Who Benefits from Taxanes: Controversy in Breast Cancer Management

The benefit of adjuvant paclitaxel (Taxol), in addition to anthracycline-based chemotherapy was evaluated in the CALGB 9344 study, which has previously been reported.  CALGB 9344 evaluated 4 cycles of escalating doses of doxorubicin (Adriamycin) combined with a fixed dose of cyclophosphamide (AC) with or without 4 cycles of sequential Taxol in 3170 women with node-positive primary breast cancer. After 52 months of follow-up, important changes were noted when compared with earlier interim analyses at 21 and 30 months follow-up.  Specifically, the addition of sequential paclitaxel to AC significantly improved the disease-free survival (P = .0324), but not overall survival (P = .0745). The disease-free survival rates for patients treated with sequential AC and Taxol versus those treated with AC alone at 48 months follow-up were 73% vs 70%, respectively. Overall survival rates for the 2 groups at 48 months were 84% vs 81%, respectively.

Molecular subtypes of breast cancer are now better defined.  Her-2 positive breast cancer (about 15% of all breast cancer) is an aggressive subtype, with growth driven by the over-expression of her-2 growth regulating receptors on the cancer cells.  Older studies, such as CALGB 9344 did not include the use of adjuvant anti-her-2 treatment, trastuzumab (Herceptin), in addition to chemotherapy, which is now the standard-of-care for her-2 positive disease.  It has been hypothesized that her-2 positive cancers benefit more from chemotherapy than other cancers, possibly because of increased levels of intracellular topoisomerase II (topo II), or because of a higher proliferation rate.  The question of whether her-2 positive breast cancer patients (when compared to her-2 negative patients) benefit to a greater degree by the addition of Taxol to AC was analyzed in a retrospective analysis of the CALGB 9344 study, which was published in the New England Journal of Medicine, October 11, 2007. 

In this analysis, Her-2 positivity was associated with a significant benefit from paclitaxel. The interaction between Her-2 positivity and the addition of Taxol to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01), a 41% reduction in risk. Patients with a Her-2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status.  Taxol did not benefit patients with HER2-negative, estrogen-receptor–positive cancers.   However, Her-2 negative, estrogen-receptor negative patients did have a significant reduction in the hazard ratio for recurrence (P=0.002), indicating that Taxol has benefit for some patients who are not Her-2 positive. 

Oncologists have been cautioned about premature interpretation and possible clinical practice changes until further study can confirm these results.  The CALGB analysis was retrospective, and the aggregate results of the study did show general benefit of Taxol adjuvant therapy for breast cancer patients.  Similar findings of benefit have been reported for adjuvant use of docetaxel (Taxotere) for adjuvant treatment of node-positive patients.  In addition, the use of taxol in the CALGB study (every 3 weeks) was not optimal, based on more recent studies that have demonstrated that Taxol is more effective when given on a more frequent schedule (weekly).  Therefore, the conclusion that adjuvant addition of weekly Taxol to AC might not be beneficial to estrogen-receptor positive patients requires confirmation.  Newer taxanes have been developed (for example, Abraxane, a nanoparticle of taxol in albumin protein), which may be more effective that Taxol.  A US Oncology study suggests that a more intensive taxane therapy and schedule may be a significant addition for her-2 negative and estrogen-receptor negative patients. Further study of taxanes in all molecularly-defined groups of patients is warranted, to determine what the degrees of benefits may be.  Finally, the substitution of taxane therapy for anthracycline-based treatment in the adjuvant setting appears to be a promising strategy in reducing possible cardiac toxicity of treatment. 

In summary, the CALGB study analysis is provacative, but not unexpected. Not all patients derive the same benefit from adjuvant treatments with different agents.  Taxane therapy should not be an immediate addition to every patient, but it should be considered based on a careful and individualized basis of each patient’s breast tumor characteristics, stage, and recurrence risk.  Additional study of taxane treatment in clinical trials, such as those offered at CORT, will be important in helping to improve treatment selection for patients.  In the meantime, it is premature to routinely deny patients with estrogen-receptor positive cancers the addition of a taxane in adjuvant therapy, without additional confirmatory study.

Tags: breast cancer treatment controversies, CALGB 9344, estrogen-receptor, her-2, paclitaxel, Taxol