Editorial Should Therapy of Ovarian Cancer Patients Be Individualized Based on Underlying Genetic Defects? Gordon B. Mills, 1 Rosemarie Schmandt, David Gershenson, and Robert C. Bast Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 This year in the United States, ;26,800 women will be newly diagnosed with ovarian cancer, and 14,500 will die from the disease (1). The dismal prognosis for ovarian cancer patients results from an inability to detect the tumor at an early, treatable stage as well as from lack of effective therapies for advanced disease. Ovarian cancers show high response rates to chemo- therapy, which, unfortunately, do not translate to high cure rates (2). Indeed, although chemotherapy has improved survival times, there has been no significant improvement in cure rates in the last 30 years, with only 20% of patients with stage III and IV ovarian cancers surviving 5 years (1, 2). The most likely way to develop new, effective therapies for advanced epithelial ovarian cancer patients is to improve our understanding of and ability to identify the genetic changes leading to the initiation and pro- gression of ovarian cancer and to sensitivity and resistance to chemotherapy. In the United States, the majority of ovarian cancer patients are treated with a platinum analogue combined with a taxane derivative. The best response rates to platinum-based combina- tion chemotherapy are ;70% (3), indicating that at least 30% of ovarian cancer patients are exposed to the toxic effects of platinum-based chemotherapy without significant benefit. Sim- ilarly, the response to Taxol alone is ;50% (3), suggesting that half of patients may not benefit from the addition to Taxol to a platinum analogue. Furthermore, an initial round of platinum- based therapy may delay selection of an effective chemotherapy drug and may also decrease the patient’s physiological reserve. In patients previously treated with a platinum-based regimen, new anthracyclines (doxorubicin and liposomal doxorubicin preparations), nucleoside analogues (gemcitabine), topoisomer- ase I and II inhibitors (oral etoposide, topotecan, and campto- thecins), Vinca alkaloids (vinorelbine), and orally active pro- drugs (hexamethylmelamine) as well as hormonal manipulation (tamoxifen and gonadotropin-releasing hormone analogues) have all demonstrated activity in clinical trials (2). A number of novel chemotherapy drugs aimed at specific molecular targets are being evaluated in ovarian and other cancers. It is not clear whether the same or different patients will respond to the new chemotherapeutic regimens. In the future, a method to select an appropriate chemotherapy regimen up front or for “salvage” patients who have failed conventional chemotherapy could con- tribute to an improved outcome in ovarian cancer, both by increasing efficacy and decreasing toxicity. It is not clear what degree of predictive value would be sufficient to justify individualization of patient therapy. As the response rate for salvage therapy is 15–20%, would a test indicating that 40% of patients will respond be useful? Con- versely, is the use of a chemotherapy drug appropriate if the patient has a 10, 5, or a 1% chance of response? At what point does the decreased quality of life in the majority of patients receiving a therapeutic regimen overwhelm the potential benefit to a few? One potential indication is that breast cancer patients with ,5% chance of responding to tamoxifen (estrogen receptor negative, premenopausal) do not usually receive tamoxifen ei- ther because of physician preference or patient choice. A number of rapidly emerging technologies including CGH, 2 RNA expression array analysis, multiplexed loss of heterozygosity analysis, serial analysis of gene expression, dif- ferential display, suppressed subtractive hybridization, high- throughput expressed sequence tag sequencing, and proteomics are beginning to allow analysis of global genetic changes in an individual tumor and correlation of these changes with patho- physiology, response to therapy, and patient outcome. Indeed, the opportunity to link molecular diagnostics to patient manage- ment is the underlying tenet of the current National Cancer Institute Director’s challenge. Of these approaches, CGH is particularly attractive because it is currently available and al- lows a genome-wide scan in a single step (4, 5). However, the sensitivity and resolution of conventional chromosome-based CGH is likely limited to changes that are 5–10 Mb (4, 5). As an example, an amplicon located at 19p, which contains AKT2, is frequently present in ovarian cancer cells but is too small to be detected by classical CGH (5–7). Similarly, the frequency of copy number abnormalities at 3q is greater when it is analyzed by fluorescent in situ hybridization with region-specific probes than when it is assessed by chromosome-based CGH (8). A new technology, designated array CGH (9), has greatly increased sensitivity, allowing detection of copy number abnormalities that affect smaller genomic regions. Importantly, copy number abnormalities detected by classical CGH may reflect a sum of multiple distinct small areas of copy number abnormality. Array CGH due to increased ability to resolve areas of copy number abnormalities (9) may exhibit improved predictive value and also facilitate the identification of the gene or genes driving specific genomic amplifications or deletions. Array CGH is also likely to be more robust and less tedious than classical chromo- some-based CGH. Development of an effective strategy for individualization of patient therapy will require not only application of the emerg- Received 6/16/99; accepted 6/16/99. 1 To whom requests for reprints should be addressed, at Department of Molecular Therapeutics-317, University of Texas M. D. Anderson Can- cer Center, 1515 Holcombe Boulevard, Houston, TX 77030. 2 The abbreviations used are: CGH, comparative genomic hybridization; PI3K, phosphatidylinositol 3-kinase. 2286 Vol. 5, 2286 –2288, September 1999 Clinical Cancer Research Research. on November 26, 2021. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from