Towards prediction and modulation of treatment response.

Abstract

The purpose of this paper is to evaluate new predictive assays and their potential to modulate treatment response. Their impact is presented in the context of three EORTC clinical trials in head and neck, lung and breast cancer, showing an improvement in survival by accelerated fractionation, concomitant use of cisplatin and radiotherapy and adjuvant hormonal treatment, respectively. Assays have been developed to predict the response to treatment by measuring tumor characteristics, such as the growth potential by the labeling index after i.v. injection of IdUrd, the extent of radiation-induced stable and unstable chromosome aberrations and the induction of apoptosis. These assays could guide us in the adaptation of the individual radiation doses and fractionation schedules. The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a recently completed phase II dose escalation trial with concomitant radiotherapy and daily cisplatin in lung cancer, we found that patients with high DNA adduct levels measured in the buccal mucosa, had a much better survival rate than patients with a low or undetectable amount of cisplatin DNA adducts. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help to design studies aimed at modulating the apoptotic response. We and others have recently shown that alkylphospholipids, which inhibit mitogenic signaling, induce apoptosis in a variety of tumor cell lines. In combination with ionizing radiation, these compounds cause an enhancement of apoptotic cell kill. This type of signaling-based intervention study may form the basis for new therapeutic strategies. Pretreatment levels of apoptosis may be helpful in predicting treatment outcome, although the data so far show inconsistent results. The importance of evaluating other tumor-biological parameters, including cell kinetics should be stressed. Based on assays predicting reliably the response to hormonal therapy, a more appropriate choice can be made for therapeutic intervention with hormonal therapy and for selecting the appropriate adjuvant therapy in breast cancer patients. The development of a functional estrogen receptor assay (ER-FASAY), based on a yeast growth-assay, provides a way of estimating abnormal function of the receptor in tumors with a positive estrogen receptor score as measured by a classical immuno-histochemistry assay. This yeast assay can also detect different DNA mutations of the estrogen receptor existing in an individual tumor specimen.