3 Questions on…

Answers straight from the experts on the latest news and topics in oncology

Wednesday, July 18, 2018

With Saro H. Armenian, DO, MPH, of City of Hope

By Sarah DiGiulio

Research has shown that survivors of childhood cancers are more likely to have heart problems later in life compared with their peers who have not had cancer. There's further evidence that increased cardiovascular disease risk is largely attributable to cancer treatments survivors were exposed to. But what research has not yet revealed is how better to lower risk of these problems and how best to screen survivors of childhood cancer.

So says Saro H. Armenian, DO, MPH, a pediatric hematologist/oncologist and Associate Professor in the Departments of Pediatrics and Population Sciences at City of Hope, Duarte, Calif., in a new review paper (J Clin Oncol 2018; doi.org/10.1200/JCO.2017.76.3920).

"We've known through large cohort studies and epidemiologic studies that the magnitude of risk is greater than you would expect in the general population, and it continues to increase with time," Armenian told Oncology Times. "This paper was to really highlight what are some of the directions that we're going to be headed in as we think about ways to improve the lives of our survivors as well as patients are going through treatment today."

So what are some of those directions that need to be explored to solve the problem? Here's what Armenian, who is also Director of both the Childhood Cancer Survivorship Clinic and the Division of Outcomes Research in the Department of Population Sciences at City of Hope, explained to Oncology Times.

1. What are the key paradigms in how cardiovascular disease affects survivors of childhood cancer?

"The paper breaks it down into specific areas. The first area had to do with the scientific community getting a better sense [of] what the mechanisms are for cardiovascular disease in these individuals and how best to study these mechanisms. Because if we understand the mechanism of premature cardiovascular disease, then we can think about more targeted and precise approaches to disease prevention.

"We then grapple the issue of how do you best identify individuals who are at risk. So right now we're in a world of precision medicine, specifically precision oncology. And we think about the tumor makeup as what drives our treatment decisions. And we believe that we can use this same precision medicine approach to identify who is going to be at risk for developing cardiovascular disease. And in turn, think about more targeted approaches for prevention.

"So it might be understanding the treatments [survivors] received in more detail or thinking about the individual's own genetic makeup, and how that may potentially put them at risk for subsequent cardiovascular disease.

"The next area we wanted to focus on was specifically on what are the emerging therapies that are going to be used in the treatment of childhood cancer over the next few decades—and what are the potential long-term side effects that we might be able to anticipate (if we are more active in how we start studying individuals who are being treated with these new drugs).

"We really don't have a good sense to what the long-term side effects are. But we can use paradigms of research that have been successful from previous drugs.

"And then finally we talk about sort of novel paradigms of early detection and screening—and clinical trials that are necessary to help prevent cardiovascular disease."

2. What are the biggest questions that need to be answered to really move the needle in terms of this problem?

"Overall we understand what the disease burden is in this population. What we have not done enough of is developing studies to help prevent these conditions from happening in our patients.

"We are now thinking about new paradigms of disease prevention that combine information obtained from population-based studies about who is at risk with more granular information about individual genetic differences as modifiers of this risk. This precision medicine approach can facilitate the implementation of innovative approaches to disease prevention.

"We are in a position to really launch the next wave of prevention studies so that these severe and life-threatening conditions—like heart failure, stroke, and heart attack—are no longer an issue for our growing number of survivors of childhood cancers."

3. What would you say all practicing oncologists should know about this area of childhood cancer survivorship?

"We in the community who are entrenched in this research can get very stuck in the weeds of it. But from a general oncology practice standpoint, when the patient walks into our office—let's say they're a long-term survivor of a specific cancer—having basic information about their treatment and where that puts them in the spectrum of risk is really important because that drives the kind of monitoring, screening, and conversations that you're going to be having with that patient.

"There are established guidelines for how we define individuals at high risk. Practitioners need to think not just about the conversation they're going to have about heart-healthy lifestyle behaviors, but also about early screening strategies for individuals at highest risk.

"And at the primary care level, it may just be as straightforward as lowering that threshold for that young person who's going to walk in with symptoms that would not cross your mind that would be associated with cardiovascular disease due to their age or due to their health profile. Because they're a survivor of cancer and have been treated with certain drugs or have had certain exposures, they're at an exponentially higher risk. So really lowering that threshold for which you start thinking about doing additional diagnostic studies and not dismissing certain symptoms."

Thursday, July 5, 2018

With Sohrab Shah, PHD, Chief of Computational Oncology at Memorial Sloan Kettering Cancer Center

By Sarah DiGiulio

Sohrab Shah, PhD, joined Memorial Sloan Kettering Cancer Center earlier this year as the cancer center's first-ever Chief of Computational Oncology in the Department of Epidemiology and Biostatistics. His charge is to marry big data and computational resources with biology to further MSK's mission of providing and improving cancer care.

"We cannot overstate the significance of computational oncology to the future of cancer research or our great fortune in recruiting someone with Dr. Shah's unparalleled expertise and imagination," noted José Baselga, MD, PhD, Physician-in-Chief at MSK. "We are thrilled to welcome him to New York City and look forward to a future filled with exciting new developments."

Before this role at MSK, Shah was Associate Professor in the Department of Pathology and Laboratory Medicine and a senior scientist in the Department of Molecular Oncology with British Columbia Cancer at the University of British Columbia (UBC). He was also an associate member in the Department of Computer Science at UBC and at the Genome Sciences Centre at BC Cancer.

Shah told Oncology Times his background in both biology and computational modeling are what uniquely prepare him for this new role at MSK. Here's what he said about his role, the potential in the field of computational oncology, and what's first on his to-do list in the new position.

1. You're in a brand-new role of Chief of Computational Oncology. What does that mean?

"The role is really to lead and develop a new research initiative in computational oncology. And you could define computational oncology as a coming together of computer science and data that is focused entirely on the cancer problem. That can range from research topics where we're trying to measure properties of a cancer at the molecular or genomic level all the way through to patient data that is generated in that context of patient care.

"In the latter example, you could think of imaging data from a cross-sectional PET scan or digital pathology information or genomic info that can inform treatments.

"The goal is really that in the context of patient care these data are being generated to help treat the [individual] patient, but an aggregate of thousands of patients may become an incredible resource using state-of-the-art computational techniques to learn how we can better treat patients from those measurements and make better predictions as to what will happen to a patient after diagnosis and throughout their clinical trajectory.

"In both diagnostics and in research, the dimensionality data or the number of measurements taken per patient or per sample is increasing at an exponential rate. The only way to synthesize the information is computationally. And all machines will generate data with some degree of error—and the nature of error profiles is complicated. [Using] tried and true statistical techniques that employ leading edge and methods, we try to extract the most relevant signal from a potentially noisy measurement.

"This signaling-processing problem exists in many domains—cancer's not unique to that. But what's interesting about cancer in this day and age is that we really have this urgent need now to build to leverage these measurements that are taken in a new way.

"The computing power required for these types of approaches and also the amount of input data required to train those approaches properly—it's really not been possible before. So now is really the time where this type of approach could really transform cancer care and cancer research."

2. So, what's first on your to-do list in this new job?

"The first objective is to build a critical mass of computational scientists to address these problems in a computational research environment. So we have a faculty recruitment under way. And we have a post-doctoral recruitment under way.

"[Cancer] is a monumental societal problem. So my first real goal is to try to attract people who would otherwise go and work with tech companies or elsewhere—and stimulate and inspire them to work on these problems in cancer. Because there's similar computational challenges in cancer [as there are in other fields], but in oncology the impact is much more in health care and helping this societal problem.

"So that's really the first task is to build out our team.

"It's beneficial if people have training in both computational domains and an oncology or biology focus. But that's rare. We already have an incredible environment at MSK whereby clinicians, clinician scientists, and basic scientists can provide all the problem spaces and frame the problems very well. Where we need to build is in the people who are doing leading, cutting-edge computational work. So ultimately this work becomes a team science. It's a collaborative endeavor where multidisciplinary people are required."

3. What would you say is most important for anyone in cancer care to know about this new role at MSK and how it might change oncology research and practice?

"The main message is that we need to drag cancer diagnostics and prognostics into the future by taking advantage of the datasets that exist and develop in the context of patient care. And the field will likely change and can support clinicians in new and more effective ways using these advanced computational techniques.

"And that's really what our goal is—to support clinicians in a much more effective way so they can treat their patients more effectively.

"I think embracing the leading-edge computational techniques to advance precision cancer care is our objective, and we look forward to working with the clinicians to help accomplish that goal."

Wednesday, June 20, 2018

With Sarah Buchan, PhD, Senior Post-Doctoral Research Fellow at University of Southampton

By Sarah DiGiulio

When it comes to a tough problem to solve, two heads are better than one. And when it comes to fighting cancer, two anticancer immunotherapy drugs might be better than one, too.

A recent preclinical trial in mice found that combining antibodies that target PD-1/PD-L1 with an antibody targeting CD27 dramatically improved the effectiveness of the drugs against cancer cells. The results published online ahead of print in the journal Clinical Cancer Research showed that the combination of drugs was six times as effective at preventing cancer cell growth in multiple tumor models of melanoma and lymphoma than either of the drugs alone (2018; doi:10.1158/1078-0432.CCR-17-3057).

"Blocking PD-1, or its major ligand PD-L1, has been a game changer in oncology and has prolonged patient survival in difficult to treat cancer types," study author Sarah Buchan, PhD, a senior post-doctoral research fellow at University of Southampton in the U.K., told Oncology Times. "However, only a minority of patients respond, suggesting that combining PD-1/L1 blockade with another approach may be of benefit." PD-1/PD-L1 antibodies currently are given to people with melanoma, lung cancer, and other cancers.

The researchers initially compared the activity of several agonist antibodies targeting co-stimulatory receptors and found that anti-CD27 was the most effective at increasing T cells—which is why they went on to test the anti-CD27 immunotherapy with the PD-1/PD-L1 blockade, Buchan explained.

The new data is early, as it was done in animal models, not people, but it supports further clinical trials in patients to test the effectiveness of this immunotherapy combination. In an interview, Buchan elaborated on how this initial work was done and why the findings are significant.

1. You didn't pick this drug combination at random. Can you explain what led you to test this combination of immunotherapies?

"Anti-PD-1/L1 exerts its effect by releasing the brakes on T cells that are otherwise rendered ineffectual in a tumor environment. However, a large body of evidence, including from [Aymen Al-Shamkhani, PhD, Professor in Immunology at Southampton, and his group], shows that T cells require co-stimulation to maximally respond to infections and tumors. Thus combining PD-1/L1 blockade with a driver of T-cell co-stimulation such as an agonist antibody targeting CD27 seemed a logical approach.

"We have reported previously that anti-CD27 and PD-1/L1 blockade can restore functions to T cells that have become 'exhausted' due to prolonged activation in mice (J Immunol 2015;194:125-133). However, we had not tested whether this combination would be similarly effective for increasing anti-tumor immunity. The present paper describes that this is the case across several tumor models and provides mechanistic insight into how these two agents might be acting on T cells."

2. It has been noted that this new data suggests this drug combination is ready to be tested in clinical trials in patients. What types of cancers do you suspect the immunotherapies will be most effective against?

"PD-1/L1 blockade has proven successful in a broad range of tumor types and we will have to see if this proves to be the case for anti-CD27 (known as varlilumab in the clinic). Currently the combination of varlilumab and nivolumab (anti-PD-1) is being [tested in clinical trials] (NCT02335918) in patients with a range of cancer types: squamous cell carcinoma of the head and neck, ovarian carcinoma, colorectal carcinoma, renal cell carcinoma, and glioblastoma.

"Evidence from the existing literature suggests those tumors that have a higher frequency of T cells at the start of therapy respond better to treatment with PD-1 blockade, so this may be a factor which will similarly influence the efficacy of varlilumab."

3. Does the success of this combination of drugs suggest that other immunotherapy combinations might be effective? What's the takeaway about new drug combinations and their potential?

"It seems likely that PD-1/L1 blockade will similarly combine with other T-cell co-stimulators to improve tumor therapy, and there is some evidence from mouse models that this is indeed the case. However, more research is needed to determine the effects of these combinations on distinct T-cell subsets and in human disease where the tumor environment is less homogeneous than in mice.

"Understanding the local environment of a given patient's tumor is going to be key in determining the most effective treatment. We already know that responders to anti-PD-1 tend to be patients who have a pre-existing T-cell population in the tumor, and in which the tumor cells express PD-L1.

"Going forward, it may be necessary to have a more sophisticated understanding of the immunological milieu that exists in different tumor types and within the same tumor type at different stages of disease in order to provide appropriate immunotherapy regimens."

Tuesday, June 5, 2018

With Nathan Berger, MD, of Case Western Reserve University School of Medicine

By Sarah DiGiulio

For most cancers, risk is higher if you are older. Yet, increasingly, cancers are being diagnosed at younger ages. While there are likely several reasons this is happening, researchers say one important contributor is the increasing prevalence of obesity in young people.

New research that reviewed existing cancer and obesity incidence data suggests increased rates of obesity are causing more cases of obesity-related cancers in young adults (in this research, defined as those under 50). A major conclusion of the paper was that many of the malignancies found to occur with increasing frequency in young adults are among the 13 obesity-associated cancers.

Additionally, the researchers looked at animal studies that investigated how obesity mechanistically changes how cancer cells grow and found that, in the obesity-related cancers (including breast cancer, colon cancer, multiple myeloma, renal cell carcinoma, endometrial cancer, and thyroid cancer, among others) obesity actually accelerates the rate of cancer growth in animal models compared with the rates of cancer growth in non-obese animal models. The findings were published online ahead of print in the journal Obesity (2018; doi.org/10.1002/oby.22137).

"This prospect, in association with the worldwide expansion of obesity, suggests an impending explosive increase in obesity-associated cancers in young adults," the study authors noted in the paper.

The research reviewed data from more than 100 existing preclinical, clinical, and epidemiological studies that investigated cancer incidence and the effect of obesity on cancer development, including potential mechanisms.

In an interview with Oncology Times, study author Nathan Berger, MD, of Case Western Reserve University, School of Medicine, explained why these findings are significant and the next steps of the research. Berger is the Hanna-Payne Professor of Experimental Medicine; Director of the Center for Science, Health and Society; and Professor of Medicine, Biochemistry and Oncology, all at Case Western.

1. This review showed that obesity accelerates the growth of certain cancers—not just the incidence. Can you explain how this is different than previous reports?

"Previous studies have shown that obesity increases the risk for cancer and that obesity makes cancer worse. That means if you have cancer and you're obese your prognosis is worse than if you're not obese.

"There are several different models where it's quite clear that obesity accelerates the onset of cancers.

"[Our research team had previously done] a lot of translational work with animal models and with people. When the reports started coming out about the increase in young adult cancers, we noticed that many of those were among the obesity-associated cancers. So, we reviewed the obesity-associated cancers in young adults. We reviewed the reports of increased cancers in young adults and we reviewed the animal models [of cancer growth rates]. And we reviewed the SEER and other population-based cancer data to come up with the observations that we reported.

"In the manuscript, we talk about how obesity accelerates the development of myeloma; obesity accelerates the development of renal cell carcinoma; and obesity has been shown to accelerate the development of breast cancer. It's been shown to speed of the development of thyroid cancer, pancreatic cancers, colon cancer, [and] multiple myeloma; and we think it's probably across the board for all the types of cancer that are associated with obesity."

2. What would you say are the implications of these findings?

"The key finding from our work is that there is a marked increase in obesity associated with this increased cancer in young adults. And based on our analysis, particularly in animal models, we've shown that obesity accelerates the development of cancer.

"The important thing is the young adult cancers and cancers associated with obesity [are] sometimes more aggressive and you need to keep that in mind. When you have an obese young person with cancer or an obese person with cancer, you need to remember that the disease can be more aggressive, so you have to treat the disease very aggressively. And you have to do your best to get the patient to lose weight.

"It used to be that a lot of oncologists felt that the cancer treatment was going to be so stressful that you should not advise the patient to try and lose weight. I think it's just the opposite. You need to advise the patient to lose weight and exercise more."

3. What's the next step of your research?

"One of the things we're interested in doing is to better define the mechanisms [that accelerate the growth of cancer in individuals who are obese], which will help us develop strategies to prevent obesity and related cancers.

"The other thing is we think the preliminary evidence suggests that the obesity promotion of cancer probably involves epigenetics, among other factors, so we're trying to document these epigenetic effects and also identify drugs and lifestyles that may modify the epigenetic effects."

Monday, May 21, 2018

With Mark Burkard, MD, PHD, of the University of Wisconsin Carbone Cancer Center

By Sarah DiGiulio

Two individuals given the same cancer diagnosis and who end up following identical treatment plans may have identical outcomes. Or they may have very different ones. Across all cancer types, some patients survive years beyond their prognosis and some survive for far less time.

New research seeks to look more closely at why that is. Instead of starting with a specific drug or treatment, researchers at the University of Wisconsin will begin their investigation by looking at the best outcomes—by identifying exceptional survivors who have lived for a longer-than-expected time—and then looking at treatment decisions, genetics, lifestyle choices, or other factors that may have led to those outcomes.

"How do these exceptional patients survive so long with incurable cancer? We're hoping the answers can help more people live better and longer with cancer," the study's principal researcher Mark Burkard, MD, PhD, a breast cancer oncologist at Wisconsin's Carbone Cancer Center in Madison, said in a statement.

This study will focus on women with metastatic breast cancer. Though in the future, Burkard hopes the work will guide similar projects in pancreatic cancer, colon cancer, and other types of cancer, he told Oncology Times. Here's what else he said about the new project.

1. Can you walk through the steps of the study and how individuals can participate?

"In the first step, women or men with metastatic breast cancer can go to our website (bit.ly/2CiUdya); and if they are interested select 'Participate Now,' read the information, and then provide their contact information.

"Once we verify they meet eligibility requirements—an adult with metastatic breast cancer—we will email them a unique link to fill out a full web survey about their cancer history, treatment, habits, and diet. For this portion of the study, they need not be a 'long-term survivor.' We hope to have 2,000 individuals participate, of which 1,000 are long-term survivors.

"We plan to invite 50 individuals who are the longest-term survivors who have available archived tumor specimens to participate in step two. Individuals who choose to participate [in this second step] will send a saliva sample and give us permission to obtain medical records and archived tumor specimens from a surgery or biopsy in the past. We will use these to study the genes in the cancer and the genes in person.

"We hope to use this [information] to identify unique genes that control long-term survival, such as those that make slow-growing cancer or allow the immune system to restrain the growth of cancer."

2. What led you to look at these extreme survivors and how is the project different from other research?

"I met a 40-year survivor in clinic and was amazed to learn her story. I started asking my colleagues and discovered there are many more [long-term survivors] out there. I slowly came to the realization that we could learn a lot from these amazing people and use the information to help others.

"I opened a study of exceptional survivors at our hospital and found it would be helpful to identify more. At the same time, other exceptional survivors heard about some of the local news stories and asked to participate—I had emails from across the U.S. and one from the U.K. So it was clearly important to find a way for them to participate as well.

"There are ongoing projects that are working on genetic analyses of tumors in people with metastatic breast cancer. Also, there are studies on 'exceptional responders,' or people who have a surprising benefit from a particular drug. Though most exceptional survivors I have identified so far have not had such an exceptional response.

"Our study is the first comprehensive study, to my knowledge, that seeks to identify behavior, diet, treatment patterns, immune system, and genes that allow some individuals to be exceptional survivors."

3. What's the takeaway for practicing oncologists and cancer care providers about how this research will benefit their patients with breast cancer in the future?

"I'm hoping to identify the fundamental reasons why some people live so long with metastatic breast cancer. There are a number of alternative reasons that have been proposed—treatments, diets, habits, medical practices, immune system, or the genes driving the growth of the tumor. We are going to survey all these possibilities.

"Some of these [findings] could be directly used to advise other people on how to become long-term survivors. Others will not be easy for us to control (e.g., genes inside the tumor).

"However, even if the tumor genes are controlling long-term survival, we could at least identify which individuals are likely to be [long-term survivors] at the outset and develop a different treatment plan. It is possible, for example, that many of these people don't need to have harsh chemotherapies if they will outlive their cancer anyway."