Can highly personalized precision medicine bring more benefits to people with metastatic cancer?
With this type of approach, researchers aim to better anticipate which types of treatments would best suit an individual, depending on their genetic makeup and the environmental and lifestyle factors that are relevant to them.
A new study — the findings of which appear in the journal Nature Medicine — now suggests that further personalizing precision medicine may be useful in treating cancers that do not respond to commonly prescribed therapies.
The researchers, many of whom are from the University of California, San Diego, in La Jolla, conducted a clinical trial to test whether personalized combination therapy can have a positive effect in people with refractory tumors. These are tumors that did not respond to previous treatment.
In order to find the best combination therapy match, they analyzed the participants' specific tumor mutations and tried to target them individually.
"Response rates to therapies that target one alteration can be low and not durable," notes first author Dr. Jason K. Sicklick. "Our approach went beyond targeting a single alteration. In collaboration with a multispecialty team of oncology experts, we formulated a personalized combination therapy for each patient," he explains.
"With this approach, we saw an increased response rate, as well as improved overall survival and progression-free survival in patients who were highly matched to treatment, versus those who were unmatched or less well-matched."
Dr. Jason K. Sicklick
Results of the prospective study
For their prospective study — which they called the Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) — the researchers recruited participants with metastatic cancer. Each had previously received treatment at one of two oncology centers: the Moores Cancer Center in La Jolla, CA, or the Avera Cancer Institute in Sioux Falls, SD.
In total, the team enrolled 149 participants with metastatic, refractory cancer, and they managed to match 73 participants (or 49 percent) with combination therapy.
The researchers were not able to provide treatment for 66 of the enrolled participants, either because the disease was progressing quickly or because it was in a very advanced stage.
To find good treatment matches, the researchers conducted tumor DNA sequencing to identify the specific mutations in each person's tumors.
Then, the investigators consulted a team of specialists, including oncologists, pharmacologists, cancer biologists, surgeons, and geneticists, who helped them determine the best treatment combinations and matches.
For a person to be "highly matched" with a combination therapy, the researchers had to match over 50 percent of the individual's tumor mutations to drugs that could address each.
The investigators report that half of the highly matched participants responded to the prescribed therapies, while only 22 percent of those who either had no treatment matches or matches of a poorer quality responded to treatment.
"Having 50 percent of patients with heavily pretreated disease responding when highly matched speaks to the importance of personalized precision medicine combination approaches," says the study's senior author, Dr. Razelle Kurzrock.
"Our next step is to determine if we can increase the benefit rate further if this strategy is instituted earlier in the course of the disease," adds Dr. Kurzrock.
'No two tumors are exactly the same'
In total, 83 participants received treatments, informed by their oncologists' advice and their own preferences. Of these, 10 received unpersonalized treatments that did not match their tumor mutations.
The 73 individuals who accessed personalized combination therapies received a mix of treatments including gene product-targeted drugs, hormone therapies, immunotherapies, and chemotherapies.
"The percentage of patients matched was much higher than in most precision medicine studies because we implemented a team who instituted immediate review of genomic results, as well as navigators who helped patients and physicians access clinical trials and off-label [Food and Drug Administration (FDA)]-approved drugs," notes one of the study's lead authors, Dr. Shumei Kato.
There are, nevertheless, many concerns regarding the feasibility of the new approach. According to Dr. Sicklick, "Personalized multidrug therapies have not been used as standard treatment because there are concerns about the safety of administering drug combinations that have not been previously studied together."
In the current study, the researchers monitored the treatment outcomes until a participant's cancer developed further, until they no longer tolerated the therapy, or until they passed away.
At the same time, however, the first author argues that it is important to lean toward as personalized an approach to cancer therapy as possible.
"Personalized combinations are necessary, since no two tumors are exactly the same and so no two regimens will be the same," emphasizes Dr. Sicklick.
"Our findings demonstrate that this approach is feasible and safe when patients are monitored closely and started on reduced doses," he suggests.
Yet, the researchers admit that future clinical studies must further test this method and confirm its viability.
Furthermore, many of the study team members have acknowledged that they received research funds from various pharmaceutical and clinical research companies, including Novartis Pharmaceuticals, Blueprint Medicines, Amgen, and Pfizer.