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

Wednesday, May 5, 2021

With Maria Fomicheva of Vanderbilt University

By Sarah DiGiulio

CRISPR (which stands for “clustered regularly interspaced short palindromic repeats") is a genome screening tool that allows researchers to edit or delete individual genes—as well as identify the specific genes in the body responsible for certain traits. Now researchers have used the technology to identify a genetic switch that may induce cancer cell division (and thus, tumor growth). The protein they identified, TRAF3, may play a role in 80-90 percent of cancers. Further research is needed to better understand what causes TRAF3 to be disrupted, but the current findings could play an important role in better understanding the mechanisms of cancer cell behavior.

“It is important for us to understand the mechanisms that control this kind of cell behavior," noted the study's lead author, Maria Fomicheva, who is a graduate student in the lab of Ian Macara, PhD, the Louise B. McGavock Chair and Professor of Cell and Developmental Biology at Vanderbilt University.

The research was conducted at the Vanderbilt-Ingram Cancer Center and additionally funded by the National Cancer Institute. The study was published in the journal eLife (2020; doi: 10.7554/eLife.63603). In an interview with Oncology Times, Fomicheva shared her thoughts about the research.

1. What are the key findings from your research and what's new about these findings?
“It is known that normal cells divide only until they reach a certain density, then they stop and become quiescent. In contrast, cancer cells ignore density restraints and keep dividing endlessly. It is very important to understand these processes, but the mechanisms have not yet been fully explained.

“To find new, unknown regulators of density-dependent proliferation, we designed and developed a whole-genome CRISPR KO screening approach. We found a novel protein important for this control, TRAF3. We studied the mechanisms of TRAF3-dependent density control and found that acts as an 'off' switch for a cell process called non-canonical NF-κB signaling. The loss of TRAF3 keeps this pathway 'on,' which prevents cells from entering a non-dividing quiescence state. TRAF3 had been previously studied in immune cells, but very little was known about its function in epithelia, and it had not been linked to cell proliferation.

“We were led to study TRAF3 because it was a top hit from our genome-wide CRISPR knockout screen, which was designed to identify genes that normally maintain the correct cell density. 

“We are generally interested in the collective behavior of epithelial tissues, and how this is disrupted in cancer, specifically in breast cancer. Epithelial cells make collective decisions about whether to continue dividing (so the tissue grows) or to stop division, but the underlying mechanisms that determine these behaviors are not fully understood. Cancer cells lose this collective decision-making ability. They behave selfishly, not responding to neighboring cells."

2. Could you explain how CRISPR technology allowed you to conduct this research?

“CRISPR is an immensely powerful technology that enables us to precisely and fully wipe out individual genes, which is extremely helpful for studying the functions of those genes.

“Whole-genome CRISPR screening allows us to target mutations to every gene in the genome, and select only those mutations that disrupt the processes we are interested in. In our case, our design allowed us to screen through thousands of genes and find one novel regulator of cell density—TRAF3."

3. What are the implications of your work? How might it one day improve treatment and outcomes for patients with cancer?

“It is known from previous studies that TRAF3 is important for the development of blood malignancies. It was also shown that TRAF3 is mutated in 4-5 percent of head and neck, lung, cervical, uterine, and some other cancers.  In addition, low TRAF3 levels are associated with poor survival in lung and gastric cancer. However, prior to our work, there was no known causal connection of TRAF3 to epithelial cancer progression (carcinomas).

“CRISPR screens are very powerful tools for discovery in cancer research. Because a key hallmark of cancer is unregulated cell proliferation, the identification of new pathways that control proliferation will provide novel therapeutic targets.

“Our research suggests that inhibiting the signaling pathways downstream of TRAF3 will block hyperplasia and might suppress cancer growth. We hope to test this hypothesis in the future.

“Our novel approach to CRISPR screening can help other scientists to perform similar screens, with the possibility of discovering additional regulators of tissue growth."​​

Thursday, April 8, 2021

With Bishal Gyawali, MD, PhD, of Queen's University Cancer Research Institute, Kingston, Ontario, Canada

By Sarah DiGiulio

Results from the randomized, controlled ADAURA trial, which evaluated the EGFR tyrosine kinase inhibitor osimertinib versus placebo in the adjuvant setting for patients with stage IB-IIIA EGFR mutation-positive non-small cell lung cancer were first presented at the 2020 ASCO Annual Meeting and published online ahead of print in the New England Journal of Medicine (2020; doi: 10.1056/NEJMoa2027071). The data revealed osimertinib indeed improved disease-free survival significantly, stirring much enthusiasm.

But in a new “Comments and Controversies" article in the Journal of Clinical Oncology, Bishal Gyawali, MD, PhD, cautions the excitement may be premature (2021;39:175-177). Gyawali is a medical oncologist and Assistant Professor of Public Health Sciences in the Division of Cancer Care and Epidemiology at the Queen's University Cancer Research Institute in Kingston, Ontario, Canada.

“As an adjuvant therapy for stage IB-IIIA EGFR mutation-positive non-small cell lung cancer, osimertinib currently provides only evidence of exceeding the very low bar of disease-free survival in this setting with no evidence yet of improvement in overall survival against an appropriate control arm. The decision of the independent data monitoring committee in favor of early termination focused only on a clinically dubious surrogate endpoint that is not instructive about whether it confers a survival benefit to patients," Gyawali and coauthor, Howard (Jack) West, MD, a medical oncologist and Associate Clinical Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, noted in the article.

The article also brings up the question of quality of life for patients on osimertinib. The drug is considered a well-tolerated drug, but the trial data shows it was associated with diarrhea in 46 percent of patients (2% with grade 3 or higher), paronychia in 25 percent of patients, and stomatitis in 18 percent of patients.

In an interview with Oncology Times, Gyawali shared more about the ADAURA trial and why he co-penned the JCO commentary article now.

1. What were the main red flags you wanted to raise about the ADAURA trial in your article?

“The ADAURA trial has been hailed as a game-changer in the lung cancer community. As we predicted, FDA also ended up approving osimertinib for this indication based on this [ADAURA] trial. We thought that the enthusiasm for ADAURA was emblematic of the deeper issue in oncology of too much enthusiasm for the new and jumping onto the cheerleading bandwagon without critically reviewing the data.

“We argue that, not only ADAURA, but all cancer drug trials should be evaluated on the principles of 3Es—evidence, ethics, and economics.

“In the case of ADAURA, the problems related to evidence were use of a surrogate endpoint in the adjuvant setting, early termination of trial, and lack of data on what percentage of patients received osimertinib at relapse. With regards to ethics, early termination of trial, substandard brain imaging, [and] low proportion of patients receiving standard adjuvant treatment were issues with ADAURA. Three years of adjuvant therapy with an expensive drug will have economic ramifications, which should be considered before recommending this as standard of care based on no survival data yet.

“Mature data showing overall survival benefit and transparent disclosure of brain imaging and results stratified by brain imaging and receipt of osimertinib at relapse should be provided."

2. Why is the cost question an important one when it comes to osimertinib?

“Cost is only one part of the equation, but an important one. We should also consider the quality of data and the magnitude of benefit.

“Having said that, what's the point in having a drug that does not reach patients because of unaffordability? Both high cost and low probability of clinical benefit should make us question the value of a drug, not hail it as a game-changer."

3. What's the bottom-line message that oncologists and the cancer care community should know about the ADAURA trial and how the criticisms you raise in the article apply to other drug trials, too?

“Drugs for the adjuvant setting should be held to a higher standard than metastatic setting because, in the adjuvant setting, by definition, we are overtreating many patients to help a few, response assessment during therapy is impossible, and quality of life can only have detrimental effects. Thus, without solid evidence of survival gains, the risk-benefit trade-off here tilts naturally towards greater harms and lower benefit.

“Trials should be evaluated critically for the use of surrogate endpoints (i.e., are they valid?), appropriateness of control arm, post-protocol therapy, and cost-effectiveness before declaring a new drug as a game-changer. Newer is not necessarily better."

Thursday, March 25, 2021

With Fiona Schulte, PhD, Assistant Professor in the Department of Oncology, Division of Psychosocial Oncology, in the Cumming School of Medicine at University of Calgary​

By Sarah DiGiulio

The most recent Long-Term Follow-Up Guidelines from the Children's Oncology Group identified long-term pain in survivors of childhood cancer as an area of growing interest. In an effort to systematically look at the research that's been done so far and better understand the need, Fiona Schulte, PhD, Assistant Professor in the Department of Oncology, Division of Psychosocial Oncology, in the Cumming School of Medicine at University of Calgary in Canada, and her colleagues recently published a review in the journal Cancer (2020; doi: 10.1002/cncr.33289). Schulte was a member of the task force that helps prepare the Children's Oncology Group guidelines in 2018. She discussed what was noteworthy about her group's findings in an interview with Oncology Times.

“To our knowledge, no one has yet looked systematically at all the evidence describing pain in survivors of childhood cancer," Schulte said. “We thought it was important to characterize the prevalence of pain among survivors, as well as to describe the factors that might be related to pain in this group. We also thought it was important to highlight important areas for future investigation so that research in this field moves in a direction that will advance our knowledge."

1. What were the key findings?

“The rates of pain in survivors of childhood cancer are reported anywhere between 4.5 and 75 percent, which is not very helpful in telling us if this is a problem for survivors or not. Thus, one of the main findings of the review was a call for future research to use consistent definitions of pain (or chronic pain) in order to better estimate what the true rates of pain are in this population.

“Based on the literature that does exist, we did find fairly consistently that survivors experience more pain than their healthy peers and that pain is consistently related to increased fatigue and the female sex. The remaining evidence was relatively weak or inconsistent and requires further investigation, so another key conclusion is that more work in this area is needed.

“The inclusion criteria for our review required studies that included children who had been diagnosed with cancer from 0 to 21 years of age and described survivors of any age who were at least 5 years from diagnosis and/or 2 years from the completion of therapy. We also did not discriminate by type of diagnosis. Based on the data we reviewed, there did not appear to be strong evidence to suggest there were differences in the experience of pain for different cancer types, age at diagnosis, or type of treatment undergone. This does not mean, however, that these differences do not in fact exist. We don't yet have reliable evidence to make strong conclusions.

“In our review, we intentionally left our definition of pain broad to capture the range of studies that have assessed pain among this population, but this limited our ability to describe specific outcomes. In addition, we did not include qualitative studies as part of our research. Finally, I think it is important to point out that we did not acknowledge the era of diagnosis and treatment for survivors. This may be important in future research as treatment protocols are shifting in favor of less toxic therapies, which may impact rates of pain over time."

2. What's the next step to address adverse outcomes for survivors of childhood cancers?

“Findings from the review suggest that we need better research on pain in survivors of childhood cancer in order to make good clinical recommendations. One of the conclusions we made from this review is that there is evidence to suggest pain is associated with reduced quality of life for these patients.

“This review has really inspired a whole new focus on pain in survivors of childhood cancer in our lab and one of my current students is leading this effort. Specifically, she has been careful to consider a more comprehensive definition of pain that considers pain as a complex, multidimensional construct.

“We have also been conducting qualitative interviews with survivors of childhood cancer to better understand the pain experiences from the perspective of both survivors and one of their parents. And now that we have identified through our own work that pain is an issue for survivors of childhood cancer and negatively affects their quality of life, we plan to test a psychological intervention for this population with the goal of reducing the burden of pain in survivorship. “

3. What bottom-line message should oncologists and cancer care providers know about this review?

“The results of our review do suggest that this population experiences pain in survivorship, and so our message to health care providers is that they should ask about the presence of pain during follow-up appointments. We do know that pain is a common symptom associated with cancer and its treatments, but our data shows that pain may persist long into survivorship.

“We think that a critical message from our work, and consistent with the purpose of the Children's Oncology Group Long-Term Follow-Up Guidelines, is that practicing oncologists and cancer care providers should be screening for the presence of pain among survivors. Please ask survivors if they experience pain!

“In addition, it would be great for health care providers to introduce pain management strategies where appropriate. Preliminary results from our qualitative data suggest that survivors may not be reporting their symptoms of pain either because they feel so thankful to be alive that they feel the experience of pain is a side effect they have to live with, or they are just not aware that pain could be a potential side effect of their cancer and its treatments. While pain may be an inevitable misfortune, we know based on research done in youth with chronic non-cancer pain that chronic pain can be treated, and non-pharmacological options may be excellent alternatives or complementary options to pharmacological interventions." 

Thursday, March 4, 2021

With Alexander Pearson, MD, PhD, Assistant Professor of Hematology and Oncology at University of Chicago Medicine

By Sarah DiGiulio

Once a topic of sci-fi and fantasy novels, artificial intelligence (AI) is now breaking ground in many fields of science, including oncology. But to successfully put applications of AI technologies to use in clinical practice, careful consideration of when and how these technologies are used must be considered. That's the bottom line Alexander Pearson, MD, PhD, Assistant Professor of Hematology and Oncology at University of Chicago Medicine, makes with his coauthor in a new commentary article published online ahead of print in the journal Cancer (2020; doi.org/10.1002/cncr.33284).

“In this rapidly developing field, there are few established standards, and oncology researchers and providers must educate themselves about emerging AI technology to avoid common pitfalls and ensure responsible use," the authors noted in the article. In an interview with Oncology Times, Pearson elaborated on the prospects of AI in oncology and why this topic is so important right now.

1. What prompted you and your coauthor to write this article now?

“As an oncologist and quantitative scientist, I want to see developments in AI do the maximum amount of good for my patients. In my opinion, a major component of that is by having applied AI research in cancer be led by academic cancer researchers—meaning the teams caring for patients.

“I think academics will add rich, clinically relevant research foci to the terrific work being done by our industry partners.

“In the same way we have seen gene expression profiles integrated into risk stratification and patient care over the last 2 decades, I expect AI-based digital biomarkers to make their way into standard practice in the coming decades."

2. What are some of the biggest opportunities and challenges for AI in oncology?

“AI is changing the landscape of oncology by broadly increasing what type of data can be used for automated, quantitative analysis. A mix of convolutional neural networks and digital processing allows for the rapid extraction of visual data. Furthermore, the flexible architecture of a neural network model means that, in any clinical domain (think risk score or biomarker) where in the past you might include clinical variables or lab values, you might now also include pathology data, radiology imaging data, or a stream of time-stamped lab data. So, models might be applied to all of the above, from prevention and diagnosis to prognosis and treatment selection.

“For example, with AI, we have shown that we can accurately predict the gene expression states of thyroid neoplasms and the microsatellite instability states in gastrointestinal cancers with high accuracy directly from images of the standard pathology sample. In the future, an AI platform using a combination of pathology, imaging, and clinical variables might help a clinician instantly select from a panel of different possible cancer treatments.

“Some of the main barriers to implementation are the availability of high-quality datasets and lack of shared communication between oncologists and computer scientists or machine learning developers.

“As cancer researchers learn how to describe the importance of their research questions and the opportunities for algorithm development to the AI community, along with the right data to answer the questions, I anticipate AI research continuing to accelerate.

“One further shortcoming is the potential for bias or 'overfitting,' meaning that AI models can learn idiosyncrasies of the training dataset as important generalizable features. In order to integrate AI models in clinical workflows and make medical decisions based on their outcomes, rigorous prospective AI biomarker validation is essential (which is no different than with any biomarker)."

3. What's the next step to better utilizing AI in oncology research? What's the next step that will help propel this type of research?

“While the jargon and technical details of AI don't make it easy to break into, the fundamental principles are within reach to most clinicians, so it is worth reading to understand this important emerging technology. Fortunately, the machine learning field in academics has a very open philosophy, and there are many good reviews and resources online.

“Projects that would lend themselves to evaluation with machine learning methods might share some of the following aspects: a large volume of well-organized data, digital (or digitizable) data from multiple streams (i.e., imaging, lab data, medical charts, etc.), and a high potential for clinical impact." 

Friday, February 19, 2021

With Brooke Cherven, PhD, MPH, RN, CPON, of Children's Healthcare of Atlanta and Emory University School of Medicine

By Sarah DiGiulio​

A new scoping review from the Children's Oncology Group Adolescent and Young Adult (AYA) Oncology Discipline Committee investigated existing literature about sexual health and functioning for AYA cancer survivors. The researchers found that the evidence available is lacking in many ways.

This review was intended to summarize sexual dysfunction and the relevant psychosexual aspect, which includes romantic relationships and body image in AYA cancer survivors, said Brooke Cherven, PhD, MPH, RN, CPON, Nurse Scientist at the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Assistant Professor of Pediatrics at Emory University School of Medicine. The conclusion, Cherven told Oncology Times in an interview: “There hasn't been a lot of rigorous research; particularly, there's a lack of longitudinal data that's been collected."

The review article was published online ahead of print in the journal CA: A Cancer Journal for Clinicians (2020; doi.org/10.3322/caac.21655). Previous research reviews regarding sexual function have largely looked at hormonal and physiological factors, Cherven noted. “The influence of psychosocial factors and developmental factors has not received the same amount of attention."

Cherven shared her thoughts about this review and the work she hopes to see in the future to address these literature and care gaps.

1. What were the key research findings?

“There's a significant burden of impaired sexual function among adolescents and young adults after they complete cancer treatment. And there are complex relationships between sexual dysfunction, romantic relationships, and body image in these AYA survivors. These are critical domains that have been identified by survivors as impacting their quality of life.

“We focused on AYA-age survivors of pediatric and AYA cancers, meaning we included survivors who were 15-39 years of age at the time of the study—who had been diagnosed with cancer from birth to 39. Because it was a scoping review, we wanted to look at kind of the state of the science among this broader group of AYA-age survivors.

“In this broad age range, it is important to consider the developmental factors. So if you're thinking about a more adolescent or very early young adult survivor who may not have even been in an intimate relationship or hasn't had any sexual experience, their sexual health needs are different from survivors who are in mid- to late 30s who are partnered and had a strong partner before diagnosis.

“There is a wide range of sexual dysfunction for these groups. And one of the other findings is that there's wide variation in terms of how sexual dysfunction was measured. Some studies used more validated tools to measure sexual dysfunction; other studies looked more at things like sexual satisfaction and other components of sexual functioning.

“So, it's a little difficult to make broad, very strong conclusions on trends other than this is consistently reported as a problem amongst a variety of populations. So depending on cancer diagnosis, treatment, and age, it's coming up as an issue. Sexual dysfunction and sexual health are important to patients' quality of life and it's a problem across the AYA developmental period."

2. Based on this review, were you able to make any more specific conclusions about how these problems differ among cancer survivors of different ages or cancer types?

“[Based on] the way that most of the studies were done, we weren't able to tease out those nuances. But clinically, we can see differences in experiences in survivors who had cancers in their adolescent and young adult years where their psychosexual development was interrupted due to their cancer diagnosis and treatment. We also see that survivors diagnosed in childhood also can experience differences in terms of sexual health needs. And depending on cancer treatment, they may be at risk for some of the hormonal and physiological factors that influence sexual function."

3. What are the next steps and the types of trials you're eager to see done?

“There's a really big need for more prospective studies using validated measures that are developmentally appropriate.

“There is an opportunity to do prospective studies that look at assessing not just sexual function or sexual dysfunction, but some of these other psychosexual factors. For instance, we found that romantic relationships and body image are important aspects of sexual health in this population. So larger studies collecting this information as patients progress from active treatment to completing treatment and into survivorship—this longitudinal data—will be critically important.

“And then we need to test developmentally appropriate interventions that account for these biological and psychosocial factors. A great avenue is collaborations between cooperative research groups, like the Children's Oncology Group and the National Clinical Trials Network, that would allow for design and implementation of this research on a larger scale.

“In tandem, there's also a need for provider-focused interventions that may increase the screening for sexual dysfunction and discussions about sexual health with patients—and referral for treatments amongst survivors who are experiencing issues."