Shannon Connelly

When treating older patients with breast cancer cancer, one approach does not necessarily fit each patient, explained Arti Hurria, M.D.

“Treatment needs to be individualized for an older adult. A part of that process is knowing the data within oncology, but also the other part is knowing the data within geriatric oncology. That data being such that it can help you to individualize those treatment decisions. A key point is that to make a treatment decision with an older adult, you have to weigh not only what the benefits are, but also the potential risks of treatment,” said Hurria, who spoke on the topic during the 16th Annual International Congress on the Future of Breast Cancer.

Can you provide an overview of the treatment needs for older women with breast cancer?/strong>

What are some of the factors physicians should consider with older patients?

Is there a specific treatment or regimen that you prefer for older patients?

What are the main challenges when treating older patients?

Are there any ongoing trials in which you think the older population is well represented?

What do you envision the future of this space will look like?

, Hurria, director of the Cancer and Aging Research Program at City of Hope, discussed the unique challenges with treating elderly patients with breast cancer and the exciting opportunities she envisions for advancing care in this setting.

What I talked about was how you make a treatment decision for an older adult with breast cancer and the factors that you should consider in that treatment decision-making process. We talked about what the data is regarding treatment for older adults with breast cancer and then brought in some of the data from geriatrics in order to think about that decision-making process with that older adult.

The idea is that the aging process is very heterogeneous, so there is a real difference between chronological age and functional age as an individual gets older. Hence, there could be two 80-year-old individuals who are very different and who have very different functional statuses and other medical problems. All of that needs to be taken into account when you’re making that treatment decision. The idea is that if you can incorporate the principals of geriatrics into your oncologic care, you’ll be able to understand an individual’s functional age in comparison to their chronological age and utilize that when you’re making a treatment decision.

It completely depends upon many different factors, but one has to be how aggressive the tumor is. Also, when we’re devising a treatment regimen for an older adult, it’s important to think about the side effects. If an older adult has pre-existing neuropathy, we’re very careful about taxanes. If they have pre-existing cardiac disease, we think about caution with anthracycline-based regimens. It’s taking into account what their other medical problems are and then coming up with an individualized treatment plan for that patient. 

The main challenge that we face is that older adults have been underrepresented in clinical research, in particular, the FDA registration trials. The studies lead to the approval of drugs and inform the package insert of how to dose those drugs. There have been very few patients that are older adults included within those studies. The challenge that oncologists face is how do I then dose the drug in an older patient population when the drug has primarily been studied in younger adults.

There are now a number of studies that are focusing on the older patient population, across a whole range of research. There's something called the U13, which was a grant that was a collaboration between the Cancer and Aging Research Group, the NCI and the NIA. We had three conferences that laid out the research agenda for older adults and formed the platform for how this research should unroll within the next 10 years to help this patient population. One key part of that was the therapeutic studies and open studies that specifically focus on older adults, so we can understand how to dose these drugs and what are the side effects the patient might experience.

I think it’s going to be incredibly exciting. Right now, we’re in the midst of the baby boomers aging. By 2030, the largest growth in population is going to be people over the age of 80. These are the patients that we’re seeing, because cancer is a disease that is associated with aging. Any bit that we can move the needle in this space is going to have huge implications for our field and how we treat patients. With that in mind, it’s an incredibly exciting time for geriatric oncology and we welcome people to join us in doing this work so we can help this growing patient population.

The key point from my presentation was that treatment needs to be individualized for an older adult. A part of that process is knowing the data within oncology, but also the other part is knowing the data within geriatric oncology. That data being such that it can help you to individualize those treatment decisions. A key point is that to make a treatment decision with an older adult, you have to weigh not only what the benefits are, but also the potential risks of treatment.

Is there anything else you'd like to add?

To understand what those risks are, you can utilize a calculator that can calculate the risk of chemotherapy toxicity. You can go to the Cancer and Aging Research Group website and you can plug in 11 easy questions about your patient, and you can find out where they fall on the risk of side effects from cancer treatment, chemotherapy in particular. It will also tell you how you can intervene to try to decrease those risks. The biggest point is that chronological age does not equal functional age. Age tells us very little about an older adult, and if we can deepen the way we think about this patient population, we can individualize treatment decisions for them.

I’d like to add that it’s an absolutely wonderful patient population to take care of. You get to spend time with people’s moms, and their grandmothers, and their aunts, and those are all people that we love and we can learn so much from. I would advise anyone who is junior or just starting their career in this field of geriatric oncology, they have such a chance to make a difference, but not only that, the patient population is just incredible.

Articles

Individualized treatments are key for older patients with breast cancer, expert Arti Hurria, M.D. said.

Addressing the Needs of Older Patients With Breast Cancer

Imfinzi (durvalumab) — a PD-L1 inhibitor – gained Food and Drug Administration (FDA) approval last month to treat patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy, or for patients who have disease progression within a year of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

The approval was based on the single-arm phase 1/2 Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy.

In the study, the objective response rate per blinded independent central review was 17 percent. At the data cutoff, the median duration of response was not reached.

Please provide some background on Imfinzi leading up to its approval.

, Christophe Massard, M.D., Ph.D., medical oncologist, senior consultant of the Drug Development Department and Department of Medical Oncology, and chairman of the Early Drug Development Multidisciplinary Tumor Board, Gustave Roussy Institute, discussed the latest developments with Imfinzi in urothelial carcinoma.

Imfinzi is a selective, high-affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. An ongoing, multicenter, phase 1/2 open-label study (NCT1693562) is evaluating the safety and antitumor activity of Imfinzi monotherapy in patients with advanced solid tumors, including locally advanced/metastatic urothelial carcinoma. An interim analysis of 61 patients with urothelial carcinoma in this study indicated that Imfinzi was well tolerated and associated with antitumor activity, particularly in patients with PD-L1—high disease (at least 25 percent of tumor cells or tumor-infiltrating immune cells express PD-L1), resulting in its breakthrough therapy designation by the FDA.

What adverse events were seen with Imfinzi on the trial?

What should patients and doctors look out for regarding serious or immune-related AEs?

In [the] phase 1/2 open label study of locally advanced/metastatic urothelial carcinoma patients [that led to the approval of Imfinzi, the treatment] was administered at 10 mg/kg every two weeks. Imfinzi showed favorable efficacy and an excellent safety profile in locally advanced/metastatic urothelial carcinoma patients.

Grade 3/4 treatment-related adverse events [AEs] occurred in less than 10 percent of patients. Grade 3/4 immune-mediated adverse events occurred in a minority of patients. Among patients with any-grade treatment-related AEs of special interest, patients received systemic steroids. 

Imfinzi, like other immune checkpoint blockers, generates atypical types of tumor responses—pseudoprogression, but also hyperprogression. Moreover, they have a specific toxicity profile that is challenging the historical oncologists’ practices, with the need to learn how to deal with the clinical management of immune-related AEs.

What is the impact of Imfinzi's FDA approval?

Is there potential for the agent to replace chemotherapy?

Most immune-related AEs remain mild in intensity but between 5 percent and 10 percent of patients treated with anti—PD-1 immune checkpoint blockers will develop severe, sometimes life-threatening grade 3/4 dysimmune toxicities. For example, it was decided at Gustave Roussy to set up a network of oncologists and organ specialists to manage patients with immune-related AEs. This program is led by Aurélien Marabelle, MD, PhD; Stéphane Champiat, M.D.; and Olivier Lambotte, M.D., Ph.D.

[The research] supports the manageable safety and tolerability of Imfinzi administered at 10 mg/kg every two weeks as monotherapy in patients with solid tumors and confirms its favorable clinical activity in previously treated patients with locally advanced/metastatic urothelial carcinoma for whom prognosis is poor. Imfinzi is clearly a new option for these patients.

Based on these findings, Imfinzi appears to be an attractive alternative to chemotherapy. Further studies, including DANUBE (

), are evaluating Imfinzi as a monotherapy and in combination with other agents (tremelimumab, AZD4547, Lynparza [olaparib], AZD1775, and vistusertib) in urothelial carcinoma.

Imfinzi (durvalumab) may change the treatment paradigm for some patients with urothelial carcinoma.

Expert Discusses Urothelial Carcinoma's Newest Agent

The field of prostate cancer has been transitioning with the identification of novel biomarkers. However, physicians are now facing a new challenge: which one is best appropriate for their patients? 

Leonard Gomella, M.D., recommends that healthcare providers familiarize themselves with how each biomarker should be used and then decide which one to use — a more individualized approach in clinical practice.

 Annual Interdisciplinary Prostate Cancer Congress, Gomella, professor and chair, Department of Urology, and director, Kimmel Cancer Center Network, Thomas Jefferson University, discusses the future of biomarkers in prostate cancer.

Can you give an overview of your talk on biomarkers in prostate cancer?

: Biomarkers in prostate cancer is a very rapidly evolving field. We’re seeing new markers for prostate cancer almost on a weekly or monthly basis. Right now, biomarkers for prostate cancer fall into two general categories: biomarkers that are used for the biopsy and initial diagnosis of prostate cancer, and biomarkers that are used after the diagnosis of prostate cancer.

In the first case, we primarily have new blood and urine tests that are out there to help us decide who may or may not have prostate cancer and who may or may not need a biopsy. In the latter case, after we make a diagnosis we have genomic tissue markers that allow us to be more clear on what the best treatment might be for a patient, either active surveillance or active therapies, such as radical prostatectomy or radiation therapy. And lastly, for patients who have had radical prostatectomy, we have biomarkers to help us decide if those with adverse pathology need more treatment, such as radiation.

Right now in prostate cancer, a lot of it revolves around what we call the somatic markers in the tumor to help us guide treatment. We have a whole different class of biomarkers now, both genomic and basic tests, such as the SelectMDx, 4Kscore test, the PHI (Prostate Health Index) test and other blood and urine tests, to help us with the decision for the initial biopsy.

With so many new biomarkers available, what are the challenges?

With all the biomarkers, the challenge is which is the best one. There are so many out there, and I think it’s up to the individual provider to start to work with one or two of the biomarkers and decide if they work well in his or her hands.

There are not a lot of comparative trials out there right now with the different biomarkers, either the standard blood and urine test, or the newer genomic assays on the tumor. We don’t have head-to-head comparisons, but the ones that are approved by the Food and Drug Administration (FDA), such as the PHI test, which is approved for the screening of the initial determination if someone needs a biopsy, doctors just have to start using them and decide which one works best.

Since there are not a lot of clinical trials ongoing in this area, what do you envision for the future of biomarkers in prostate cancer?

The future of biomarkers is going to be tough in the absence of clinical trials. There are a few centers that are doing some head-to-head comparisons. The FDA has the burden on them right now to approve these markers, and once they get approved, it’s going to be in your hands to decide which one works the best. Absent of these clinical trials, I think it’s going to be very challenging going forward as more biomarkers become available.

Let’s face it, we’ve had many biomarkers over the last 10 to 15 years that have come and gone because, although they got FDA approval, when they got out to the real world of patient care, the providers did not find that they helped in their decision making. Each new biomarker is going to have to stand on its own and I think once they get FDA approval, the marketplace is going to decide if it’s a good test, or ‘you know what, when I use this it doesn’t help me that much’ — it’s like flipping a coin. So again, each biomarker is going to have to stand on its own. The papers are all based on clinical trials and very defined populations, so once they get out into the day-to-day practice of urology and screening and diagnosis of prostate cancer, that’s where they will either live or die.

How can urologists best decide which biomarkers to use?

You have to first look at what the biomarker is approved for. Some biomarkers are approved for that initial yes or no decision making for biopsy. Other biomarkers are approved after the diagnosis is made for deciding whether you follow this patient with a less aggressive approach, such as active surveillance, or if they need some type of active treatment. The decision making has to be put in the context of what you’re doing with the individual patient.

The important thing is that any provider, whether it be a urologist, radiation oncologist, or medical oncologist, should be familiar with the different assays that are out there and understand that it’s not one-size-fits-all. They often have very narrow FDA labels for how they should be used.

Leonard Gomella, M.D., recommends that healthcare providers familiarize themselves with how each novel biomarker should be used and then decide which one to use for a more individualized approach in clinical practice.

Expert Discusses Biomarker Development in Prostate Cancer

Immunotherapy combination regimens may represent the future of urothelial carcinoma treatment, according to Evan Y. Yu, M.D., as it may be a novel approach to induce higher and more durable response rates in patients.

Additionally, while the success of immunotherapy has made a significant mark in the field, an unmet need still lies in the fact that these agents only provide a clinical benefit for approximately one out of every three patients, adds Yu, a professor in the Division of Oncology, Department of Medicine, University of Washington School of Medicine. Several ongoing clinical trials are examining immunotherapy agents in combination with other immune-based therapies, as well as with chemotherapy.

, Yu discussed the current treatment options for metastatic urothelial carcinoma, the unmet needs that still exist in this space and the possibilities for the future treatment landscape.

What are the current treatment options in metastatic urothelial carcinoma and what needs still have to be addressed with regard to treatment?

Yu: Right now, the first-line option for metastatic urothelial bladder cancer is still platinum-based chemotherapy — gemcitabine with cisplatin or gemcitabine with carboplatin. That may change in the near future as there are some frontline studies in patients who are cisplatin-ineligible and there are a couple agents that may get Food and Drug Administration (FDA) approval in that setting in the near future. But at this point in time, it’s still platinum-based chemotherapy for first-line.

Once you go into the second-line, most people are starting to use immuno-oncology (IO) agents. The FDA approved agents are the PD-L1 antibody, Tecentriq (atezolizumab), based on response rates and durability of response and the PD-1 antibody Opdivo (nivolumab), based on response rates and durability of response as well. Keytruda (pembrolizumab) is a PD-1 antibody that actually has the best level one evidence right now with survival benefit. However, Keytruda is still currently being evaluated by the FDA. We may see survival benefit in other studies in the near future, as Tecentriq has a randomized phase III trial that will probably read out reasonably soon.

That’s where we are in terms of FDA-approved agents. There are a lot of other exciting things being developed with fibroblast growth factor receptors (FGFR) antibodies, antiangiogenic agents and antibody drug conjugates.

There’s certainly an unmet need in the fact that there is no third-line approved therapy. There’s certainly an unmet need that the IO agents still only induce response rates in maybe 20 percent of patients and stable disease in up to another 15 percent. I generally tell patients that one out of three will have some sort of clinical benefit from an IO agent. How can we make it so that those patients who currently wouldn’t receive clinical benefit can respond in the future? Perhaps we need to do combination therapy. There certainly are combination trials that are ongoing that have promise for the future.

What impact has immunotherapy made in the field of urothelial carcinoma?

Immunotherapy has made a huge impact on the field. First off, we didn’t have any agents that induced an overall survival benefit and now we do. The first one was Keytruda. Second off, these agents are pretty low in toxicity. Other than the few patients who get immune-mediated side effects, they’re generally less toxic than cytotoxic chemotherapy. Thirdly, we see durable clinical benefit — people that respond or have stable disease resulting in long-term clinical benefit that may last one-to-two years or more. We just have not seen this with traditional chemotherapy. Last of all, we usually don’t see stable disease with chemotherapy. Either you respond or you progress, so stable disease is something new that has occurred with IO agents.

Where do you envision the treatment landscape for urothelial carcinoma will go in the next few years?

I think in the treatment landscape, IO agents will likely find their way as first-line therapy. First, they’ll get it in the first-line for patients who are cisplatin-ineligible, but there are trials underway that are comparing IO agents directly to chemotherapy. They may find themselves in first-line in combination with chemotherapy or as a single agent. However, we have to have some caution with single-agent IO therapy in the first-line, because there is a subset of patients that harbor rapidly progressive disease that could still be better served by chemotherapy since the response rates are initially higher with chemotherapy.

I would say that IO agents will likely move into the first-line eventually, but whether that’s as a single agent, or in combination with another immunotherapy agent or with chemotherapy, we will have to wait to see what pans out. Although, IO agents may not be right for everyone in the first-line, they will probably be administered for most patients in the first-line. As a result, I think it will lead to a shuffle to try to understand what’s best for second-line and third-line, but it leaves an opportunity to develop other drugs in other classes like I mentioned earlier; antiangiogenic agents, FGFR inhibitors and antibody drug conjugates are all very promising in this disease as well.

Finally, I think we will begin to better understand predictive biomarkers — who will respond and who won’t. At this point in time, I do not think the data is very compelling for prediction of response to therapy with PD-L1 immunohistochemistry, but hopefully in a few years we’ll have better markers to provide some predictive capability.

In an interview with CURE, Evan Y. Yu, M.D., discusses the current treatment options for metastatic urothelial carcinoma, the unmet needs that still exist in this space and the possibilities for the future treatment landscape.

The Future of Immunotherapy for Urothelial Carcinoma Treatment

An upcoming trial is testing the use of tumor treating fields (TTFields) for the grade 3 patient population. So far, the treatment method has been largely focused on glioblastoma, says Daniel O’Connell, M.D.

Currently, the device is only FDA approved for use in grade 4 brain tumors, but O’Connell, a neuro-oncologist at UCLA’s David Geffen School of Medicine, anticipates the FDA will grant its approval for use in grade 3 tumors within the next two to three months.

What impact have TTfields made so far in brain cancer, and what do you envision the future use will be?

, O’Connell discusses the upcoming trial, which will test the efficacy of TTFields in these patients, as well as the impact the device has already made in the grade 4 patient population.

The first trial in humans for TTFields in the brain tumor community was for glioblastoma, and the focus has thus far been largely on glioblastoma, for obvious reasons. Glioblastoma carries the most devastating prognosis, median survival times are the shortest, and it is the highest-grade glioma. Therefore, the focus has been on that.

Increasingly, there has been a buildup of evidence in favor of the use of TTFields in improving the side effect profile relative to standard chemotherapies, or at least not making it worse. With regards to outcomes such as survival times, there has increasingly been more evidence mounting in favor of prolonged survival with the device. However, this has not been used beyond the grade 4 domain. I did see some additional posters at this meeting regarding the use of TTFields in meningioma, and I know in the lung cancer world there are some works in progress regarding TTFields. However, for the grade 3 tumors, that is our focus.

Currently, this device is only FDA approved for grade 4 tumors, so we anticipate the FDA approval for the device for grade III tumors in the next two to three months—I can’t see a reason why this would not go through. And then we will obtain approval to finally start enrolling patients in the trial, which we have received funding for. It is a phase 2 study demonstrating the use of TTFields in grade 3 anaplastic astrocytoma population.

Great question. It’s going to be some time, because the grade 3 patients have a better prognosis; they live longer. Proportionally, there are fewer of them. There are proportionally more glioblastoma patients amongst the patients with glioma. There is not as big of a patient population.

Is this trial a next step to the EF-14 trial?

Our catchment area is within Southern California—Orange County community hospitals, and we hope to recruit folks in LA County, as well. Our minimum goal of recruitment is 26 patients, with up to 36 allotted. We anticipate this trial lasting years, because these patients, regardless of therapies, typically live a median survival of five to nine years. The use of this will hopefully push us over to that nine-year mark and beyond&mdash;that’s our hope, of course, for these patients. So this will be a long-standing trial running through, I anticipate, 2018, 2019, 2020. It will take some time.

You can view this trial as an additional step moving beyond the EF-14 trial, which is quite a landmark trial. Finally, we’re seeing a significant difference on multiple levels for the Optune device for TTFields.

We started with EF-11, which demonstrated against physician’s choice chemotherapy and TTFields that TTFields provide the same overall benefit in addition to not having the side effects of chemotherapy. EF-14 has now demonstrated that, in tandem with the chemotherapy, that patients do better with the TTFields clearly, and this is also stratified by subgroups and hazard ratios, etc.

What impact could this device have for patients?

Our plan is to take this another step, as it appears some other folks are actively pursuing, and extending it to the grade III patients. Who’s to say that there may be an even more demonstrable benefit in the grade 3 population. It will take a lot of time to tell. It takes time for the TTFields to work in and of themselves—a couple months, so in order to see that result, you have to start earlier rather than later, which is our goal to help offset and utilize the cytostatic mechanism of TTFields to prevent the cell population from further dividing tumor cells.

One of the big questions we get in our clinic at UCLA is, what other modalities can be used to help offset the devastating nature of glioma, particularly glioblastoma? Increasingly, our grade 3 patients, our young grade 3 patients, are curious as well. They go online and look and see what the average prognosis, etc. is for patients with their diagnosis. They want to know what else can be done. This is a different modality than immunotherapy, targeted therapy, and traditional chemotherapy, in that it utilizes a novel mechanism. It is not ionizing radiation, it is distinct from radiation therapy, although sometimes comparisons are made from a trial standpoint. It’s different, and it can be used differently.

I saw a fascinating poster the other night about attempting to use TTFields with radiation therapy, which initiates usually for most patients shortly after resection (should they have a resection; most do). In order to push it back further, and that would apply not only to the glioblastoma patients, for which the EF-11 and EF-14 trials have been designed and used for, but also for our patient population that we’re interested in — the grade 3 &mdash; to see if it can start early. Believe it or not, there are quite a few patients that are very proactive, that even with a prognosis that is fairly good compared with the glioblastoma group, still want everything done, understandably. They’re looking into the future and they want to do something as soon as possible. This is a mechanism of action that can be used for them.

Though now used for patients with grade 4 brain tumors, tumor treating fields are being tested for use in grade 3 tumors.

Exploring the Use of Tumor Treating Fields in Grade 3 Brain Cancer

A reduction in mortality and cancer progression was seen in patients with metastatic colorectal cancer (mCRC) who engaged in moderate exercise daily, according to the results of a recent analysis presented at the 2017 Gastrointestinal Cancer Symposium in San Francisco, CA.

Though previous studies have shown a link between exercise and improved outcomes in early-stage CRC, this is the first evidence to show this association in patients with non-local metastases.

The prospective cohort study nested within the National Cancer Institute (NCI)-sponsored randomized Alliance control trial included 1,231 patients with mCRC who received chemotherapy and self-reported their physical activity via a questionnaire. Researchers then determined each patient’s level of activity based on metabolic equivalent task (MET)-hours per week, which assesses energy expended during physical activity.

Overall, the patients who spent more time participating in moderate physical activities such as walking, cleaning or gardening had reduced rates of cancer progression and death. Patients who reported an engagement in physical activity equivalent to 30 or more minutes of moderate exercise daily, or 18 or more MET-hours per week, experienced an overall survival (OS) rate of 0.81, which represented a 19 percent reduction in mortality, and a progression-free survival (PFS) of 0.84, which represented a 16 percent reduction in cancer progression.

The study also found that patients who spent five or more hours per week doing non-vigorous activity, such as walking or yoga, had a 25 percent reduction in mortality. However, there was no association found between vigorous activity, such as running or playing sports and cancer outcomes.

“Patients should know that even as little as 30 minutes of moderate activity per day may improve outcomes for colorectal cancer patients,” said lead study author Brendan Guercio, M.D., Brigham and Women’s Hospital.

Guercio said these findings suggest that even light activities, which many patients with mCRC may be able to participate in, can be associated with improved outcomes.

The most important question to address regarding the findings of the study was the role of confounders, Guercio said.

“In other words, the question was: is physical activity making people healthier, or were individuals who were sicker than others just exercising less?” he said.

To address this issue, regression analyses were used to calculate hazard ratios for disease progression and mortality for levels of self-reported physical activity after adjusting for potential confounders, including comorbidities, weight change over the prior six months, ECOG performance status, body mass index, chemotherapy received, tumor KRAS status, gender and age.

Randomized controlled trials and more prospective clinical studies are needed to confirm the link between physical activity and outcomes in mCRC. A randomized clinical trial is currently ongoing to compare patients who exercise during treatment with those who do not, with the hope of confirming the impact of physical activity on cancer outcomes

A recent study found that frequent, moderate exercise may reduce mortality and progression in patients with metastatic colorectal cancer.

Exercise Reduces Mortality in Metastatic CRC

Genetic counselors can help with the complex process of assessing an individual’s risk for tumors, such as brain tumors, says Krista Qualmann, M.S., C.G.C.

Qualmann’s work as a genetic counselor at Memorial Hermann Mischer Neuroscience Institute and McGovern Medical School at The University of Texas Health Science Center at Houston includes trying to identify which patients have an inherited, genetic predisposition that could have caused them to be diagnosed with brain cancer. She also selects patients that could benefit from undergoing genetic testing.

Can you tell us a little bit about the syndromes you are trying to identify in your patients?

What are some of the mutations you might see?

Qualmann discussed the syndromes she is identifying in patients in her clinic, as well as how they could impact treatment, in an interview with 

We’re trying to identify patients who have an inherited, genetic, predisposition that explains why they had their brain tumor. When I’m doing this, I’m looking for patients who have some sort of red flag because the majority of our patients with brain tumors don’t have one of these syndromes. Part of my role in our clinic is to try to identify which patients would benefit the most from genetic testing.

In the neuro-oncology world, there are a lot of different types of genetic mutations that people might be talking about. The most common genetic testing that neuro-oncologists might be talking to their patients about is the molecular genetic testing of their tumor.

Is this different for a pediatric patient with brain cancer?

The genetic testing that I’m talking to patients about is genetic testing either on a blood or saliva sample to look for a gene mutation that they were born with. Very common syndromes could include things like Li-Fraumeni syndrome, von Hippel-Lindau disease, Lynch syndrome, and a couple more.

Yes. We test for different syndromes depending on the picture of the patient in front of us. There are a lot of different hereditary cancer syndromes, so we have to narrow it down a little bit.

How do the results of genetic testing influence the therapeutic approach?

I narrow things down by asking a lot of questions about the patient’s past medical history and their family history. If they have characteristic patterns of cancers in their family — certain types of tumors happening together &mdash; those can lead me to be more suspicious of specific syndromes. 

For some syndromes, knowing that a patient has a genetic predisposition syndrome tells us that maybe some therapies would be better served or should actually be avoided. For example, avoiding ionizing radiation is something we can consider, however, that is very dependent on that patient’s individual treatment plan. For patients with high-grade tumors, like glioblastomas, ionizing radiation is part of their standard of care, and so they should absolutely receive that type of treatment. For patients with lower-grade tumors, or benign tumors, if we can avoid ionizing radiation in specific syndromes, it could be beneficial for them long term.

The other thing that we can gain from identifying these genetic syndromes in patients is determining whether or not they have a higher risk for other types of cancers—other systemic diseases. For example, Li-Fraumeni syndrome is a rare syndrome, but patients are at very high risk, not only for brain tumors, but other types of cancers as well, such as early onset breast cancer in women, and sarcomas in both men and women. Those are the types of things they could be screened for if we identify that syndrome.

For Li-Fraumeni syndrome, almost every type of cancer that you can think of has been seen in at least a couple of patients. I think they have narrowed it down to four or five of the most common, but then they’re also at a very high risk for other cancers. For women specifically with Li-Fraumeni syndrome, they have a very high lifetime risk of any cancer because of their really high risk for breast cancer, which isn’t necessarily seen in men.

Genetics can help determine a patient's risk of developing a brain tumor, as well as what treatments may work.

Genetics Can Help Determine Brain Tumor Risk

Preventative treatment with the combination of loperamide and budesonide reduced the rate of grade 3 diarrhea associated with neratinib in a recent early-stage HER2-positive breast cancer trial. The rate fell from 39.9 percent to 15 percent in the the ExteNET trial, explained Carlos H. Barcenas, M.D., M.Sc.

Can you five an overview of the study and the findings?

, Barcenas, assistant professor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, discussed the detailed findings of the interim analysis from the multicenter, open-label phase 2 control trial, and the next steps following these findings.

The importance of the study was because previously the ExteNET clinical trial had shown a benefit of the drug neratinib in patients with stage 1 through 3 HER2-positive breast cancer. Some of them are hormone receptor (HR)-positive and some of them are HR-negative.

What were the findings in each of the cohorts?

There is a benefit of neratinib given in the adjuvant setting, which is after one year of Herceptin (trastuzumab)—an additional year of neratinib. The problem with this drug is that it gives a lot of diarrhea, and so the incidence of diarrhea in ExteNET of grade 3 was almost 40 percent. The idea of this study was to characterize the diarrhea and try to control it with prophylactic treatment with loperamide. There’s different cohorts that have been established and so we’re looking at how these different cohorts have improved the diarrhea.

The loperamide cohort basically consists of two cohorts itself. It’s very detailed regarding how much loperamide they receive. It’s consistent for the first one and two cycles. The reduction of grade 3 diarrhea was around 25 percent with that cohort. The next cohort was treated with loperamide with the addition of budesonide, which is an anti-inflammatory and a kind of steroid. That one reduced the grade 3 diarrhea to about 15 percent.

What are the next steps going to be following these findings?

Of course, everything comes with a cost. With this combination, there was actually an increase of constipation, nausea and fatigue. It’s like a balancing act between decreasing diarrhea, but also trying to not increase constipation.

So 15 percent is what we have seen so far with the loperamide/budesonide combination. That’s actually a good number, but the idea is to try to decrease it even more. Of course, the mechanism of action of the diarrhea, although we think it’s inflammatory, there may be other factorials, so the idea is to use other agents.

The next agent we will be testing is Colestid (colestipol), which is an acid bile sequestrant. It seems like in some of the phase 1 clinical trials in the metastatic setting it had a great response to diarrhea, so we want to see if it works in the adjuvant setting also. There’s going to be a cohort with Colestid, and then eventually there may be other cohorts down the line.

Down the line, what would be the normal dosing or indication for any of these agents?

Anecdotally, can you discuss how patients have tolerated neratinib?

There are also potential ideas, for example, decreasing the dose of loperamide, or giving single-agent budesonide and using loperamide on an as-needed basis. These are all decisions that have not been made yet and these are decisions that will be made by Puma, [the manufacturer of neratinib].

The whole idea of this study is to be able to keep the patient on neratinib for a whole year, and we know diarrhea is an issue. We also know that if diarrhea is an issue, it’s going to be in the first one or two months. If they are able to go beyond those two months, they should be doing OK. We’re trying to see what is the best strategy so they don’t have too much diarrhea during those first two months and hopefully they will continue for the next year. The whole idea is so that we have a strategy to control symptoms to keep the patients on neratinib, which we know is helpful for them.

This is a multi-center trial. It is clear that patients want to get on the trial because they think neratinib is a good drug. If someone is predisposed to diarrhea, they may be more hesitant to be enrolled. There was one investigator stating that one patient was actually very baseline constipated and that patient actually did really well. She was happy with the drug because now she’s not so constipated. So it’s very individual. Of course, we have to look at things like constipation, fatigue, and nausea, which may be secondary to loperamide, and so obviously we would have to think about backing off a little bit, probably. This is more of a balancing act, but overall, they’re doing quite well.

An early stage trial found that a new drug combination can reduce the rates of treatment-related diarrhea in patients with breast cancer.

Combination Prevents Diarrhea in HER2+ Breast Cancer

Investigating pulmonary metastases instead of the primary tumor is the key to finding treatments for osteosarcoma, according to Nancy Gordon, M.D.

Gordon, a pediatric oncologist and research assistant at The University of Texas MD Anderson Cancer Center, believes immunotherapy could play a critical role in the treatment of patients with osteosarcoma and lung metastases, and her recent research has shown that targeting the PD-1/PD-L1 pathway can have therapeutic benefit in these patients.

Can you five an overview of the osteosarcoma research you are involved in with targeting the PD-1/PD-L1 signaling pathway?

about her research, the next steps following the findings of the study, and what she envisions for the treatment landscape of osteosarcoma over the next decade.

In osteosarcoma, the main reason that patients die is because of pulmonary metastases. Immunotherapy for osteosarcomas has shown some benefit in different aspects. There has been treatment which has been delivered through cytokines, for example, interleukin-2 (IL-2). We have studies where we deliver IL-2 to the lungs, and the reason for it is we have shown that immune cells go to the tumors, but the problem is that they go and they leave. One of the ways you can help those cells stay within the tumor is by increasing their growth and proliferation; one of the ways you do it is by giving some of these cytokines, one of which is IL-2. We have studies and pre-clinical data that shows that it allows the immune cells to stay.

One of the problems with the immune cells is that they can express one of the checkpoints, which is PD-1 and PD-L1. What happens is that it restricts the ability of the cells to kill the tumors. We’re talking about all the immune cells—we’re talking about T cells, natural killer (NK) cells and even macrophages.

In our studies, we showed that only by giving an antibody against anti—PD-1, you can actually have therapeutic benefit in osteosarcoma lung metastases. The tumors express PD-L1, but the fact that immune cells can express PD-1, that limited their ability to kill the tumor. By blocking the pathway, you activate those cells so they’re able to do their job.

What would you say are the next steps following the findings of the study?

We used a human osteosarcoma mouse model to generate the pre-clinical data that will be translated to the clinic. In that end, we showed in the model you can only see two types of immune cells—NK cells and macrophages. When we blocked the pathway, we saw that not only did these cells migrate to the tumor, but, particularly, we showed that the macrophages are the ones that probably contributed to the best therapeutic efficacy of this blocking agent.

The next steps will be to actually translate it to the patients. There have been a few studies already in adults for all of these checkpoint inhibitors. One of the major things we had to take into account, particularly in children, is that it had to pass phase I studies in adults for us to be able to implement it in children.

Are there any noteworthy toxicities associated with targeting the pathways?

What would you like to see change in the treatment landscape of osteosarcoma in the next five to 10 years?

Immunotherapy doesn’t work in the face of a big, bulky, huge disease. You have to have only minimal residual disease for immunotherapy to work. None of the agents in a lot of the tumors have worked on their own. There have been many studies looking at not only checkpoint inhibitors, but also in combination with chemotherapy and other agents. The next steps will be to see what will be the best approach to create a clinical trial that will allow for pediatric patients to receive this therapy and see what the benefit will be, but it will have to be in patients with relapsed disease where there is only minimal disease.

In adults, there have been some patients that have shown very minimal signs of pneumonitis, because you can have some kind of cytokine release that can cause that. Some patients have shown fatigue, some patients have shown diarrhea, but really it’s brought more benefits to patients where therapy works, such as in melanoma and non—small cell lung cancer. That’s more benefit than anything else.

I think that we have to stop looking at the primary tumor. We have to mostly look at the pulmonary metastases. In a lot of the Patient-Derived Xenograft (PDX) models that have been developed, the genetics is one, the pulmonary metastases is another one; once you generate a different PDX from that metastasis, the genetics are different. Every cycle the genetics change, so immunotherapies in these cases might be very beneficial and will play a critical role for the treatment of these patients.

Immunotherapy may be a promising option for patients with osteosarcoma, Nancy Gordon, M.D., says. 

Exploring Immunotherapy's Role in Osteosarcoma

In the field of neuro-oncology, there has recently been a renewed interested in studying the metabolic pathways of tumors, with the hope of developing novel therapeutic targeting in this area, says Howard Fine, M.D.

“It’s interesting, like a lot of things in science, something starts out hot and then we lose track of it for several decades. With new knowledge, all of a sudden there’s a whole new level of science brought to it, and I think that’s where we are with tumor metabolism,” said Fine, director, Brain Tumor Center, Sandra and Edward Meyer Cancer Center, and chief, Division of Neuro-Oncology, Weill Cornell Medicine.

, Fine discussed the reason for renewed interested in metabolic targets, the effect it has had on treatment of gliomas, and what he sees on the horizon for neuro-oncology in this area.

Why has there been renewed interest in metabolic targets?

Metabolism in cancer is actually an interesting story in that some of the earliest approaches we used to try to fight cancer, starting 30 to 40 years ago, tried to target the metabolic pathways, and some of our earliest drugs, like Trexall (methotrexate), to target cancer interfered with folate metabolism and that was really our major way of fighting cancer.

With the advent of molecular biology and genetics, metabolism and the idea of targeting the aberrant metabolism tumor kind of became passé, kind of like pharmacology did. We got in to the genetic age and people began to forget about it, until we began to realize that many of the oncogenic pathways and many of the deregulated signal transduction pathways that we’ve been studying actually end up converging on pathways of metabolism.

There’s been an increased interest in all [areas] of cancer, and certainly neuro-oncology, to not only begin to really understand the aberrant metabolism in tumors to better understand tumor biology, but also to realize that there may be great opportunities for novel therapeutic targeting.

What was the significance of this finding?

This particularly came to light with the discovery five, six or seven years ago, of the

 mutation found in a large percentage of low-grade gliomas. The 

 mutation is in a gene that is central in the tricarboxylic acid (TCA) pathway and is a basic metabolic enzyme. That again brought to light how intrinsically important metabolism is in tumor biology, glioma biology, and the potential therapeutic options thereof.

I think that brought a lot to light. In fact, it’s the first mutation that has been shown in a TCA enzyme that produces a unique metabolite that’s now called an oncometabolite. It’s kind of the paradigm for how metabolism is important for any cancer, so it has a special place in the heart of neuro-oncologists.

What do you think is on the horizon, and what are you hoping to see?

I think that increasingly so, in all of oncology, people are beginning to pay a lot more attention to the importance of cancer metabolism and how it may offer new therapeutic opportunities. 

 is just the tip of the iceberg, although I don’t know that we’re going to find that many new mutations in oncometabolites. It is quite clear, and we’ve know this for many, many years, but now we’re beginning to really understand the molecular details of it, that the metabolism in tumors is quite dramatically different than it is in normal tissue.

When you think about therapies, what are we trying to do? We’re trying to find ways in which tumor tissue is different and behaves different and has a different biology than normal tissue because that gives a therapeutic target. If you can find the therapeutic ratio that’s different between normal tissue versus tumor tissue, that gives you something to aim at therapeutically without worrying about overlapping normal tissue toxicity. Metabolism is just that—it’s a very complex series of biochemical pathways that appear to be, in many respects, quite different in tumor tissue than in normal tissue; so it offers, theoretically, a very promising new area to therapeutically target.

What are the effects of stress on the tumor metabolic environment?

I hope to see, and I think we will see, whole new strategies based on developing drugs against these novel metabolic targets and in fact, possibly even diet modifications. There has been a lot over the last 10 or 20 years about special kind of diets, like ketogenic diets, that effectively target metabolism. I know they haven’t been studied well, they haven’t necessarily been done in the correct way—they haven’t been done in conjunction with pharmacologic intervention. I think we’re going to see those types of strategies. I know we will, because we’re doing those types of strategies at our center and in other centers, and I think it’s a great unexplored and an exciting old/new area.

We know that stress causes hormonal changes and hormonal changes are involved in metabolism. For instance, we know that stress induces glucocorticoids and causes adrenal hyperactivity. When you get high levels of adrenocorticotropic hormone (ACTH) and steroids, you increase insulin levels. We know that insulin drives tumor growth and tumor promotion. Although there’s no data, one could speculate that high levels of stress hormones over long periods of time may increase insulin, and may increase your chances of type 2 diabetes, which has been shown, and we think that high levels of insulin resistance, hypoglycemia, certainly can help fuel tumor metabolism.

Does age play a factor in metabolic pathways?

Are there any ongoing trials that you are currently watching with interest?/strong>

The answer is we don’t know, but I’m sure that it does. We know that for instance in a normal aging brain, metabolism is dramatically different than it is in developing in a middle-aged brain. That is well established and there’s an increasing number of papers being published looking at the molecular mechanism of that. If the normal surrounding brain metabolism is different, tumors don’t live in isolation, they live within the host, so I’m sure the metabolic profile and the details of the metabolism of tumors in an older versus a younger brain is quite different, but I think we are just beginning to explore those aspects.

Certainly, there is a whole series and it’s a big focus on a whole new series of drugs that target this mutant 

 gene, so these IDH inhibitors are being explored now both in low-grade and high-grade gliomas with variable success. I think we’re just beginning to learn to use those.

Centers like ours are looking at the old kitogenic diet in combination with very specific new pharmacologic interventions like PI3 kinase inhibitors and mTOR inhibitors as a way of trying to hit the metabolism in various fronts of tumors. Those kinds of trials and therapeutic interventions are just beginning to be seen.

Recent findings turned more attention toward the metabolic pathways in neuro-oncology.