This prospective, multi-institutional blinded study demonstrated a significant correlation between using the best chemotherapy regimen as assessed in the MiCK assay and overall survival both in all ovarian cancer patients studied, and in the more homogeneous subset of patients with chemotherapy-naïve stage III or IV primary disease. Using the best chemotherapy regimen based on the MiCK assay also correlated with relapse-free interval. If the physicians used a chemotherapy regimen with higher activity in the MiCK assay, response to therapy was higher. This suggests in this non-randomized observational trial that the MiCK assay can help guide selection of more active chemotherapy in ovarian cancer patients. Based on this hypothesis generating study, subsequent randomized validation trials will help further elucidate the benefits of using the MiCK assay to select appropriate therapy for these patients. This study justifies such a randomized trial, and quantifies the benefits in outcomes on which a randomized study can be developed (for power determinations and study size requirements). Such a randomized prospective trial should compare standard postoperative therapy of patients with stages III and IV epithelial ovarian cancer, versus therapy directed by the best results in the MiCK assay. Appropriate stratifications would include extent of debulking, amount of residual disease, stage, age, and preoperative CA125. Numbers of patients needed to treat would be determined by participating statisticians based on primary and secondary goals.
A review by the American Society of Clinical Oncology (ASCO, 1) has found prior chemosensitivity and chemoresistance assays to be insufficiently robust in predicting outcomes, and has not recommended their routine use. This MiCK assay was not reviewed in any of those analyses. However, the reviewers stated in their conclusions that “because the in vitro analytic strategy has potential importance, participation in clinical trials evaluating these technologies remains a priority.” This study represents such a trial that can contribute to subsequent reviews by that ASCO committee and other organizations. This study also represents evidence on which future validation and utility trials can be based.
In contrast to prior chemotherapy resistance assays, the MiCK assay is different. The MiCK assay measures direct in vitro cell killing (rather than measuring only survival of cells), studies only cancer cells (compared to mixed host and cancer cells), requires no in vitro growth of tumor cells (compared to assays requiring growth of cells, which measures only a subset of cancer cells capable of growth in vitro), gives results based on multipoint analyses (every 5 minutes for 48 hours) rather than just a single endpoint
, and has results available within 72 hours of biopsy (rather than 3–4 weeks).
The ability to identify drugs which are active in the clinical therapy of ovarian cancer suggests that this assay may also be able to play a role in drug development. The assay might be used to study new drugs pre-clinically (2 such trials have been completed, unpublished data), to evaluate if drugs known to be active in other cancers may also have activity in ovarian cancer, and to identify which patients are most likely to respond in clinical trials. This would allow phase II and phase III trials to be focused on patients with the highest chance of improvement, reducing time needed to conduct a clinical trial and increasing the probability of finding effective new drugs. The MiCK assay may also be able to give pharmaceutical companies indications of which approved drugs may be more effectively combined with investigational agents, thus prioritizing clinical trials for more rapid approval by regulatory agencies.
The assay also showed that in some patients (approximately 1/3 to 1/2), single agents were as effective in killing ovarian cancer tumor cells in vitro as standard combination therapies. If confirmed clinically, the MiCK assay may be useful to physicians in individualizing therapy, especially in patients at increased risk of toxicity from combination drug treatments or patients fearful of side effects of combination therapy. Single agent chemotherapy has been found equivalent to combination chemotherapy in some trials
[18, 19] but not others
Since the MiCK assay indicates which drugs are associated with improved survival, it is possible that use of the assay may reduce healthcare costs by avoiding inactive therapies. Results of studies
 have been used to model potential cost savings in care of cancer patients in a large self-insured employer database. This study indicated possible cost savings of 25 to 85% of chemotherapy-associated expenses.
Since this study initially had a high rate of unsuccessful assays, education of participating sites about submission and processing procedures have been improved which resulted in consistently higher success rates over 75%. Although the learning curve is very fast, the company which provides the test has improved its support of centers using the assay so that inevaluable specimens are less frequent.
In summary, use of the best chemotherapy regimen as assessed in the drug-induced apoptosis MiCK assay correlated with overall survival in all ovarian cancer patients, and in patients with chemotherapy-naïve stage III or IV primary therapy patients with a hazard ratio for death of 0.23. The assay is predictive of survival if physicians use the best treatment based on the assay. Relapse-free interval and response rate were also predicted by the MiCK assay. Further studies of this predictive theranostic bioassay are warranted.