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Novel Treatment Approaches for Managing Early-stage Breast Cancer
Two studies have investigated short-course concomitant adjuvant proportional gains were achieved in both ER-positive and -negative
docetaxel-based regimens. The US Oncology (USO) 9735 trial investigated tumours for both weekly paclitaxel and docetaxel every three weeks.
four cycles of TC versus four cycles of AC in 1,016 patients with stage I–III
breast cancer. The study demonstrated a DFS and OS advantage for Prognostic Factors – Possibilities and Evidence
However, a greater incidence of febrile neutropenia was observed Breast cancer is a biologically heterogeneous disease. The ‘one-size-fits-all’
in the TC arm. The Eastern Co-operative Oncology Group (ECOG) 2197 approach in adjuvant chemotherapy has been gradually eliminated in
study demonstrated no advantage for four cycles of AT compared with recent years. It is now increasingly refined and tailored based on the
four cycles of AC. Grade 3 neutropenia associated with fever or infection molecular characteristics of tumours and individual clinical circumstances.
occurred more often with AT.
Numerous prognostic factors are involved and the right treatment must be
identified to reduce the risk of recurrence.
The phase III BCIRG 005 has investigated the relative benefits of
concurrent versus sequential docetaxel adjuvant regimens, specifically 6 x Hormone Receptor Status
TAC versus 4 x AC- 4 x T in patients with HER2-normal, node-positive Hormone receptor status, ER and PR in breast cancer are believed to be
Data from the main efficacy analysis showed that adjuvant TAC is important factors in improving chemotherapy outcome.
equivalent to AC–T in terms of DFS. These data suggest that while the very few clinical trials have used the receptor status as a stratification factor
sequential docetaxel regimen delivers a higher dose intensity (eight from the outset. Reduction of RR of recurrence with paclitaxel was more
cycles), it is no more effective than the concurrent docetaxel regimen. efficacious in HR-positive patients than in HR-negative patients in the
The safety profiles of the two docetaxel-based adjuvant chemotherapy National Surgical Adjuvant Breast and Bowel Project (NSABP) B28 trial,
regimens were comparable, although a higher incidence of febrile whereas reduction of RR of recurrence in the BCIRG 001 with doxcetaxel
neutropenia and G-CSF use was observed in the TAC arm.
trial was very similar in both HR-positive and -negative patients (0.72 and
0.69, respectively). In GEICAM 9906 trial, RR of recurrence with paclitaxel
Another phase III study, NSABP B-30, also evaluated the benefits of was again very similar between the two groups.
Similar results in patients
concurrent versus sequential docetaxel adjuvant regimens on DFS and OS with docetaxel were found in the PACS 01 trial
and the ECOG2197
in operable, node-positive EBC.
The study also investigated whether a trials. Pooled data from the BCIRG 001 and PACS 01 trials analysed
regimen without cyclophosphamide was at least as efficacious as regimens retrospectively by Andre el al.
showed that RR of death was reduced by
containing cyclophosphamide. NSABP B-30 contained three arms: 4 x AC - 30% (HR 0.70) in ER-positive patients and by 31% (HR 0.69) in ER-negative
4 x T, 4 x TAC and 4 x AT. The AC–T arm reduced mortality by 14%, which patients, thus concluding that docetaxel conferred proportional effects on
is a marginal benefit compared with the TAC regimen (pP=0.086). The the risk of recurrence or death based on ER expression. The ECOG 1199
AC–T arm also significantly decreased mortality by 17% compared with AT study analysed outcomes as a function of ER status and found proportional
(p=0.034), while AT was shown to be as efficacious as TAC. In terms of gains were achieved in both ER-positive and -negative tumours for both
DFS, AC-T significantly decreased DFS by 17 and 20% versus TAC and AT, weekly paclitaxel and docetaxel every three weeks.
Again, no differences in DFS were observed between AT and
TAC. Although the sequential docetaxel regimen was found to be Human Epidermal Growth Factor Receptor-2 Status
marginally superior to the concurrent regimen, it should be noted that the Understanding of human epidermal growth factor receptor-2 (HER2) as a
TAC regimen used in NSABP B-30 was not the approved 6 x TAC. predictive factor and target of treatment is a recent development. The HER2
Interestingly, patients experiencing amenorrhoea for ≥6 months had gene encodes for the HER2 protein, a tyrosine kinase inhibitor.
significantly improved OS and DFS across all treatment arms.
Overexpression of the HER2 protein can be established by using
immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) is
Dose-dense Chemotherapy and Taxanes used to measure HER2 gene amplification. Trastuzumab, an HER2 antibody,
Innovations in adjuvant treatment strategies are critical for optimal and lapatinib, a tyrosine kinase inhibitor potentially play a vital role in
outcomes. The post-operative dose-dense approach is intended to adjuvant chemotherapy to achieve a maximum DFS.
optimise the administration of a standard chemotherapy regimen.
Dose-dense (dose of drug administered per unit of time [mg/m
/week]) Results from the combined NSABP B-31/North Central Cancer Treatment
can be obtained by either increasing the dose or decreasing the interval Group (NCCTG) N9831 study
showed significant improvements in both
between doses. This strategy, evaluated in the CALGB C9741 trial, has DFS (p<0.001) and OS (p=0.02) with trastuzumab. Similar results were
shown that paclitaxel chemotherapy given every other week (dose-dense obtained in the Herceptin Adjuvant (HERA) trial.
Trastuzumab for one year
schedule) obtained superior DFS (RR 0.74; p=0.010) and OS (RR 0.69; significantly improved DFS (p<0.0001) and OS (p=0.11). The combination of
p=0.13) compared with conventional schedule (every three weeks). No trastuzumab and docetaxel was found to achieve a 60% objective response
significant increase in adverse events was observed.
However, this rate, and 22% of patients were alive after four years.
Subgroup analysis in
approach requires G-CSF prophylaxis and may be associated with the BCIRG 007 trial also suggests similar benefits.
Hayes et al. reported
toxicities not typically observed in conventional schedules.
that in a subgroup analysis of the CALGB 9344 trial, the interaction between
HER2 positivity and the addition of paclitaxel to the treatment was
Data from the ECOG 1199 trial, a randomised trial of AC chemotherapy associated with an HR for recurrence of 0.59 (p=0.01). HER2-positive
followed by either paclitaxel (weekly or every three weeks) or docetaxel patients benefited from paclitaxel, regardless of ER status, but HER2-
(weekly or every three weeks), showed that weekly paclitaxel and docetaxel negative or ER-positive patients did not benefit.
Use of lapatinib in HER2
every three weeks conferred the best advantage in terms of lowest rates of overepression obtained a response rate of 62%.
The combination of
disease recurrence. Weekly paclitaxel dosing was associated with the trastuzumab and vinorelbin was found to be well tolerated and cost-
highest five-year OS. In terms of outcomes as a function of ER status, effective.
A small study called the FinHER trial randomised high-risk
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