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

Thursday, May 7, 2020

With Alexander James David Wray of Western University and Leia M. Minaker, PhD, of University of Waterloo

By Sarah DiGiulio

What types of communities have the lowest cancer risk? What aspects of the environments we live in contribute most to our cancer risk? These are some of the questions researchers set out to answer in a multidisciplinary scoping review published last year in the journal Cancer (2019; doi.org/10.1002/cncr.32376). They looked at data across cancer epidemiology, urban planning, public policy, engineering, and more. It examines studies on land use, transportation, housing, greenspace, accessibility, and more.

In an interview with Oncology Times, the study's coauthors—Alexander James David Wray, a master's candidate in the Human Environments Analysis Lab at Western University in Canada, and Leia M. Minaker, PhD, Assistant Professor in the School of Planning at University of Waterloo—explained what they hope this review will accomplish, how they went about investigating complex questions, and what cancer care providers should know about it.

 

1. What were the key findings from this research and what's new about them that we didn't previously know from other research?

MINAKER: "The overarching goal of this project was to describe and synthesize the pathways by which features of our environment 'get under the skin' of residents. In other words, how do features of the built environment create risks for cancer? Alternatively, how do features of the built environment prevent cancer?

"This research wasn't so much about finding new discoveries as it was about synthesizing what exists to point to new directions for research on this topic. We wanted to work at the intersection of urban planning and medicine—because the health care system has a vested interest in planning healthy, cancer-preventing communities."

 

2. That's a fairly onerous task to try to sort out how all the features of the environments around us may affect cancer risk. How did you go about reviewing the existing data on this topic?

WRAY: "We identified 13 subject-specific databases based on previous reviews in this area, and discipline-specific expertise we were looking to incorporate in the review (including HeinOnline and LexisNexis for law-related studies, or JSTOR for social science and humanities-based papers). We developed a pathway model to frame our research findings based on theories in urban planning and geography about the interconnections between health and the built/social environment, guidance from the Institute of Medicine on the largest lifestyle and environmental risk factors of cancer, and narrowing in on the top 10 cancers in our countries of interest.

"On another note, we elected to just examine evidence from Australia, Canada, New Zealand, the United Kingdom, and the United States of America given they share similar governmental systems and division of powers in managing urban development and policy.

"The pathway model thus flows from an element of the built environment (such as land use and greenspace) to a risk factor (diet, physical activity) to one of the top 10 cancer sites. We analyzed the literature by coding each study across these three domains, and then drawing the links between the three of them to show how researchers are linking elements of the built environment through specific risk factors to particular cancer sites. We included all types of evidence, even including theoretical commentaries, to ensure we cast a wide enough net.

"While a lot of work (it took a full year of reading and systematically coding the literature), we think it paid off well by providing a broad overview of the past 20 years of research related to this topic.

"There have been a couple of other reviews on this topic. Ours was the first to incorporate several different databases and look from several different disciplinary perspectives, since we were interested in not only the health care/public health research, but also in the urban planning and social science literature. We found that over 20 percent of the literature base in the social and natural sciences was being missed in many of the reviews already on the topic. Thus, our approach broadened the viewpoint that is taken to cancer research by uncovering many interesting studies that use novel methods (including social network analysis and spatio-temporal exposure modeling based on residential histories) and assess common problems (such as screening adherence, lifestyle risk factors, etc.) with a new perspective."

 

3. What is the bottom line that practicing oncologists and cancer care providers should know about this work and the next steps of your research?

WRAY: "We definitely think there is a need for more discussion from social scientists on urban policy and planning as it relates to cancer, and on the flip side for more work from the medical field to incorporate aspects of the built, social, and natural environment into cancer research."

MINAKER: "Oncologists and cancer care providers are used to dealing with patients one at a time. But they can legitimately take a role in advocating for policies that help to create cities where the default choice is the healthy choice that helps people prevent cancer throughout their entire life course. These people are trusted members of society and have a powerful voice that should be used to push for positive changes. The earlier we can build healthy habits among people, and the more we can push our cities to making healthy and sustainable lifestyle choices easy and convenient, the greater chance we have of reducing the number of cases."


Thursday, May 7, 2020

With Richard Schilsky, MD, Chief Medical Officer and Executive Vice President of ASCO

By Sarah DiGiulio

Earlier this year the American Society of Clinical Oncology issued its first position statement on drug repository programs. (The statement, published in January, is available as a pdf that can be accessed via asco.org.)

Due to the high cost of cancer drugs, members of the oncology team need to explore many options to reduce drug waste and increase access and affordability, according to the statement. That's why ASCO has decided to publish this statement on drug repository programs now.

"ASCO members have expressed interest in drug repository programs as a means to alleviate some of the challenges associated with drug affordability, access, and waste; the society was asked to explore this issue in the format of a position statement that would help guide our state affiliates," Richard Schilsky, MD, Chief Medical Officer and Executive Vice President of ASCO, told Oncology Times.

Here's what Schilsky said about the statement and how drug repository programs could work.

 

1. The statement includes some specific recommendations on how these drug repository programs would work. Can you explain how they would work and how they would be cost-saving?

"ASCO supports drug repository programs solely for oral medications provided that are maintained within a closed system. A closed system is defined as one in which the delivery to and/or return of prescription medicines from a health care or other institutional facility is maintained in a controlled environment under the supervision of a health care practitioner and not the patient. Drug repository programs within a closed distribution system are compliant with FDA policy on the return of unused prescriptions and ensure that the surplus medicines are maintained in a safe, effective, and private manner and can then be dispensed in accordance with the prescribing clinician's guidance.

"Costs for prescription drugs have risen to the point where many patients cannot afford them, leading to treatment non-compliance, drug abandonment, and resultant negative health outcomes. Research has shown that prescriptions with such high cost sharing for patients often are not filled because of inability for patients to absorb such high out-of-pocket costs. Drug abandonment such as this can have a serious effect on patient health, leading to hospitalizations, extensive health care costs, and even death. The abandonment rate for brand-name drugs accounts for 40 percent of all abandoned claims for new patients, in contrast to new patient abandonment rates for generics, which are three times lower.

"One recent study found that distributing essential medicines at no charge led to increased adherence to treatment and some improvement in health outcomes. Therefore, while drug repository programs are no substitute for affordable and accessible prescription drug coverage for patients, they can help some patients access otherwise unattainable treatments while helping physicians do their part to reduce waste associated with unused drugs."

 

2. What leads to those drugs going unused in the first place?

"For their part, providers seek to restrain costs and growth in expenditures in their practice through quality improvement and efficient scheduling practices that help reduce waste. A prescription may go unused at a doctor's office for a variety of reasons, including drug discontinuation because of disease progression or patient intolerance (toxicity).

"Factors such as pricing, vial size availability, and drug shortages are fueling the demand to reduce costs associated with drug waste. Unfortunately, many pharmaceuticals used in the treatment of cancer-related care are not eligible for drug repository programs. Injection and infusion drugs are generally ineligible for state-level donation programs because they: 1) do not meet the program's unopened packaging requirements; and 2) can have very short time frames in which the leftover drug would be safe for use.

"ASCO's position is that drug repository programs are appropriate in cancer care, but only for oral medications and provided the drugs are maintained within a closed distribution system. Widespread use of these programs may incentivize all stakeholders to effect change that could result in decreased costs to patients and unused medications in the outpatient setting. Therefore, while many pharmaceuticals used in cancer care may not fit the mold of a drug repository program, we saw no reason to prevent those that can be donated safely from being provided to a patient in need."

 

3. What is the most important takeaway for practicing oncologists and cancer care providers to know about this statement and drug repository programs?

"The cost of pharmaceutical drugs and resulting strain on patients' ability to afford them has become a pervasive issue in the health care system. The cost of drugs represents a large and increasing portion of the financial burden of cancer care. While pharmaceutical drug repository programs, also known as 'drug donation and reuse' programs are not new, there is new focus on their potential as a practical way to increase access to prescription drugs for patients.

"We encourage all cancer care providers to educate themselves about the programs available to them in their state. Many details and links current as of its publishing are available in the tables at the end of our statement (at asco.org). If a provider is practicing in a state with no such program, we encourage them to get in touch with their ASCO state affiliate (where available) to learn more about what they can do in support of safe and effective drug donation."


Thursday, May 7, 2020

With Francisco Emilio Vera-Badillo, MD, Associate Professor and Medical Oncologist in the Department of Oncology at Queen's University

By Sarah DiGiulio

There are exciting new drug options when it comes to treating patients with advanced bladder cancer, but doctors still lack the knowledge of how to best determine which patients will do best on which therapies. That point is according to Francisco Emilio Vera-Badillo, MD, Associate Professor and Medical Oncologist in the Department of Oncology at Queen's University. It's the topic of a letter he recently co-wrote in the Journal of Clinical Oncology (2019; doi: https://doi.org/10.1200/JCO.19.02393).

In these patients, biomarkers that predict which patients might benefit most from these new tools are unidentified, he told Oncology Times in an interview. In other types of cancers, such markers have been determined (like PD-L1 for patients with lung cancer), but not for new immunotherapies or antibody drug conjugates for bladder cancer.

Here's what Vera-Badillo said about how to better design new and ongoing clinical trials to answer these research gaps.

 

1. Why did you and your colleagues write this letter now?

"We have been following very closely the evolution of new treatments in bladder cancer. [Approximately] 2 months before this letter, we also wrote about the role of immunotherapy in bladder cancer (J Clin Oncol 2019;37(29):2587-2591). Chemotherapy was the treatment of preference before immunotherapy went into this space.

"Something that we highlighted at the time was almost all of the trials were done stratifying patients by a specific biomarker. Even when trials did stratify patients by PD-L1 expression, no specific recommendation was done to highlight that, although the different platforms have some caveats, patients should be assessed based on PD-L1 expression to determine the likelihood of response.

"And when there was an FDA authorization to use this type of treatment, it was approved for all patients [with bladder cancer] who had progressed on previous chemotherapy or were not candidates for chemotherapy up front. So as a second-line [treatment] after chemotherapy it seems promising, but we don't have a biomarker to properly select patients.

"Then we had these second drugs that also seem to be very promising, but again there wasn't data suggesting a biomarker for which patients can potentially benefit more from these interventions. Lung cancer has provided very good insight on different types of tumors based on biomarker expression. In patients with non-small cell lung cancer without EGFR or ALK mutations, PD-L1 expression determines the groups of patients that can do better. For example, PD-L1 expression of 50 percent or more responds extremely well to single-agent immunotherapy, while those with low or negative PDL1 expression may require a different intervention, including double immunotherapy, immunotherapy plus chemotherapy, or even chemotherapy alone.

 

"So this letter was mostly a follow-up of the initial mandate that we had in the Journal of Clinical Oncology about the role of immunotherapy in bladder cancer, highlighting that again we are lacking biomarkers to properly select patients. How we can provide patients with very good therapeutic options? How we can select them? And also, how we can reduce toxicity risk for those patients who are less likely to receive benefits from these interventions?"

 

2. How can the protocols for these trials be better designed so that better biomarkers can be identified?

"The drug is promising. These trials are excellent. But, the drugs are excellent for some patients. And I think in this time where we have a lot of tools for genetic assessment to potentially identify which characteristics are more present in the group of responders versus the non-responders, that information should be brought into the protocol development.

"What happens [now] is that [patients] may be receiving a very good drug, but if you are a patient who will never respond to that excellent drug, there's [currently] nothing that will help physicians to understand and identify which patients are likely to respond and which toxicities and side effects are acceptable.

"It's a very difficult question. But I think that, when you [design a protocol], there always should be a window for describing what are the next steps in terms of correlative studies and how to decide better, especially in this drug that has received approval in a very early stage of development, what are the steps in order to now potentially identify responders versus non-responders. It's the design of the correlative section. So this means that it's critical to have very good communication between the clinical part of protocol development and the basic science.

"Let's bring together the pathologists and people from the basic science field that can contribute the particular genetic signatures [they saw in other lab tests] that can potentially correlate with response in treatment. You want to incorporate these questions into your trial. And then you try to fit all of that discussion into the final protocol development."

 

3. What's the most important takeaway for all practicing oncologists and cancer care providers to know about this work?

"I think the most important message is—talking about bladder cancer in particular, the topic of the letter—there are new alternatives for patients. And outcomes are improving substantially. The toxicity profiles of the new drugs seem to be about the same if not slightly better compared to chemotherapy. Long-term responses to immunotherapy are promising—though it's still early.

"In the past, we had access to only a few chemotherapy agents. Now, in addition to chemotherapy, we have immunotherapies, antibody drug conjugates, and other drugs that are emerging in this space. I think this is a very promising time for patients with advanced bladder cancer to receive a treatment that will impact substantially into their expectancy of life."


Thursday, May 7, 2020

With Katherine A. Janeway, MD, Director of Clinical Genomics at Dana-Farber Cancer Institute

By Sarah DiGiulio

Is it time for more precision medicine in pediatric oncology? The field's thought leaders said "yes" in a review article published last year in the journal Science (2019:363;1175-1181).

Precision medicine—more specifically, treating cancers with drugs targeted to those tumors' genetic alterations—is making possible a plethora of advances in the treatment of adult cancers. And there's evidence the approach could help move the needle when it comes to the treatment of cancers in childhood, too, the Science review's authors note.

"Pediatric cancers harbor certain genomic alterations that are rarely seen in adult cancers, and for many of these alterations, molecularly targeted therapies do not yet exist. [Also], pediatric cancers share some genomic alterations and mutational gene signatures with adult cancers, and for a subset of these alterations, molecularly targeted therapies already exist," the coauthors wrote in the review.

"Importantly, for only a small proportion (5-10%) of these pediatric cancers, there is clinical trial evidence showing that the genomic alteration predicts the response to the targeted drug. Thus, there is an urgent need for precision clinical trials in pediatric cancers," according to the review.

More basket trials and umbrella trials will help match molecularly targeted drugs with the cancers they are most likely to help with in children. Accelerating early-phase trials could help, as could incorporating more combination therapies into precision medicine trials. And recent regulatory changes will help, too, the review notes.

We caught up with paper coauthor Katherine A. Janeway, MD, a pediatric hematologist-oncologist at Dana-Farber/Boston Children's Cancer and Blood Disorders Center (who is also Director of Clinical Genomics at Dana-Farber Cancer Institute), about the topics discussed in this paper and progress that's being made.

 

1. What would you say are still some of the biggest barriers in the way of more precision medicine in pediatric oncology?

"There are several barriers. The greatest barrier has been access to precision therapies for children with cancer. In addition, a number of the central genomic events that could serve as molecular targets in childhood cancer are more difficult to inhibit with drugs. The best example of this is fusion oncogenes that result in abnormally active transcription factors. An example is the diagnosis-defining transcription factor fusion EWSR1-FLI1 in Ewing sarcoma, which was identified over 20 years ago, and yet trials of drugs targeting this molecular target have only recently begun.

"We've made some significant progress in understanding the pediatric cancer genome and in translating that knowledge to the clinic. But, there is much more progress to be made. Fortunately, recent updates to policy should facilitate rapid advancements in pediatric precision cancer medicine."

 

2. Can you elaborate on what those regulatory changes are and other steps you think are most promising in changing this paradigm and bringing more precision medicine to pediatric oncology?

"The implementation of the RACE for Children Act (the Research to Accelerate Cures and Equity for Children Act) and FDA guidance regarding adolescent patient clinical trials eligibility will further increase the number and types of clinical trials of molecularly targeted trials in biomarker-defined patient populations for children with cancer.

"Clinical trials written primarily for adults now fairly often allow patients 12 and older to participate.

"This paradigm is already changing as a result of: 1) an increasing amount of sequencing data from pediatric cancers plus greater accessibility to this data; 2) a greater number of biomarker-defined standard phase I, II, and basket trials; and 3) a focus on developing molecularly targeted therapies for the 'undruggable' targets prevalent in pediatric cancers with a particular focus on fusion oncoproteins."

 

3. What is the bottom-line takeaway message that oncologists and cancer care providers should know about opportunities for precision medicine in pediatric oncology?

"The next 5 years will be a very exciting time in pediatric precision oncology. We will see more sequencing performed routinely in the clinic; there will be a greater number of clinical trials of molecularly targeted therapies for young cancer patients; and basic science investigators will make inroads into developing drugs tackling the more challenging drug targets common in pediatric cancers."


Thursday, May 7, 2020

With Melissa Frey, MD, Assistant Professor in the Division of Gynecologic Oncology at Weill Cornell Medicine

By Sarah DiGiulio

Knowing that some cancers are linked to pathogenic variants means that relatives of gene carriers are also at risk of having those genetic variants and developing those cancers. But the benefit of knowing that risk ceases if relatives are not informed.

That's why Melissa Frey, MD, Assistant Professor in the Division of Gynecologic Oncology at Weill Cornell Medicine, and her colleagues developed a streamlined model of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing to notify relatives of patients who had been found to have cancer-associated pathogeneic variants and to help facilitate genetic testing for the relatives.

Frey's team recently published results of a study testing the model, showing that it resulted in more at-risk relatives getting tested and utilization of genetically targeted primary disease prevention, as evaluated after a short-term follow-up (J Clin Oncol 2020; doi: 10.1200/JCO.19.02005). In an interview with Oncology Times, Frey explained more about how the team's cascade genetic testing model worked and what the new data show.

 

1. How does cascade genetic testing work?

"When a person is found on genetic testing to have a germline pathogenic variant (for example BRCA1/2 pathogenic variant), his/her relatives are also at risk of carrying this pathogenic variant. First-degree relatives (parents, siblings, children) will have a 50 percent risk of sharing the same pathogenic variant, second-degree relatives (uncles, aunts, nieces, nephews, grandparents, grandchildren) will have a 25 percent risk and so forth. Cascade testing is the process of starting with the patient who has been diagnosed with a germline pathogenic variant (passed from parent to child) and extending genetic testing to that patient's at-risk relatives.

For cancer-associated pathogenic variants, informing relatives is critical. Informed relatives have the opportunity to undergo genetic testing to determine if they carry the same cancer-associated variant. Most importantly, if relatives are found to carry the same cancer-associated pathogenic variant, they can benefit from cancer screening and prevention.

"Currently, oncologic genetic testing is often ordered at the time of a cancer diagnosis. The goal of cascade genetic testing is to identify 'previvors' or individuals who are survivors of the predisposition to cancer, but who have not had a cancer diagnosis. With cascade testing there is the ability to identify individuals with cancer-associated pathogenic variants and offer them risk-reducing surgery and/or cancer screening that can prevent cancer or allow for early diagnosis and treatment, reducing morbidity and mortality.

"Currently, the process of cascade testing relies on the patient. The patient is encouraged to inform his/her relatives about the result and encourage his/her relatives to get genetic testing. We believe that this burden should not be placed on patients (who are often simultaneously dealing with a new cancer diagnosis), but instead there should be a paradigm shift whereby the medical system takes on this role. We developed a system for cascade testing that is facilitated by the medical team, taking the burden off of the patient with the goal of improving testing completion among at-risk relatives and hopefully reducing cancer morbidity and mortality in families with hereditary cancer syndromes."

 

2. The results of your study evaluating the model of cascade genetic testing that you developed were encouraging. Is it feasible that such a system might be rolled out?

"The key finding was that, when the medical team facilitates cascade testing, approximately 60 percent of at-risk relatives complete genetic testing. This is significantly higher than rates reported in the literature for cascade testing that is mediated by the patient. Furthermore, after just 6 months, we found that results of this testing led relatives to pursue cancer screening and risk-reducing surgery. This intervention is effective and has the potential to improve cancer morbidity and mortality for families with hereditary cancer syndromes.

"There have been studies in the oncology literature and other diseases (e.g., hypercholesterolemia) demonstrating that cascade genetic testing is most effective when facilitated by the medical team and when relative convenience is prioritized (e.g., offering testing in the relative's home without additional physician visits). We created our facilitated cascade testing strategy with this literature in mind with the goal to maximize our success, defined by relatives undergoing genetic testing to evaluate for the familial pathogenic variant.

"A major limitation of this study is that we did not address the cost associated with cascade testing (all testing was covered as part of participation). However, many genetic testing laboratories offer free testing for relatives of an affected individual and cascade testing is often covered by insurance. However, to demonstrate sustainability, future work is needed to evaluate the cost-effectiveness associated with genetic counseling, sequencing, and cancer preventative services per additional quality-adjusted life year.

"We are currently planning a prospective randomized controlled trial at multiple institutions to demonstrate the efficacy of this strategy compared to standard of care and in diverse medical settings."

 

3. Are there any privacy concerns about the family members of the patient being contacted with this information, but not necessarily consenting to receiving it?

"We only contacted relatives with the consent (written) of the patient after thorough counseling. We encouraged patients to contact their relatives to inform them about the familial pathogenic variant prior to our contact with the relative.

"When we contacted the relatives, we used a script to describe the study, but did not share any information about specific genetic findings in the family until the relative stated that she/he wanted to move forward and participate and learn about the familial findings."