Wednesday, December 23, 2009

Who Benefits from Taxanes?

Receptor status is one variable, but unique genetic aspects of breast cancer tumors might provide the most guidance on which tumors are the most sensitive to chemotherapy using taxanes.

Determining who benefits from adding taxanes as part of the treatment regimen for early-stage breast cancer may mean looking more at the biology of the disease—whether it is basal or luminal, for example—rather than on the current policy of screening based on lymph-node involvement.

A review of 21 trials affecting nearly 36,000 women with early-stage breast cancer evaluated the benefits of adjuvant chemotherapy—after surgery—using taxanes versus those not using taxanes. Published in the January 2010 issue of Nature Reviews Clinical Oncology, the analysis found that many women are overtreated with chemotherapy, while some greatly benefit from aggressive treatment. How to determine which is which is complex, and the decision is even more serious given the potential toxic effects of taxanes—heart failure, leukemia, neuropathy, and weight gain—not to mention the cost.

Some findings:

•Taxanes provide a 5 percent improvement in disease-free survival and 3 percent improvement in overall survival regardless of the type of taxane, its schedule of administration, lymph node involvement, or hormone-receptor status. Researchers call this a “modest improvement.”

• Women under 50 with and without affected lymph nodes benefit from taxanes. Relative risk of recurrence for node-negative disease in this group was reduced by 36 percent; relative risk of recurrence for node positive disease was reduced by 37 percent.

• Women 50-69 have less of a benefit—a 23 percent reduced relative risk of recurrence for node-negative and 17 percent for node-positive.

• Hormone-receptor status does not affect the benefit significantly for women under 50. Those with estrogen-negative cancers face a relative risk reduction of 39 percent and those with ER-positive had a 44 percent relative risk of reduction.

• In women 50-69, taxanes may provide less of a benefit to women with estrogen-positive (16 percent relative risk reduction) than estrogen-negative (33 relative percent risk reduction).

• For women under 50, the relative risk of recurrence after two years remains similar to the risk after 15 years. For women 50-69, however, the risk reduction occurs in the first two years, with little or no effect after that. This may be related to estrogen-receptor status, as women with ER-negative typically face the highest risk of recurrence within two years, while those with ER-positive disease face a sustained risk—over a longer period.

• Paclitaxel at 80 mg/m2 once a week or docetaxel every 3 weeks at 100 mg/m2 is superior to paclitaxel at 175 mg/m2 every three weeks following four cycles of AC.

• Doxorubicin and paclitaxel followed by once-weekly paclitaxel is more effective than standard AC with paclitaxel every 3 weeks.

• Improvements in the pathologically-complete response rate do not always translate to improvements in disease-free survival or overall survival.

• ER status or Her2 status alone aren’t significant predictors of who will benefit from taxanes.

• Genetic factors that are still being studied may provide the most information on who benefits from taxanes, once again demonstrating that our cancers are as unique as our DNA. For example, tumors with the P glycoprotein may be taxane resistant, as are those with β-tubulin mutations. Tumors with the TP53 mutation, however, may be more sensitive to taxanes. But ER-negative tumors with high levels of Aurora-A may be taxane resistant.

In their conclusion, the researchers write:

Based upon the first-generation taxane trials, taxane-based regimens are an important addition to the armamentarium against early-stage breast cancer. However, deciding which individual patients are likely to benefit from taxanes remains a challenge. Ultimately, clarifying the role of factors that affect the efficacy of taxanes in particular subgroups of patients (defined by traditional biomarkers such as age, ER status, and HER2 expression) will require international collaboration with rigorous examination of data from individual patients in first-generation taxane trials, in a future EBCTCG meta-analysis. Validation of additional biomarkers and evaluation of novel agents in the adjuvant setting will require innovative approaches to clinical trial design. Previous trials have clearly demonstrated that defining inclusion criteria for adjuvant chemotherapy trials on the basis of anatomically defined risk factors—such as lymph-node status—rather than disease biology is inherently flawed. Future advances will require identification of the patients likely to benefit from particular therapies, prospective centralized tumor banking, and a commitment to innovative platforms for translational research, to further optimize therapy for early-stage breast cancer.

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