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Integrating Precision Oncology in Lung Cancer Discovery & Management

Neff Newitt, Valerie

doi: 10.1097/01.COT.0000820652.08464.10
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Precision Oncology:
Precision Oncology

Tejas Patil, MD, believes in the transformative power of biomarkers. “I think there will be a paradigm shift in cancer management,” said the Assistant Professor of Thoracic Oncology at the University of Colorado Cancer Center.

Tejas Patil, MD:
Tejas Patil, MD

“I do biomarker testing for every patient with lung cancer,” he told Oncology Times. “As we understand more about the role that various mutations influence patients with cancer (both as prognostic and predictive variables), we are going to see the traditional methods of cancer staging dissolve and be replaced with newer models that integrate biomarkers.”

Such insights are informed by Patil's impressive research effort, one that might not have happened had he taken a totally different path in life.

“I was trained, from the age of 5, as a classical pianist,” revealed Patil, who was born in India and whose childhood education took place in various countries, including an American international high school (Dhahran Academy) in Saudi Arabia. “I always loved science, but I also had a conflicting and competing interest in music. I became very proficient in piano at a young age and considered making it my career.” These competing interests continued into his undergraduate years at the University of Pennsylvania, where he majored in both music and psychology.

In 2004, Patil participated in the Lake District Summer Music Festival in England, notable for the fact that he was the youngest performer in attendance. What he noticed was the extraordinary talent of the musicians in this workshop.

“I thought to myself, ‘Wow. Everyone here is phenomenal and this is just a snippet of what the worldwide talent pool is like.’ I had to make a practical decision to invest everything into music, or pivot toward my interest in neuroscience, my other interest,” he recalled.

He pivoted.

Finding His Direction

After earning an undergraduate degree, Patil worked as a research assistant at the Department of Neurology in Georgetown University. During his time there, he focused on aphasia research.

“Specifically, we were working with patients who had strokes, trying to understand what areas of their brain had been damaged and how to recruit other areas of the brain to make up for any damage that had occurred,” he explained. “It gave me the opportunity to experience both scientific and clinical work. I realized I really liked taking care of patients.”

Despite having a strong research focus and considering a PhD in neuroscience, Patil applied to medical school and was accepted at the University of Southern California. While his interests were initially in neuroscience, he participated in the Children's Hospital Los Angeles (CHLA) Pediatric Oncology Fellowship during the summer of his first year of medical school. It was then that he found his way into the world of cancer.

“I started working with a lot of cancer specialists with an interest in brain cancers. One of my mentors was very interested in novel brain imaging for patients with gliomas,” he noted.

In his third year of medical school, he received the Ray & Fern Wilson Scholarship Award for his focus on cancer research. Patil moved to the University of Colorado to do post-medical school training—which included his internship, residency, and fellowship—and has remained in Denver since.

During residency, he connected with D. Ross Camidge, MD, PhD, and Robert Doebele, MD, PhD, who are leading lung cancer researchers. “Their influence directed me into lung cancer research, which is what I've been doing ever since,” Patil noted.

Precision Oncology & Acquired Resistance

“My current research interests include identifying novel biomarkers in lung cancer, developing targeted therapies, and leveraging molecular information to understand mechanisms of acquired resistance,” Patil noted.

He explained there has been a growing recognition within the field of lung cancer that there are oncogenes that effectively “drive” the cancer to grow in an unregulated manner. These growth pathways can be inhibited through the use of highly selective tyrosine kinase inhibitors (TKI) (often pill-based treatments) that act in a fundamentally different way than chemotherapy.

Patil further detailed in lung cancer that there are several detectable mutations that disproportionately affect patients who are light smokers or have never smoked in their life.

“Whenever you see lung cancer in a patient with a light smoking history, then alarm bells should really go off that this patient might have one the following oncogenes: ALK, EGFR, ROS1, RET, NTRK, BRAF V600E, MET Exon 14, or HER2 (ERBB2),” said Patil. “These mutations are overrepresented in non-smokers. However, we do see oncogene drivers in smokers as well, particularly BRAF V600E, MET Exon 14, and KRAS G12C. The message here is you should really test everyone for these mutations.”

Once one of these mutations is identified, a patient can receive a targeted therapy. “What inevitably happens is the cancer cells will have an initial response—sometimes lasting for a period of years—but eventually the cancer cells start to adapt, evolve, and make changes in their machinery that allow them to grow in the presence of a TKI. This is called acquired resistance,” Patil detailed. “We can address this in several ways. Oftentimes, we will biopsy these patients at the time they have progressed on their treatment and repeat molecular testing to try to understand what exactly is going on from a resistance level. That can inform next steps.

“There is a lot of interest in looking at patients who have progressed on these targeted treatments, so when we talk about acquired resistance, we can generally break them down into three categories. And again, this is a bit of a simplification, but I think it helps get the point,” offered Patil.

“One is called ‘on-target resistance’: essentially a mutation occurs exactly where the drug is supposed to bind (usually the ATP-binding pocket), so the drug cannot inhibit the target as effectively. The classic example of this is the acquired T790M mutation that we see among first-generation TKIS (such as erlotinib or gefitinib).

“This resistance mutation occurs at the site where erlotinib (or gefitinib) are supposed to bind, rendering these therapies less effective. Osimertinib, a third-generation TKI, was specifically designed to prevent (and overcome) this mutation and is now a standard first-line treatment for metastatic EGFR-positive NSCLC. However, as more and more patients remain on osimertinib, we are starting to see novel ‘on-target’ resistances such as C797S that remain challenging and difficult to treat.”

A second category of resistance is called “off-target resistance” which occurs when cancer cells start to use other pathways to circumvent the targeted therapy.

“Going back to the EGFR example, you may have a patient who is on erlotinib, and then all of a sudden the cancer starts to recruit different signals to grow,” said Patil. “The MET pathway has been well-described and is one of many mechanisms of resistance to EGFR TKIs. This has led to the observation that perhaps combination strategies (such as using dual EGFR and MET inhibitors) can overcome these resistances. Several of these approaches are being evaluated in clinical trials.”

A third category of resistance involves histological transformation and is more difficult to manage.

“We have seen lung adenocarcinomas switch to a small cell phenotype under selection pressure from TKIs. This is thankfully a rare situation, but when it occurs, it is very challenging. The optimal management of patients with small cell transformation on targeted therapies is largely the use of platinum-etoposide chemotherapy, though much of this is borrowed from management of small cell lung cancer. Whether alternative approaches (such as continuing the TKI with chemotherapy or using novel targeted approaches) would be effective is not well understood at this time,” said Patil.

Translating Research

Patil has been involved with several trials in this area—multiple investigator-initiated trials, which he helped design. “Right now, at our institution we're rolling out several to address problems we see in the resistance setting; that's ongoing work,” he noted.

He explained that as a clinical researcher, though he predominantly works with patients, he collaborates with colleagues in the lab as a team.

“They do work that involves taking patient biopsies and other samples and growing them to construct novel cancer cell lines. At that point, we manipulate these cells in different ways to better understand what's going on for each individual patient. I play a supportive role and collaborate with our lab-based colleagues. For some patients, we have found a really clear resistance signal and we could use that information to help make important treatment decisions. When it works, it's great. But I have to say, like everything in science, you need grit and patience.”

He also noted with a tone of optimism that even somewhat new, emerging successes can change the cancer landscape within the course of 5 years.

“There is still work to do. However, I look at the results from KEYNOTE-024 for optimism. When we focus on patients who have a PD-L1 score greater than 50 percent who received pembrolizumab, the results are astonishing. There was a 5-year overall survival of 32 percent among patients with metastatic, stage IV NSCLC in the PD-L1 ≥50 percent group, which is significantly higher than historical results,” he reported.

“For patients with targeted mutations, we can often make strategic decisions about sequencing therapies, much like we do in patients with HIV, to help them live longer and render their disease a chronic condition. And if their initial treatment buys them years, maybe some of these newer add-on treatments will buy them even more.”

Patil said molecular testing has been a driving force in the hopeful evolution of cancer treatment. “It evolved rapidly over the last 15 years,” he stated. “What we're able to do with a tissue sample today was not possible 20 years ago. I hope oncologists everywhere will think about cancer on a molecular level and base care on that—not on what it looks like through a microscope, which is how we used to think of cancers, but through a molecular and evolutionary lens.”

Valerie Neff Newitt is a contributing writer.

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