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

Monday, March 27, 2017

With Eric J. Roeland, MD, Assistant Clinical Professor of Oncology at University of California, San Diego

By Sarah DiGiulio

When researchers tried delivering integrative palliative care treatment to a cohort of patients with incurable lung cancer and another cohort of patients with incurable gastrointestinal cancer, all of the patients' quality of life improved—but some more than others (J Clin Oncol 2016; doi: 10.1200/JCO.2016.70.5046).

The research highlights specifically which outcomes were better for which patients and what parts of that palliative care intervention worked best for each cohort. But the conclusion from the study illustrates a larger problem in the current delivery models of palliative care, Eric J. Roeland, MD, Assistant Clinical Professor of Oncology at University of California, San Diego, argues in an editorial about that research (J Clin Oncol 2016; doi: 10.1200/JCO.2016.71.2174).

"Palliative care requires a tailored approach to meet the dynamic and specific needs of each unique population of patients with cancer. Here, too, one size does not fit all," Roeland wrote.

And that tailored approach is not happening, he explained in a phone interview with Oncology Times. Roeland elaborated on why current models of palliative care delivery are not sufficing, not efficient, and not sustainable, as well as what he thinks would work better.

1. What's driving this focus on inpatient rather than outpatient palliative care?

"It's easier to organize this on the inpatient setting. The advantage of having a palliative care team see patients in the inpatient [setting] is that they're there—you can spend lots of time with them.

"Outpatient palliative care requires a lot of infrastructure and organization. And so, as an organization, am I going to devote time, space, and resources to organize appointments around [the patients'] other appointments—their infusions, their radiation, their surgery? Am I going to give palliative care teams clinic space? Frequently, palliative care teams are not seen as a core component of oncology care, but rather an add-on.

"So, until that shift occurs and it's seen that the palliative care appointment has equal value as the oncology appointment, there's going to be some major disconnect between the guidelines and what's recommended and what's actually happening day-to-day."

2. How does that shift happen? And what would you say is the bottom line that all oncology care providers should know about how to make that shift happen?

"The major issues here are culture. Culture takes decades. And if you talk to some of the founding members of the palliative care movement they would say where we are today is a night-and-day [difference] compared to where we were. But there's still a lot to move forward with.

"One of the remaining things is this idea that palliative care is end-of-life care and you wait until people are dying before you refer. The big issue is this cultural shift [that needs to happen] from doctors still equating palliative care with end-of-life care.

"What I would like to see is more collaboration and more interaction between palliative care and oncology in an era of personalized cancer therapies and immunotherapy. We have more to learn from each other—more opportunities to work together and do research together and improve quality of life and even survival of our patients.

"It shouldn't be like two rival gangs—we should all be working together here."

3. You make the argument in the editorial you wrote that current models of palliative care aren't working. What's wrong with palliative care delivery now?

"For people practicing oncology and palliative care, what we're up against are the very pragmatic issues about how we get it done. And I think one major opportunity is to really invest in outpatient palliative care.

"There's been immense focus and resources spent on inpatient palliative care, rather than outpatient. And there's been a steady growth over time with inpatient palliative care services. But the growth of outpatient care in the palliative setting has basically been 1 or 2 percent since 2000 to 2009, versus an increase in inpatient consults up to around 12 or 13 percent (J Natl Compr Canc Netw 2016;14:439-445).

"If you're constantly focusing on making sure palliative care touches and evaluates patients on the inpatient side, you're not going to shift culture. You're not going to shift the way that we're taking care of patients over time—and I would argue that the 'advanced care planning' that's done on the inpatient service is not advanced care planning. It's really point-of-care planning.

"Advanced care planning is a process that takes time and multiple discussions, and needs to be done in the outpatient setting with the people patients trust most, which are the oncologists and their oncology team.

"We need to build outpatient [palliative care] to try to avoid hospitalization [for patients] and try to encourage people to be planning for emergencies outside of an emergency."​

Friday, March 10, 2017

With Christopher Vellano, PhD, of The University of Texas MD Anderson Cancer Center

By Sarah DiGiulio​

Cervical cancer is responsible for more than 500,000 new cases of cancer and more than 250,000 deaths around the world every year, according to data from the International Agency for Research on Cancer (Int J Cancer 2014:136;E359-E386). A large majority of those tumors have been linked to HPV injection—but, importantly, not all cases.

A new study has identified a unique set of eight cervical cancers that are predominantly HPV-negative, characterized by mutations in the KRAS, ARID1A, and PTEN genes, and molecularly similar to endometrial cancers. The study was published online ahead of print in Nature (doi:10.1038/nature21386).

"Effective preventive vaccines against the most oncogenic forms of HPV have been available for a number of years, with vaccination having the long-term potential to reduce the number of cases of cervical cancer," noted NCI Acting Director Douglas Lowy, MD. "However, most women who will develop cervical cancer in the next couple of decades are already beyond the recommended age for vaccination and will not be protected by the vaccine," he continued. "Therefore, cervical cancer is still a disease in need of effective therapies, and this latest [from The Cancer Genome Atlas (TCGA)] analysis could help advance efforts to find drugs that target important elements of cervical cancer genomes in addition to the HPV genes."

For the study, TCGA researchers analyzed 178 primary cervical cancers. More than 70 percent of the tumors had genetic alterations in either the PI3K/MAPK or TGF-β signaling pathways, or both, suggesting the importance of targeting molecules within these pathways.

ERBB3, CASP8, HLA-A, SHKBP1, and TGFBR2 were all identified as significantly mutated genes for the first time in cervical cancer, with ERBB3 being a potential therapeutic target. And BCAR4 was found to be amplified in some cases.

The researchers also found nearly three-quarters of cervical cancers had genomic alterations in either one or both of the PI3K/MAPK and TGF-β signaling pathways. The findings are important because they could point to important new targets for therapies—especially at a time when immunotherapies are playing increasing roles in cancer therapy and effective targets are needed for therapies to work.

Study coauthor Christopher Vellano, PhD, Research Project Manager in the Department of Systems Biology at The University of Texas MD Anderson Cancer Center, Houston, explained further what the most important revelations from this study were—and why they are important.

1. What conclusions were made from this research that was previously unknown about the genetics of cervical cancers?

"There have been several other genomic studies [that] have analyzed fewer samples across fewer molecular platforms. Our study integrates DNA methylation, mutation, mRNA, miRNA, protein, pathway analysis, and HPV data to present a larger and broader molecular profile of cervical cancer subgroups.

"An important finding is the identification of HPV-negative cervical cancers—of which most can be characterized molecularly as endometrial-like with KRAS, ARID1A, and PTEN mutations. [Another] key finding in this study is that, although HPV is a significant player and present in 95 percent of cervical cancers, there are a small percentage of HPV-negative tumors that will need to be further studied.

"Our study highlights novel genomic alterations and key markers of cervical cancer subgroups and for the first time identifies SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel significantly mutated genes in cervical cancer."

2. In what ways might these findings affect the way cervical cancer is treated clinically?

"Genomic alterations in the PI3K/MAPK and TGF-β signaling pathways indicate the clinical potential of therapies targeting molecules in these pathways. Alterations in BCAR4 are therapeutically relevant given BCAR4 can be indirectly targeted by lapatinib.

"Amplifications in CD274/PD-L1 and PDCD1LG2/PD-L2 suggest that immunotherapies warrant evaluation in cervical cancer. In addition, genomic alterations in ERBB2 and ERBB3 within adenocarcinomas suggest [there is the] potential for treating this subgroup with HER2- and HER3-targeted therapies."

3. What is most important for practicing oncologists and cancer care providers to know about this research?

"Molecular analysis of patient samples will be important in guiding patients to the appropriate therapies, and we hope the results of this study will serve as a significant resource for clinical translation.

"More comprehensive studies will be needed to evaluate the characteristics and importance of the HPV-negative/endometrial-like cervical cancers. In addition, studies should validate therapeutic markers identified here as well as continue to identify new targets."

Tuesday, February 28, 2017

With Jonathan Kimmelman, PhD, Associate Professor at McGill University

By Sarah DiGiulio

Phase I clinical trials are an important step in the development of new anticancer therapies, Jonathan Kimmelman, PhD, Associate Professor in the Biomedical Ethics Unit/Social Studies of Medicine at McGill University, explains in a recent article in the Journal of Clinical Oncology (2017;35:135-138).

But, he adds: "The assertion that phase I trials offer a vehicle for pursuing cancer treatment (the 'therapeutic position') rests on weak evidence and has counterproductive implications for human protection. It also erodes the ability of oncologists to rigorously evaluate new treatments and support evidence-based practice."

His view: Phase I trials are primarily investigational.

The JCO article lays out the evidence where the 2015 policy statement from ASCO on the role of phase I clinical trials in cancer fall short (JCO 2015;33:278-284). And Kimmelman also makes a series of recommendations he says ASCO should use in their policy statement on the design and enrollment of phase I trials.

In an interview with Oncology Times, Kimmelman summed up the key points from his argument—and why defining and following the appropriate role for phase I clinical trials is so important.

1. What prompted you to write this article on phase I clinical trials now—and what are your topline reasons for disagreeing with ASCO's current policy statement?

"In 1997, ASCO issued a statement on the ethics and policy around phase I studies (JCO 1997;15:853-859). A lot of time passed before they updated that statement. And a lot has happened from 1997 to 2015—both in terms of the way phase I studies are done, which prompted the updating, but also in terms of the way people think about the ethics of phase I studies. And I was surprised at how little the updated version had kept apace with the thinking around the ethics of phase I cancer studies.

"The ASCO policy [holds the position that] phase I studies ought to be viewed as therapeutic endeavors for patients who enroll in them. And in a nutshell my response to that was—well—not exactly.

"A professional society like ASCO should state more clearly that these are primarily research endeavors, not therapeutic endeavors, and they ought to be out in front of the various ways that the implementation of phase I cancer studies could be improved.

"Some of the issues of implementation that I identify include a more proper and rigorous review of the preclinical evidence to support phase I studies. There has been a lot that's emerged in the last 10 years about the problems with the way people conduct and report preclinical studies that support phase I trials. We [could] do a lot with phase I studies by improving the way we do the preclinical studies to support them. And we could be improving the way we do consent in phase I studies, including explaining to patients that the prospect of major therapeutic benefit is highly improbable.

"To my knowledge, no one had done any kind of systematic review or meta-analysis of current phase I studies (in the past 5 years or so) to test the hypothesis that the risk-benefit analysis has actually shifted in a dramatic way. If it has shifted in a dramatic way, that's interesting—and could alter my analysis."

2. So what would you say is the role of phase I clinical cancer trials?

"The primary role of phase I studies...is to determine some basic safety features as well as dosing, and perhaps to identify promising indications or malignancies in which to advance a drug into efficacy testing.

"Here's the way an ethicist thinks about research and phase I studies: Every time you expose a patient to risk in the context of research, you want to make sure that risk is counterbalanced by some kind of benefit. And there's two different ways you can counterbalance that benefit. One is direct benefit: if the patient responds medically to an intervention that can purchase you some risk in a clinical trial. The other way is by appealing to the prospect of advancing medical science by producing information about whether a drug is promising and whether a drug ought to be developed. One benefits the patient directly; the other benefits society.

"What I have essentially argued is that when we think about risk in phase I cancer studies, we ought to be thinking about purchasing that risk with benefit to society (by learning something about the drug) as opposed to benefit to the subjects. We ought not to use the prospect of a patient benefitting as a way of justifying exposing them to the risk [of the trial].

"There can be exceptions, but we should not be presenting these [trials] to patients as therapeutic opportunities.

"There may very well be exceptional cases where phase I studies can and should be used as therapeutic endeavors—and it may very well be legitimate for some patients if they have been given proper information to regard their participation as a therapeutic opportunity for them."

3. What would you say is the bottom line that practicing oncologists and cancer care providers should know about this debate?

"The take-home message is that if you're an oncologist and if you want to refer a patient to a phase I cancer study or enroll them, you ought to present this to them as an opportunity to advance medical science—not as an opportunity to access cutting-edge therapies.

"And there is a lot we can be doing to improve the consent, design, and justification for phase I oncology studies."

Friday, February 10, 2017

With John P. O'Bryan, PhD, of University of Illinois College of Medicine

By Sarah DiGiulio

The RAS family of proteins is an attractive one—as far as cancer biologists are concerned. Mutations for genes in the RAS family are found in nearly 30 percent of all cancers. And they're highly prevalent in some of the most common cancers including colon, lung, and pancreatic cancer, as well as melanoma. Discovering or creating a drug to target RAS would be a big deal.

Now a group of researchers at the University of Illinois at Chicago say a new synthetic binding protein they created in the lab may put them one step toward that goal.

"Developing a RAS inhibitor has been the holy grail of cancer biology," noted John P. O'Bryan, PhD, Associate Professor of Pharmacology in the University of Illinois College of Medicine. "We did not look for a drug or specifically for an inhibitor," O'Bryan said about the new study from he and his colleagues.

"We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function."

In an interview with Oncology Times, O'Bryan further explained why his group decided to investigate monobodies and how they interact with RAS—and why these new findings put translational oncology one step closer to an effective RAS inhibitor.

1. What is new about the findings from this study?

"Our work revealed for the first time the importance of the α4-β6-α5 region of RAS for [RAS] function. Our studies found that an engineered protein called NS1 monobody binds that α4-β6-α5 interface on RAS and actually blocks RAS's oncogenic and signaling ability—which is quite surprising since it didn't seem to interfere with the ability of RAS to interact with its downstream targets. This new area potentially could be used as a way to therapeutically inhibit RAS in the future.

"Also, this work demonstrated for the first time that RAS actually interacts with itself to activate its downstream targets. And that's been a question in the literature for quite a few years now—how RAS activates its downstream targets. This research provides some of the first strong evidence that there is indeed RAS-RAS interaction that is important for activation of downstream effectors."​

2. What is the NS1 monobody and why did you decide to try using it to interfere with RAS instead of looking at another way of interfering with RAS?

"NS1 is a new [monobody]. Monobody techonology was actually developed by our collaborator Dr. Shohei Koide (who was previously at the university and a coauthor on this paper).

"So, monobodies are engineered proteins. They're much smaller than antibodies, which are very difficult to use within cells because of the reducing potential inside a cell. Monobodies in contrast lack disulfide bonds and are, therefore, resistant to the reducing environment of the cell. They're much easier to work with in terms of expressing them in cells and targeting them to your protein of interest. So they're much easier to genetically encode— to use as a way of targeting the pathway of interest, in this case RAS.

"We isolated a monobody that could specifically recognize RAS and it turned out that it actually inhibits RAS signaling and oncogenic activity. Monobodies have been around for a while, but this monobody to RAS is quite new and quite specific—and turned out to be very interesting in its ability to block RAS function."

3. What's the next step—how do you use this research to develop a drug that targets all these cancers with mutated RAS proteins?

"That's the million-dollar question. RAS is mutated in roughly 30 percent of human tumors. So we think it's a very important target for developing drugs that will block its function. RAS has not been a very good target for inhibiting because it's more like a little ball without very deep pockets that inhibitors typically like to sit in. So it's been very challenging to inhibit the protein with small molecules.

"There are RAS inhibitors that have been developed: small molecule inhibitors. But those have not proven very effective clinically. There are others that are being developed that target other areas of the protein. But no one has really targeted an interface at this point. So it raises the question of whether we can actually design novel inhibitors to this region that will block RAS function.

"The strategy that we're taking is to try to use the information that we know from how NS1 binds to RAS to see if we can exploit that for developing small molecules that bind in that same region and may then act as inhibitors to the protein. Such inhibitors would actually be more appealing than NS1 itself because—although [NS1] is small—in terms of a drug it's actually quite large. So it's difficult to deliver sufficient quantities into cells of a patient to inhibit RAS. Whereas if we can develop a small molecule that can more easily penetrate cells of tumors—that would be more likely to work as a therapy.

"In terms of time frame for that, with a little bit of luck, hopefully we'll have some in a few years. But that remains to be seen."

Wednesday, January 25, 2017

With Kirsten Ness, PT, PhD, of St. Jude's Department of Epidemiology and Cancer Control

By Sarah DiGiulio​

Long-term survivors of childhood cancers are living longer today than in years past—but long-term health status among survivors is not necessarily improving. Those are the findings from a new analysis of the Childhood Cancer Survivor Study (CCSS) published online ahead of print in the Annals of Internal Medicine (DOI:10.7326/M16-0742).

"Improved survival following a diagnosis of childhood cancer is one of the success stories of modern medicine," study co-author Kirsten Ness, PT, PhD, Faculty Member in the Department of Epidemiology and Cancer Control at St. Jude Children's Research Hospital, Memphis, Tenn., said in a statement. "Surprisingly, the data from [this] survey show a lack of improvement in perceived health status by childhood cancer survivors over the past 30 years, which serves as an important reminder that cures for cancer do not come without some consequences to patients."

This CCSS report includes data from 14,566 patients between 18 and 48. They were treated for childhood cancers (including both solid tumors and blood cancers) during three time periods: 1970 to 1979, 1980 to 1989, and 1990 to 1999. The results showed that survival rates increased in the cohort of survivors treated between 1990 and 1999 compared to the patients who were treated earlier. But there were higher rates of survivors in the most recent cohort reporting poor general health and anxiety.

Additionally, high-risk behaviors including smoking, heavy drinking, lack of exercise, or poor diet were associated with the cancer survivors who reported poorer health status.

Ness and the study coauthors note the worse health outcomes for the survivors treated most recently could in part be explained by those survivors living longer. But the data also suggest there is a lot of work to do in terms of follow-up care for cancer survivors.

1. Why look at this large cohort of thousands of childhood cancer survivors?

"The study was designed to evaluate late outcomes among survivors of childhood cancer with the goal of providing the foundation for interventions to prevent or remediate adverse health outcomes—and also to guide current therapies to minimize late effects. In the study, cancer survivors treated in the more recent era did not report better health outcomes."

2. Several studies have looked at long-term outcomes for survivors of childhood cancers—how are these findings new and/or different? What does this research add to what is currently known about childhood cancer survivors' outcomes?

"These data sets include survivors treated on protocols more similar to the protocols children are treated on today. We expected a lower percentage of survivors would report poor health outcomes—but this was not the case.

"These data sets extend findings from the CCSS into a new decade of survivors. Perceived health outcomes are still a problem for some survivors of pediatric cancers.

"[And] I think that emotional health outcomes are considered less often than others.

"We did report our findings by diagnostic groups here, [but] additional exploration of disease group specific outcomes where we can drill down to specific chronic conditions will be important."

3. What's the next step? What should practicing oncologists—and primary care providers who care for patients who are childhood cancer survivors—know about your findings?

"It is important for health care providers to be aware of some of the perceived health outcomes pediatric cancer survivors are reporting. For survivors, monitoring potential health outcomes is important—early management of pain and emotional health problems, tailored interventions to promote health-optimizing behaviors (diet and exercise), and minimizing risky health behaviors (smoking).

"The good news is the cure is achievable for over 80 percent of children with cancer. Childhood cancer survivors are vulnerable to adverse outcomes in terms of perceived health—they should be monitored and referred for appropriate services to address their needs. Survivors at greatest risk may benefit from intervention."