3 Questions on…

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

Friday, January 5, 2018

With Kevin S. Hughes, MD, FACS, at Massachusetts General Hospital

By Sarah DiGiulio

The time is now for population-level screening for hereditary cancer susceptibility mutations. That's the argument from Kevin S. Hughes, MD, FACS, Co-Director of the Avon Foundation Comprehensive Breast Evaluation Center at Massachusetts General Hospital, Boston, who penned a recent editorial in the Journal of Clinical Oncology (2017;35:3789-3791).

"Our problem, which desperately cries out for a solution, is that huge numbers of high-risk patients who could be identified by genetic testing are instead developing cancer and often dying of that disease," writes Hughes, who is also Associate Professor of Surgery at Harvard Medical School and Medical Director of the Bermuda Cancer Genetics and Risk Assessment Clinic.

Hughes' article is published in the same issue of JCO as a recent study that estimated the rate of patients in the U.S. who are at high risk of having heritable mutations that have been linked to breast or ovarian cancer and who have not been tested for those mutations (2017;35:3800-3806). That research, led by Christopher Childers, MD, a resident physician in the Department of Surgery at the David Geffen School of Medicine at UCLA, found that fewer than one in five individuals with a history of breast cancer or ovarian cancer who meet the National Comprehensive Cancer Network criteria for testing have actually undergone genetic testing—and most patients had never discussed genetic testing with a health care provider.

"Genetic testing is becoming the norm for medical care, whether it be cancer susceptibility, susceptibility to 'benign' genetic diseases (such as cardiomyopathy, etc.), risk of genetic diseases in newborns, pharmacogenetics, or somatic mutations in tumors," Hughes told Oncology Times. "Our failure to get the right patients [in oncology] tested requires a major change in our approach."

Here's what else Hughes shared about why this issue is so urgent.

1. Were you surprised by the findings from Childers et al.? Why is addressing this underutilization of genetic testing in cancer so important now?

"They are not surprising. Huge amounts of ink have been spilled on the risks and harms of cancer genetic testing. Little has been written about how poorly we were actually doing bringing this major aspect of medical care to our patients. The end result has been caution and slow uptake of a lifesaving test.

"Tremendous good could be done if everyone who needed cancer genetic testing was tested and managed appropriately. Our current system concentrates so strongly on the possible harms of testing and the complexity of testing that we lose sight of the benefits.

"It is time to do this. The world has changed. DNA sequencing is cheap and getting cheaper. Childers' paper shows how poorly we have done and that, simultaneously, the genetics professionals are about to be bypassed by inexpensive and ubiquitous testing. Tumor sequencing, whole genome sequencing, panel testing, whole exome sequencing, and direct-to-consumer testing are about to wash over the current pre-test counseling system and make it obsolete.

"Testing will be the norm and everyone will have it done. We need to understand that and get ahead of it, not try to stop it."

2. You argue that the benefit of genetic testing is well-proven. What are the main reasons (given its proven efficacy) it has not been more widely utilized?

"We have concentrated on purported harms and tried to block use of the test at the population level. It is obvious that some cases will be managed incorrectly whether tested by a physician or a genetic counselor. The media and the literature concentrate on a hand full of cases where something was done wrong. Tremendous attention was paid [for example] to a case where a woman had her breasts and uterus removed inappropriately. This is a case where education and support of physicians doing testing was sorely needed.

"The vast majority of the hundreds of thousands of patients tested were managed appropriately, but this case is what is used to dissuade patients and doctors from testing.

"[And] requiring every patient see a genetic counselor before testing is a major barrier. In cities like Boston, it [can take] months to see a genetic counselor (if you do not have cancer)—and requires taking more time off from work and making another trip into the hospital. In rural areas, it might take hours to get to a counselor. Phone counseling is available, but is not used extensively. Testing at the point of care would markedly increase uptake. As best I can tell, cancer genetic testing is the only area where seeing a counselor is felt by some to be required before testing. Prenatal testing, neurologic genetic disease testing, cardiac genetic disease testing, tumor sequencing, and pharmacogenomic testing are done mostly by physicians and genetic counselors to help as needed, such as when tests are positive."

3. What are the next steps that help solve this problem?

"Testing at the point of care would markedly increase uptake. We need to educate physicians regarding the benefits of testing and the need for testing. We need to educate physicians in how to test appropriately rather than tell them they are not able to test. We need decision support tools to help physicians and genetic counselors keep up with the rapid changes (see the tool www.Ask2Me.org).

"But we also have to realize that genetic testing is going to become ubiquitous whether we take the lead or not.

"All aspects of the practice of medicine require a knowledge of genetics. Physicians must assure that their patients get the correct genetic test in a timely fashion and that that information is used to benefit them by helping choose the proper screening, the proper preventive measures, and the proper use of medications. This is not a turf issue, it is good medical care."

Thursday, December 28, 2017

With Jay S. Lee, MD, Surgical Oncology Research Fellow at University of Michigan

By Sarah DiGiulio

There are a lot of factors driving the current opioid epidemic and crisis. And new data suggests that persistent postoperative opioid use in patients with cancer who have undergone curative-intent cancer surgery is one of those factors, according to the research published online ahead of print in the Journal of Clinical Oncology (2017; doi:http://doi.org/10.1200/JCO.2017.74.1363).

The study followed 68,463 patients with melanoma, breast, colorectal, lung, esophageal, or hepato-pancreato-biliary/gastric cancers who underwent curative-intent surgery and filled opioid prescriptions. For the patients who had never taken opioids previous to the surgery, the risk of new persistent opioid use (meaning those who continued to fill prescriptions 90-180 days after surgery for a daily dose of the medication) was 10.4 percent.

Significantly, that’s higher than the risk of persistent opioid use among opioid-naïve patients undergoing non-cancer procedures. Approximately 6-8 percent of those patients stay on opioids following their procedure.

“Patients with cancer who undergo curative-intent surgery have several potential reasons for persistently requiring opioids,” the researchers noted in the paper, including substantial postoperative pain and the fact that, because of the burden of disease, it’s documented that patients with cancer are at higher risk for psychosocial distress. But an important point is that there’s also research that suggests patients are unlikely to achieve relief from chronic pain by using opioids.

The findings from this new research suggest that some attention needs to be paid to cancer doctors’ opioid prescribing habits, as well as how cancer care providers are educating and counseling their patients on how opioids should be used and resources to address pain and other distresses, explained the study’s lead author Jay S. Lee, MD, Surgical Oncology Research Fellow at University of Michigan. Here’s what else he told Oncology Times about the research and the problem it identified.

1. Why did you and your colleagues conduct this research and what was significant about these findings that wasn’t known previously?

“We wanted to look at patients who had potentially curable disease, such as early stage breast cancer, colon cancer, or melanoma. These patients deserve special attention, because if they’re going to be free from cancer, we’d also like them not to be on opioids long term.

“Our key finding of this study is that 10 percent of people who had never taken opioids prior to curative-intent surgery for cancer continued to take the drugs 3-6 months later. The risk is even greater for those who are treated with chemotherapy after surgery. Although previous studies have examined opioid use after non-cancer operations, our findings show that patients with cancer are particularly vulnerable to developing long-term opioid use after curative-intent surgery.

“The findings were very surprising. We’re trying to help these patients. We’ve performed this operation to cure them of their cancer. But we’ve left one in 10 as chronic opioid users. That’s a tremendous burden to leave with cancer survivors.”

2. Given these findings, what steps would you say need to be taken to address these concerns about such a high number of cancer patients continuing on opioids after surgery?

“First and foremost, we need to make sure we’re prescribing the appropriate amount. We’re conducting follow-up studies to evaluate how much patients are actually taking, and using that information to prescribe lower amounts. What we’ve found in our initial work is people take far less than we prescribe. Having extra pills puts these patients at risk.

“An equally important step is providing better pain management education to patients about opioids. That means that we shouldn’t just hand them a pill bottle and say: ‘This is for pain; take it and good luck.’ We should be telling them that this is for severe pain only. You should use Tylenol and Motrin first—and if the pain gets really bad, then you can take opioids as a last resort.

“We also need to do a better job of counseling patients on the risks associated with opioid use. If we can do a better job educating patients, they will take less opioids with improved pain control.”

3. What would you say is most important for practicing oncologists and cancer care providers to know about these findings and postoperative opioid use among cancer patients?

“Many patients with early-stage, curable cancer continue using opioids long after curative-intent surgery. This iatrogenic complication is a substantial burden on cancer survivors and requires changes to prescribing guidelines, physician education, and patient counseling during the surveillance and survivorship phases of care. All cancer care providers must engage with patients to ensure appropriate, safe use of opioids.

“Opioids are often not effective for treating long-term pain. Patients with cancer need to be aware of these risks and engage with their care team to use opioids appropriately and safely.”

Thursday, December 7, 2017

With Johan Thevelein, PhD, at the Laboratory of Molecular Cell Biology at KU Leuven and the VIB Center for Microbiology

By Sarah DiGiulio

Whether or not there's a link between how much sugar we eat and cancer has long been a topic of interest among cancer biologists and others caring and designing treatments for patients with cancer. A new study reveals some key data on the matter and answers important questions, according to the researchers.

"It was previously known that cancer cells have an elevated rate of sugar breakdown compared to regular human cells and prefer fermentation over respiration," Johan Thevelein, PhD, Professor and Head of the Laboratory of Molecular Cell Biology at KU Leuven and Group Leader at the VIB Center for Microbiology, Flanders, Belgium, told Oncology Times—meaning that tumors convert much higher amounts of sugar into lactic acid than noncancerous human cells convert sugar into carbon dioxide.

"This behavior of cancer cells is bizarre because fermentation produces about 15 times less energy than respiration and, since cancer cells multiply much faster than regular human cells, they actually need much more energy than regular cells," Thevelein added.

The key finding from the group's new research conducted over 9 years is the identification of the mechanism by which the elevated rate of sugar breakdown stimulates tumor growth.

"Our conclusion is that the beneficial effect of sugar-poor diets may not be a hype or a phantom, but may have a real scientific basis," Thevelein said.

"The key finding is that an intermediate compound in the sugar breakdown pathway (fructose 1,6-bisphosphate) is a potent activator of the Ras proteins, which are important controllers of cell proliferation in human cancer cells," he explained.

The group first conducted experiments in yeast cells because they have the same preference for fermentation over respiration as cancer cells—and then conducted experiments in cancer cells to show that the same mechanism was occurring. The experiments took a much closer look at cancer cells under a much finer microscope than many practicing oncologists may deal with on a daily basis, but they have important implications for patients undergoing treatment highlighting the risk of stimulating cancer with high sugar feeding, Thevelein said. The paper shows a clear link between sugar breakdown and the Ras protein, an oncogenic driver, he explained.

Here's what else Thevelein told Oncology Times about the findings—which were published online ahead of print in Nature Communications (2017; doi:10.1038/s41467-017-01019-z)—as well as what practicing cancer care providers need to know.

1. What is the Warburg effect—and why is your research that set out to better understand this phenomenon important?

"The Warburg effect is the preference of cancer cells for fermentation over respiration. It was discovered by the German biochemist Otto Warburg about 80 years ago. Up to the appearance of our paper, it had remained unclear whether the Warburg effect was merely a symptom of cancer or whether it could also play a role in stimulation of the cancer.

"This Warburg effect is also present in yeast cells (where it is called the Crabtree effect). When you add sugar to yeast cells, they will ferment it to ethanol (and make beer, wine, etc.) in spite of aerobic conditions. The fermentation pathway for sugar breakdown in yeast and human cells is the same except for the last step: in yeast, ethanol is the final product, [whereas] in mammalian or cancer cells lactic acid is the final product.

"We have been doing research on the mechanisms by which yeast cells sense nutrients for 30 years, and we have elucidated the glucosesensing network in great detail. Now, it turns out that an important part, the activation of Ras by fructose 1,6-bisphosphate, is conserved between yeast and mammalian and cancer cells."

2. Do the findings have any implications for whether or not sugar in the diet might cause cancer—or whether a lower-sugar diet could help prevent cancer?

"No, we certainly do not claim that sugar can cause cancer in healthy people or that sugar-poor diets may reduce the risk of cancer. Regular human cells have proper mechanisms to break down sugar in a controlled manner through respiration, and they can also properly handle an occasional switch to fermentation, as happens for instance in muscle cells.

"It has to be mentioned, however, that there is a clear link between obesity and a higher risk of getting cancer—and this applies to multiple types of cancer. Why this link exists is unknown. Obesity can disturb the proper release of insulin from the beta cells of the pancreas, and insulin of course is crucial for proper control of glucose levels in the blood. However, at this moment there is no scientific evidence to link obesity to susceptibility to cancer in this way."

3. What is the bottom line that oncologists and cancer providers should know about your work? Does it have implications for how they should care for patients with cancer?

"Sugar can stimulate the aggressiveness of cancer, and that should be taken into account in providing sugar to cancer patients, especially high levels of rapidly used sugars like glucose.

"There are some reports in the scientific literature that [suggest] sugar-poor diets may be beneficial for cancer patients, helping them to recover, for instance, during chemotherapy. However, this is a controversial issue since there was no scientific evidence up to now for a mechanism linking sugar breakdown to cancer.

"This is what we have provided with our paper: a clear mechanistic link between sugar breakdown and a protein, Ras, that is very well known for its oncogenic potency.

"When cancer patients need an energy-rich diet to strengthen their health in order to better support the burden of chemotherapy, it might be advisable to avoid high-sugar diets and use other energy-rich diets instead. This is an area that now clearly needs more extensive clinical investigation."​

Tuesday, November 21, 2017

With Leah Christl, PhD, at the FDA's Center for Drug Evaluation and Research

By Sarah DiGiulio

In September, the FDA approved bevacizumab-awwb as a biologic similar to bevacizumab for the treatment of patients with multiple types of cancer, including certain colorectal, lung, brain, kidney, and cervical cancers. It was the first biosimilar to be approved in the U.S. for patients with cancer after years of debate and discussion as to the place for such products in oncology.

"The availability of these products can provide more treatment options to patients, potentially lowering treatment costs and enabling greater access for more patients," noted Leah Christl, PhD, Associate Director for Therapeutic Biologics in the Office of New Drugs at the FDA's Center for Drug Evaluation and Research.

FDA approval for a biosimilar differs from the agency's approval process for a conventional therapy. Approval for a biosimilar is based on whether or not that product can demonstrate biosimilarity to a reference product (not to independently establish the safety and effectiveness of the proposed product), Christl explained.

"The ability to rely on certain existing scientific knowledge about the reference product submitted by the biosimilar manufacturer to support the approval of the biosimilar product allows for a potentially shorter and less costly drug development program," Christl said. "This is what is meant by an 'abbreviated approval pathway'—and is one way to increase treatment options and improve access for the public at potentially lower cost."

The FDA uses a totality-of-the-evidence approach when reviewing a proposed biosimilar product for approval, she added. The approach considers all available data and information submitted by the sponsor, including analytical data, animal data, human pharmacokinetics and pharmacodynamics data, clinical immunogenicity, and clinical safety and effectiveness data. Demonstrating biosimilarity will be determined on a product-specific basis.

Legislation granting the FDA the authority to approve biosimilar products in the U.S. was enacted in 2010 as part of the Biologics Price Competition and Innovation Act (BPCI Act). However, biosimilars have been available in countries outside of the U.S., including in Europe, for years—sparking some questions about the role of these products in the U.S.

Here's what Christl told Oncology Times about some of those questions and the future of biosimilars in oncology.

1. Legislation from 2010 addressed getting biosimilars approved. Is 7 years a long time in terms of getting this product and/or other biosimilars approved?

"Since the passage of the BPCI Act, the FDA has worked very hard to implement the legislation by developing a framework and regulatory pathway for the review and approval of biosimilar and interchangeable products. This includes issuing guidances to help companies that develop these products understand the FDA's current thinking on many scientific and policy issues. The FDA also regularly engages with companies on product development questions through the Biosimilar Product Development program.

"The FDA has so far approved seven biosimilar products and many more are in the pipeline. The FDA undertakes a rigorous and thorough evaluation to ensure that a biosimilar product meets the agency's standard for approval."

2. What role do you see biosimilars playing in the treatment of cancer in the U.S. moving ahead?

"Many of today's most important medications are biological products, or biologics. These drugs, while expensive, have revolutionized how we treat many of today's most serious life-threatening and life-altering conditions and diseases. Biologics represent the cutting-edge of biomedical research and offer hope that treatment options for many serious medical conditions could soon be available.

"Introducing biosimilars into the U.S. will benefit patients who rely on biological products as part of their health care in a variety of ways. First, patients who currently need biologics, or who may need them in the future, will have access to a larger number of medicines. An increase in market competition may lead to significantly reduced costs for both patients and our health care system. Similar to the significant savings that we've seen through the introduction of generic drugs in the U.S., biosimilars have the potential to save our health systems billions of dollars over the coming years. It is an exciting time for biosimilar and interchangeable products—they are only going to grow."

3. What is most important for practicing oncologists and cancer care providers to know about biosimilars and the role they might play in cancer care?

"Biosimilars, once available on the market, have the potential to reduce costs for both patients and the overall health care system. This is true for cancer care and also for other conditions where biological products are used for treatments.

"It is important for health care providers to understand that the FDA undertakes a rigorous and thorough evaluation to ensure that a biosimilar product meets the agency's standard for approval. Health care providers and patients can expect that there will be no clinically meaningful differences between taking a reference product and a biosimilar when these products are used as intended. [And] once a biosimilar or interchangeable has been approved by the FDA, patients and health care providers will be able to rely upon the safety and effectiveness of an FDA-approved biosimilar just as they would for the reference product that the biosimilar was compared to.

"As with other drug products, health care professionals should review the prescribing information in the labeling for detailed information about the approved uses."​

Monday, November 13, 2017

With Gil Bar-Sela MD, at Rambam Health Care Campus in Haifa, Israel

By Sarah DiGiulio

Previous research offers some fairly strong evidence that cannabis use has the potential to suppress immune system functioning (Eur J Immunol 2010;40:3358-3371). That could be a problem if the increasingly commonly used drug is being taken by cancer patients on immunotherapies. And that's why Gil Bar-Sela, MD, Head of Supportive and Palliative Care at Rambam Health Care Campus in Haifa, Israel, and his colleagues decided to investigate potential interactions between cannabis and the immunotherapy nivolumab. They presented their data at the ESMO 2017 Congress in Madrid in September (Abstract 1545PD).

The researchers led a retrospective, observational study that analyzed records of 140 patients treated with nivolumab at Rambam Health Care Campus between 2015 and 2016. Eighty-nine patients reported only taking the cancer drug, and 51 patients reported taking the cancer drug, as well as using cannabis. The patients in the trial were taking nivolumab to treat either advanced melanoma, non-small cell lung cancer, or renal clear cell carcinoma.

The analysis showed that cannabis use was the only significant factor that reduced the patients' response to nivolumab for the group: 37.5 percent of the patients not using cannabis had a response to the drug, while 15.9 percent of the patients having reported using cannabis had a response to taking nivolumab. Though, cannabis use did not significantly affect progression-free survival or overall survival among the patients.

Bar-Sela said the results, while not conclusive, are noteworthy for patients taking immunotherapies—and warrant further prospective clinical study.

1. What were the key findings from this research—and which, if any, of the findings were surprising?

"The key finding was the lower response rate to immunotherapy in the group of patients that had taken cannabis [at] the same time. The only parameter that influenced the response rate to immunotherapy was cannabis. Other parameters [including smoking, hypertension, brain metastases, and more] influenced survival and that was not surprising.

"In retrospective data, we collect all available data from the files and run them in the multivariate regression model. Of course, not all of [the results] have meaning. For example, smoking is higher in the lung cancer patients, resulting in lower progression-free survival compared [to patients with] renal cell carcinoma, and so on. These other parameters are related directly to the patients' illnesses and general situations.

"This topic [has not been] reported before. It is the first time. However, some concern was raised in the '90s when some patients with AIDS took cannabis for symptom relief.

"The finding [supports] the hypothesis that such interaction is possible. Cannabis depressed the immune response, according to several basic [studies]."

2. What conclusive were these findings and what implications do these findings have for how cannabis use might affect the effectiveness of other immunotherapies besides nivolumab?

"The data is retrospective, and results should be taken with caution. [Currently], we are prospectively collecting blood samples from patients undergoing immunotherapy [who are either cannabis users or not] to better understand the specific influence on the immune system.

"The prospective trial is collecting data from all patients using immunotherapy drugs, [either] as single medications or in combination. The main difficulty of such a study is the heterogeneous population of the study and the unknown differences in the immune system we are looking for. So, [this research] probably will serve as a search for differences that will lead to proper laboratory study of the interaction.

"An interaction [with cannabis] is possible for all immunotherapy drugs and is not specific to nivolumab. As far as I know, there is no negative interaction with chemotherapy."

3. What should all practicing oncologists and cancer care providers know about your research and how cannabis use among their patients might be affecting treatments?

"According to basic studies, cannabis probably is immunosuppressed—and in this one study of retrospective data, there was a negative interaction with immunotherapy drugs. Personally, I give this information for patients who are on cannabis and starting immunotherapy or vise versa. I think it is important information for the patients to make the right decisions regarding their treatment.

"This information should be studied more. However, I think it is important for the patients now, not just in a year or two when the data from the prospective trial will be available."