2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

DCIS: OPPORTUNITIES AND UNCHARTED WATERS
because of confinement within the duct and the absence of
a blood supply. Espina and colleagues proposed that autophagy
is a major survival mechanism that is used by DCIS
cells to persist and proliferate in the high-stress environment
of the intraductal space and can be a main determinant
of acquired DCIS cell fate in response to metabolic
stress. 20
Evidence for Preprogramming of Precancerous Breast Lesions
Triple-negative breast cancers frequently exhibit aggressive
clinical behavior and are many times metastatic at
diagnosis. In addition to being poorly differentiated, as
outlined above, triple-negative breast cancers are thought to
have a lower proportion of associated DCIS compared with
other types of breast carcinoma. These observations challenge
whether the stepwise model of mammary carcinogenesis
adequately models initiation and progression of triplenegative
breast cancer. In contrast to the stepwise model,
aggressive cancers may emerge from low-grade DCIS or
atypical proliferative lesions. There is growing recognition
that the activated (e.g., phosphorylated) state of cellular
protein signaling networks can play a key role in breast
cancer initiation and progression 27 and provide information
about the functional state of the cancer cell that cannot be
accurately predicted based on genomic sequencing alone.
Likewise, it has been recently shown that single biomarkers
are not adequate to capture the complex changes in signaling
networks activated during breast cancer initiation. 28
Ibarra-Drendall et al. are currently testing the hypothesis
that mammary atypia from high-risk women exhibits activation
of phospho-protein signaling networks activated in
aggressive triple-negative breast cancer. 29 We performed
Reverse-Phase Protein Microarray (RPMA) profiling of cyto-
Authors’ Disclosures of Potential Conflicts of Interest
Employment or
Leadership
Positions
Consultant or
Advisory Role
Author
Abigail W. Hoffman*
Catherine Ibarra-Drendall*
Virginia Espina Theranostics
Health
Lance Liotta*
Victoria Seewaldt*
*No relevant relationships to disclose.
1. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of the
breast. N Engl J Med. 2004;350:1430-1441.
2. Schnitt SJ. Local outcomes in ductal carcinoma in situ based on patient
and tumor characteristics. J Natl Cancer Inst Monogr. 2010;41:158-161.
3. Fisher ER, Dignam J, Tan-Chiu E, et al. Pathologic findings from the
National Surgical Adjuvant Breast Project (NSABP) eight-year update of
Protocol B-17: intraductal carcinoma. Cancer. 1999;86:429-438.
4. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in
women with completely excised ductal carcinoma in situ of the breast in the
UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;
362:95-102.
5. Chen YY, DeVries S, Anderson J, et al. Pathologic and biologic response
to preoperative endocrine therapy in patients with ER-positive ductal carcinoma
in situ. BMC Cancer. 2009;9:285.
6. Brinton LA, Sherman ME, Carreon JD, et al. Recent trends in breast
cancer among younger women in the United States. J Natl Cancer Inst.
2008;100:1643-1648.
7. Evans A, Pinder S, Wilson R, et al. Ductal carcinoma in situ of the
logic atypia obtained prospectively from unaffected highrisk
women in our cohort. 30,31 We observed coactivation of
Akt/mTOR/insulin- and IL6/Stat3/vimentin-network signaling
in cytologic atypia and found a statistically significant
association between body mass index of �30 kg/m 2 and
vimentin expression (p � 0.028). 30,31 Limited immunohistochemistry
studies demonstrated vimentin expression in
atypical mammary epithelial cells, 31 which in turn correlates
with activation of Stat3 and IL6 levels in patientmatched
mammary fluids. 32 Both Akt/mTOR and IL6/Stat3
signaling have been implicated in the aggressive biology of
triple-negative breast cancer and epithelial-to-mesenchymal
transition. These studies provide preliminary evidence that
the biologically aggressive atypia may be present before the
development of an invasive triple-negative breast cancer.
Conclusion
Currently, there are many unanswered questions regarding
the diagnosis and management of DCIS. Despite the
complexity and heterogeneous nature of DCIS, all women
are treated with a “one size fits all” scenario that includes
mastectomy versus breast-conserving surgery with radiation
therapy. Most recently, Oncotype DX Breast Cancer
Assay for DCIS 33 has been developed and is being utilized to
obtain an estimate of 10-year risk of local recurrence, with
the hope of providing guidance to treatment decision. But
the success of this multigene assay in predicting the fate
of DCIS remains to be seen. An essential goal of future
research should focus on the development of accurate riskstratification
methods based on a comprehensive understanding
of the biologic, pathologic, radiologic, and clinical
factors associated with DCIS.
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