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Breast Cancer
Table 3: Adjuvant Human Epidermal Growth Factor Receptor-2-positive Therapy
Author Year Patient Population Treatment Number DFS (%) p-value OS (%) p-value
Romond 2005 HER2-positive AC → P/H versus P alone 3,676 18.2 <0.0001 4.8 0.015
Smith 2007 HER2-positive, node-positive or Standard chemotherapy or 3,401 6.3 <0.0001 2.7 0.0115
high-risk node-negative neoadjuvant chemotherapy → H or no H
Slamon 2007 HER2-positive AC → T versus AC → T/H versus TC/H 3,222 39/33 <0.0001/ 41/34 0.0041/
0.0003 0.017*
Joensuu 2006 HER2-positive, node-positive or T or V → CEF→ H or no H 232 11 0.01 6 0.07
high-risk node-negative
* Relative risk reductions compared with doxorubicin, cyclophosphamide → docetaxel. A = doxorubicin; C = cyclophosphamide; P = paclitaxel; T = docetaxel; H = trastuzumab; E = epirubicin;
C’ = carboplatin, V= vinorelbine; F = fluorouracil; DFS = disease-free survival; OS = overall survival.
cancer (zero to three positive lymph nodes) compared with four Similar results have been observed in a variety of other studies. This
cycles of standard AC.
35
This trial demonstrated that at five years the included the two-year follow-up data of trastuzumab following
non-anthracycline-containing regimen was associated with a DFS rate standard adjuvant or neo-adjuvant chemotherapy in the European
that was significantly superior for TC compared with AC (86 versus Herceptin Adjuvant (HERA) trial,
42
which reported that one year of
80%, respectively, hazard ratio [HR] 0.67, 95% confidence interval [CI] trastuzumab improved the risk for disease recurrence by 36% (6.3%
0.50–0.94; p=0.015). The initially reported OS rates for TC and AC were absolute benefit; p<0.0001) and reduced the risk for death by 34%
90 and 87%, respectively (HR 0.76, 95% CI 0.52–1.1; p=0.13). These (2.7% absolute benefit; p=0.0115). Similarly, the Breast Cancer
differences persisted at 6.9 years of follow-up, with DFS improving International Research Group (BCIRG)-006 trial demonstrated that
from 79 to 85% (p=0.018) and OS improving from 84 to 88% (p=0.045) trastuzumab significantly improves DFS and OS among patients with
with the use of TC.
36
node-positive or high-risk node-negative disease treated with AC
followed by docetaxel or a non-anthracycline regimen of docetaxel
Human Epidermal Growth Factor plus carboplatin compared with the standard chemotherapy
Receptor-2-positive Disease approach of AC followed by docetaxel.
43
The Finnish Fin-Her trial also
HER2-positive breast cancers overexpress the HER2 transmembrane demonstrated that the addition of even a short nine-week treatment
growth factor receptor and are associated with a generally poor with trastuzumab to node-positive or high-risk, node-negative
prognosis.
37,38
In 1998, trastuzumab, a monoclonal antibody designed patients completing chemotherapy with docetaxel or vinorelbine
to target the extracellular domain of this protein, was approved as followed by 5FU, epirubicin, and cyclophosphamide (FEC) reduced the
first-line therapy of metastatic HER2-positive breast cancer in risk for recurrence (HR 0.42, 95% CI 0.21–0.83; p=0.01).
44
These studies
conjunction with paclitaxel. Based on this approach, two large confirm the advantage of using trastuzumab in conjunction with
randomized trials were developed in the US to examine the effect of adjuvant chemotherapy in high-risk HER2-positive patients.
this agent in the adjuvant setting (see Table 3). The NSABP B-31 trial
and the North Central Cancer Treatment Group (NCCTG) N9831 trials Future Directions
were both designed to test the effects of trastuzumab when added to The success of specifically targeted therapy with trastuzumab has
a standard regimen of AC chemotherapy followed by paclitaxel in introduced a new age in breast cancer treatment, with novel agents
patients with HER2-positive disease. Patients were randomized to targeting the underlying molecular processes in malignancy. Lapatinib
is a dual tyrosine kinase inhibitor—it inhibits both HER1 and
HER2 tyrosine kinase activity—that was approved in 2007 for use with
The success of specifically targeted therapy
capecitabine in patients with HER2-positive locally advanced
or metastatic breast cancer progressing on standard therapies such
with trastuzumab has introduced a new
as anthracyclines, taxanes, and trastuzumab.
45
Its use is currently
age in breast cancer treatment, with novel
being investigated in the adjuvant setting in the international
Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation trial
agents targeting the underlying molecular
(ALTTO), which will determine the optimal combination/sequence of
processes in malignancy.
lapatinib and trastuzumab (lapatinib alone versus trastuzumab alone
versus trastuzumab followed by lapatinib versus trastuzumab
concurrently with lapatinib) in newly diagnosed HER2-positive patients
complete the standard chemotherapy approach with or without the (NCT 00490139).
addition of trastuzumab for one year. When the results of these
studies were combined, the addition of trastuzumab reduced the risk Bevacizumab, a monoclonal antibody designed to inhibit the vascular
for recurrence by 52% and improved DFS by 18.2% (absolute benefit) endothelial growth factor (VEGF), which is necessary for tumor
at four years. The relative risk for death also decreased by 33% (4.8% angiogenesis, has been found to be beneficial in several solid
absolute benefit) with the addition of trastuzumab.
39
However, the use tumors, including metastatic breast cancer,
46
and is currently being
of adjuvant trastuzumab was also associated with a small (0.4–3.8%) evaluated in several trials in the adjuvant breast cancer setting. These
but significant risk for congestive heart failure.
40,41
trials include the Eastern Co-operative Oncology Group (ECOG)-5103
52 US ONCOLOGY
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