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Tuesday, July 21, 2015

With Carlo Gambacorti-Passerini, MD, of University of Milano Bicocca


“Imatinib mesylate changed the prognosis for chronic myeloid leukemia (CML) so dramatically that patients with newly diagnosed CML starting treatment with imatinib now have a normal life expectancy, compared with the historical median survival of 2 to 3 years. In addition to its outstanding therapeutic activity, imatinib possesses a remarkably safe profile.”


So writes Carlo Gambacorti-Passerini, MD, Professor of Hematology and Director of the Clinical Research Unit at the University of Milano Bicocca—with coauthor Rocco Piazza, MD, PhD, also of the University of Milano-Bicocca—in a recent “Viewpoint” editorial in JAMA Oncology (2015;1:143-144).


In a phone interview Gambacorti-Passerini noted that the article is particularly timely given that generic imatinib is set to be available in the U.S. in 2016—which will make the drug available to patients in the U.S. at a fraction of the cost of the branded product (Gleevec, manufactured by Novatis). Generic versions of imatinib have been available in Canada and South Korea since 2013, costing 10 to 25 percent of the branded product.


The coauthors succinctly summarize the argument why imatinib should remain the first choice for first-line treatment for patients with newly diagnosed CML, as well as why second- and third-generation tyrosine kinase inhibitors (TKIs)—developed primarily for second- and third-line use—are best suited for that purpose.


“Bosutinib monohydrate, dasatinib, nilotinib, and ponatinib hydrochloride constitute a set of formidable ‘spare wheels’ for patients whose imatinib treatment fails, giving a viable option to more than 50 percent of them,” the article states. But the Gambacorti-Passerini and Piazza go on to explain why the evidence does not quite support those drugs as a replacement for imatinib.


“If obtaining ‘faster and deeper’ responses using second-generation TKIs does not convert into a better prognosis, then this phenomenon should not dictate a change in therapy by itself,” they write, adding: “The safety profiles of these drugs are also a matter of debate.”


Gambacorti-Passerini summed up the bottom line from the editorial for OT, and commented on his recent work that suggest there is a subset of CML patients who can safely discontinue TKI treatment, published online ahead of print (Amer J Hem DOI: 10.1002/ajh.24120).


1. What is your key message about imatinib?

“Imatinib is definitely the safest inhibitor around in terms of long-term toxicity—and as active as any other TKI in the setting of first-line use. So, in my opinion, there is no scientific, clinical reason for using second-generation TKIs as frontline treatment. Imatinib remains, as the title indicates, the first-line TKI of choice for treating newly-diagnosed CML patients. And we need to in every object way try not to be biased for economic reasons.


“Other hematologists have different opinions on the topic, which is quite hot—as one can imagine.”


2. What would you say are the key points about the findings you recently published on safely discontinuing imatinib treatment for some patients with CML?

“Number one, imatinib can be safely discontinued in real-world scenarios [in some patients], assuming that close monitoring is guaranteed.


“Number two, the risk of relapse is linked to both the age of the patient and the result of the digital PCR test—being old lowers the risk of relapse.


“And third, even for patients who did not relapse and for the most part show at least some PCR positivity after discontinuation [of imatinib], this positivity does not seem to be growing as you would expect from leukemic cells.


“So our study suggests the patient who is at the lower risk of relapse is the patient who is older (approximately 45 and older) with a negative digital PCR.”


3. Are the findings conclusive enough to suggest clinicians should change practice for these patients?

“As for any study, these data need to be confirmed. Though our study is one of the biggest studies performed so far. We had 112 patients enrolled in the study.”

Tuesday, May 05, 2015


With DOUGLAS LOWY, MD, NCI Acting Director



Douglas Lowy, MD, became Acting Director of the National Cancer Institute on April 1 after serving as NCI’s Deputy Director since July 2010. The NCI’s previous Director, Harold Varmus, MD, stepped down from the role to become the Lewis Thomas University Professor of Medicine at Weill Cornell Medical College (OT 4/10/15 issue). Lowy is also a member of the National Academy of Sciences, as well as the Institutes of Medicine of the NAS.


“We are fortunate to have a scientist of such stature stepping into the role of Acting Director of the NCI,” National Institutes of Health Director Francis S. Collins, MD, PhD, said in a news release. “Dr. Lowy possesses not only a sharp intellect, deep knowledge of science, and proven leadership experience, but he takes a warm and humane approach to all things. He is superbly positioned to lead the NCI at a time of exceptional progress in cancer research.”


Lowy has more than four decades of experience as a cancer researcher under his belt. He received the National Medal of Technology and Innovation from President Obama in 2014 for his work on the biology of papillomavirus and the regulation of normal and neoplastic growth that led to the development of the human papillomavirus vaccine. His laboratory was involved in the initial development, characterization, and clinical testing of the preventive virus-like particle-based HPV vaccines that are now used in the three FDA-approved HPV vaccines.


Lowy is also involved in research that focuses on cancer genes, including investigating the DLC1 tumor suppressor, which encodes a Rho-GAP that is down-regulated in a variety of cancers, leading to the high Rho activity seen in many advanced cancers. His research has identified key scaffold functions for DLC1, including protein-protein interactions and phosphorylations, which contribute to the regulation of its activity and its role as a tumor suppressor.


In a phone interview in April, Lowy spoke to OT about the current fiscal climate at the NCI now and what’s ahead for the Institute, as well as for his own research.


1. The NCI has seen a particularly tight fiscal climate in recent years. How does this affect your new job?

“Our budget has been flat or reduced for close to 10 years. And the budget this year is more than $150 million lower than it was five years ago.


“That is a challenge because there are enormous opportunities in cancer research to make progress from the most applied research to the most basic research—and everything in between. So, we run out of money long before we run out of good ideas to test. It is challenging to try to make the strategic decisions [that need to be made] when there are so many competing meritorious opportunities. But that’s basically what we need to do.


“One way we are trying to help researchers be able to feel more confident and comfortable with their funding situation is the Outstanding Investigator Award. Instead of being for five years, as are most of our major grants, this award is for seven years and it’s for a larger amount of money than most of our research awards. It gives the recipient the opportunity, we hope, to be able to take risks and to test important problems that otherwise might be more difficult for them to do because of the funding situation and continually needing to apply for grants.


“Also, the President’s budget for the 2016 fiscal year proposes a 2.9 percent increase for the NCI; and if that proposed budget is passed it will be easier for us to do more.


“And I certainly will advocate for that.”


2. What are the biggest opportunities for the NCI in terms of areas of research to pursue?

“I see four deep opportunities. One is the Precision Medicine Initiative, which has been proposed for fiscal year 2016 as part of the President’s budget proposal. That initiative aims to change the paradigm for more patients to better understand the molecular abnormalities in their cancer and better tailor treatments to those molecular abnormalities. The initiative has several components—adult cancer clinical trials, pediatric cancer clinical trials, an effort to overcome targeted drug resistance, and the building of a knowledge system to support precision medicine.


“Another important area is cancer prevention and screening. Many of the same principles can be applied, in terms of what we understand about the causes of cancer and how cancer comes about, to enable us to be more strategic and more effective in our interventions for cancer prevention and cancer screening.


“And we also have a serious problem with cancer health disparities. It’s very important for us to try to understand where these disparities are—we need to understand the biological role, the lifestyle role, and the role of health care access and utilization. And we need to understand how those [factors] come together to lead to imbalances, and what can be done to reduce these imbalances to improve outcomes for all populations.


“And we want to strongly support basic research—because many of the breakthroughs that will help us in the years ahead will come from that basic research.”


3. You have a very noteworthy research career of your own. Are you able to continue with your own research while taking on these new leadership roles?

“Yes, I was able to continue doing research as Deputy Director, and I anticipate continuing my research activities [in the new role]. My degree of involvement was certainly not what it was when I did not have the responsibilities as Deputy Director, and my degree of involvement now will need to be even less, but that doesn’t mean that I won’t be involved.


“Research really is integral to what I do, and also to what the NIH does and to what the NCI does. And I think having first-hand experience of doing has benefits.


“Though if you are asking me: am I going to go to lab meetings when I should otherwise be testifying in front of Congress? I will be testifying in front of Congress.


“I’m very fortunate that the people that I work with in the lab are outstanding and extraordinarily supportive. I expect that I will continue [my research], as long as my site visits reports continue to be positive.”

Monday, April 27, 2015

With SANDRA SPOELSTRA, PHD, RN, Assistant Professor at Michigan State University College of Nursing



ORLANDO, Fla.—Oral anticancer agents are increasingly playing a growing role in oncology treatments, but the problem is that research consistently shows that patient adherence to those drug regimens is less than 80 percent, Sandra Spoelstra, PhD, RN, Assistant Professor at Michigan State University College of Nursing, said delivering the 2015 Victoria Mock New Investigator Award lecture here at the Oncology Nursing Society Annual Congress. “And we don’t know what the outcomes are for those agents if the recommended doses and schedules are not followed.”


ONS’s Victoria Mock New Investigator Award recognizes contributions of new investigators in building a scientific foundation for oncology nursing practice. Spoelstra’s work has focused on issues related to oral anti-cancer symptom and adherence management, including recent studies on: determining symptom severity from side effects of prescribed oral agents; patient preferences in regards to symptom management; and, most recently, a text message intervention for symptom management and adherence to oral agents.


Spoelstra presented two Podium Session Abstracts here at Congress on the topic—“Assessment and Measurement of Medication Adherence: ONS Putting Evidence Into Practice (PEP) Oral Anti-Cancer Agents” and “ONS PEP: Evidence-Based Interventions for Oral Anti-Cancer Agents.” Both studies evaluated current ONS PEP recommendations and will be published in the Clinical Journal of Oncology Nursing in June, Spoelstra said.


Why does she say mHealth is the solution? And why a text message intervention? Because people use cell phones in their daily lives—and making the intervention part of patients’ daily lives is key to a successful intervention, she explained.


In an interview after the lecture, Spoelstra shared these thoughts about why she says using mHealth to tackle the problems of oral drug symptom management and adherence is working—and why she is urging more nurses to publish their work on the topic.


1. Why would you say mHealth could play a major role in the solution to the problem of oral anti-cancer agent adherence and symptom management? Why has the text message intervention been successful?


“A lot of interventions are about trying to do something to patients—but the solutions need to be about helping patients do it for themselves. This is the lesson I’ve learned as a caregiver. I train all the people I care for to manage their own care. It’s about self-intervention. It’s a different approach—it comes from the person—it’s patient-centered.


“And that’s what the text message intervention is about. It engages patients to participate. And it delivers their care into their normal flow of activities of daily living. And attaching it to daily living—I think—is key.”


2. Based on your review of the current research, you talked about a need for more evidence? What are the gaps?


“We just finished our review of the evidence [for the ONS PEP resource] on medication adherence. We found that not a lot [of the interventions in the literature] were effective. That’s why I’m calling for people to publish their protocols so we understand what’s going on in trials. Maybe something worked, but it’s not widely disseminated. And I think a lot of projects start not with the person, but trying to fix the system.”


3. What do you mean by “trying to fix the system”? How does an intervention start with the person?


“Many interventions are focused on provision of patient education in traditional health care settings (i.e., hospitals or cancer clinics) and do not seem to focus on the individualized needs of cancer patients and how they can fit interventions naturally into their daily life.


“For example, often nurses tell patients take your pill at 9am, instead of asking, ‘What do you do once a day, that you can attach your medication taking to so that you can automatically remember to take your pill?’ This approach allows the patients to problem solve themselves, and to find a way to fit the pill taking into daily life successfully.


“All cancer patients and their caregivers need to understand how to conduct self-assessments—and be able to determine which symptoms they can self-manage and when they need to seek help from a clinician. This is what they need to do every day at home to be able to manage their cancer care.”

Monday, March 09, 2015

With Chuck Perou, PhD, Professor of Genetics and Pathology at UNC Lineberger Comprehensive Cancer Center


Is genomic analysis a better way of categorizing a tumor than its tissue of origin? For some patients, yes—according to new research that proposes a new way to classify cancer that could more accurately predict clinical outcomes for certain subsets of patients.


A study of 3,527 cancer specimens from The Cancer Genome Atlas that came from 12 tumor types, were classified by researchers into 11 major subtypes based on their molecular characteristics (Cell 2014;158:929-944). And for approximately 10 percent of those patients, the clinical outcome predicted by the molecular reclassification was significantly more accurate than the clinical outcome predicted by the original tissue-of-origin classification—even when considering all the previous clinical knowledge.


“Ten to 20 percent of patients may be having their tumors misclassified and hence may not be getting the optimal treatment,” study co-author Chuck Perou, PhD, Professor of Genetics and Pathology and University of North Carolina School of Medicine Breast Cancer Program Leader, both at UNC Lineberger Comprehensive Cancer Center, explained in a phone interview.



Five genome-wide platforms and one proteomic platform were used to analyze the specimens: whole-exome DNA sequence, DNA copy-number variation, DNA methylation, genome-wide mRNA levels, microRNA levels, and protein levels for 131 proteins and/or phosphorylated proteins. And to investigate the clinical relevance of the new subtypes, a Kaplan-Meier Survival analysis was performed on the samples and showed that both the conventional tissue-of-origin and new genomic categorizations were both prognostic and provided independent information.


The key findings:

·         The integrated multiplatform analysis of the samples provided independent and clinically relevant prognostic information above and beyond tumor stage and primary tissue-of-origin; and

·         One in ten cancer patients would be classified differently by this new molecular taxonomy versus the current tissue-of-origin tumor classification and if used to guide therapeutic decisions, this reclassification would affect a significant number of patients to be considered for nonstandard treatment regimens.


The research by Perou and his colleagues was selected earlier this year for inclusion in the American Society of Clinical Oncology’s Clinical Cancer Advances 2015 report, which documents important progress being made in clinical cancer research and highlights emerging trends in the field (OT 2/25/15 issue).


More on how the researchers analyzed the data and determined the new classification system, as well as how the 12 conventional tumor types fit into those new subtypes is detailed in the paper. Meanwhile, we asked Perou about how these findings can and will affect clinical practice—and if such a system is ready for prime time.


1. Could you elaborate on why this research is significant? How do the findings relate to drug development, cancer diagnosis, and prevention?

“It’s going to help all of those things. This is a valuable method of classification—and potentially very reproducible and accurate. It is a first and critical step toward personalized medicine.


“By using these many technologies, we now know the common genetic mutations that occur in each of these disease groups. We can try to partner each of these disease groups with the drugs that target these common mutations and the common pathways that are altered within them.


“This [research] holds the promise of being the new foundation of personalized medicine that not only includes just DNA sequencing, but also utilizes gene expression and other means of looking at the DNA as well—providing a link between the many different available technologies, and more importantly, many different parts of the tumor. A prime example is the immune system. There have been some extremely exciting advances in the treatment of melanoma by targeting the immune system, not the tumor cells. And as part of our classification you could also see that certain of these molecularly-defined tumor subtypes had close correlations with the presence or absence of immune cells.


“This [reclassification] gives us a more complete picture of each of these types of cancer. And that’s really going to be important for optimal therapeutic targeting.”


2. Is this new molecular taxonomy ready for prime time?

“Whenever you discover something in the laboratory it takes a few years to get it to the clinic because it needs further validation and further testing. Some of the differences in classification between sites of tumor origin versus the molecular classification were known previously and are being tested prospectively in clinical trials—so, on that level we’re already doing some of this clinical validation work.


“There are some barriers, including cost, because we’re using five technologies [to analyze each cancer cell] instead of one. But costs are coming down and I think (and hope) that in a few years we will more often be using these types of ‘multi-analytic’ molecular tests because they are improving patient care by finding these more homogenous, biologically-related disease groups.


“This paper really sort of puts many individual studies together into one big study and I do think it suggests we should be re-evaluating cancer patients’ classification based on this new scheme—and we’re going to try to make it happen.”


3. What’s the next step?

“There’s two ways to do this more rigorous validation research. One is to actually do prospective clinical trials where you test the new biomarker versus the standard of care to see if it improves patient outcomes. That’s expensive, though, because you have to run brand new clinical trials.


“A more intermediate approach is to retrospectively analyze existing clinical studies—if those studies collected tumor specimens. Many of those patients’ outcomes are already known. So you can apply your patient predictor in a predetermined manner—i.e. you can pretend the study was run in a prospective manner and you get a result much quicker.


“Many of these genomic assays are currently being tested in this retrospective manner and there are also some prospective studies being planned for some of the DNA-based markers.”

Wednesday, December 10, 2014

With TATIANA M. PROWELL, MD, Breast Cancer Scientific Lead of the FDA’s Division of Oncology Products 1, and LAURA J. VAN ‘T VEER, PHD, Director of Applied Genomics at UCSF Helen Diller Family Comprehensive Cancer Center



SAN ANTONIO—There are certainly opportunities—some already underway—for successful registration of novel-novel biomarker-specific drug combinations and novel companion diagnostics for specific subsets of patients with breast cancer, Laura J. van’t Veer, PhD, of UCSF’s Helen Diller Family Comprehensive Cancer Center, said in an interview after moderating a session on the topic here at the 2014 San Antonio Breast Cancer Symposium. But, a key point [Ed: and challenge!], she said: “To make it all really work, we need more collaboration across countries—and across continents—to actually provide the regulatory path for drug approvals.”




Van’t Veer serves as Professor of Laboratory Medicine, Angela and Shu Kai Chan Endowed Chair in Cancer Research, Director of Applied Genomics, and Program Leader of Breast Oncology all at UCSF HDFCCC. And the panel she led also included Tatiana Prowell, MD, Breast Cancer Scientific Lead in the U.S. Food and Drug Administration’s Division of Oncology Products 1 and Assistant Professor of Oncology in the Breast Cancer Program at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, as well as Jan H.M. Schellens, MD, PhD, of The Netherlands Cancer Institute, providing an international perspective on the topic, and Eric H. Rubin, MD, of Merck & Co., providing the pharmaceutical perspective.


In an interview after the session, Prowell and van’t Veer summarized the key messages discussed and why collaborations—both domestic and internationally—are so important. They also commented on whether (and how) such cooperation is possible.


1. First, why are biomarker-specific drugs relevant in breast cancer—and important?

Prowell: “Despite success in certain disease subsets—for example HER2 positive breast cancer—we should not assume ‘problem solved.’ Clearly there are subsets of patients for whom current treatments don’t work, or they don’t work very long. It’s very important for us not to get complacent.  




“As we gain a better understanding of biomarkers and more widespread use of platforms that can test for multiple biomarkers efficiently, we’re likely to see more progress for those very small subsets of patients who may constitute only one or two percent of the overall drug population. Those populations have the opportunity to benefit greatly if an appropriately targeted treatment is found.


“For example in lung cancer look at crizotinib, which for the four percent (or so) of patients who have an ALK-positive lung cancer—and likewise for the only one or two percent of lung cancer who have ROS1-rearranged lung cancer—that drug has quite a high response rate. So I think it’s important for us not to get complacent in breast cancer subtypes where it seems like we’ve made a great deal of progress.”


2. The session was about international collaborations. Why is that cooperation such a big part of getting these drugs developed?

van’t Veer: “I have spent most of my career in the Netherlands, but have now moved the U.S. to San Francisco—so I sort of understand both worlds. What I’ve been observing over the last year and a half is that the global collaboration is taking off immensely because everybody understands that if you screen 10,000 breast cancer patients, you’ll find 400 with a particular characteristic to be able to put in a trial. No one institution will be able to do that. So collaboration is the only way to move this forward, particularly in breast cancer where biomarker subtypes become very small groups—ER-positive, HER2-positive, HER2-negative, and all the subgroups under those.”


P: “We really need to do this globally. Even if you had unlimited resources, it’s just impractical for multiple different groups to be screening 10,000 patients simultaneously over and over. For example, you may have five clinical trials using anti-PD1 or anti-PDL1 agents at a given institution and patients are being individually screened for each trial. Reducing redundancy—the need to do so—is a key message that should come away from this session, not only from country to country, but also company to company.”


3. Is that type of global cooperation feasible? Who is responsible? What are some of the next steps?

P: “What everyone would like to see accomplished, whether they are patients, clinicians, or a pharmaceutical company—we all want better drugs for patients. People may come at it from a different angle—the patient wants access to more treatment options or more effective or less toxic therapy. Clinicians want a longer menu of options they can offer to patients. Pharma is looking to capitalize on the R&D dollars that they put in and make a profit. The bottom line is that in order for any of those things to happen, you need the drug to get approved. So I think regulators are in a unique position to bring everyone to the table. And increasingly I think our FDA Office of Oncology and Hematology Products is taking a very much more proactive role than was the case certainly even five or ten years ago.


“One critical step: patients and clinicians should be aware that it is possible for patients to access investigational agents outside of a trial—both in the U.S. and abroad. There is a relatively straightforward process to do this and the FDA is looking to streamline that process even more so that we increase patient access to compassionate use programs and ensure greater levels of equity in terms of patients who are able to access those drugs in that setting.


“Another opportunity [in addition to streamlining that process of accessing compassionate use programs] would be requiring clinicians to report how those patients [in those programs] did in a public fashion. We have so much data that gets collected that never gets reported or never gets shared or doesn’t get shared broadly enough—and that’s just a lost opportunity. We need to make full use of the data that we have.”

About this Blog

Sarah DiGiulio

SARAH DIGIULIO, Associate Editor of Oncology Times, asks oncology’s thought leaders for their perspectives and takes on the field’s current news and controversies.

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