Practical Problems Must Be Overcome to Move Personalized Medicine Forward in Oncology

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Incorporating personalized medicine into everyday oncology clinical practice will require new paradigms in an effort to match cancer patients with the best therapies and attempts to treat solid tumors at an earlier stage with targeted agents, said Razelle Kurzrock, MD, at the second annual Global Biomarkers Consortium conference.

“In a very real way, it’s very hard to institute personalized medicine both in clinical trials and in the community,” she said.

A practical problem to implementing personalized medicine is that common cancers are difficult to treat because each may be >100 different diseases, especially in the metastatic setting, as multiple subtypes of each exist. “Even if some of these tumors have things in common, the individual landscape of each patient may be very distinct,” said Kurzrock, director, Center for Personalized Therapy and Clinical Trials, University of California San Diego (UCSD), Moores Cancer Center.

Molecular testing of tumors can make a difference in early clinical trials. “The old way of thinking was that we needed new drugs to treat patients,” she said. “We do need new drugs; no question about it, but very fundamentally, it doesn’t matter how good your drug is; if you don’t give it to the right set of patients, it’s not going to work. Matching the drugs with the right patient is crucial to the future of oncology and maybe to all of medicine.”

The tools to match patients with target-based agents are becoming available, “but in a practical way, this is hard to do.”

The PREDICT study used a histology-independent targeted approach in which multiple molecular aberrations were assessed and used to match patients with targeted agents. When the study started in 2008, molecular profiling was primitive compared with today, said Kurzrock. Single gene assays were used to identify 12 genetic mutations. Conventional therapy had failed in all 1144 patients enrolled in PREDICT.

Many of the molecular aberrations did not segregate by tumor histology. Molecular aberrations were found in up to 73% of patients depending on organ of tumor origin. Most of the molecular aberrations identified were actionable.

Patients for whom a matched therapy was available in a phase 1 setting had a complete/partial response rate of 27%, whereas those who did not have a matching therapeutic had a response rate of only 5% (P<.0001). Progression-free survival improved with phase 1 matched therapy but not unmatched therapy compared with prior conventional therapy. Overall survival improved with matched treatment (RAF/MEK inhibitor) compared with unmatched (P<.01). PREDICT was not a randomized trial, said Kurzrock, “but our clinical impressions were very positive.”

Another practical problem with personalized medicine in oncology is that patients with metastatic disease usually relapse. Chronic myelogenous leukemia (CML) is a fatal disease that has been transformed with imatinib therapy, with median survival extended to 20 to 25 years, but such success is rare with solid tumors. The conventional wisdom is that solid tumors are more complex than CML, and elucidating combinations of therapies to treat solid tumors is a Herculean task because of this complexity, she said.

However, the conventional wisdom does not account for the precipitous decline in response rates with advancing disease in CML. In the blast crisis, median survival is only about 12 months, and patients develop resistance. “That sounds a little bit like solid tumors to me,” said Kurzrock. She compared blast crisis in CML to metastases in solid tumors.

The transformation in CML outcomes was made possible by treating newly diagnosed disease. “We have not done that in solid tumors,” she said. “Comparing metastatic solid tumors to newly diagnosed CML is not an apt comparison.” A practical solution to enhancing outcomes with personalized medicine in solid tumors, therefore, is to treat newly diagnosed patients.

The future of personalized medicine in oncology is actionable cancer gene sequencing, but a practical problem is individual host differences. “The host reaction may be critical to how the tumor responds and also critical to toxicity,” she said.

Tumor microheterogeneity is another practical problem. The molecular profile can differ even within a single lesion. A potential solution is liquid biopsy to obtain cell-free or circulating DNA from patients with tumors and performing gene sequencing on this DNA. The technology is moving rapidly.

Lack of training in genomics is a barrier to personalized cancer therapy trials and treatment. At UCSD, a molecular tumor board was started in 2012. It involves a multidisciplinary discussion of patients who have had molecular profiling performed, after which targeted tailored treatment recommendations are issued. “In the future, we’ll have to train oncologists in genomics,” she said.

Another challenge is proving the concept of personalized medicine. To this end, the Worldwide Innovative Network in personalized cancer medicine has been initiated as a signature global trial with genomics and transcriptomics used to navigate end-stage cancer patients to clinical trials.

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