Leveraging Veterans Health Administration Clinical and Research Resources to Accelerate Discovery and Testing in Precision Oncology

During the 20th century, with few exceptions, physicians caring for patients with cancer had blunt instruments at their disposal. Surgery and radiation could lead to survival if the cancer was caught early enough. Systemic therapies, such as chemotherapy, rarely cured but could prolong life in some patients. However, chemotherapy is imprecise and targets any cell growing rapidly, including blood, hair, and gastrointestinal tract cells, which often leads to adverse effects. Sometimes complications from chemotherapy may shorten a person’s life, and certainly the quality of life during and after these treatments could be diminished. The improvements in cancer care occurred more rapidly once scientists had the tools to learn about individual tumors.

In the summer of 2000, researchers announced that the human genome had been sequenced.⁶ The genome (ie, DNA) consists of introns and exons that form a map for human development. Exons can be converted to proteins that carry out specific actions, such as helping in cell growth, cell death, or DNA repair. Solving the human genome itself did not lead directly to cures, but it did represent a huge advance in medical research. As time passed, sequencing genomes became more affordable, and sequencing just the exome alone was even cheaper.⁷ Treatments for cancer began to expand with the help of these tools, but questions as to the true benefit of targeted therapy also grew.⁸

Physicians and scientists have amassed more information about cancer cells and have applied this knowledge to active drug development. In 2001, the FDA approved the first targeted therapy, imatinib, for the treatment of chronic myelogenous leukemia (CML). This rapidly improved patient survival through targeting the mutated protein that leads to CML, rather than just aiming for rapidly dividing cells.⁹ Those mutations for which there is a drug to target, such as the BCR-ABL translocation in CML, are called actionable mutations.

Precision Oncology Program for Prostate Cancer

In 2016, the VA and the Prostate Cancer Foundation (PCF) established the Precision Oncology Program for Prostate Cancer (POPCaP) Centers of Excellence (COE). This partnership was formed to accelerate treatment and cure for veterans with prostate cancer. The VA Greater Los Angeles Healthcare System in California and VA Puget Sound Health Care System in Washington led this effort, and their principal investigators continue to co-lead POPCaP. Since its inception, 9 additional funded POPCaP COEs have joined, each with a mandate to sequence the tumors of men with metastatic prostate cancer.

The more that is learned about a tumor, the more likely it is that researchers can find mutations that are that tumor’s Achilles heel and defeat it. In fact, many drugs that can target mutations are already available. For example, BRCA2 is an actionable mutation that can be exploited by knocking out another key DNA repair mechanism in the cell, PARP. Today, the effort of sequencing has led to a rich database of mutations present in men with metastatic prostate cancer.

Although there are many targeted therapies, most have not been studied formally in prostate cancer. Occasionally, clinicians treating patients will use these drugs in an unapproved way, hoping that there will be anticancer activity. It is difficult to estimate the likelihood of success with a drug in this situation, and the safety profile may not be well described in that setting. Treatment decisions for incurable cancers must be made knowing the risks and benefits. This helps in shared decision making between the clinician and patient and informs choices concerning which laboratory tests to order and how often to see the patient. However, treatment decisions are sometimes made with the hope of activity when a cancer is known to be incurable. Very little data, which are critical to determine whether this helps or hurts patients, support this approach.

Some data suggest that sequencing and giving a drug for an actionable mutation may lead to better outcomes for patients. Sequencing of pancreatic tumors by Pishvaian and colleagues revealed that 282 of 1,082 (26%) samples harbored actionable mutations.¹⁰ Those patients who received a drug that targeted their actionable mutation (n = 46; 24%) lived longer when compared with those who had an actionable mutation but did not receive a drug that targeted it (hazard ratio [HR] 0.42 [95% CI, 0.26-0.68; P = .0004]). Additionally, those who received therapy for an actionable mutation lived longer when compared with those who did not have an actionable mutation (HR 0.34 [95% CI, 0.22-0.53; P < .001]). While this finding is intriguing, it does not mean that treating actionable mutations outside of a clinical trial should be done. To this end, VA established Prostate cancer Analysis for Therapy CHoice (PATCH) as a clinical trials network within POPCaP.