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include those related to cell motility, invasion, proliferation,
and angiogenesis. Van Laere and colleagues
reported similar findings: a set of 50 discriminator
genes distinguished IBC from non-IBC even after
excluding estrogen receptor (ER)- or HER2-related
genes. 8 When IBC-related genes are activated, tumor
behavior may be more aggressive regardless of subtype,
and the influence of HER2 status may be less
relevant. Another possibility relates to the distribution
of molecular subtypes within the Dawood study.
Sixty percent of the HER2-negative tumors were also
ER negative. Although progesterone receptor status
was not reported, one can assume that the majority
of these tumors would probably fall into the “triplenegative”
subtype. Thus, triple-negative tumors
were overrepresented compared with their incidence
in non-IBC tumors, and a binary comparison of the
prognosis of HER2-positive and HER2 negative
patients would be heavily influenced by the prognosis
of patients with triple-negative IBC. In this light,
it would be of interest to explore the prognosis of the
IBC patients according to molecular subtype (ie,
luminal A, luminal B, basal-like, HER2-positive).
Third, as the authors point out, the use of anthracyclines
across all patients may have preferentially benefited
those with HER2-positive tumors. In a pooled
analysis of eight randomized trials for early breast
cancer, anthracyclines were superior to nonanthracycline-containing
regimens in patients with HER2positive
but not HER2-negative tumors. 9 Thus, any
difference in natural history between HER2-positive
versus HER2-negative IBC may have been attenuated
by treatment effect.
With respect to OS, HER2-positive status was a
favorable prognostic factor in this study, likely due to
the availability of effective targeted therapy (eg,
trastuzumab) for patients with HER2-positive IBC at
the time of recurrence. Nevertheless, it is sobering
that even in a group of women treated in a comprehensive
fashion at a highly regarded cancer center
that the 5-year overall survival rate for the entire
cohort was only 53.1%. How can we improve? First,
given the impact of trastuzumab on OS after IBC
recurrence, as demonstrated by Dawood and colleagues,
and the proven benefits of trastuzumab in
the adjuvant setting for early breast cancer, it is likely
that the current standard use of trastuzumab in the
preoperative setting for patients with IBC is already
having a favorable effect upon outcomes in patients
with HER2-positive disease. Preliminary results
from the NOAH (NeOAdjuvant Herceptin) study
The challenge of IBC
indicate that the addition of trastuzumab substantially
improves the rate of pCR in patients with IBC
compared with chemotherapy alone. 10 Given that
pCR is highly correlated with RFS and OS, these
results are highly encouraging. Next, there is also
early evidence of efficacy from a phase II study of the
oral epidermal growth factor receptor/HER2
inhibitor lapatinib in patients with recurrent or
anthracycline-refractory IBC in which 50% of
patients experienced a clinical response. 11 Ongoing
trials will further clarify whether lapatinib has a role
in patients with newly diagnosed IBC.
Looking beyond HER2, a number of other biologic
characteristics appear to be strongly associated
with both RFS and OS in patients with IBC. These
include molecules related to angiogenesis (hypoxiainducible
factor 1, vascular endothelial growth factor,
etc), cytoskeletal organization and cell motility
(eg, Rho proteins), and chemokines (CXCR4,
CCR7). 7,12 Several small studies have already been
completed evaluating the safety of angiogenic blockade
in patients with IBC, and these studies have also
demonstrated associated changes in tumor blood
flow. 13,14 In the future, pharmacologic targeting of the
angiogenesis and other pathways may improve outcomes
in both HER2-positive and HER2-negative
IBC.
In summary, while Dawood and colleagues did
not observe a relationship between HER2 status and
RFS, the observed association between HER2 positivity
and improved OS is powerful evidence that
effective targeted therapy can yield meaningful
improvements in outcomes from IBC. The elucidation
of pathways important in the development and
maintenance of the IBC phenotype and the development
of drugs to target these pathways continue to
move forward. However, because of the relative rarity
of IBC, the pace of further advances in the field
will depend not only on the pipeline of new targeted
drugs but upon a concerted effort to sustain multidisciplinary
and cross-institutional collaborations. ✦
References
1. Levine PH, Veneroso C. The epidemiology of inflammatory
breast cancer. Semin Oncol. 2008;35:11-16.
2. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al. Trends
for inflammatory breast cancer: is survival improving?
Oncologist. 2007;12:904-912.
3. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer:
correlation of relapse and survival with amplification of the
HER-2/neu oncogene. Science. 1987;235:177-182.
4. Cabioglu N, Gong Y, Islam R, et al. Expression of growth factor
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