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

Monday, November 21, 2022

With Matthew B. Yurgelun, MD, Senior Physician at Dana-Farber Cancer Institute

By Sarah DiGiulio​

Patients with pancreatic cancer are notoriously diagnosed at a late stage and with advanced disease because of a lack of early warning signs and symptoms associated with the disease. And because of these late diagnoses, many patients do not do well; 5-year survival rates are staggeringly low. This paradigm means that efforts to improve screening and surveillance efforts that lead to earlier detection of more cases of pancreatic cancer could greatly benefit patients. In a recent editorial published in the Journal of Clinical Oncology (JCO), Matthew B. Yurgelun, MD, Senior Physician at Dana-Farber Cancer Institute, reviewed two large-scale studies that analyzed prospective data investigating imaging-based pancreatic ductal adenocarcinoma surveillance in individuals with high genetic and familial risk (2022; doi: 10.1200/JCO.22.01287).

The first study published earlier this year, also in JCO, looked at the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants in CDKN2A (2022; doi: 10.1200/JCO.22.00194). The data came from the Leiden University Medical Center Pancreatic Ductal Adenocarcinoma surveillance program in the Netherlands. The researchers concluded that surveillance in the high-risk population led to detection of early-stage pancreatic ductal adenocarcinoma with improved resectability and survival.

The second study reported data from the pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5); it was also published online ahead of print in JCO earlier this year (2022; doi: 10.1200/JCO.22.00298). Those individuals were considered high risk because they met the criteria outlined in the recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. The researchers concluded that the majority of patients diagnosed with pancreatic ductal adenocarcinoma while under this pancreas surveillance have Stage I disease and can achieve long-term survival; median survival for patients in the program diagnosed with the cancer was 9.8 years. And it's worth noting that the predominance of Stage I disease is in marked contrast to more advanced stage cancers of the majority of patients who present with symptomatic pancreatic cancer. In an interview with Oncology Times, Yurgelun shared the learnings from those reports.

1. In this editorial, you reviewed data from two long-term studies on surveillance for pancreatic ductal adenocarcinoma. What were the takeaways that were most important?

“To me, the most noteworthy pieces are that: 1) early pancreatic cancer detection is possible with aggressive imaging-based surveillance, and 2) early detection seems to translate into far better likelihood of cure than what we expect from historical control data. Imaging-based pancreatic cancer surveillance is not new, but until these studies (with long-term follow-up data), it was not clear whether or not early detection of pancreatic cancer truly led to better long-term outcomes, or if these people with pancreatic cancer had bad outcomes regardless of how early it was found."

2. You mention in the editorial that most current guidelines (with the exception of those from the American Society for Gastrointestinal Endoscopy) call for screening for individuals who both carry mutations associated with pancreatic ductal adenocarcinoma and have a family history of the cancer. Does this new data suggest that approach is no longer the right one (in terms of that family history piece)?

“I would not say that I'm in favor of dropping the family history piece. I would say that we don't know whether or not we should drop the family history piece. Using family history to triage who does/does not get pancreatic cancer surveillance ultimately restricts the pool of 'eligible' individuals by quite a lot. On the other hand, doing such surveillance in all individuals with inherited genetic risk factors above a certain age would potentially overwhelm the system.

“This is particularly important since the screening itself (and interpretation of the imaging-based screening tests) is extremely nuanced, and expanding this further and wider may shift the risk-to-benefit ratio in an unfavorable direction."

3. Let's talk about access to this type of care and cancer surveillance. Is it possible to increase screening and surveillance capacity if indeed more people would benefit from it?

“I'm convinced that high-quality imaging-based pancreatic cancer surveillance is reasonable to achieve on a large scale. These two studies are great examples of how well this surveillance can work when done in high-volume centers with experienced experts performing, interpreting, and overseeing such surveillance. I think this now needs to be rigorously studied in more 'real-world' settings to know if and how to expand such screening further and wider.

“The bottom-line message is that early pancreatic cancer detection is indeed possible in genetically high-risk individuals, and in many cases such early detection can truly change outcomes for the better. There is still a lot of work to do to figure out how to expand this further and wider, but these are important data that lay the foundation for where we need to go from here."

Friday, November 4, 2022

With Todd W. Ridky, MD, PhD, of the Perelman School of Medicine at University of Pennsylvania​

By Sarah DiGiulio

The lack of melanin in people with light skin—and the resulting increased vulnerability to UV damage—may not be enough to explain why risk of melanoma is as much as 30 times higher for people with light skin compared with individuals with dark skin. That is the key finding from researchers who have investigated why melanoma risk is so much higher in people with light skin (Sci Adv 2022; doi: 10.1126/sciadv.abn4007). In a series of lab experiments using human melanocytes, they found there are intrinsic differences between melanocytes in both light and dark skin samples that affect cells' abilities to grow and replicate, as well as their susceptibility to malignant transformation. The melanin precursor dihydroxyphenylalanine (DOPA) was involved and the results suggest that CHRM1 and FOXM1 may be new therapeutic targets for melanoma. Todd W. Ridky, MD, PhD, Associate Professor of Dermatology at the Perelman School of Medicine at the University of Pennsylvania and attending physician at the Hospital of the University of Pennsylvania, explained the findings and implications for future melanoma treatment and care.

1. What led your research of melanoma in different skin types?

“The classical teaching is that light-skinned people are more prone to melanoma and other skin cancers because they're more vulnerable to UV damage from the sun. Light skin is relatively deficient in melanin pigment, which serves as a physical shield against UV rays from the sun. So, if the melanin absorbs the UV, then that protects the DNA. But if you don't have as much melanin in the skin, then the UV goes right through, hits the DNA in your cells, and causes damage, which then turns into mutations that drive cancer.

“But we thought that explanation was not sufficient to explain the huge gap in the difference in the cancer incidence between dark-skinned and light-skinned people with regards to melanoma. There are a few different lines of reason that suggest this to be the case. The first is anal-rectal melanoma. It's not super common, but that cancer appears to be 13 times more common in light-skinned people than dark-skinned people. You can't really invoke a UV sun-shielding explanation for a cancer in that location. So we thought there must be other factors involved.

“Second, in the course of our research, we routinely isolate and study melanocytes. If you isolate [them] out of light skin and dark skin on the same day and grow them in identical conditions, the light ones always proliferate much faster than the dark ones. We thought it not coincidental; the cells that proliferate much faster are also the ones that are much more prone to give rise to cancer."

2. How did you show there's something going on besides more UV shielding in people with dark skin?

“We took a set of four oncogenic proteins that are associated among the most common changes in melanoma in people. These include BRAF mutations, which drive half of all melanoma; CDK4; dominant-negative p53; and hTERT. We did some tissue engineering to generate composite human skin tissues in a dish. And then we took those pieces of skin—some had the melanocytes with the oncogenes from the light skin and some [were] from the dark skin—and we grafted them onto the backs of host mice. After 100 days, the skin grafts with the light melanocytes expressing the four oncoproteins turned into melanomas. However, the dark cells engineered with the same oncoproteins did not turn into melanoma.

“So, yes, there is probably…some sun-shielding activity from the UV, which likely helps prevent the dark melanocytes from getting the mutations in the first place. But this experiment showed that, even if dark melanocytes get the mutations and express those oncoproteins, they are still very resistant to making melanoma compared to light melanocytes.

“The fact that they were growing different in the dish, and the fact that even when they got the oncogenes in them they still did not progress to melanoma, told us there are clearly factors beyond simply UV damage that are underlying this huge difference in melanoma between dark skin and light skin, and it's not simply about UV shielding. There are other genetic determinants in the cells that correlate with pigment type, but that are independent of UV. This is paradigm-shifting. This is something that's been missed by the field."

3. What were other key findings?

“Miriam Doepner, a PhD candidate in the Department of Dermatology at Perelman, had the idea that this was maybe due to an upstream synthetic intermediate in the melanin pathway, rather than melanin itself. And that's what led us to DOPA. The melanin synthetic pathway starts with tyrosine, an amino acid. Then the first step in that process, the rate-limiting step in making melanin, is conversion of tyrosine to DOPA. And DOPA turned out to be critical.

“DOPA, we discovered, has this previously unrecognized signaling activity that is anti-melanoma and has nothing to do with UV. Dark melanocytes have a lot more DOPA than light melanocytes. We found that, if you add DOPA to dark melanocytes, nothing happens. If you add it to light melanocytes, they slow down and get darker. That was also true of melanoma cells; DOPA makes them proliferate more slowly and also get darker. You can even treat mice with melanoma with DOPA; their tumors grow more slowly and they live longer.

“This is very interesting because DOPA is actually an FDA-approved agent, which is DOPA combined with a stabilizer as treatment for Parkinson's disease. So can you repurpose a Parkinson's disease drug to treat melanoma? It works in mice; whether it works in people is yet to be determined. It's potentially easier to do a new drug trial with an already-approved agent rather than a brand new one. This is also really interesting because we know there's an association between melanoma and Parkinson's disease.

“The bottom line for the oncology community to know right now is to have this fundamental awareness that there's a lot of heterogeneity in people and a lot of heterogeneity in cancer. In exploring the mechanisms underlying the heterogeneity, you can learn things about diseases and cancer you would not have learned otherwise. There are groups of people that do much better or much worse with the same disease." 

Thursday, October 27, 2022

With Karen Glanz, PhD, MPH, the George A. Weiss University Professor at the Perelman School of Medicine and School of Nursing at University of Pennsylvania​

By Sarah DiGiulio

Cancer screening recommendations are well-established for breast, cervix, colorectal, and prostate cancers—as well as for lung cancer in smokers who are known to be at high risk. But for other cancers collectively responsible for the majority of cancer deaths, early detection tests are lacking. This point is made in a recent editorial in the journal Cancer by Karen Glanz, PhD, MPH, the George A. Weiss University Professor at the Perelman School of Medicine and School of Nursing at University of Pennsylvania, and her colleagues (2022; https://doi.org/10.1002/cncr.34395). The editorial is a response to new research from another group of oncologists who set out to identify key risk factors for any type of cancer and specific populations that may be at risk to better inform the development of multi-cancer early detection tests (Cancer 2022; https://doi.org/10.1002/cncr.34396).

To do this work, the researchers (led by Alpa V. Patel, PhD, Senior Vice President of Population Science at the American Cancer Society) analyzed data from two large American Cancer Society prospective cohort studies: the Cancer Prevention Study II Nutrition Cohort and the Cancer Prevention Study-3. Collectively, those datasets included nearly 500,000 people and 15,226 invasive cancers were diagnosed among participants within a 5-year time period. The data showed the following information. 1) Nearly all people over age 50 had an absolute risk of greater than 2 percent of being diagnosed with cancer within 5 years. 2) Older age and smoking are the two most important risk factors associated with the risk of developing any cancer within 5 years. Glanz and her colleagues explained in their editorial that there's a lot more work that needs to be done before multi-cancer early detection tests—that truly improve outcomes and improve health—can be developed, starting with demonstrating the practical utility of describing cancer as a single endpoint. In an interview with Oncology Times, Glanz shared her viewpoints from the editorial.

1. What is problematic about looking at cancer as a single endpoint when it comes to screening, cancer risk, and prevention? What is helpful about looking at it this way?

“Cancer is many diseases, not one. The many diseases share a common main feature—they are characterized by the development of abnormal cells that divide uncontrollably and have the ability to infiltrate and destroy normal body tissue. Treating cancer as a single endpoint ignores the huge variety across different types of cancer—who gets them, risk factors for each cancer, what is the average survival or mortality, and so on. As far as risk, smoking is a major contributor to the risk of certain cancers (lung cancer, head and neck cancers), but not as much for others. Some cancers are highly treatable and have more than 90 percent 5-year survival rates (e.g., thyroid cancer), while others have much lower survival rates (e.g., liver and pancreatic cancer).

“The authors of the article that our editorial discusses (Patel, et al) propose that it's helpful to look at risk of cancer as a single endpoint. We don't know of any research that has asked whether either clinicians or patients would agree with that point, but it would be an interesting question to study."

2. Could the findings from the research be used to develop a multi-cancer early detection test?

“As we've noted in our editorial, we feel there is a need for more definitive data about the benefits of an multi-cancer early detection test screening approach in order for it to be widely used, reimbursed by insurance payers, and recommended by expert guideline committees. Aside from uncertainties about the benefits, there are practical concerns.

For example: 1) What diagnostic tests should be done if the findings form multi-cancer early detection tests suggest that a person may be at high risk for one or more types of cancers? 2) What clinical recommendations should be made based on the multi-cancer early detection test findings and further diagnostic tests? 3) Is there a possibility that multi-cancer early detection tests will 'miss' some early cancers? From the patient perspective, the idea of a non-invasive test—based on a blood sample instead of something that 'goes inside your body' like a colonoscopy or Pap test—may be appealing in its own right, whether or not it has a positive health impact.

“We used the term provocative [about the Patel, et al, paper] because it proposes that the research may support taking further steps, such as in the development, testing, and use of multi-cancer early detection tests. It is not definitive, because research hasn't yet demonstrated that the multi-cancer detection tests can lead to better health or cancer outcomes (such as showing earlier detection leading to longer survival and/or better quality of life)."

3. What's the most important thing to know about multi-cancer early detection tests?

“This research uses available data to examine the 'potential' for treating cancer risk as a single endpoint. The findings don't provide a strong conclusion that this approach is 'ready for prime time' use in cancer care—and they were not intended to tackle that specific question. The takeaway from our editorial is for oncologists and physicians to consider the limits of current knowledge if they are considering ordering these tests or are asked about them by their patients—understanding the uncertainties."

Wednesday, October 5, 2022

With Stephanie Wheeler, PhD, MPH, of the UNC Lineberger Comprehensive Cancer Center

By Sarah DiGiulio​

For metastatic breast cancer that is endocrine-refractory or triple-negative, there are multiple chemotherapy options, but little guidance on which ones to use first or how to optimize sequencing of trying various regimens. “Because the economic and quality-of-life burden associated with these ongoing treatments may be different, we were interested in exploring whether optimal chemotherapy sequences could be identified considering factors important to patients, such as drug costs, productivity losses, and side effects," noted Stephanie Wheeler, PhD, Professor of Health Policy and Management at Gillings School of Global Public Health at University of North Carolina at Chapel Hill and Associate Director of Community Outreach and Engagement at UNC's Lineberger Comprehensive Cancer Center.

That's the analysis she and her colleagues conducted with the results published in the Journal of Clinical Oncology (2022; doi: 10.1200/JCO.21.02473). The researchers developed three different computer models to predict how a hypothetical set of 10,000 patients with specific types of metastatic breast cancer would respond to various sequences and types of chemotherapy. For the models, patients' cancers were either no longer responding to hormone therapies or were triple-negative breast cancer. Here's what Wheeler said about her group's data and their ongoing work to optimize the value and minimize societal and patient costs of cancer care.

1. How did you set up this analysis to estimate cost-effectiveness of various first- to third-line sequences of single-agent chemotherapy regimens for people with endocrine-refractory or triple-negative metastatic breast cancer?

“With expert oncologist input, we modeled common chemotherapeutic regimens for three different metastatic patient cohorts, based upon prior treatment exposure—people who had previously received a taxane and an anthracycline, people who had received neither, and people who received a taxane but not anthracycline. For each cohort, we estimated total quality-adjusted life years, considering survival expectancy and side effects from treatment, as well as costs, considering both medical costs and non-medical, productivity costs, based upon published trials and other literature.

“Cost-effectiveness analyses then compared treatment sequences within each cohort and yielded findings that suggested that starting treatment sequences with the least expensive chemotherapy drugs was cost-effective or cost-saving, even in some cases, without compromising survival or quality of life. These results were robust in sensitivity analyses.

“In most cases, our analyses actually show that starting sequences with the cheapest chemotherapies confers the largest benefits clinically in terms of quality-adjusted life years. Specifically, our results suggest that for taxane- and anthracycline-exposed patients, treatment with [carboplatin], followed by [capecitabine], followed by eribulin corresponds to the highest expected quality-adjusted life years gain and lowest costs. For taxane- and anthracycline-unexposed patients, treatment with [paclitaxel], followed by [carboplatin], followed by [doxorubicin] corresponds to the highest expected quality-adjusted life years gain and lowest costs. And for taxane-exposed/anthracycline-naive patients, treatment sequences beginning with [capecitabine], or [doxorubicin], followed by eribulin corresponds to the highest expected quality adjusted life years gain and lowest costs."

2. What are the implications of these findings?

“We found that there is little value in starting chemotherapy sequences in this setting with more expensive medications because survival and quality-of-life profiles were similar across treatment sequences over time; therefore, treatment sequences that minimize costs early should be prioritized.

“The implications are clear. In this metastatic setting where multiple chemotherapy options are recommended by guidelines and share similar survival and adverse effect trajectories, treatment sequences that minimize costs early may help improve the value of care, not only for society, but also for individual patients.

“As the cost of cancer drugs continues to skyrocket and as patients continue to be devastated by the cost of their illness, providers should be empowered to choose clinically equivalent therapeutic alternatives that are less expensive and less financially burdensome to patients. These data provide quantified evidence that can inform those decisions and can reduce patient financial toxicity while maintaining high-quality care."

3. What's the next step of your work and are there any other takeaways for practicing oncologists?

“The current study attempts to provide economic evaluation evidence that can motivate providers and policymakers to choose higher-value treatments to address patient-level financial toxicity and societal drug costs. We know that this is a necessary but insufficient solution to the problem and that other solutions are also required, including major health policy payment reforms and direct patient-facing interventions.

“In the latter space, we are currently in the process of scaling up and studying the implementation of a financial navigation intervention we developed at UNC that directly assists patients with financial literacy, health insurance and social resource support, and financial case management to build patient and caregiver capacity to manage the costs of their cancer care. This work is underway as an NCI-supported clinical trial in nine rural and non-rural oncology sites in North Carolina.

“Our analysis addresses notable gaps in existing treatment guidelines in the metastatic triple-negative or endocrine-refractory breast cancer setting when clinical outcomes are similar and costs are quite different. These data should hopefully motivate providers to choose lower-priced, equally effective chemotherapy options in this setting."

Thursday, September 22, 2022

With Hermioni L. Amonoo, MD, MPP, of Brigham & Women's Hospital/Harvard Medical School

By Sarah DiGiulio​

Positive psychological well-being is not the same as the absence of psychological distress. That's a key argument a group of psychological oncology and psychiatry researchers have made in the Journal of Clinical Oncology (2022; doi: 10.1200/JCO.21.02507). It's important because positive psychological well-being, measured by indicators like positive affect, gratitude, optimism, and life purpose, generally tends to be linked to improved morbidity and mortality. The researchers suggest that, when it comes to managing mental and emotional health for cancer patients, paying more attention to these positive psychology measures and developing interventions to improve them may improve quality of life and outcomes.

“Having a cancer diagnosis can be challenging," said Hermioni L. Amonoo, MD, MPP, the Carol C. Nadelson Distinguished Chair in Psychiatry at Brigham and Women's Hospital and Assistant Professor of Psychiatry at Harvard Medical School. “A lot of focus on well-being in this population has been pertained to taking away the stress, which is really important. But we've also found there are other aspects of well-being, positive psychological well-being, which has not been studied extensively in oncological populations, but are pertinent to the lived experience of having cancer."

Enhancing the positive psychological aspects of well-being is different from taking away the stress, she told Oncology Times. It's about enhancing positive thoughts and resilience. They're related, of course. But Amonoo explained that focusing solely on eliminating anxiety or depression doesn't mean someone necessarily feels happiness, gratitude, and hope. She shared her thoughts on how this area of research applies to patients with cancer and potential outcomes.

1. How are these positive psychology constructs related to cancer outcomes or other disease outcomes?

“Positive psychological well-being constructs, such as optimism and its links with clinical outcomes, have been extensively studied in patients with other chronic diseases. If you look in the cardiovascular literature, there's very clear evidence that positive psychological well-being is associated with important clinical outcomes, including better quality of life and less cardiovascular mortality. Specifically looking at optimism, there's evidence that having more of it is associated with less stroke mortality, less cardiovascular mortality, and in some cases, better quality of life.

“One potential mechanism underlying these associations between positive constructs and clinical outcomes in patients with chronic diseases is behavioral. We know that patients who have high levels of positive psychological well-being constructs are more likely to engage in healthy behaviors, such more physical activity, treatment adherence, and smoking cessation. They are also more likely to make better dietary choices. All of these health behaviors have well-established links to better clinical outcomes.  

“The evidence is not so vast in oncology populations. Some of our work has tried to characterize this. In a systematic review to determine the association of positive psychological constructs and outcomes in patients with hematologic malignancies who have undergone stem cell transplantation, we found that optimism and positive affect were associated with improved quality of life (Biol Blood Marrow Transplant 2019; doi: 10.1016/j.bbmt.2018.09.030).

“Other initial qualitative studies have shown that, even in the midst of a cancer diagnosis and intensive treatment, patients do experience these positive emotions (Psyco-Oncol 2019;28:1633-1639). Our current work is trying to establish how interventions that increase these positive psychological well-being constructs are feasible and could potentially impact clinical outcomes in vulnerable oncological populations."

2. What research in this area would you like to see in oncology?

“Our research program aims to shed light on how these positive psychological well-being constructs play a role in the lived experience of patients with cancer in the short and long term. It would be great to characterize the variety of positive constructs people with cancer experience at pretty much every stage of the cancer cycle. So when someone is first diagnosed, what positive constructs are they having versus during acute cancer treatment or when they are in remission or even at end of life?

“Also, we need to develop more interventions. For those of us who work on supportive oncology interventions, we know that one resource does not fit all. Our goal is to have a toolbox of different resources for different patients. Patients all differ. Oncologic disease is different. Treatment is different. The goal is to have a plethora of resources for as diverse a group of patients as possible so that, when someone enters the cancer cycle, they would have options to choose from to help with improving positive well-being.

“We also need to assess the impact. How do you assess the impact of these positive constructs in a meaningful way in an oncology population? Developing tools to also assess where patients are in a longitudinal way would also be useful."

3. What's your bottom-line message about this work?

“People should keep an eye out for this. I think patients also want their clinicians to be curious about the aspects of their experience navigating cancer and treatment. We provide some guidance in the article as to how clinicians could use simple questions to explore where patients are when it comes to their positive psychological well-being. So, for the average clinician, to keep as part of their mental health check-in for patients: ask patients, what are you grateful for? What matters to you in terms of purpose? What are your goals in terms of treatment? Are you satisfied?

“Using very simple questions to be curious about where patients are when it comes to these positive constructs could potentially impact how much clinicians learn about their patients, and how much patients feel seen and heard by their clinicians. Understand where patients are when it comes to making different decisions at different stages in their care."