3 Questions on…

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

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."

Friday, May 4, 2018

With Douglas Blayney, MD, FACP, at Stanford University

By Sarah DiGiulio

How to deliver better value in cancer care is a question with a lot of different answers. In a new study, researchers took a closer look at patterns and structures within oncology practices across the U.S. to better quantify and make sense of some of those answers.

The research identified three attributes—early and normalized palliative care, ambulatory rapid response, and early discussion of treatment limitations and consequences—associated with practices that deliver the highest value care and had the highest potential for lowering spending without compromising the quality of care, according to the data published in JAMA Oncology (2018;4(2):164-171).

"We tried to find out what the distinguishing difference was [among the practices that delivered high-value care]," Douglas Blayney, MD, Professor of Medicine (Oncology) at Stanford University, told Oncology Times. "Early integration of palliative care, discussing limitations, and ambulatory rapid response of outpatient treatment problems before they became emergent were important."

For the study, the researchers looked at the top seven oncology practices in the Midwest and Pacific Northwest regions that consistently scored the highest on either QOPI measures or Choosing Wisely measures, and for which cost data was available, as measured by insurance claims data. Staff in those practices (including doctors, nurse practitioners, nurses, front office staff, and others who worked in the practice) completed questionnaires about what factors they felt allowed them to deliver high-value care. The researchers also conducted site visits to each of the practices, observed the staff 's actions, and asked additional questions of staff. The researchers grouped the responses into themes and then identified 13 attributes overall that helped the teams deliver high-value care. Of those 13, researchers ranked each in terms of the attribute's potential to improve quality of care and lower cost.

The aforementioned attributes were the ones most able to push the needle in both directions. Here's what else Blayney said about the findings.

1. Your research identified three attributes that distinguished the highest-value oncology practices in the subset of practices you reviewed. Can you explain those attributes in more detail?

"The high-value practices seemed to have three things that really stood out. The first included early incorporation of palliative care; and importantly, palliative care was a normal part of the practice and patient care. It wasn't anything that only happened at the end of life. The second thing was what we called ambulatory rapid response, which was ability to rapidly evaluate and care for patients who are having urgent problems before they turned into emergent problems and have to go to the emergency department or be hospitalized. [The third] was that the consequences and limitations of cancer treatment were discussed with patients and their families. And this was an early discussion [in the course of a patient's cancer care].

"Many of the high-value attributes represent a cultural shift in the way oncologists and medical oncologists practice, including early implementation of palliative care and making sure patients understand that, even though we're trying to cure them, some of the treatments we use do have limitations. Those are difficult cultural shifts, but they don't require huge investment in equipment or expensive changes."

2. There were other attributes you identified as being helpful in terms of delivering value. Can you explain those attributes and if any were unexpected?

"There was support for the patient. [Another attribute was that] care team members functioned at the highest level of their license and training. All of the practices, for instance, utilized the nurse practitioners and nurses to deal with symptom management within the scope of their licenses.

"[Another attribute was that] the physical layout and technical support facilitated high-value care. There was a team approach around the patient throughout the care trajectory—meaning, for instance, it wasn't just tech at the infusion center. It was the doctor and the team around the doctor.

"And, finally, we found that practices that function as a small unit, even if they work within a large health care system, tend to deliver higher-value care. And practices where EHRs were effectively used for communication among various components of the practice was foundational.

"I was surprised that there were no major academic medical centers—at least by our standards for this study—that were 'high value.' That's a disappointment to me because I work in one and I think we do deliver high-value care. But it points out that we all have work to do."

3. There's been a lot of research on how to deliver value in oncology. Why is this research important and why are these findings important and relevant now?

"If we move into a prospective payment system, much of the economic risk that was formerly born by insurance companies will be pushed downstream to patients and practices. So it's particularly timely that this research be highlighted so these systems are constructed and these payment models that we build implement these attributes.

"There may be more [attributes] that we have missed or we may be wrong. We've incorporated measures of quality and measures of cost into these questions in asking and answering questions about value. The next thing I think we need to [do is] incorporate the voice of the patient into the discussions around value and the procedures and processes that deliver high-value care.

"I think we have a good start, or [have proposed] a good start, to research methods to answer these questions."

Friday, April 20, 2018

With Paul C. Nathan, MD, MSc, FRCPC, of The Hospital for Sick Children in Toronto

By Sarah DiGiulio

Survivors of childhood cancer are known to be at higher risk for physical health problems later on, but whether or not (or how much) an early cancer diagnosis affects their mental health risks later on is not so clear. That's according to Paul C. Nathan, MD, MSc, FRCPC, a clinician investigator, staff oncologist, and Director of the Aftercare Program in the Division of Haematology/Oncology at The Hospital for Sick Children in Toronto, who recently investigated the question with his colleagues (Cancer 2018: doi:10.1002/cncr.31279).

"A lot of the risk factors were the same things we see in the general population," Nathan told Oncology Times. "The problem is that we tended to see these problems more frequently in childhood cancer survivors."

The researchers looked at the medical records of 4,117 5-year survivors of childhood cancer treated in any of the five pediatric cancer centers in Ontario, Canada, between 1987 and 2008. Everyone was diagnosed and treated before they were 18. The study cohort also included a control group of 20,269 healthy individuals matched for age, gender, and where they grew up geographically. (Because Canada has a publicly funded health care system, information about medical diagnoses, cancer treatments, and health care visits are available from cancer registries and administrative databases.)

The data showed that the childhood cancer survivors had a 34 percent increased risk for a medical visit for a mental health complaint than the general population. More than 40 percent of the survivors in the group studied had at least one visit for a mental health complaint. And the cancer survivors had a 13 percent increased risk for a severe mental health event, which included emergency room visits or hospitalizations due to a mental health complaint or problem. And childhood cancer survivors who were treated at the youngest ages (between 0 and 4 years) were at the highest risk for these severe mental health events.

Nathan said he and his colleagues were not surprised by the findings, as some previous evidence and their own clinical experience suggested they would find these elevated rates of mental health problems in survivors of childhood cancer. But, he added that the findings point to some very important implications. Here's what else he told Oncology Times.

1. There's a lot of research when it comes to survivors of childhood cancer—what's new about the question you asked and what you found?

"I think much of the focus in some of the survivor outcomes has been on the long-term physical consequences of cancer therapy. We know survivors have an elevated risk for chronic health conditions, such as cardiac disease, new cancers, and endocrine problems. There has been some work in mental health and psychological outcomes, but there's definitely been far less of a focus on that than there has been on the physical manifestations and the physical consequences of therapy.

"This study adds to the small, but growing, body of literature that [shows] surviving childhood cancer can impact long-term emotional and psychological health. And [it suggests] that risk-based care for cancer survivors—which considers previous cancer diagnoses, treatments received, and physical consequences—has to focus on mental health consequences as well."

2. Your data found one of the groups at the highest risk for mental health problems later on were survivors of childhood cancers who were treated at the youngest ages. Do you any suspicions why that group was at the highest risk?

"That finding was novel in that survivors who were treated for their cancer at a really young age (4 years or younger) seemed to be at a particularly higher risk for developing a severe mental health problem later on (requiring either hospitalization or an emergency room visit). And we don't really know why. Is there something about having had the traumatic experience of cancer at a very young age that somehow predisposes you to problems later? Is it possible that parents change how they parent their kids who have had cancer?

"They may not remember the actual experience of having had cancer. But maybe there's something about the trauma of having cancer—even if you can't remember the details—that has an impact.

"Maybe it's that we haven't historically thought about mental health care in these very young patients, so no attention is paid.

"These are all potential explanations. But, we would need to do more research in these younger patients to understand why we saw this. But it was a pretty striking finding about how much this risk was elevated."

3. What are the most important implications of this research?

"Message one: The complete care of survivors of childhood cancer must expand beyond just thinking about physical consequences, such as new cancer and heart disease. There needs to be a focus on the mental health of these survivors. And that means that those practitioners looking after them as adults, very often family doctors, need to be aware that they should be screening for things like anxiety, depression, PTSD, substance abuse, [and other problems]. Realizing now that this is a population at risk, there needs to be some focus on that risk.

"Two: [We need to look at] whether mental health care resources need to be available or offered more broadly during the pediatric years. Perhaps a more proactive pediatric approach will save patients from running into these mental health issues in adulthood.

"And lastly, another important message is [also] that, though the [mental health] risks are higher for survivors of childhood cancer, many of these survivors are also doing absolutely fine. We can be reassuring [to parents and others] that most kids and adults do absolutely fine, but we do need to be on the lookout for those who are struggling and have a means to get them help sooner rather than later."