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BCIRG-001 trial of 6% at 5 years. BCIRG-001 trial compared adjuvant TAC vs. FAC regimens in node
positive early breast cancer patients, with subgroup analysis of patients with 1-3 positive nodes showing
the largest OS benefit from adding taxanes. However, the incidence of NF was 25% in the TAC arm which
is considered a limitation against its use. Nonetheless, G-CSF prophylaxis was not allowed in this trial and
likely contributed to the high incidence of NF. Therefore, it is reasonable to prescribe G-CSF whenever TAC
is considered for adjuvant chemotherapy in breast cancer to minimize NF risk.

Other regimens which were associated with significant OS benefit are 4 cycles of andriamycin-
cyclophosphamide followed by 4 cycles of paclitaxel (AC-P) regimen in CALGAB-9344 trial, 3 cycles of 5FU-
epirubicin-cyclophosphamide followed by 3 cycles docetaxel (FEC-D) regimen in PACS-01 trial, and 4 cycles
of epirubicin-cyclophosphamide followed by 4 cycles docetaxel (EC-D) regimen in AGO trial. Subgroup
analyses of each trial demonstrated the following; AC-P regimen was more beneficial to patients with ER
negative tumors, whereas the EC-D regimen gave better results for ER positive patients. The FEC-D regimen
was better for patients with 1-3 positive LNs and those who aged 50 years or more.

Three randomized trials reported significant DFS with adding taxanes to anthracyclines in the adjuvant
settings of breast cancer. These trials are NSABP-B28, GEICAM-9906 and GEICAM-9805. It is noteworthy
that most of the taxanes trials were conducted on patient with node-positive disease, whereas 3 trials showed
negative results in node-negative patients: UK-TACK trial, MA-21 trial, and E-2197 trial. However, TAC
regimen resulted in a significant DFS advantage for node-negative patients in GEICAM-9805 trial. Therefore,
TAC regimen might be considered for node-negative breast cancer patient. Another important advantage of
TAC regimen over AC-P regimen is that the short overall duration which is only 6 cycles of chemotherapy,
whereas AC-P is a total 8 cycles. Moreover, The AC-P regimen which was used in NSABP-B28 trial did not
result in a significant OS benefit because of the high dose of Paclitaxel that lead to 25% of patient did not
complete the chemotherapy course.

There were 3 meta-analyses which investigated the role of adding taxanes to anthracyclines in the adjuvant
setting of breast cancer, and all reported a significant OS benefit from adding taxanes. EBCTCG meta-
analysis, which is the largest meta-analysis in this area, showed that all patient subgroups had a significant
improvement of OS from adding taxanes. The Italian meta-analysis showed that adding taxanes was not
beneficial to ER-positive patients and those with 4 or more positive axillary LN metastases. Nonetheless,
Cochrane database meta-analysis did not report which patient subgroup had the greatest OS benefit from
adding taxanes.

The positive impact of adding taxanes to anthracyclines in treating breast cancer can be explained by
the different mechanisms of action at both the cellular and molecular levels. Such combination helps to
overcome drug resistance of both agents if used separately. Anthracyclines works by intercalating into DNA,
disrupting topoisomerase-II-mediated DNA repair and generating free radicals which trigger apoptotic
[16]
pathways of cell death . Whereas, taxanes works by binding to microtubules, preferentially to b-tubulin,
and stimulate phosphorylation of b-tubulin which leads to stabilization of microtubules by the prevention
of depolymerization. The stabilized microtubules interfere with mitotic spindle formation during the cell
division and leads to cell death.

The genes that are involved in the action of doxorubicin at the cellular level are those capable of the oxidation
reaction (NADH dehydrogenases, nitric oxide synthases, xanthine oxidase) and those capable of deactivating
the free radicals such as glutathione peroxidase, catalase, and superoxide dismutase. Also, genes which
are involved in the topoisomerase-II pathway of Doxorubicin action include the enzymes involved in the
DNA repair and cell cycle control such as TOP2A, MLH1, MSH2, TP53, and ERCC2 genes. Whereas, the
main genes involved in the action of Paclitaxel are the b-tubulin and c-erb 2. However, both anthracyclines-