Utility of Chemotherapy Sensitivity and Resistance Assays for Optimizing Treatment for Patients with Solid Tumors
by Harold J. Burstein, MD, PhD, and Jaffer A. Ajani, MD
|Harold J. Burstein, MD, PhD
|| Jaffer A. Ajani, MD
Cancer is a highly prevalent disease in the United States, and it is often diagnosed in advanced stages. Once the diagnosis of cancer is rendered, patients and their families are often bewildered to find out that most treatments are not curative for advanced cancers.
Many patients prepare a list of questions for their oncologists about topics such as the use of chemosensitivity and resistance assays and the selection of chemotherapy agents. It is very disappointing that many treatment regimens are not based on the specific characteristics of an individual patient’s tumor. Furthermore, the phenomenon of unpredictable outcomes from empiric therapy in patients with the same tumor type and stage (for example, stage IV lung cancer) is a widely recognized and frustrating problem for patients, their caregivers, and medical professionals.
For patients, it is very disheartening to experience unpleasant treatment-related side effects but receive little or no benefit. There has been a long-standing hope that the oncology community could develop very reliable methods to optimize therapy for each patient. Scientists have made concerted efforts to develop methodologies for many chemotherapy sensitivity and resistance assays (CSRA) over the past several decades. More recently, new approaches to personalized care have been developed, such as analyses of DNA, RNA, proteins, and microRNAs.
The basic premise of CSRA includes procurement of fresh tumor samples (primary or metastatic), disaggregation of tumor cells, and exposure of these tumor cells to therapeutic agents under various in vitro conditions. At least four types of CSRA have been described: adenosine triphosphate bioluminescence (ATP), extreme drug resistance (EDR[A]), methyl thiazolyl-diphenyl- tetrazolium bromide (MTT), and ChemoFX®. Reports on several of these CSRA have been published over the years, and several assays have made it into the market place. It is important for the practicing oncologist to understand the data on the utility of such assays because many patients and their families learn about CSRA through various sources.
The academic oncology community has been reviewing the extent of clinical development of CSRA, as well as their utility in treatment selection and other benefits, such as improving overall survival of those patients treated based on the assay results compared with empiric approaches. ASCO addressed the issue of CSRA utility in 2004 and is updating the guideline in 2011. Each time the subject has been addressed, ASCO commissioned a number of experts to conduct detailed reviews of existing English literature on CSRA and to establish the level of evidence based on randomized trials.
In 2004 ASCO found that, although there were many commercially available CSRA, there was insufficient evidence of benefit to patients; therefore, ASCO did not recommend the use of any CSRA for selection of chemotherapeutic agents for individual patients with cancer outside of clinical trials.
The major setback for CSRA lies in the lack of rigorous clinical testing (i.e., small sample sizes and lack of prospective comparisons) necessary to document patient benefit, and most published studies significantly fall short of this requirement.
Does this mean that we will not have tests that can predict benefit for our patients from a specific therapy?
It might be that the era of CSRA is coming to an end; however, the current advances in biotechnology have allowed us much deeper understanding of how cancer is organized, how it maintains itself (i.e., tumor-initiating cells with self-renewal potential), and how it acquires several survival advantages under stressful circumstances.
Examples of these survival advantages include its ability to withstand inflammatory conditions as a result of reactive oxygen species, its ability to overcome chemotherapy injury by upregulating drug transporters, and its improved capacity to repair damaged DNA due to radiation exposure.
Detailed sequencing of tumor DNA has also led to greater understanding of activating mutations, gene amplifications, deletions, and translocations. Functional studies have led to discrimination between driver mutations and passenger mutations. One can now recognize that we would not have identified drugs like imatinib (e.g., for gastrointestinal stromal tumors), traxtuzumab (e.g., for certain breast cancers), crizonib (e.g., for certain lung cancers), or PLX4032 (e.g., for certain melanomas), and so on through any of the CSRA.
The future appears very promising, and we can envision the availability of a multitude of tools for individualization of therapy, early detection of primary cancer, monitoring for relapse, and surveillance of specific subjects (these individuals are not necessarily patients in conventional sense) at high risk of cancer development.
However, the most important aspect will be to document patient benefit through elaborate and appropriate randomized and controlled investigations (such as those ongoing for Oncotype DX®), otherwise such endeavors will be classified alongside CSRA.
About the Authors:
Dr. Burstein is Associate Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute. He is a member of the Nominating Committee, and he is the Chair-Elect of the Cancer Education Committee. Dr. Ajani is a medical oncologist and Professor of Medicine at the University of Texas M. D. Anderson Cancer Center.