Knowledge about a patient’s tumor profile may identify genomic alterations that help the treating physician to guide the patient to a therapy or clinical trial with a higher likelihood of success.
Although the tumors of most ACC patients have similar characteristics, they also have differences. Understanding the characteristics of each patient’s tumor is becoming increasingly important in selecting the best systemic therapies. This section will discuss how tumor profiling (molecular analysis of alterations in DNA, RNA and proteins) and targeted agents are essential components of personalized medicine and clinical trial selection.
At the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO), M.D. Anderson researchers presented a scientific abstract that compared the response rate of Phase I clinical trial patients with and without treatment guided by tumor profiling. Among patients with one molecular aberration in their tumors, 29% of those matched to a targeted agent had a response (significant tumor shrinkage) compared to only 8% for those patients for whom there was no matched targeted drug. And patients matched to targeted therapy had a median survival that was 6 months longer than unmatched patients. Only about 40% of patients entering the Phase I clinical trials at M.D. Anderson had one of the molecular aberrations analyzed. And just less than a third of those had a response. But, clearly, the odds favored patients whose tumors were profiled.
Most cancers do not have an effective targeted therapy at the moment, but there is a growing list of drugs and associated tumor types with success stories: Tamoxifen in estrogen-receptor-positive breasts cancers, Trastuzumab (Herceptin) in HER2-positive breast and gastric cancers, Imatinib (Gleevec) in chronic myelogeneous leukemia (CML) and Gefitinib (Iressa) in EGFR-positive lung cancers, among many others. The fact that most ACCs have a similar genetic alteration (a rearrangement of the MYB gene and over-supply of its protein) implies that one day there may be a targeted therapy that will be active across many ACC patients. However, aside from MYB, ACC tumors are like most other tumor types in that they have multiple additional genetic alterations that are different from person to person. For example, one patient’s tumor may have a mutation in the PI3K pathway while another may have extra copies of the EGFR gene. Each patient may respond to a different drug based on the mix of genetic alterations driving their particular tumor.
A 2011 news story highlighted the promise of personalized medicine. An ACC patient with a particular genetic alteration visited South Texas Accelerated Research Therapeutics (START) in San Antonio, TX. The START physician profiled the tumor, identified a genetic alteration and then matched it to a novel targeted therapy, leading to a significant response in the ACC patient. While this story demonstrates the power of tumor profiling, it should be accompanied with an important caveat. Most ACC patients are unlikely to harbor the same genetic alteration as the patient in the news story, and therefore are unlikely to respond in the same manner to the same drug.
For those patients with the inclination and wherewithal, tumor profiling is a very reasonable choice. Dramatic advances in genomic sequencing are permitting forward-thinking physicians to provide meaningful guidance on targeted therapy to their patients. Currently, the probability of finding a genetic alteration with a matched therapy may be low in any given patient. On the other hand, if one is found, the probability of a response with appropriate targeted drugs may be higher than that expected with traditional chemotherapies or unmatched targeted drugs. Over time, scientists will identify more genetic alterations as well as the drug therapies that will treat them.
There are many tumor profiling services. Your physician may order the test on your behalf or you may contact the services directly. Here is a list of a few options:
- Foundation Medicine
- Oncopath Laboratory
- Knight Diagnostic Labs
- Translational Research Lab at the Massachusetts General Hospital.
- Caris Target Now
ACC patients should check with their insurance companies to learn whether tumor profiling services are covered. If not, costs may reach $1,000 or more, depending on the service.
It is worth noting that, at the moment, the most helpful tumor profiling services look for somatic mutations (DNA misspellings) in about 200 of the 400+ known cancer genes. Some services focus on gene expression (the amount of each RNA in the tumor), but the linkage to matched therapies is much weaker than with somatic mutations. For example, over-expression of the CKIT gene is common in ACC, but drugs that inhibit the c-kit protein (e.g. Imatinib) are not active in ACC; they are active only in gastrointestinal stromal tumors with somatic mutations in the CKIT gene. Patients should understand that many genetic alterations do not have a matched, effective therapy. No targeted therapies have been discovered yet that inhibit MYB (one of the presumed drivers of ACC tumors), though significant efforts are under way to identify such therapies.
Tumor profiling should not be confused with chemotherapy sensitivity and resistance assays (CSRAs). Tumor profiling involves analysis of tumor DNA, RNA or protein to identify druggable molecular targets. CSRAs involve the procurement of fresh tumor samples (through biopsies or operations) and their exposure to drugs in vitro (in plastic dishes). The reaction of those samples is purported to predict the activity of the drugs in patients. ASCO recently published a Technology Assessment of CRSAs, concluding that “Review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice… The use of chemotherapy sensitivity and resistance assays to select chemotherapeutic agents for individual patients is not recommended outside of the clinical trial setting.”
In summary, knowledge about a patient’s tumor profile may identify genomic alterations that help the treating physician to guide the patient to a systemic therapy or clinical trial with a higher likelihood of success.
For more background and details on clinical trials, please read ACCRF’s Guide to Systemic Therapy for Patients With Progressive ACC.