2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

ecognize that there are large discrepancies in the relative
frequency of triple-negative subtype between DCIS and
invasive disease. The prevalence of DCIS is substantially
lower than invasive triple-negative breast cancers, suggesting
that the latter often lack an obvious in situ element.
Without supporting evidence or definitive conclusions, many
studies have attributed this discrepancy as a result of
triple-negative breast cancers progressing rapidly from
DCIS to invasive cancer or obliterating the DCIS precursor
from which they arose. 17,18
Molecular Studies of the Biologic Potential and
Diversity of DCIS Lesions
Although the transition from DCIS to invasive cancer is
central to understanding the origins of breast cancer, little is
known about the time of onset or the triggering mechanisms
that promote invasion of DCIS. Some DCIS progresses to
invade the stroma, but other DCIS lies dormant. This raises
the question of whether there are subsets of precancerous
lesions that are preprogrammed to invade and metastasize
or whether the ability to invade and metastasize is acquired
late in the process of progression. 20
Molecular Markers Predicting Invasion of DCIS
Numerous studies have compared the gene expression,
genetic, and epigenetic profiles of DCIS and invasive breast
carcinomas, showing a high degree of similarity between
DCIS and invasive cancer in the same patient. 21 As expected,
there is a significant difference in gene expression
between normal mammary epithelial cells and DCIS, but
surprisingly, DCIS and invasive breast cancer of the same
histologic subtype essentially share the same genetic/epigenetic
alterations and gene expression patterns. In contrast,
the molecular profiles of breast tumors of distinct subtypes
(e.g., luminal, HER2�) are significantly different. The expression
and mutation status of numerous tumor suppressor
and oncogenes have been analyzed in DCIS and invasive
breast cancer including TP53, PTEN, PIK3CA, ERBB2,
MYC; differences in the frequency of these changes were
associated with tumor subtype, but none were associated
with invasion. 20,22 For example, amplification of ERBB2 is
specific for the HER2� subtype; however, amplification of
ERBB2 is observed in both DCIS and invasive breast cancer.
The expression of several selected candidate genes based
on their biologic function has been analyzed in DCIS. 23 Two
recent studies identified molecular markers that hold promise
for identifying the risk of recurrence of DCIS. 24,25 Gauthier
and colleagues demonstrated that high expression of
COX-2 and Ki67 in DCIS correlates with higher risk of local
in situ and invasive recurrence. 24 Lu and colleagues identified
a molecular synergy between ERBB2 and 14–3-3� that
may increase the risk of invasive progression via epithelialto-mesenchymal
transition regulation. 25 A major limitation
of both of these studies was the use of small cohorts. Despite
the promise and need of DCIS risk biomarkers, prospective
validation is difficult. Validation of a predictive biomarker
may require a long waiting period to see if a patient’s DCIS
lesion will progress to invasive cancer. Most patients diagnosed
with DCIS do not even want to experience a delay
before surgical therapy. Therefore, patients judged at low
risk may be unwilling to forego treatment. Since the population
of DCIS and other preinvasive proliferative lesions is
42
HOFFMAN ET AL
heterogeneous in the same patient, the portion of the DCIS
lesion sampled at the initial biopsy diagnosis, which is used
for the predictive biomarker measurement, may not be the
same region of the lesion that has malignant potential.
There is very little data comparing the molecular genetic
characteristics of the cancers that recur to the original DCIS
lesion.
Evidence for Acquired Invasive Potential and
Intratumor Heterogeneity
The stepwise model of breast tumorigenesis assumes a
stepwise transition from epithelial hyperproliferation, to
atypical hyperplasia, to DCIS, and finally to invasive and
metastatic cancer. 22,23 This progression model is supported
by human clinical and epidemiologic data and molecular
clonality studies addressing the relationships between in
situ and invasive regions of the same tumor and between
DCIS and its local invasive recurrence. 21 There is emerging
evidence that neoplastic cells with invasive potential arise
frequently within DCIS lesions, but are held in check and
only invade when further molecular changes occur. 20
Emerging data suggest a critical role for the microenvironment
in promoting invasion of DCIS.
Numerous studies have shown that DCIS exhibits intratumoral
heterogeneity. The prevailing model for explaining
this heterogeneity, the clonal evolution model, has recently
been challenged by proponents of the cancer stem cell
hypothesis. 26 To investigate this issue, Kornelia Polyak’s
group performed combined analyses of markers associated
with cellular differentiation states and genotypic alterations
in DCIS and invasive breast cancer and evaluated diversity
with ecological and evolutionary methods. Such studies
demonstrated a high degree of genetic heterogeneity both
within and between distinct tumor cell populations that
were defined based on markers of cellular phenotypes including
stem cell-like characteristics. 26 The degree of diversity
correlated with clinically relevant breast tumor
subtypes. 26 This supports the concept that molecular alterations
at the level of DCIS may precede and determine the
breast tumor subtype.
There is emerging evidence that adaptation to hypoxic
and metabolic stress promotes progression of DCIS to invasive
breast cancer. It is hypothesized that premalignant and
malignant cells down-regulate proteins that induce apoptosis
or senescence and upregulate pro-survival pathways that
protect against hypoxia, DNA damage, metabolic and genotoxic
stress. 20 Nevertheless, even if a cell can resist programmed
cell death or senescence it will still not survive in
a hypoxic, nutrient-deprived environment unless it can find
alternative sources of energy for cellular functions, such as
through autophagy, anaerobic respiration, or increasing the
efficiency of aerobic respiration. 20 To appreciate how DCIS
might progress and circumvent stress-induced death or
senescence, and use alternative sources of energy, it is
important to consider the stresses that affect DCIS cells and
molecular signaling pathways that may act to protect
against these stressors. 20 Autophagy promotes survival in
the face of hypoxic and nutrient stress and is an emerging
target for cancer therapy. 20 Autophagy is upregulated and
colocalizes with areas of hypoxic stress, and immortalized
mammary epithelial cells are more susceptible to cell death
under conditions of metabolic stress. 20 DCIS growth or the
growth of any intraductal proliferative lesion is limited