Clinical trials in breast cancer; do we have the right approaches?
- PE Lønning1
© Current Science Ltd 2000
Published: 12 March 2000
While adjuvant chemotherapy as well as hormone therapy improve long-term survival in breast cancer patients [1, 2], only about 25-30% of patients at risk are cured by such treatment modalities. While improved regimens using more effective chemotherapeutics have been shown to improve outcome marginally , the disappointing results from high-dose chemotherapy with stem cell support [4, 5] underlines the limitations associated with current chemotherapy.
While expression of the estrogen and progesterone receptors have been used to select patients for endocrine treatment, so far we have lacked predictive factors with respect to outcome in chemotherapy. Over the last decade, laboratory investigations have revealed several potential mechanisms explaining resistance to chemotherapy. Thus, there is evidence that loss of function of the TP53 gene may confer resistance to chemotherapeutics like the anthracyclines but does not deteriorate response to the taxanes [6, 7], a finding supported by recent studies in breast cancer patients [8, 9].
These findings may challenge the way we are running clinical trials in breast cancer patients. If certain gene mutations predict for resistance to specific drugs, the key target for future studies should be to outline these mechanisms in vivo. While combined therapy regimens may improve response rates to some extent, such approaches would imply over-treatment with increased toxicity in many patients who would not benefit from one or more of the drugs in the 'cocktail'. It may even be detrimental to clinical outcome as it may require reduction in the dose of active drugs. Retrospective evaluation of predictive factors in adjuvant studies are complicated by several confounding factors like inappropriate tissue sampling (paraffin-embedded only), use of combined regimens and inferior surrogate markers for therapeutic efficacy (time to relapse versus direct antitumour effects). Evaluation of predictive factors should preferably be done in relation to monotherapy with single chemotherapeutics in the advanced or neoadjuvant setting, and such results are likely to have a strong influence on how we design adjuvant studies in the future.
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