mutation, and women with a contralateral ER
Tamoxifen use is associated with a significant increase in the risk of thromboembolic phenomena,
uterine cancer, and cataracts in women over 50, and menstrual abnormalities and ovarian cysts in
premenopausal women7. Both older and younger women taking tamoxifen exhibit an increase in
the prevalence of perimenopausal symptoms, vaginal discharge, candadiasis, abnormal bleeding, and sexual
dysfunction7, 13. Hysterectomy rates in tamoxifen treated patients are reported to be double
that of placebo treated patients13.
No improvement in survival was demonstrated in the NSABP P-1 study7 and the IBIS-1
prevention study noted a significant increase in deaths in women taking tamoxifen compared to placebo
even through relative risk for breast cancer was reduced by 32%13.
In order to achieve a favorable risk:benefit ratio, Gail et al. have recommended that, in the absence
of prior invasive or non-invasive cancer, the minimum five year Gail risk for breast cancer be increased
to approximately 2.5% in women >50 without a uterus and 5% for women with an intact uterus, before
considering use of tamoxifen as prevention therapy14. The minimum five year estimated risk of
>1.66% for women younger than 50 would still be appropriate14. Rockhill et al.
indicate that only a small minority of women developing cancer in the Nurses Health Study would have been
candidates for tamoxifen five years prior to detection of their tumor using the Gail model
Prophylactic mastectomy is generally reserved for those at very high risk of breast cancer such as
BRCA1-2 mutation carriers (risk approximately 2-3%/year after age 35) or women with prior contralateral
cancer and significant family history and/or ipsilateral precancerous changes. Prophylactic mastectomy
is associated with a 90% relative reduction in risk has been calculated to provide an improvement in
survival of 0.5 – 3.4 years in BRCA1 and BRCA2 mutation carriers depending on age at
intervention16. Prophylactic mastectomy even with reconstruction is associated with some
degree of disfigurement and in the absence of cancer is not an option often selected by even the highest
Prophylactic oophorectomy for premenopausal women is associated with a 40-50% relative risk reduction
for breast cancer and may be associated with an improvement in survival which has been calculated to be
0.2 – 0.8 years for BRCA1 and BRCA2 mutation carriers depending on age at intervention16.
Prophylactic oophorectomy in premenopausal women in the absence of hormone replacement is associated with
the abrupt onset of menopause symptoms and increased risk of premature cardiac disease, bone loss,
arthralgias, skin aging, and if low dose hormone replacement is not instituted.
Common Risk Assessment and Prevention Questions
Common questions from women undergoing consultation for risk assessment and prevention include the
These are good questions for which we have few answers, underscoring the need for risk and response
biomarkers for breast cancer similar to those for heart disease and osteoporosis.
- Given my young age, my calculated risk is too low to consider preventive treatment now, but I have a
close relative who developed cancer at the same age, how can you reassure me the same thing won't happen
- My calculated risk is high, but I am worried about tamoxifen's side effects and don't want surgery.
Is there some way to tell if precancerous changes are occurring in my breast?
- Since I can only take tamoxifen for five years how do you know that now is the time to intervene or
would it be better to wait awhile?
- Is there any test you can perform to help predict whether I will respond favorably to tamoxifen?
- How will you monitor my response to preventive tamoxifen or oophorectomy?
- I am having significant menopause symptoms. If I start hormone replacement is there any way to tell
if I am actually increasing my risk?
Biomarkers: Supplementary Risk Assessment Tools
The Gail model utilizes current age, age at menarche, age at first live birth, number of first degree
relatives, number of breast biopsies and whether atypical hyperplasia was present in those biopsies to
calculate short and longer term risk. The Gail model is accurate for populations undergoing regular
screening but has modest discriminatory value at an individual level15. This is primarily
because many women may have risk factors that are not considered by the Gail model and because the model
is heavily weighted by number of breast biopsies and affected first degree relatives. The majority of
women have neither first-degree relatives, nor have had a breast biopsy prior to their diagnosis of
There are several risk biomarkers that could be used to help refine estimates based on epidemiologic
models such as the Gail model. These include indirect markers of breast hormone exposure such as serum
bioavailable estradiol and testosterone18, nipple aspirate fluid production19,
mammographic breast density20, 21, direct and indirect markers of breast epithelial and
stromal proliferation such as Ki-67/MIB-1/PCNA22, mammographic density23, serum
IGF-1/IGFBP-324, and occult or clinical intraepithelial neoplasia19, 25-29. These
biomarkers also have the potential to be favorably modulated with a successful prevention intervention
and thus might be used to monitor response to prevention interventions.
The majority of breast cancers are thought to evolve in a sequential fashion: non-proliferative
→ hyperplasia → atypical hyperplasia → in situ cancer → invasive cancer.
Intraepithelial neoplasia refers to hyperplasia through in situ cancer30. Most risk
biomarkers either promote this process (hormones, growth factors) or are indirect (breast density) or
direct (intraepithelial neoplasia) reflections of this process.
Since intraepithelial neoplasia is most closely and directly related to invasive cancer the
demonstration of the presence this process is most likely to carry the most weight with both patients and
clinicians relative to other risk biomarkers in making decisions about whether to undergo prophylactic
surgery or take a prevention drug. Hyperplasia without atypia discovered in a diagnostic biopsy carries
a relative risk of 1.4X – 2.0X but hyperplasia with atypia a relative risk of 5X25.
Autopsy studies in presumably average risk women in their 30's, 40's and 50's indicate a high
prevalence of occult hyperplasia with and without atypia27. Lesions are generally
multicentric, bilateral and highly correlated with occult in situ and invasive cancer27.
Likewise, women at risk for hereditary breast cancer were found to have atypical lobular or ductal
hyperplasia, LCIS, or DCIS in 57% of prophylactic mastectomy specimens28. Those women
without prior prophylactic oophorectomy were likely to have multiple lesions, and the presence of single
or multiple lesions correlated with age over 4028.
We reasoned that women with the highest precancerous lesion density would be both most likely to have
lesions detected as a result of random tissue sampling and would be at higher short-term risk of
developing an in situ or an invasive cancer. In our initial study29, 480 high risk women
underwent random periareolar fine needle aspiration of both breasts, cytologic assessment and were then
followed for development of DCIS or invasive breast cancer. There were sufficient ductal cells for
cytomorphologic assessment in 94% of aspiration attempts. The median age was 44 and median calculated
ten year Gail risk estimate was 4.0%, and 76% had a positive family history. Hyperplasia was detected in
49% and hyperplasia with atypia in 21% of women. High-risk women in whom hyperplasia with atypia was
detected had a relative risk of breast cancer of five times that of women without atypia over the next
Wrensch and Petrakis have also demonstrated that atypical cells in nipple aspirate fluid are
associated with an increase in relative risk for breast cancer19, 31 but only 60-80% of high
risk women produce NAF and samples are often acellular19, 31-33. Ductal lavage is a technique
more likely to produce epithelial cells for cytologic examination but is only performed in NAF producing
women, and 22% of lavages do not produce sufficient cells for assessment32. Thus, only 47-62%
of women presenting for supplementary risk evaluation via ductal lavage are likely to both undergo
successful lavage and have sufficient cells for evaluation. Furthermore, although it is likely that
atypical cells found in lavage will carry the same short-term risk implications as hyperplasia with
atypia found in periareolar fine needle aspirations, a follow-up study for cancer development in women
undergoing tissue sampling by ductal lavage has not yet been completed.
Random periareolar fine needle aspiration has been successfully utilized in Phase II chemoprevention
studies to assess predictive biomarkers, proliferation, and cytomorphologic change34. For
evaluation of cytomorphologic change, the semiquantitative Masood scoring system is used35.
Fine needle aspiration lends itself well to evaluation of proliferation and other biomarkers (such as ER)
by immunochemistry29.35. It is unclear whether immunochemistry techniques may be employed
with a similar degree of success utilizing ductal lavage samples.
The major potential advantage of ductal lavage as a tool for sampling breast tissue for risk
assessment is that highly atypical cells suspicious for breast cancer might be localized and the duct
excised. A preliminary report by Khan et al. indicates that ductal lavage is not likely to be a
sensitive early detection technique for cancer as women undergoing ductal lavage just prior to planned
mastectomy for breast cancer did not necessarily produce either NAF or atypical cells in the same breast
quadrant as the cancer36.
Although NAF, ductal lavage and random periareolar FNA are all promising supplementary risk assessment
tools, they are probably most helpful when they are positive. Failure to produce NAF or atypical cells
on lavage or FNA cannot be used at present to provide complete reassurance that a woman is at a low
short-term risk for breast cancer37,38.
A multi-institutional study comparing ductal lavage and random periareolar fine needle aspiration as
methods of obtaining breast tissue in high risk premenopausal women before and after 12 months of a
potential breast chemoprevention agent, celecoxib, is currently underway. The object is to determine the
proportion of women having adequate cells for cytologic morphology (>1000), Ki-67
(>500) and two additional markers (COX-2 and ER each >100 cells) by both procedures.
Both procedures are tolerated well with a median pain score of 1 (0-10 scale) for FNA and 2.5 for ductal
lavage, so they are both performed the same day during the follicular portion of the cycle. Breast
density, serum hormones, and IGF-1 and IGFBP-3 are also being evaluated.
It is clear that cytology will play a major role in risk assessment and prevention over the next
decade. Presently, Phase III prevention trial designs with modulation of cytomorophology as a primary
endpoint are being proposed. New technologies may provide us with more objective and reproducible
measures of proliferation and other key molecular markers.
Nipple aspirate fluid, though often acellular, is a rich source of multiple steroid and protein
hormones and cytokines. A large number of these substances including estradiol, estrone, CEA, and bFGF
are present in far higher levels than in the serum39-43. Nipple aspirate hormone levels are
currently being monitored in a Phase II trial of the aromatase inhibitor letrozole.
Several investigators have reported preliminary evidence of unique protein patterns in breast cancer
patients from as little as 1μl of NAF fluid using surface-enhanced laser desorption/ionization time
of flight mass spectrometry (SELDI-TOF-MS) 43-45. Undoubtedly, in the near future patterns
will be identified which can separate low from high risk women with proliferative breast disease and help
supplement cytomorphologic assessments.
Quantitative real time PCR may also replace or supplement immunocytochemical measurement of
proliferation and other biomarkers as a more quantitative and reproducible tool, especially when
repetitive measurements are needed over time to assess response to an intervention.
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