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New Treatments for Breast Cancer
Management of Ductal Carcinoma In Situ
The optimal management of ductal
carcinoma in situ (DCIS) of the breast is one of the greatest challenges
in breast disease faced by clinicians today. Ductal
carcinoma in situ comprises 20% to 40% of all mammogram-directed
biopsies. The National Cancer Database reports that DCIS comprised 7% of all
newly diagnosed breast cancers in 1985.
Confusion surrounding the optimal treatment of DCIS continues.
Ductal carcinoma in situ is
not life-threatening per se unless it progresses to invasive cancer. DCIS may,
however, be treated even more aggressively (i.e., with mastectomy) than might be
recommended for invasive
Natural History of Ductal Carcinoma In Situ
Undoubtedly, the improved availability of mammographic
screening has dramatically increased the detection rate of DCIS, resulting in an
earlier and possibly overly aggressive intervention at this stage of breast
cancer. Autopsy series suggest that the prevalence of undetected DCIS is close
to 9% in the overall population, and it is likely that many of these lesions can
remain undetected and be clinically insignificant for many decades. The
consequences of treating DCIS by observation alone are unclear.
Indirect evidence pertaining to the natural history of DCIS
can be obtained from early studies examining the long-term recurrence rates in
women treated for DCIS with biopsy only. Page and Dupont reported a small series
of 28 women who had undergone surgery.
These studies demonstrate that low-grade DCIS also progresses to invasive
cancer but do not elucidate which patients are at highest risk for progression
to more aggressive disease. What is clear, however, is that the risk of
developing invasive cancer may persist even two decades after diagnosis of DCIS
if an initial complete excision is not performed. One of the most challenging
areas for research and intervention will be to identify those factors
responsible.
Treatment Considerations and Management of Ductal Carcinoma In Situ
Surgery
Mastectomy
The recurrence rate following mastectomy for DCIS has been
shown to be between 0 and 2% on long-term follow-up. There is thus no role for
adjuvant irradiation following mastectomy for DCIS. This procedure remains the
standard against which the outcomes of all other therapy must be compared but is
the most aggressive of the treatment options.
Breast Conservation
The widespread successful use of breast-conserving treatment
for invasive cancer has focused efforts to identify which women with DCIS may be
appropriately treated with wide excision rather than mastectomy.
Technical Considerations and Recommendations
Wide excision for DCIS is appropriate in patients with limited
extent of disease. Careful attention must be paid to the margin status, although
intraoperative decision-making is hampered because intraductal lesions are for
the most part not distinguishable from normal surrounding tissue. Precise
anatomic orientation is critical in identifying the location of any positive
margins.
Axillary Lymph Node Dissection
Current data indicate that the incidence of axillary lymph
node metastases in pure DCIS is 0 to 1%, obviating the need for axillary
dissection in these patients. For complicated cases with an associated mass and
questions of microscopic invasion, axillary lymph node dissection.
The Role of Adjuvant Radiation
The role of irradiation in the treatment of DCIS continues to evolve. Many
studies have now conclusively demonstrated approximately a 50% reduction in
local recurrence with the addition of radiotherapy to surgical excision. The
most compelling data come from The National Surgical Adjuvant Breast and Bowel
Project trial (NSABP) B-17, a prospective trial that randomly assigned 818
patients to surgery only or to surgery plus irradiation. The most recent update
of this study, with a mean follow-up of 90 months, shows a reduction in
noninvasive ipsilateral breast tumors (IBT) from 13.4% to 8.2% ( P =
0.007), with a similar reduction in invasive IBT from 13.4% to 3.9% ( P = <
0.0001).
The Role of Chemoprevention
Tamoxifen
Tamoxifen, a nonsteroidal compound with mixed estrogenic and
antiestrogenic effects, has repeatedly shown effectiveness in decreasing
recurrence rates of invasive breast cancer, particularly in women with estrogen
receptor (ER)-positive tumors. Tamoxifen has also consistently demonstrated the
ability to reduce the incidence of contralateral breast cancer, an observation
that has led to the institution of several tamoxifen-based prevention trials.
The NSABP trial (P-01), by far the largest prevention study to date,
demonstrated that tamoxifen reduces the risk of developing both invasive and
noninvasive breast cancer by 40%. Two other European prevention studies have not
been able to demonstrate a statistically significant risk reduction, but these
trials lack the statistical power of P-01.
One would anticipate that tamoxifen therapy alone could also
reduce both the recurrence of DCIS and the progression of DCIS to invasive
cancer following lumpectomy, even in the absence of radiation therapy, but these
studies have not yet been conducted. The NSABP B-24 study found that, for the
population studied, the risk of developing contralateral invasive breast cancer
(CBC) was nearly as high as the risk of developing ipsilateral invasive breast
cancer (IBC) after irradiation. In the placebo group, the cumulative 5-year risk
of invasive CBC.
In a recent meta-analysis of the NSABP trials, the cumulative
risk of CBC (both invasive and intraductal) for women with a cancer diagnosis
was 5.1% after 5 years, which was reduced to 1.9% in women who took tamoxifen.
New Compounds
The deleterious side effects of tamoxifen have spurred great interest in the
development of new agents that have antiestrogenic effects at the level of both
breast and uterine tissue while maintaining the beneficial estrogen-like effects
on bone mineral density and the cardiovascular system. This group of compounds
has been termed selective estrogen receptor modulators, or SERMs, and the best
studied is the agent raloxifene (marketed as Evista), which was developed to
prevent osteoporosis in postmenopausal women. Raloxifene also lowers serum
concentrations of total and low-density lipoprotein cholesterol and does not
stimulate the endometrium.
Initially intended to be an alternative to hormone replacement
therapy, raloxifene has been tested for its effect on bone mineral density and
fractures but not for its effect on breast cancer. Nevertheless, some striking
data were gathered from the Multiple Outcomes of Raloxifene Evaluation Study
(MORE trial). In this large randomized study, 7705 postmenopausal women with
osteoporosis were treated with raloxifene (60 or 120 mg/d). Raloxifene
significantly reduced bone mineral density loss and the fracture rate compared
with placebo.
Imaging
The most common presentation of DCIS is that of abnormal
calcifications on routine screening mammography. In the NSABP B-17 randomized
trial, 83% of patients had mammographic findings only. Several different
patterns of calcifications suggest DCIS.
Predictors of Recurrence Following Treatment for Ductal Carcinoma In Situ
The recurrence rate following simple mastectomy for DCIS
ranges from 0 to 2%. A critical evaluation of the factors leading to recurrence
of intraductal carcinoma following mastectomy.
Family History of Breast Cancer
Few studies have been specifically designed to determine
whether a history of breast cancer in a first-degree relative places a woman at
increased risk of recurrence following breast-conserving surgery for DCIS. At
least two reports, however, indicate that family history may have a measurable
effect. In a small study of women undergoing breast-conserving surgery.
Age at Diagnosis and Menopausal Status
In studies published to date, the two variables of age and
menopausal status have not been separately evaluated in multivariate analysis.
In one report of 133 patients with DCIS treated with wide excision and
irradiation, Silverstein found that age was not a predictor of recurrence on
univariate analysis ( P = 0.3). At least three other studies, however, have
demonstrated that postmenopausal status or older age confers a beneficial effect
on local recurrence.
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