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

Wednesday, May 10, 2017

With Kostas Tsilidis, PhD, of Imperial College, London

By Sarah DiGiulio

Cancer researchers have long studied the link between obesity and cancer, but there is still a lot of uncertainty about what drives that link and for which cancers the link is the strongest. A new study has investigated the strength of the research supporting that connection between being overweight and developing or dying from cancer, finding a significant amount of evidence is low quality.

The new umbrella review analyzed 204 meta-analyses in total and found that 77 percent reported a statistically significant link between obesity and the incidence of or mortality from cancer (BMJ 2017;356:j477).

Yet, of 95 meta-analyses that investigated the link between continuous obesity measures and the risk of developing or dying from 36 different cancers (or cancer subtypes), only 12 of those analyses (13%) were supported by strong evidence. The other studies were found to either have highly suggestive (18%), suggestive (25%), weak (20%), or no (25%) evidence of an association between the obesity measures and cancer.

"This potentially makes excess body fat the second most important modifiable cancer risk factor after tobacco use," noted Yikyung Park, ScD, Associate Professor of Surgery, and Graham A. Colditz, DrPH, MD, MPH, Deputy Director of the Institute for Public Health, Chief of the Division of Public Health, and Professor of Surgery, both at Division of Public Health Sciences at Washington University School of Medicine (BMJ 2017;356:j908).

The evidence suggests that better data on the link between being overweight and cancer risk is needed, the authors of the umbrella review concluded.

"As obesity becomes one of the greatest public health problems worldwide, evidence of the strength of the association between obesity and cancer may allow finer selection of people at high risk, who could be selected for personalized primary and secondary prevention strategies," the researchers noted in the original paper.

Study co-author Kostas Tsilidis, PhD, Senior Lecturer in Cancer Epidemiology in the Department of Epidemiology and Biostatistics within the School of Public Health on the Faculty of Medicine of Imperial College, London, explained more about what the data showed and what additional research in this area is needed.

1. Cancer researchers have been talking about the link between cancer and obesity for a long time. What does this new review you and your colleagues published in BMJ add to what is known about this link?

"These findings are complementary to what we already know about obesity and cancer risk. Obesity leads to lots of disruption of hormonal and metabolic pathways. Excess fat has been linked to higher estrogen levels, higher insulin levels, and increased inflammation, all of which can affect cell division, but different cancers may be more or less susceptible to the aforementioned mechanisms.

"We found that strong evidence supports the association between obesity and 11 cancers (esophagus, stomach, colon, rectum, biliary tract system, pancreas, breast, endometrial, ovary, kidney, and bone marrow). There could be associations between obesity and other cancers, but substantial uncertainty remains in the biomedical literature. These findings are important because cancer is a leading cause of death worldwide, and the prevalence of obesity has more than doubled over the past 40 years."

2. Where are the most urgent gaps—and what additional research is most important in terms of better understanding the link between obesity and cancer? And what are the challenges standing in the way of that research?

"Future large prospective observational studies and consortia thereof with better assessment of the dynamic nature of body fatness could assist in complementing the current literature evidence. But, since we need to start acting to reduce the obesity epidemic, we especially need better research to evaluate potential effective guidelines and public health interventions for weight management in children and adults.

"Randomized controlled trials of potential weight management interventions will be expensive. It also would be difficult to identify effective interventions with weight management results that are sustainable. Working with children and their parents is also challenging, but it is paramount to evaluate weight management programs at young ages."

3. There are a few conclusions that can be drawn from this research. What is most important for oncologists and oncology care providers (and everyone) to know about this work and the findings from this large-scale analysis?

"Strong evidence supported the association between obesity and 11 cancers. We should probably start to seriously act to reverse the obesity epidemic."​

Tuesday, April 25, 2017

With Joanne Elena, PhD, MPH, at the Clinical & Translational Epidemiology Branch of the Division of Cancer Control and Population Sciences at NCI

By Sarah DiGiulio

African-Americans experience disproportionately higher rates of cancer than other racial and ethnic groups in the U.S. They are more likely to be diagnosed with more advanced cancers. And they experience higher cancer mortality rates than other groups. Yet, African-Americans continue to be underrepresented in cancer clinical trials (J Oncol Pract 2013;9:267-276).

Now researchers are taking a new approach to better understand these disparities. The NCI is launching the Detroit Research on Cancer Survivors (ROCS) study, which will follow 5,560 African-American cancer survivors (the largest ever single study of this patient population), which will look at several of the major factors that affect cancer progression, recurrence, mortality, and quality of life among these survivors. The Detroit ROCS study will focus on patients with the four most common cancers—lung, breast, prostate, and colorectal—each of which is marked by poorer survival among African-Americans than whites.

"This study is uniquely poised to investigate the major factors affecting African-American cancer survivors," Douglas R. Lowy, MD, NCI's Acting Director, said in a statement. "Efforts like this will help us move toward bridging the gap of cancer disparities, ensuring that advances in cancer prevention, diagnosis, and treatment reach all Americans."

The project is being funded by a 5-year, $9 million grant from NCI that has been awarded to Ann G. Schwartz, PhD, MPH, Deputy Center Director at NCI, and Terrance Albrecht, PhD, Associate Director for Population Sciences of the Wayne State University School of Medicine and the Karmanos Cancer Institute in Detroit.

The study will include data collected in interviews with the patients from medical records and biospecimens from the patients. The researchers are currently identifying African-Americans in the Detroit area who have recently been diagnosed with one of the four cancers using the population-based cancer registry and enrolling patients in the trial.

Joanne Elena, PhD, MPH, Program Director of the Clinical and Translational Epidemiology Branch in the Division of Cancer Control and Population Sciences at NCI, who is overseeing the grant, explained why this study is so significant—and why it will help.

1. Could you explain how this study came about and how it's different than other studies that investigated cancer disparities?

"The investigators have been working with the Detroit community for many years and wanted to better understand the factors affecting the poorer outcomes observed in African-American cancer survivors.

There are common threads of this study throughout their scientific careers and they have been developing this specific study for more than 5 years.

"There are other studies that examine many of the same factors in cancer survivors, but none with this number of African-American cancer survivors. For example, there are studies that follow breast cancer or colon cancer survivors and ask about many of the same factors here. However, I am not aware of any that also include family members to understand how a cancer diagnosis affects the family as well as the person diagnosed with cancer."

2. There are often calls for more diversity in clinical trials. Even though African-Americans have been historically underrepresented in research, what is the advantage of doing a trial with only African-Americans (versus a larger trial that includes a more equally racially diverse sample)?

"This an observational study—meaning all participants are reporting back information to the study, but living and making their own decisions. Whereas, a clinical trial will randomize the participants into two groups—one who receives an intervention and a second group who doesn't—and then compares the outcomes.

"There are merits to both approaches—studying any group on its own or having a diverse population to compare results based on race. The NCI funds studies of both designs to get a more complete understanding of the factors affecting cancers for people of all races/ethnicities. In this case, Detroit ROCS [will collect] a large variety of comprehensive data from their participants and follow them over time. By focusing on African-Americans, this study ensures they capture the factors that are specifically affecting this population in sufficient depth."

3. How would you sum up the main questions you hope this trial will answer?

"How social, behavioral, biological, and environmental factors affect the health of cancer survivors—including how the cancer progresses, whether it recurs, and [what is] the quality of life. Adding family members to the study will also help us better understand how cancer affects the well-being of those caring for the survivor as well.

"This study is important not only because it is the largest study of African-American cancer survivors in the U.S. to date, but also because it will help us understand the myriad factors that affect cancer survivors—including treatment, genetics, type of social support, neighborhood context, poverty, stress, racial discrimination, literacy, quality of life, and behavioral factors such as smoking, alcohol use, diet, and physical activity."

Monday, April 10, 2017

With Francisco M. Marty, MD, of Harvard Medical School, Dana-Farber Cancer Institute, and Brigham and Women's Hospital

By Sarah DiGiulio

Cytomegalovirus (CMV) infection is the most common viral infection in patients who undergo allogeneic hematopoietic stem cell transplant—and it is associated with higher rates of mortality, even when currently available preemptive antiviral therapies are used (Blood 2016:127;2427-2438).

But researchers have been developing a new drug they hope will be more effective in preventing CMV infection in transplant patients. New phase III trial data shows the drug—letermovir—was associated with lower all-cause mortality in patients 6 months after they had undergone stem cell transplant.

Results from the study were presented in February at the Bone Marrow Transplant Tandem Meetings (the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation) (Abstract LB2).

The study included 565 patients who underwent allogeneic stem cell transplant and were not viremic with CMV at the start of the study. The efficacy analysis included 325 patients who had undergone allogeneic hematopoietic stem cell transplant who were CMV-seropositive and received the new drug, letermovir—and 170 patients who had undergone transplant, were CMV-seropositive, and received a placebo.

The patients receiving letermovir had minimal toxicity to the drug. Significantly fewer patients developed clinically significant CMV infections (or died or left the study for other reasons) who had received letermovir (37.5%) compared with the patients who had received the placebo (60.6%). And the data found a 9.8 percent all-cause mortality rate after 6 months for the patients receiving letermovir, compared with a 15.9 percent mortality rate for patients who received the placebo.

These results show letermovir is a highly-effective drug, said study author Francisco M. Marty, MD, Associate Professor of Medicine at Harvard Medical School and attending physician in Transplant and Oncology Infectious Diseases at Dana-Farber Cancer Institute and Brigham and Women's

Hospital, Boston. In an interview with Oncology Times, Marty elaborated on why this new drug and these recent findings are important.

1. Why are the results of this trial significant and what does it mean for managing patients who undergo bone marrow transplant?

"For the first time in nearly 30 years, we have a potent, reliable, and safer anti-CMV antiviral we can use to prevent CMV reactivation after transplant and protect patients when they are the most susceptible to

CMV infection. Available antivirals to date are consistently myelosuppressive or nephrotoxic.

"A primary prophylaxis strategy early after bone marrow transplantation had been attempted in previous trials, but was never implemented because any benefits were offset by the side effects of the drugs and their consequences. This trial confirmed letermovir was not myelosuppressive at all—and there was not nephrotoxicity associated with its use.

"Not only did letermovir protect patients from developing CMV infection who require preemptive treatment, but the prophylactic strategy led to lower all-cause mortality when patients were followed for 24 weeks post-transplant. So, a strategy of primary prophylaxis posttransplant seems to be better than our current standard and suggests for the first time that the survival disadvantage of patients who are CMV-seropositive at the time of transplant can be abrogated."

2. How is letermovir different than other drugs that try to prevent CMV infections?

"Mechanistically, letermovir targets a different process in the replication of CMV by blocking the activity of the terminase complex that is in charge of cutting the CMV genomes being synthesized and packaging into the preformed virus capsids.

"The current standard approach to preventing CMV disease consists of preemptive therapy in which weekly surveillance with blood CMV testing by PCR or other methods is linked to antiviral treatment against CMV. The strategy has been successful in terms of preventing clinical CMV endorgan damage, but we have confirmation from large, recent cohort studies that patients who go into bone marrow transplantation having had CMV infection pre-transplant (being CMV-seropositive) fair worse in terms of all-cause mortality compared to patients in the same circumstances who have not been infected with CMV pre-transplant (CMV-seronegative).

"Letermovir is not myelosuppressive or nephrotoxic. We did observe some mild increases over placebo (≤5%) in terms of vomiting, nausea, peripheral edema, headaches, and atrial arrhythmias, but they were rarely serious or led to discontinuation of treatment."

3. The drug is currently being submitted to the FDA for regulatory approval. Are any trials still in the works? And what else should doctors who treat patients who undergo stem cell transplant know about the drug?

"There will be a comparative trial of prophylaxis in patients undergoing certain solid organ transplants to further assess the benefits of letermovir in other transplant populations. I hope the drug can be tested soon in children who undergo transplantation and in children affected by CMV early in life.

"This phase III trial demonstrates that letermovir is a highly-effective prophylaxis in the prevention of CMV reactivation after HCT in patients who are CMV-seropositive and had an overall favorable safety profile. The treatment differences were more pronounced in most patients at higher risk of CMV disease and associated with a lower all-cause mortality suggesting that for the first time we may be able to better tame the 'troll of transplantation' in this patient population."​

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."