As growing numbers of people diagnosed with cancer receive testing to have their cancer genetically sequenced, researchers and clinicians are learning volumes more about specific mutations and genetic alterations that can occur in each type of cancer.
This in turn has contributed to the development of increasingly targeted treatments and therapies, which can have tremendous benefits for patients. However, drugs developed to target particular genetic alterations or mutations still may not be right for every patient whose cancer shows those alterations or mutations.
“With the increased frequency of genetic testing, sometimes we get a lot of suggestions of possible treatments,” explains Corbin Eule, MD, an oncology fellow in the University of Colorado School of Medicine. “It’s important for patients to discuss the options that are available with their oncologist, because even if you have a particular mutation and there’s a medication thought to affect this pathway, it still may not be the best option for you.”
Eule and CU Cancer Center member Elaine Lam, MD, an Associate Professor in the division of medical oncology in the CU School of Medicine, recently published research studying the effectiveness and durability of the benefit of mTOR inhibitors (mTORi) in patients diagnosed with metastatic prostate cancer showing PI3K pathway alterations.
Their patient data analysis found that mTORi therapy was not effective, with few prostate-specific antigen (PSA) responses and short duration of therapy.
“The ideal clinical trial to help us understand if new treatments for cancer work is a prospective clinical trial that’s designed to evaluate a drug in a specific setting and looking at a specific endpoint,” Lam says. “However, there are lots of questions that need to be asked, that aren’t covered in that setting. Oftentimes, it is helpful to look at data retrospectively, because even when a big clinical trial shows that a drug works and the drug gets approved, there are real-world application that need to be considered. It’s important that we’re asking whether real-life use of the drug corresponds with the results of the prospective clinical trial.”
Utilizing big data
PI3K pathway alterations are common in prostate cancer and the use of PI3K pathway directed therapies such as the mTORi everolimus is often recommended in genomic sequencing reports. However, the clinical use and efficacy of these agents for this specific subset of prostate cancer patients has not been established. Drs. Eule and Lam evaluated patient data from a nationwide clinico-genomic database representing approximately 280 U.S. cancer clinics. They found 17 eligible metastatic prostate cancer patients with tissue-assessed PI3K pathway alterations, 88% of whom were treated with the mTORi everolimus monotherapy.
Through analyzing the patient data, they found that this therapy was not effective for the patients who received it.
“In some ways it was a surprise,” Lam says. “Our hypothesis was that even though this drug didn’t work previously in unselected populations, that in a more selected patient population – those whose cancer had mutations in that pathway and were treated with everolimus – we would expect good responses and that wasn’t the case.”
Eule adds that they also analyzed time to next treatment, using that datapoint as a surrogate marker for how long patients were on the treatment. “That was a way for us to understand how long the oncologist thought this medication was working, and we found that duration of therapy was short.”
Developing better therapies
Lam emphasizes that though the research findings were not what they expected, they highlight the importance of sharing data to accessible national and international databases “so we’re not reinventing the wheel.”
“Another thing we can draw from big data is the real-world element, especially when we’re analyzing the data retrospectively,” Eule says. “It can give us insight into the clinical decisions of practicing oncologists. With these databases, we’re more and more able to link clinical data with genomic data and understanding how comprehensive genetic profiling is influencing patient care and clinician decision making.”
Further, Lam says, as more people get consumer genetic testing, “it’s really important to talk with your health care provider about the results and, depending on what they show, what the best treatments are for you based on those results. Even when on paper, and based on what we know, a drug should work, that may not always be the case. This is also why participation in clinical trials is so important. We need more people participating in prospective clinical trials to help answer questions like this and to develop better therapies for patients with cancer.”