Download Ductal Carcinoma In Situ of the Breast: Can Biomarkers Improve

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Clinical Chemistry 60:1
60–67 (2014)
Ductal Carcinoma In Situ of the Breast:
Can Biomarkers Improve Current Management?
John M.S. Bartlett,1* Sharon Nofech-Moses,2 and Eileen Rakovitch2
BACKGROUND: Screening for invasive cancer has led to a
marked increase in the detection of ductal carcinoma
in situ (DCIS). DCIS is, if appropriately managed, a
low-risk disease which has a small chance of impacting
on patient life expectancy. However, despite significant
advances in prognostic marker development in invasive breast cancer, there are no validated diagnostic assays to inform treatment choice for women with DCIS.
Therefore we are unable to target effective treatment
strategies to women at high risk and avoid overtreatment of women at low risk of progression to invasive breast cancer. Paradoxically, one effect of this uncertainty is undertreatment of some women.
CONTENT: We review current practice and research in
the field to identify key challenges in the management
of DCIS. The impact of clinical research, particularly
on the over and undertreatment of women with DCIS
is assessed. We note slow progress toward development
of diagnostic biomarkers and highlight key opportunities to accelerate advances in this area.
SUMMARY: DCIS is a low-risk disease, its incidence is
increasing, and current treatment is effective. However, many women are either over- or undertreated.
Despite repeated calls for development of diagnostic
biomarkers, progress in this area has been slow, reflecting a relative lack of investment of research effort and
funding. Given the low event rate in treated patients
and the lateness of recurrences, many previous studies
have only limited power to identify independent prognostic and predictive biomarkers. However, the potential for such biomarkers to personalize treatment for
DCIS is extremely high.
© 2013 American Association for Clinical Chemistry
Ontario Institute for Cancer Research, Toronto, ON, Canada; 2 Sunnybrook
Odette Cancer Centre, Toronto, ON, Canada.
* Address correspondence to this author at: Transformative Pathology, Ontario
Institute for Cancer Research, MaRS Centre, South Tower, 101 College St., Suite
800, Toronto, Ontario, Canada M5G 0A3. E-mail: [email protected].
Received September 26, 2013; accepted November 1, 2013.
Previously published online at DOI: 10.1373/clinchem.2013.207183
Background: DCIS, the Current Clinical Challenge
EPIDEMIOLOGY OF DCIS
Ductal carcinoma in situ (DCIS)3 of the breast is a nonobligate precursor of invasive carcinoma which, by definition, involves proliferation of abnormal epithelial
cells limited by the basement membrane of the breast
ductal system without stromal invasion. The widespread adoption of screening mammography, to improve early detection of invasive breast carcinomas,
over the past 2–3 decades has led to a significant increase in the incidence of ductal carcinoma in situ
(DCIS) of the breast (1, 2 ). DCIS now accounts for
about 20%–25% of all newly diagnosed cases of breast
cancer in the US and 17%–34% of cases detected by
mammographic screening (3, 4 ). Approximately 1 in
every 1300 mammography examinations performed
will lead ultimately to a diagnosis of DCIS (1 ). During
25 years of screening, the incidence of invasive breast
cancer has continued to increase (5 ), and screening for
invasive breast cancer, in line with screening for colon
and cervical cancer, is thought to lead to earlier detection and improved outcomes. In contrast, the markedly increased detection and treatment of DCIS, incidental to screening for invasive cancers, has not led to a
clear reduction in the incidence of invasive breast cancer following DCIS (5 ). Mortality from breast cancer
following a diagnosis of DCIS is very low regardless of
the type of treatment women undergo. Only 1%–2.6%
of women diagnosed with DCIS will die of invasive
breast cancer within 8 –10 years of the primary diagnosis (6 – 8 ). Thus 1 sequela of breast screening programs
worldwide has been a marked increase in the overdetection and overtreatment of DCIS.
NATURAL HISTORY OF DCIS
The natural history of untreated DCIS remains unknown because most individuals diagnosed with DCIS
are treated by surgical excision. The most informative
1
60
3
Nonstandard abbreviations: DCIS, ductal carcinoma in situ; NSABP, National
Surgical Adjuvant Breast Project; ER, estrogen receptor; PgR, progesterone
receptor; HER2, human epidermal growth factor receptor homolog 2; XRT,
radiation; BCS, breast-conserving surgery; CNA, copy number alteration; IHC,
immunohistochemistry; COX-2, cyclooxygenase 2; FISH, fluorescence in situ
hybridization.
Ductal Carcinoma In Situ
data are from 3 small retrospective case series of
women who underwent excisional biopsy of presumed
benign breast lesions and who, on retrospective pathology review, were discovered to have DCIS. These small
studies reported that 11%–32% of patients developed
an invasive carcinoma within the same breast 17.5–25
years after diagnosis, suggesting that in some cases inadequately excised DCIS may progress to invasive cancer (6, 9 –11 ). It remains unclear to what extent these
findings can be applied to women with mammographically detected DCIS, which comprise the majority of
cases of DCIS diagnosed today. However, these data
suggest that whereas some women with DCIS will develop invasive breast cancer, the majority of women
with DCIS, if left untreated, are not destined to recur let
alone die of their disease. However, our current inability to predict which women diagnosed with primary
DCIS will subsequently progress to invasive cancer results in almost all women diagnosed with DCIS undergoing some form of surgical treatment and/or adjuvant
treatment.
PRESENTATION OF DCIS
Most women (80%– 85%) diagnosed with DCIS present with a mammographic abnormality (usually pleomorphic calcifications) in the absence of clinical symptoms. About 15%–20% of cases present with clinical
symptoms including breast lump, nipple bleeding/discharge, or Paget disease. About 96% of DCIS lesions
diagnosed on mammography are detected by performing a biopsy of areas of the breast containing detectable
calcifications (3, 4 ).
PATHOLOGICAL ASSESSMENT OF DCIS
Accurate pathologic assessment of DCIS is critical, to
exclude the presence of invasive cancer and determine
the most appropriate treatment. Given the markedly
higher risk of metastasis and death among women diagnosed with invasive breast cancer (compared with
DCIS), additional treatment such as chemotherapy or
hormonal therapy is usually recommended (6 ). Therefore, the misclassification of invasive breast cancer as
DCIS, or vice versa, has profound prognostic and therapeutic implications. Misclassification may result from
either sampling or interpretation errors. Variations in
tissue handling, grossing protocols, and extent of sampling of blocks for microscopic evaluation continue to
pose a challenge for practicing pathologists evaluating
resection samples for DCIS. One key limitation in
excluding invasive foci in cases of DCIS is the reliance on tissue sampling. The College of American
Pathologists currently recommends microscopic examination, when practical, of the entire imaging abnormality in nonpalpable lesions as well as all areas
of gross lesion identified (12 ). It is currently imprac-
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tical to entirely submit large lumpectomies or mastectomies for such extensive microscopic evaluation,
and even when the entire radiologic and gross abnormalities are sampled, only one 5-␮m section is
reviewed from each 2- to 3-mm-thick tissue sample
embedded in paraffin blocks.
Assessment of extent of DCIS and distance to clear
margins is strongly dependent on the method of sampling. Samples are grossed and sampled on the basis of
the presence of a palpable macroscopic lesion and presurgical breast imaging. Nonpalpable lesions, require
radiography of the excised sample—radiography either
by placing the whole sample on a grid or radiography of
serially sliced samples. Visible or palpable lesions can
be sampled to include the entire abnormality and sections examined to demonstrate the relationship to the
margins. According to the National Surgical Adjuvant
Breast Project (NSABP) B17 protocol, 80% of DCIS
cases were nonpalpable (13 ). In such cases, the size
may be determined by radiology, but this method may
significantly underestimate the size in 23% (14 ). The
sensitivity of estimation of extent of DCIS is lower for
nonpalpable lesions (15 ), whereas accuracy of determining microinvasion by use of various grossing techniques is currently unknown.
Stromal invasion, defined as presence of malignant cells beyond the basement membrane, is usually
recognized on routine staining as individual cells or
irregular nests arranged haphazardly in the stroma. In
difficult cases, immunohistochemistry is helpful to
demonstrate absence of myoepithelial cells by use of 1
or more myoepithelial cell markers (the most commonly used are smooth muscle myosin, p63, and calponin). Overdiagnosis of invasion may occur when
malignant cells are displaced to the stroma by core needle biopsy, and therefore stromal invasion should not
be determined in an area of linear fibrosis, fat necrosis,
and hemosiderin deposits, features characteristic of a
needle tract. Other reasons for overcalling stromal invasion may be related to tangential cutting, cancerization of lobules, and involvement of sclerosing adenosis
or a radial scar (16 ). Interpretational errors include
overdiagnosis of benign lesions as DCIS (for example,
florid usual hyperplasia) or underdiagnosis of invasive
carcinoma (for example, when microinvasion is overlooked or when invasive cribriform carcinoma is not
recognized). A central pathology review of samples obtained from the 2 randomized trials resulted in the reclassification of 9% of lesions diagnosed as DCIS, with
7% reclassified as benign disease and 2% as invasive
cancer (17, 18 ). The pathology review of the European
Organization for Research and Treatment of Cancer
trial identified 45 cases of invasive cancer misdiagnosed
as DCIS. Nine percent of these women (4 of 45) developed an invasive recurrence (17 ). These findings have
Clinical Chemistry 60:1 (2014) 61
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Table 1. Randomized controlled trials comparing lumpectomy to lumpectomy and XRT as treatment for DCIS.
Median
follow-up, Negative
years
margins, %
Local recurrence
rate
HRa
n
HR
%
NSABP B-17 [Wapnir et al. (34 )]
818
17.3
87
35 vs 19.5 0.49 19 vs 9b
0.48
3 vs 5c
EORTC 10853 [Bijker et al. (45 )] 1010
10.5
84
26 vs 14
0.52 13 vs 8e
0.58
26 vs 11.5 0.41 12 vs 7
1067
8
80
UK/ANZ [Cuzick et al. (33 )]
1030
12.7
100
EBCCTG [Correa et al. (31 )]
3729
8.9
89
14 vs 6b
%
Breast cancer
mortality
Trial
SweDCIS [Emdin et al. (71 )]
%
Invasive local
recurrence
rate
3 vs 3.4
0.6 vs 0.2
0.41 10 vs 5.6b 0.32 2.7 vs 1.5d
28.1 vs 12.9f 0.46 11 vs 5
HR
Overall
mortality
%
1.44 16 vs 17d
HR
1.08
5 vs 5
9.6 vs 8.4
9.9 vs 11.8d
NE 3.7 vs 4.1c 1.22 8.2 vs 8.4c
1.11
a
HR, hazard ratio; EORTC, European Organisation for Research and Treatment of Cancer; SweDCIS, radiotherapy after sector resection for ductal carcinoma in situ
of the breast; UK/ANZ, UK, Australia, and New Zealand; EBCCTG, Early Breast Cancer Trialists’ Collaborative Group; NE, not estimated.
b
P ⬍ 0.001.
c
Not significant.
d
P ⬎ 0.05.
e
P ⬍ 0.0065.
f
P ⬍ 0.00001.
resulted in practice guidelines that include a recommendation that all DCIS samples be reviewed by a pathologist with expertise in breast disease (19, 20 ).
Pathologic assessment of DCIS is focused on determining the extent of disease and margin status, both parameters that have been shown to be associated with
local recurrence (21 ) as well as grade and presence of
comedo necrosis, variables that are currently taken into
consideration when adjuvant treatment is considered
(22 ). Unless hormonal therapy is indicated (see below)
immunohistochemical measurement of conventional
breast markers such as estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth
factor receptor homolog 2 (HER2) is of limited value in
DCIS.
TREATMENT OF DCIS
Before the 1980s, DCIS was rare, and the most common presentations were a palpable mass, nipple discharge, or Paget disease. Treatment for these symptomatic DCIS lesions was mastectomy because DCIS
was frequently distributed throughout the entire breast
and there were concerns that any residual DCIS in the
breast might progress to invasive cancer. Mastectomy
provides excellent local control with minimal rates of
recurrence (⬍5% at 10 years) but may be associated
with reduced body image and quality of life (23, 24 ).
The advent of screening, as noted above, has increased
incidence of DCIS dramatically. Furthermore, past
studies report that DCIS that presents with frank symptoms, such as palpable mass, nipple discharge, or Paget
disease, may have a higher risk of recurrence in comparison with DCIS detected by screening mammography in otherwise asymptomatic individuals (8 ).
62 Clinical Chemistry 60:1 (2014)
The implementation of screening mammography
has been associated with a substantial decrease in the
average size of DCIS lesions at presentation, from 60 to
10 mm, such that the majority of DCIS tumors now
diagnosed are considered amenable to complete excision without mastectomy (25 ). Randomized controlled trials have established that lumpectomy plus radiation leads to equivalent survival vs mastectomy for
the treatment of early breast cancer (26 ). Therefore most
DCIS detected in the current era of screening mammography will be able to be completely excised without removal of the entire breast, resulting in good cosmesis and
low recurrence rates (27, 28 ). It is generally agreed that
patients with extensive, high-grade DCIS should be
treated with mastectomy, particularly if complete local
excision will result in a poor cosmetic result.
The efficacy of radiation (XRT) in reducing the
risk of breast recurrence following breast-conserving
surgery (BCS) for DCIS has been demonstrated in 5
randomized controlled trials and combined metaanalyses (29 –31 ). Overall, at 10 years, the absolute risk
reduction of ipsilateral local recurrence was 15.2%
(28.1% BCS vs 12.9% BCS ⫹ XRT, P ⫽ 0.00001), of
ipsilateral invasive local recurrence was 7.9% (11.0%
BCS vs 4.9% BCS ⫹ XRT) and ipsilateral DCIS recurrence 8.5% (11.8% BCS vs 5.3% BCS ⫹ XRT) (Table 1)
(31 ). Although overtreatment with XRT remains a concern, in the absence of robust methods to identify those
patients who could safely avoid XRT, current guidelines
recommend inclusion of XRT in treatment planning. Axillary nodal dissection and sentinel node biopsy are usually not recommended at the time of BCS for DCIS because the risk of nodal metastases is low (32 ).
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Ductal Carcinoma In Situ
ADJUVANT TAMOXIFEN AND OTHER ENDOCRINE THERAPIES
Table 2. Completed randomized controlled trials
evaluating adjuvant tamoxifen after lumpectomy
and lumpectomy ⴙ XRT for DCIS.
Despite the finding from 2 randomized controlled trials that adjuvant tamoxifen following BCS for DCIS
decreases significantly the number of ipsilateral and
contralateral breast cancer recurrences (33, 34 ), the
use of tamoxifen in this setting remains controversial
because of concerns related to toxicities such as an increased risk of thromboembolic events and endometrial cancer. Few guidelines provide clear recommendations on endocrine therapy for DCIS. Neither the
NSABP B-24 nor the UK, Australia, and New Zealand
studies showed any increase in other causes of mortality with the use of tamoxifen (33, 34 ). A subgroup analysis from the NSABP B-24 study has shown that
the benefit of tamoxifen seems to be limited to ER⫹
DCIS. The National Comprehensive Cancer Network Guidelines (version 2.2011) recommend the
use of 5 years of tamoxifen after BCS as a category 1
recommendation, especially for immunohistochemically ER⫹ DCIS (Table 2).
NSABP B17
[Fisher et al. (7 );
Wapnir et al. (34 )]
n
1804
Median follow-up, years
13.6
Negative margin, %
75
All breast events, %b
12.7
100
HR
0.71
P
0.002
10.0 vs 8.5
HR
0.68
P
0.025
Contralateral invasive
breast cancer, %b
5.3 vs 3.3
HR
Despite the proven efficacy of radiotherapy and guideline recommendations, surveys of current clinical practice suggest half of women treated by local excision for
DCIS do not receive radiation (35, 36 ). In the Surveillance, Epidemiology and End Results database, a survey of treatments offered to women diagnosed with
DCIS in the US suggested that 46% of women treated
by BCS did not receive radiation therapy (36 –38 ). The
reasons for the omission of radiotherapy are unclear but
may be influenced by published reports of low rates of
local recurrence in selected women with DCIS treated by
BCS alone (without radiotherapy) (36, 39, 40 ). The Eastern Cooperative Oncology Group studied women with
low risk DCIS who were treated by BCS alone (39 ).
Women included in this study had high-grade DCIS ⱕ1
cm or low or intermediate nuclear grade ⬍2.5 cm and a
minimum negative resection margin width of 3 mm. After a median follow-up interval of 6 years, the rate of local
recurrence was 10.5% (39 ). The Radiation Therapy Oncology Group 98 – 04 clinical trial randomized women
with low-risk DCIS to receive radiation or observation;
62% received tamoxifen. At 5 years, the addition of radiation led to a significantly lower rate of local recurrence,
0.4% for women who received radiation vs 3.2% for those
who did not (hazard ratio 0.14, 95% CI 0.03– 0.61, P ⫽
0.002) (41 ). However, even without radiotherapy, in this
group almost 97% of women did not experience relapse
within 5 years.
Studies reporting low rates of recurrence following
BCS alone are based on institutional case series or
cohort studies of highly selected patients (e.g., small
tumors, low/intermediate grade, and wide negative resection margins). More comprehensive, population-
1576
24.6 vs 18
Ipsilateral invasive cancer
recurrence, %b
BCS WITHOUT ADJUVANT THERAPY
UK/ANZ
[Cuzick
et al. (33 )]a
0.8
2.7 vs 1.5
0.03
Death from breast
cancer, %b
2.7 vs 2.3
HR
1.8 vs 2.7
0.81
P
b
Overall mortality, %
P
0.95
0.47
P
HR
6.9 vs 6.8
⬎0.05
NSc
17.1 vs 14.4
9.6 vs 11.4
0.86
⬎0.05
NSc
2⫻2 randomization ⫾ tamoxifen and ⫾ radiotherapy for 54% of patients;
35.4% elected not to receive radiotherapy and 3.6% elected to receive
radiotherapy: they were randomized to tamoxifen or not; 1.7% elected not
to receive tamoxifen and 5.2% elected to receive tamoxifen: they were
randomized to radiotherapy or not.
b
15-year cumulative incidence.
c
No statistical difference in mortality between the groups reported in the
results section of the article. These numbers are from all patients included
in the trial, including electively chosen treatments.
a
based studies suggest that local recurrence rates following BCS alone are higher than those achieved in highly
selected cohort studies (42, 35 ). In 1 population-based
study of 1036 women treated by BCS alone, 20% developed a local recurrence after a median follow-up interval of 78 months (8 ). In another population-based
study of 460 women treated by BCS alone, 18% developed local recurrence after a median follow-up of 9.4
years (43, 44 ). These data suggest that treatment by
BCS alone is offered to individuals with higher risk
DCIS than those entered into the clinical trials, which
resulted in higher rates of recurrent breast cancer that
might have been avoided with treatment.
The above data suggest that individuals with highgrade DCIS are not good candidates for treatment by
Clinical Chemistry 60:1 (2014) 63
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BCS alone. Individuals with high grade DCIS who develop a local recurrence have an increased risk of developing subsequent distant metastases (45 ). Nevertheless, population studies report that one third of women
with high-grade DCIS, treated by BCS, do not receive
radiation treatment. In our population study, we found
that 22% of all women with high-grade DCIS treated by
BCS alone (without XRT) and 29% of those with highgrade disease under the age of 50 years developed a
subsequent local recurrence (35, 36, 46 ).
It is not clear why radiotherapy is omitted in individual cases. Possible reasons include patient preference, access to therapy, and the physicians’ interpretation of the risks and benefits of radiotherapy. In some
cases, the omission of radiation is due to suboptimal
compliance with treatment guidelines.
Conversely, since it is challenging to identify a
low-risk group on the basis of clinical and pathological
grounds alone, many women receive unnecessary radiation treatment. Fourteen patients require radiotherapy to prevent 1 local recurrence, and 25 would need to
be treated to prevent 1 mastectomy (46 ). Additional
population-based data are needed to evaluate the longterm toxicities of radiotherapy and determine the impact of radiation on long-term breast preservation
and breast cancer mortality. Focusing radiotherapy
toward those women at high risk of relapse, if they
could be prospectively identified, would reduce
overtreatment of women with DCIS, reduce the burden of breast cancer, and improve compliance with
treatment guidelines.
CLINICAL, PATHOLOGICAL, AND MOLECULAR PREDICTORS OF
RECURRENCE FOR DCIS
There are several candidate diagnostic markers for detecting recurrence following DCIS but, to date, none
has shown value in specifically detecting invasive recurrence risk. However, the need for such markers is
paramount, since a reduction in breast screening programs is not regarded as likely in the future and thus the
reality is that there will be continued diagnosis of large
numbers of cases of DCIS annually worldwide. The
2009 NIH State-of-the-Science Conference highlighted the need to develop and validate risk stratification models and in particular molecular methods for
the diagnosis and management of DCIS: “The outcomes in women treated with available therapies are
excellent. Thus, the primary question for future research must focus on the accurate identification of patient subsets diagnosed with DCIS, including those
persons who may be managed with less therapeutic intervention without sacrificing the excellent outcomes
presently achieved.”
Similarly, an exercise polling more than 170 international experts on research and treatment of breast
64 Clinical Chemistry 60:1 (2014)
cancer identified as the third most important matter
for breast cancer research as, “Determine the factors in
DCIS and/or atypical ductal hyperplasia which lead to
progression into invasive carcinoma” (47, 48 ).
There is therefore a pressing need for novel diagnostic approaches to improve risk stratification of individuals with DCIS to allow improved targeting of effective treatments to those most likely to benefit.
Molecular Progression of DCIS—Through a Glass,
Darkly
Cancers are the result of an accumulation of somatic
mutations involving key growth, differentiation, and
cell communication pathways (49, 50 ). Point mutations, copy number alterations (CNAs), epigenetic
modifications, and general genome instability occur in
nearly all tumor types studied and are frequently associated with disease progression (51 ).
There is limited information on the functional
molecular events that drive progression of DCIS from
the primary diagnosis of a pure noninvasive carcinoma
in situ to a frankly invasive carcinoma. Reviews of the
literature can be deceptive, since many studies fail to
adequately distinguish DCIS with (or in the presence
of) invasive carcinoma from cases of pure DCIS (i.e.,
DCIS in the absence of invasion). Clearly, from both a
clinical and molecular perspective, these DCIS entities
are likely to represent separate entities, and current evidence would appear to support this (52–54 ).
Evidence on the molecular characterization of
pure DCIS is sparse, although the number of small molecular studies is growing. Data comparing molecular
pathways in both primary DCIS and subsequent invasive breast cancers within the same patient is far more
limited. Therefore it remains challenging and premature to build a comprehensive picture of the events
involved in progression of pure DCIS to invasive cancer with any certainty.
Recent molecular studies of DCIS suggest 2 areas
of controversy. The first is a debate relating to a simple
linear multistep model of progression from DCIS to
invasive breast cancer vs distinct pathways for low- vs
high-grade invasive cancer developing from low- vs
high-grade DCIS, respectively. The second relates to
molecular differences observed between pure DCIS
and DCIS with invasion. In this area, distinct molecular
profiles are emerging which seem to suggest that pure
DCIS (i.e., DCIS diagnosed with no evidence of invasive cancer in the breast) may be molecularly distinct
from DCIS with invasion (i.e., DCIS that is present
contemporaneously with invasive carcinoma).
The linear models of cancer progression hypothesize that premalignant stages occur sequentially in the
development of invasive disease (55, 62 ). There is evi-
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Ductal Carcinoma In Situ
dence that challenges this simple model in the context
of DCIS; DCIS is characterized by a more aggressive
phenotype than invasive carcinoma, with more frequent HER2 amplification, and lower ER positivity
(42, 56 –59 ). However, models that seek to explain
such data by suggesting different pathways to low- and
high-grade invasive cancers, linked to low- and highgrade precursors (60, 62 ), have been challenged by others
(61, 62 ). The promotion of complex branched models is
probably much closer to reality (55, 61, 62 ), with multiple
mutational events driving multiple routes to invasive cancer. Recent data suggest that at least some fraction of pure
DCIS may be molecularly distinct from DCIS that is
identified with invasive cancer (53, 63 ). This is, conceptually at least, a rational argument, since the majority of DCIS does not seem destined to develop the molecular alterations that lead to invasive cancers and
therefore may represent an earlier molecular state with
low risk of progression.
Clarification of the molecular drivers for recurrence and, more critically, progression following a diagnosis of pure DCIS will be essential to inform future
diagnostic approaches to risk stratification in this disease. Although there are already several potential diagnostic profiles available for risk stratification following
a diagnosis of DCIS, the lack of sufficiently large patient
cohorts to allow validation of key approaches has also
hampered clinical implementation of research findings.
Even existing candidate diagnostic approaches, such as
the Genomic Health DCIS Score (64 ) or the Kerlikowske
triple positive IHC (immunohistochemistry) profile (42 )
remain unvalidated, lost in translation, due to the lack of a
sufficiently large dataset for validation.
If patients are to be offered a more personalized approach to the management of their DCIS, there is a critical
need for a diagnostic approach to assess the risk of recurrence and, more critically, progression to invasive disease
following a primary diagnosis of DCIS. Efforts toward this
goal to date have had limited success for 2 primary reasons. First, the majority of studies have involved small,
statistically underpowered, sample sizes. Second, as outlined above, studies frequently confuse pure DCIS and
DCIS with invasive breast cancer present.
A recent review of more than 10 years of research
in the field identified around 60 biomarker-related papers (⬍10% of those published) (58 ) that had more
than 30 –50 DCIS cases in the study cohort; the remaining 90% of published papers each included fewer than
30 –50 cases and therefore were regarded as statistically
underpowered. The average number of cases per report
in these large studies was just over 100. To our knowledge, the largest single biomarker study performed, to
date, was on a subset of 329 women (42 ). This study
identified a 2-fold increased risk of invasive recurrence
among DCIS cases that expressed p16/cyclooxygenase 2
(COX-2)/Ki-67. The authors also suggested that
women with ER–/HER2⫹/Ki67⫹ DCIS had a greater
risk of developing DCIS/noninvasive recurrence.
In 3 separate studies, we also examined the prognostic value of molecular markers in DCIS. In the first
study, we examined 7 biomarkers and their impact on
the risk of local recurrence (DCIS and invasive) among
213 women treated with breast-conserving therapy. In
this study, HER2⫹/Ki-67⫹ cases [determined by IHC
and fluorescence in situ hybridization (FISH)] were associated with a significantly increased risk of DCIS recurrence, independent of grade and age (hazard ratio
3.22: 95% CI 1.47–7.03, P ⫽ 0.003) (57 ). In a second
study, we showed that for Luminal B (HER2 positive/ER positive) and HER2-like (HER2⫹ve/ER-ve)
DCIS, HER2 expression determined by IHC/FISH was
associated with an increased risk of recurrence (56 ).
This was consistent with an earlier study from our
group (59 ) and with earlier studies by Provenzano
(65 ), Kepple (66 ), Holmes (67 ), and Ringberg (68 )
[see (58 ) for review]. There are now at least 7 IHC/
FISH studies supporting HER2 as prognostic marker,
either alone or in combination with other markers, in
DCIS. All studies are consistent with a role for HER2 in
prediction of DCIS recurrence, but evidence regarding
the role of this marker in predicting invasive recurrence
is more variable. Han et al. (56 ), Kerlikowske et al.
(42 ), and Rakovitch et al. (57 ) suggest that HER2 specifically selects patients at risk of DCIS rather than invasive recurrence. Interestingly 2 studies, by Kerlikowske et al. and Rakovitch et al. (42, 57 ) suggest
differential effects of some biomarkers with respect to
invasive and noninvasive recurrence, suggesting that
ER⫹ cases are less likely to develop invasive recurrence
but may be more likely to develop noninvasive recurrence. Immunohistochemical markers that are potentially selective for invasive or noninvasive recurrence
include ER, PgR, Ki67, HER2, p16, COX2, and p53 [see
(42, 57 )]. Further evidence supporting these markers
as selective markers exists (58 ). These data would suggest that modeling approaches, similar to those applied
in invasive cancer (69, 70 ), could provide information
on the basis of multiple biomarkers that could provide
reliable risk stratification for patients diagnosed with
DCIS.
Summary and Conclusion
As an unintended consequence, screening for invasive
breast cancer has resulted in a marked increase in the
diagnosis of asymptomatic ductal carcinoma in situ.
The majority of women diagnosed with screendetected DCIS are not destined to relapse or die of their
disease. Clinical or pathological biomarkers that can
reliably identify the subset of patients with DCIS at
Clinical Chemistry 60:1 (2014) 65
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greatest risk of developing invasive breast cancer have
not been identified. Treatment paradigms have not
been modified to adapt to the increased detection of
relatively benign disease. As a result, many women with
DCIS receive XRT with no clinical benefit (are overtreated). Paradoxically, for some women the omission
of radiotherapy (following breast conserving surgery)
is associated with a higher risk of local recurrence, including invasive breast cancer, that might have been
avoided with treatment (undertreatment) because of a
misconception that DCIS is so low risk that effective
treatments, particularly radiotherapy, may be avoided.
This disease presents a clear diagnostic challenge where
the impact of diagnostic assays measuring risk of recurrence, and in particular, progression, following a diagnosis of DCIS could dramatically improve the selection
of therapies appropriate for individual women. For such
markers to be developed, we need to develop a clear un-
derstanding of the molecular events that drive recurrence
and progression of DCIS. A parallel effort focused on developing robust, portable, and informative assays that
measure risk of progression has the potential to drive a
personalized medicine solution to the clinical uncertainty
facing women and their physicians when presented with a
diagnosis of ductal carcinoma in situ.
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures or Potential Conflicts of Interest: No authors
declared any potential conflicts of interest.
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