2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

DCIS: OPPORTUNITIES AND UNCHARTED WATERS
invasive breast cancer. 1 In women who receive standard
treatment for DCIS, women with microinvasion have a
prognosis almost identical to women with DCIS alone, and
mastectomy is curative in 95% to 100% of women. 9 Furthermore,
approximately 50% of the local recurrences following
initial treatment for a pure DCIS is invasive cancer. 1
Clinical and Treatment Risk Factors
Some of the clinical manifestations and treatment factors
associated with an increased risk of local recurrence following
breast-conserving treatment for DCIS have been identified.
Young women are at increased risk for local-regional
recurrence and invasive disease. 6-10 Women with nonpalpable
mammographically detected DCIS have a better prognosis
than women with palpable DCIS, which is often
associated with microinvasion and occasionally with axillary
nodal involvement. Women who undergo mastectomy are at
low risk for local-regional recurrence. The use of radiation
therapy following breast-conserving surgery is associated
with approximately 50% reduction in the risk of local
recurrence. 2-4 In the National Surgical Adjuvant Breast and
Bowel Project (NSABP) B-24 trial, the addition of tamoxifen
further reduced the risk of local-regional recurrence in
women treated with lumpectomy and radiation therapy. 11
However, tamoxifen did not reduce the risk of local-regional
recurrence in a second randomized trial. 4 Currently, tamoxifen
treatment may be considered as a strategy to reduce the
risk of breast cancer recurrence in women with ER-positive
DCIS. 1,5 The benefit of tamoxifen for ER-negative DCIS is
not known.
Prospective and retrospective analyses have identified
pathologic characteristics of DCIS that correlate with an
increased risk of local recurrence following breastconserving
therapy. Pathologic features that are associated
with an increased risk of local-regional recurrence include
KEY POINTS
● DCIS is a heterogeneous disease with a complex
array of biologic potential, clinical behavior, and
prognosis.
● Although the biologic behavior of DCIS is heterogeneous,
our clinical management has remained relatively
uniform.
● Biomarkers are needed to tailor clinical treatment of
DCIS to biologic potential for recurrence and invasion,
but the genomic and pathologic nature of the
neoplasia that emerges during local recurrence compared
with the original DCIS lesion is unknown.
● Triple-negative breast cancers may not appear to
have a DCIS intermediate.
● Numerous studies comparing the gene expression,
genetic, and epigenetic profiles of DCIS and invasive
breast carcinomas reported a high degree of similarity
between the molecular alterations in the DCIS
and the invasive cancer in the same patient. This
provides evidence that the aggressive phenotype of
the breast cancer may be determined at the level of
the preinvasive lesion.
high nuclear grade, comedo necrosis, larger tumor size, and
involved margins of excision. 1-3 The effect of pathologic
factors on the risk of local recurrence in patients with DCIS
varies with treatment as well as length of follow-up. 10-13
Studies by Silverstein and colleagues provide evidence that
DCIS size, nuclear grade, and margin status are associated
with the risk of local-regional recurrence, but only in cases
with small surgical margin widths. 12,13 For women with
DCIS who undergo surgical excision leaving margin widths
of 10 mm or more, the risk of local recurrence is unchanged
by size, grade, the presence of comedo necrosis, and radiation
therapy. 12 The effect of grade on local-regional recurrence
of DCIS appears to be related to the length of followup.
10 The NSABP B17 trial provides evidence that comedo
necrosis in DCIS is associated with an increased risk of
local-regional recurrence in women treated with excision
alone. 3 Local recurrence rates in women undergoing excision
alone, after 8 years, was 40% for those with moderate or
marked comedo necrosis compared with 23% for women
without comedo necrosis. In women who underwent surgical
excision and radiation therapy, local recurrence rates were
similar for women with moderate or marked comedo necrosis
relative to women without comedo necrosis (14% compared
with 13%, respectively). 3 In summary, these studies
suggest that there are multifaceted interactions between
pathologic factors and other elements that ultimately determine
the risk of local recurrence. 1-3,10-13
Evidence That Triple-Negative Breast Cancers May
Lack a DCIS Precursor
Triple-negative breast cancers are defined as tumors that
lack ER, PR, and HER2 expression. These tumors account
for 10% to 15% of all breast carcinomas, depending on the
thresholds used to define ER and PR positivity and the
methods used for HER2 assessment. 14-16 The clinical interest
in these tumors stems from the lack of targeted therapies
for patients affected by this breast cancer subtype, which is
more prevalent in younger women, 14 black women, 16 and
BRCA1 mutation carriers, 17 and more aggressive than tumors
of other molecular subtypes. 14 Patients with triplenegative
cancers also have a significantly shorter survival
following the first metastatic event when compared with
those with non-triple-negative controls (p � 0.0001). 14 A
predictive rather than prognostic classification system is
required for the success of targeted therapy, and therefore,
the origins and developmental mechanisms must also be
clearly defined.
The biologic developments of triple-negative breast cancers
have debatable beginnings. Triple-negative breast cancers
are thought to develop either from cells that are
triple-negative from the early phase of intraductal proliferation,
leading to invasion, or cells that have lost hormone
receptor expression before invasion. 18 A group of high-grade
DCIS lacking ER, PR ,and HER2, and expressing “basal”
markers has been identified. 18 Bryan and colleagues studied
66 cases of high-grade DCIS and found a small proportion
(four cases, 6%) that exhibited the triple-negative phenotype
with increased invasion. 18 In a study by Meijnen and colleagues,
only eight out of 163 cases (5%) demonstrated
triple-negative lesions. 19 In addition, tumors with BRCA1
germ-line mutations are significantly more likely to be
triple-negative breast cancers (p � 0.005) and have early
high-grade DCIS (p � 0.0045). 17 However, it is important to
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