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Conversations With Prostate Cancer Experts


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Clinical Trial: Free Genetic Testing

Dr. Heather Cheng is an Assistant Professor at the University of Washington and Fred Hutchinson Cancer Research Center, and the Director of the Seattle Cancer Care Alliance Prostate Cancer Genetics Clinic.

Prostatepedia spoke with her about a clinical trial she’s running that looks at inherited genetics of men with metastatic prostate cancer.

What attracted you to medicine?

Dr. Heather Cheng: There are a couple of things I love about medicine and especially oncology. One is getting to know patients, finding out what’s most important to them as people, and using that information to help guide discussions and decisions about their treatment in a way that is true to what is most important to them. These days I guess you call this shared decision-making. That’s the most rewarding part about what I do.

Have you had any patients over the years who have changed how you see your own role or how you view the art of the medicine?

Dr. Cheng: I have a lot of patients who fit those criteria. My interest in this area started when I was a first-year Hematology and Oncology fellow. I was in the clinic and it was when we were at the beginning of this wave of new exciting drugs that prolong survival, such as Zytiga (abiraterone) and Xtandi (enzalutamide).

I met this patient who was 43 years old; he had new, aggressive metastatic prostate cancer. His disease blew through every one of the new drugs. It was extremely humbling and disappointing because we were so excited about these drugs, but they didn’t do much to slow his disease. And it was heartbreaking because he was so young. He had a family history of cancer but not prostate cancer. He had a teenaged son. We had a lot of discussions about the effect of his disease on his son. I wondered if there was something genetic, something that was making his cancer so aggressive. And then, what could this mean for his son? His memory has stuck with me.

When I think about the work and research that I do, it’s not just for the individual patient in front of me. I’m also thinking about how we can improve things and advance the field so things can be better for the next generation. How can we make progress as quickly and with as much positive impact as possible?

I met another patient who had a great effect on me. He had just been diagnosed with high-risk prostate cancer, Gleason 9. He was planning to get radiation. As part of a research study, we offered to sequence the DNA of his cancer because he had an unusual appearance of his cancer– ductal histology. He was kind and generous enough to volunteer and participate. It wasn’t going to affect his treatment, but he agreed to help us learn more.

In his cancer, we found a mutation in the BRCA2 gene, the one that many people may have heard of because of its association with breast and ovarian cancer risk. There was suspicion that the mutation could be inherited, so we brought him back for dedicated genetic testing for inherited cancer risk. And, it turns out he did have an inherited version of that mutated BRCA2 gene. He was the first person in his family to be found to carry the mutated version of BRCA2. Neither he nor his family would have known until later if we had not looked in his tumor.

After this, some of his relatives had genetic counseling and were also tested. The sister who had breast cancer had a recurrence and was found to carry the BRCA2 mutation. This information was important for her because it offers additional treatment opportunities for her cancer that might not have otherwise been considered. His daughter was also found to carry the BRCA2 mutation and after learning of this, had a mammogram and was diagnosed with breast cancer. She’s still curable, so she’s going through treatment, but it is possible that she might not have known until much later otherwise.

The importance of test results can extend to relatives in a way that might help more than one person, not just the person that I see in the clinic, but other members of their family. I do want to be clear that these mutations are not found in most people— even those with cancer—but for the people who have these mutations, it can be life saving information for their family members.

What will you be doing, and what can men expect to happen, during your clinical trial?

Dr. Cheng: You can learn about the study from your doctor, support group, or by visiting our website, http://www.GentlemenStudy.org. There is information about the study. You can consent online, confirm that you have metastatic prostate cancer, and check that you’re interested in genetic testing for cancer risk.

There is a questionnaire that many take about 40 minutes to complete, that asks about your knowledge of genetics, basic health, family history of cancer, and demographic information about where you live.

You can upload supporting information about your diagnosis, or you can check a box saying you’d like help from the research team to gather that information on your behalf. Because there are strict privacy laws around medical records, you need to give permission to our team to get medical information for the study on your behalf.

To be eligible, you must have metastatic prostate cancer and must live in the United States. There’s one other exclusion, which is that if you have some blood disorders such as leukemia, we cannot be sure that the test results are valid.

If you meet criteria, you will be mailed a saliva kit, a medical-grade genetic test through Color Genomics, with instructions on how to provide a saliva sample. Follow the instructions carefully and then mail the kit back. Results are typically available within 4 weeks. You will have access to a genetic counselor following your results, and you are invited to follow up in person to our clinic if you live in the area. If you don’t live near us, we can direct you to resources to find a genetic counselor for in-person visit or by telehealth.

The testing for this study is not recreational testing. It is not the same as Ancestry.com or 23andMe. This is clinical, medically appropriate testing if you have metastatic prostate cancer.

Do you share this information with their doctor, or is it up to them to share the information with their doctor?

Dr. Cheng: We strongly encourage participants to share the results and information with their doctors, but our ethical board does not allow us to do this for participants without their specific consent.

Are there any fees for patients?

Dr. Cheng: There is no fee for the patient.

It sounds similar to the process for the Metastatic Prostate Cancer Project, except I don’t think they share their results.

Dr. Cheng: Yes, it is similar to that project. The difference is that the patient or the participant gets results that apply to them individually. The Metastatic Prostate Cancer Project, which is fantastic and an important and innovative study, is de-identified, and the patient doesn’t get individual-level results back.

Their goal is to amass as much data as they can for research.

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

Dr. Cheng: We’ll be looking at demographics, the proportion of people who have mutations (pathogenic variants), information about family history, and validated measures of knowledge, distress measures and satisfaction with testing.

If patients consent to re-contact, they will be contacted at the conclusion of the study. If there are other follow-up studies, they can opt to learn about those. There will also be an invitation for those who agree to subsequent studies, like treatment studies or PARP-inhibitor studies, for example.

We’re still learning about certain genes, such as ATM mutations and CHEK2 mutations. As we learn more, we may want to update participants on what the field has learned. There are still many important questions that the field needs to answer, and patient engagement and participation will make this happen more quickly. There will be opportunities for those downstream studies.

How many patients are you looking for, overall?

Dr. Cheng: The plan was for 2,000. We have sent kits out to over 350. We still have room for participation!

Join us to read the issue and learn how to participate in Dr. Cheng’s study.

 


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Dr. Daniel George on PSA Recurrence

Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.

Have you had any patients whose cases have changed either how you view your own role as a doctor or how you view the art of medicine?

Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?

In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.

You’re basically saying that prostate cancer is becoming more of a chronic disease.

Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.

We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.

Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.

Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?

Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?

We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.

Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.

So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.

I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.

What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?

Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.

Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.

Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.

Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.

The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.

Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.

What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?

Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.

For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.

Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.

There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.

A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.

It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.

We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.

The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.

Isn’t doubling time an indication of the aggressiveness of the disease?

Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.

There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.

Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.

That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.

What other considerations are important for patients who fall into this category?

Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.

Join us to read the rest of Dr. George’s comments about biochemically recurrent prostate cancer.


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Prostate Cancer Dormancy + Disseminated Tumor Cells

Dr. Julio Aguirre Ghiso is a Professor of Medicine, Hematology and Medical Oncology and Oncological Sciences at Ichan School of Medicine at Mount Sinai in New York City. His research explores why and how in some patients disseminated tumor cells can remain dormant for years after initial treatment before reactivating to form incurable metastases.

Prostatepedia spoke with him about his research and about a clinical trial testing his findings that is currently looking for prostate cancer patients.

To  learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us or download the issue.

Why did you become involved in cancer research? What is it about cancer research that has kept you interested?

Dr. Julio Aguirre-Ghiso: When I was an undergraduate student, I was looking for challenging problems to solve in biology. Serendipitously, I started working and volunteering for a cancer biology team in Argentina, where I trained. I became very interested. I was working on tumor immunology. Then I became very interested in the cell biology of cancer cells. At some point, I realized that it didn’t really matter if it was cancer or Alzheimer’s or some other basic biological questions on other organisms; what I really was curious about was solving tough problems and answering questions. This was a good mix where, if I were able to do it, I would also be helping people with cancer in the future.

Focusing on cancer would give me an opportunity to apply my curiosity to something that is relevant for people. That was the original intention. Since I was not an MD, my curiosity was about mostly biological questions. This was a fitting problem to go after.

Let’s talk about the concept of disseminated tumor cells. Can you explain to us how that works and how it is related to the development of metastasis?

Dr. Aguirre-Ghiso: Patients usually present with what’s called a primary tumor. That’s the first cancer lesion ever found in that patient. At that time, doctors will do certain tests on that primary tumor to understand if it had gone through certain changes that would make it able to spread. When cancer cells grow, they may acquire certain abilities that allow them to spread from that primary site—from, let’s say, the prostrate or the breast—to other parts of the body.

The disseminated tumor cells are these cells that have spread throughout the body. They have disseminated from the primary tumor to other organs in the body. Those could be the bones; the liver; the brain; or the lung. When they arrive to those organs, they’re not immediately able to grow. Since they’re usually solitary cells–that’s how we find them in the patient samples and in the mouse models that we’ve used—we call them disseminated tumor cells. They’re not yet metastases, but they’re not in the primary tumor. They’ve left and arrived to other organs. That’s the definition of these disseminated tumor cells.

Why are they important? We and others have provided compelling evidence that these cells are the source of the metastases. Those are the cells, not all of them, but some of them, that are able to eventually grow into metastases that affect the functioning of the organ, and sometimes systemically, the functioning of the patient. That’s what leads to death. That’s why these cells are important.

Do all disseminated tumor cells eventually grow into metastases?

Dr. Aguirre-Ghiso: No.

How do you know which disseminated tumor cells are going to grow into metastases and which are not?

Dr. Aguirre-Ghiso: Well, that’s been a major challenge and a major push from my program: to try to get in early and identify those disseminated tumor cells so that we have some idea if a patient carries disseminated tumor cells that are not going to do anything and the patient doesn’t have to worry, or if the patient carries some cells that look like they’re switching and they’re going to form metastases.

That has been our goal. It’s not yet a clinical test, but that’s why we have pushed the boundaries of our research to get to that point as fast as possible because we think that instead of waiting and not doing anything or treating blindly and then waiting until those metastases grow, we can intervene earlier. We would like to be able to say that this patient has only dormant cells and they don’t look like they’re going to reactivate based on certain markers or gene signatures.

That patient would then only need to be monitored, but new treatments may allow eliminating even those cells. If another patient has a mixture of cells some of which are fully dormant and some of which look like proliferative cells, we would treat him in a different way.

We have provided data for this from our mouse models and from clinical patient samples in prostate cancer. We published two papers in 2014 and in 2015 on this.

Not all cells are going to grow.

In fact, if you look at early lesions in breast cancer, for example, disseminated tumor cells are found in the bone marrow of 13-15% of women with ductal carcinoma in situ but only a small fraction of that 13-15% will develop metastases. It’s not a given that if these cells are there they’re going to grow, but if they are there, there is a higher risk of metastases. That has been proven by large population studies that have been published in The New England Journal of Medicine. This is true for not only breast cancer but for other cancers as well. The goal and the challenge is to have enough information to be able to predict accurately what those cells are going to do when you detect them.

Where we are in the timeline of being able to predict which patient is carrying potentially dangerous disseminated cancer cells and which is carrying dormant disseminated cancer cells?

Dr. Aguirre-Ghiso: We have different areas of research into these disseminated tumor cells. Why they are dormant? Why do they sleep in the body for a long time and then awaken? We discovered a marker in 2015 that could distinguish these deep-sleeping cells in both prostate cancer and breast cancer models. If the cells had this marker, they would behave in this dormant way, and if they didn’t have this marker, they would look more like a proliferative or an about-to-reactivate cancer cell.

At that time, it was correlative between just two groups of patients. Last year, we published a paper on breast cancer where we used the same marker detected in tumor cells disseminated to the bone marrow of breast cancer patients. We were able to show that if patients had this marker they were much less likely to relapse with bone metastases than if they didn’t have this marker. In 2015, we’ve published the original finding where we just said this is probably a good marker; we understand how it works in mouse models. In 2018, we showed that the presence of the markers can distinguish retrospectively how patients behaved. Now the challenge is for people to start using the markers prospectively to see if it helps them make decisions on how to treat or monitor patients. We are very much at the early stages of applying the information that we have generated and bringing it into the clinic.

On the other hand, in that same 2015 paper, we were able to show that if we use two drugs that are FDA-approved and combine them in sequence, we can turn on these dormancy mechanisms in different types of cancer cells—i.e. breast, prostate, and head and neck cancer cells. Because these drugs were available—and there are independent studies showing that when prostate cancer patients are treated with hormonal therapy and anti-androgens, they turn on this marker of dormancy that tells you the cancer is deciding to go into sleeping mode— we wondered if we could repurpose those drugs and treat prostate cancer patients at risk of developing metastases to see if we could delay the onset of metastasis and keep the disseminated tumor cells in a dormant state.

To read the rest of our conversation and to learn about a clinical trial for prostate cancer patients that Dr. Aguirre-Ghiso is running: Join us. Or download the issue.


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Clinical Trial: Exercise For Metabolic Dysregulation After Prostate Cancer

Dr. Christina Dieli-Conwright is an Assistant Professor of Research in the University of Southern California’s Division of Biokinesiology and Physical Therapy.

She’s particularly interested in understanding physiologic mechanisms and designing exercise interventions for cancer patients.

Prostatepedia spoke with her about her clinical trial.

What is the thinking behind your clinical trial?

Dr. Dieli-Conwright: This study spawned from my interest in the side effects and changes that patients were experiencing as they underwent treatment. For some of the more prevalent cancers like breast, prostate, and colorectal cancer, there is literature to provide evidence that individuals are experiencing what I broadly call metabolic dysregulation, which encompasses things like gaining weight, insulin resistance, elevated inflammation, and elevated blood pressure.

Whether they have metabolic dysregulation before diagnosis or whether it develops during treatment, they are at higher risk for experiencing diseases like heart disease, diabetes, and obesity. In prostate cancer in particular, when men are prescribed androgen deprivation therapy, there are side effects to that therapy that lead to metabolic dysregulation.

If you look at individuals who exercise who have not had cancer, we know that exercise can successfully offset metabolic dysregulation. It can improve insulin resistance. It can reduce body composition changes, etc. We wanted to apply exercise to this particular population so that these patients may also experience the benefits of exercise.

If a man who’s reading this ends up participating, what can he expect to happen step by step?

Dr. Dieli-Conwright: This is a randomized controlled trial. Individuals will be randomized to either the exercise group, and receive a 16-week, 3 times a week exercise program immediately, or the delayed controlled group. Everybody eventually gets the exercise program, but the “exercise group” gets it first. The delayed controlled group gets the program 16 weeks later.

We ask them to come to our facility, which is here at University of Southern California, to exercise. We pair them one-on-one with a certified cancer exercise trainer. They perform both aerobic and resistance exercises for about one hour every time they come. They perform the exercises in an interval circuit training, high-intensity manner. We’ve done that so that we can really challenge the metabolic systems for energy balance that have been shown to be more effective at targeting metabolic dysregulation as to opposed, for instance, just walking on a treadmill for 60 minutes.

We do a number of tests at the beginning, middle, and end of the 16 weeks. Those tests involve a blood draw so that we can measure glucose and insulin, as well as triglycerides, cholesterol, and markers of inflammation. We measure blood pressure, waist circumference, and body composition so how much muscle and fat the patients have. We also measure bone density. We do a battery of what we call physical function tests: how fast can the man climb upstairs? How fast can he walk six meters? How many times he can sit to stand? We do what we call a cardiopulmonary exercise test to test their maximal fitness and we do a series of strength tests to see how strong their muscles are.

We give them a packet of questionnaires about quality of life, fatigue, depression, and other cancer-related symptoms.

We are measuring the whole gamut of health outcomes even though our main focus is on insulin resistance and metabolic dysregulation simply because that’s the precursor to diabetes and heart disease.

We retest those measures at Week 8 and Week 16. We do follow participants after the 16-week period is over. Regardless of what group they were in, we check on them four months later to see how they’re doing.

Are there any specific eligibility criteria that you want to call attention to?

Dr. Dieli-Conwright: The main thing is that they’re over the age of 18 and that they have been on androgen deprivation therapy for the previous 16 weeks. That’s just so that we can allow the medication to stabilize the hormones. We also look to see whether or not they have been exercising regularly. If they are highly trained from a fitness perspective, then they are not eligible, so we do actually look for people who are relatively sedentary who are not participating in a structured exercise program already. We do that because we are trying to reach out to people who may be at a higher need for these interventions.

Do you care if a man has had surgery or radiation for prostate cancer?

Dr. Dieli-Conwright: No, we do not, as long as the surgery or radiation is completed. If they’re actively on radiation or actively on chemotherapy we would wait until that treatment is done. Often we get calls from patients who are very enthusiastic and eligible, but then tell us they’re starting radiation next week. We have to wait until that treatment is over and they’re cleared by their oncologist for exercise.

Is there anything else you’d like patients to know either about this trial in particular or about exercise for cancer patients in general?

Dr. Dieli-Conwright: We’ve had a number of patients participate already. It’s been very successful. It’s safe. It’s feasible. Everybody’s enjoyed the program. We’ve had very high compliance to date—almost 100%.

But it’s a strong time requirement—3 times a week for 16 weeks—so I would just say that if anybody is interested, even if it’s just a small amount, to contact us. We have very flexible scheduling times and can accommodate exercise almost 24/7. We have a large staff and a number of trainers who are eager to help. We try not to turn anybody away because of scheduling and try to work around work schedules if that’s a concern.

We would love to take more patients.

Subscribe or download our February issue to read more about this trial.

 


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NIH’s Ambitious Precision Medicine Research Program

Mr. John Wilbanks is the Chief Commons Officer at Sage Bionetworks. Previously, Wilbanks worked as a legislative aide to Congressman Fortney “Pete” Stark, served as the first assistant director at Harvard’s Berkman Center for Internet & Society, founded and led to acquisition the bioinformatics company Incellico, Inc., and was executive director of the Science Commons project at Creative Commons. In February 2013, in response to a We the People petition that was spearheaded by Wilbanks and signed by 65,000 people, the U.S. government announced a plan to open up taxpayer-funded research data and make it available for free.

Prostatepedia spoke with Mr. Wilbanks about Sage Bionetworks role in All of Us, the National Institute of Health’s ambitious precision medicine research program.

Not a member? Join us.

How did you come to work at Sage Bionetworks?

Mr. John Wilbanks: I got involved with Sage when it was first beginning. Sage was an informatics unit of Merck, and in 2009, they began to explore what they could get for the unit. But we convinced them to spin it out into a nonprofit organization instead of selling it off.

I got involved then as a board member because I was able to help negotiate what the IP structure would look like, how we would get rid of some of the patent constraints and other kinds of intellectual property so that we could build a nonprofit. I have been involved ever since, at first as a board member, then as a consultant, and then in 2012, as a full-time employee.

I lead the Governance team at Sage, which means that my group works on things like informed consent, clinical protocol design, data-sharing and access policies. We work on strange and weird structures that enable collaboration in a variety of ways, and we have a pretty broad view across the organization as a result.

What is the All of Us program?

Mr. Wilbanks: All of Us is a longitudinal cohort study. It is fundamentally an attempt to enroll a million people and to characterize them as completely as we can. This means we collect and look at their health records, pharmacy records, their environment, biospecimens, metabolic data, their genomes, data that we collect from their devices and smartphones, surveys over a ten-year period—you name it. Then, we make that data liberally available so that we can run all sorts of interesting queries.

We’re trying to take the Framingham Heart Study model and reimagine it for the 21st Century. Framingham is a breakthrough study, but it studied one town in Massachusetts, and then its diaspora over time. That means that it’s fairly white, and it has all these biases in it. Also, it doesn’t study anything besides heart health.

All of Us aims to take the idea and the impact of a study like Framingham and reimagine it using a completely modern, digital approach to everything. What would happen if you made that data liberally available? What would happen if you made a point of including 700,000 out of 1,000,000 being from populations that are underrepresented in biomedical research?

That’s one of the reasons it’s been hard to talk about; it’s not a study of prostate cancer. It’s a study that will involve hundreds of thousands of people, some of whom may have prostate cancer, some of whom may have survived prostate cancer, and some of whom may develop prostate cancer. But that’s not the focus. The idea is that we’d be able to subdivide that cohort endlessly in ways that let us think about public health and identify populations for sub-studies as easily as possible.

So then, the goal is to pull in as much data about these people as you can and then make inquiries into the data in various ways?

Mr. Wilbanks: That’s right. And we also want to open up who gets access to the data. It’s one thing to say the people at Harvard can run analytics; it’s very different to say that the community being studied can run analytics. That is also part of the design.

A lot of the questions that will be asked will come from advocates who know what questions need to be asked, questions the scientists don’t know need to be asked. We’ve been trying to design the system to maximize the number of people who are allowed to be data analysts and not just data donors. In many cases, we hope that the donors and analysts are the same people. That level of engagement leads people to start asking questions, not just providing information.

Will people be getting their own information back? Obviously, wearables and devices would feed information to their own electronic records, but I know they’re going to be doing some genomic tests. Will people get the results from those kinds of tests?

Mr. Wilbanks: Yes The study is guided by a set of core values and principles, and one is to prioritize the participant’s right to their data. All data provided by the participant will be provided back to the participant—nothing about me without me. We’re still figuring out how to do that because it’s really complicated.

Don’t you de-identify data first? Then, how do you re-identify it?

Mr. Wilbanks: That’s a little easier. You have to de-identify data before you get it to the data user. But, it’s easy to know for a given sample who that sample came from because that’s what allows us to connect it to the demographic data.

It’s relatively easy to get it back to the individual, but the question of what to return to them is difficult. If it’s their genome, do we give them their BAM files, which are massive? Or do we give them a VCF, which is the differences between their genome and the reference genome, which is tiny? Do we give them images? How many times do you let people download data because the cloud transfer cost would be high? How do we get consent for that? It’s complicated.

We still have to figure out exactly how we’re going to do all of those things, but it is a core principle of the study that nothing about you happens without you, and by the end of the study, you should have as much of your entire electronic health records in one place as possible, in one form. You should have your genome, all of the survey data you offered, all your wearable data, and you should have all the ancillary information we discovered about you. You should be able to take that with you and do what you want with it.

What is Sage’s role in all this?

Mr. Wilbanks: We are a sub-awardee of what’s called the Participant Center and the Participant Center is led by the Scripps Translational Science Institute in San Diego. We have two different lines of work inside the program, two core jobs. One is governance-based. We work on the clinical protocol, informed consent, and data-sharing systems. The other job is digital health technologies, and that’s a different team than mine. They work on building software modules that sit on smartphones and pull data off as measurements. They design them, figure out how to validate them, and how to feed them into the technology system.

You’re basically trying to figure out how you can pull data from the apps or wearables that participants already use?

Mr. Wilbanks: That’s part of the DHT group, and that’s led more by Scripps. We use the features of devices.

For examples, we think we can get a tremor measure for neurodegeneration with a module that measures the accelerometer in a smartphone. We can measure their gait by having them put their phone in their pocket and taking 20 steps forward and 20 steps back. We can measure phonation through a microphone. We can measure memory and tapping through the touchscreen.

We want to design modules like these that are clinically validated to measure those things so that anyone who wants to measure gait, lung capacity, memory, or what have you can rapidly access that inside the All of Us app or a related app. And they should feel confident that the data is relatively consistent and valid.

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Clinical Trial Eligibility + Black Men

Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

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Funding Clinical Trials

Dr. Jonathan Simons is the driving force behind the Prostate Cancer Foundation, one of the leading funders of prostate cancer research worldwide.

Prostatepedia spoke with him about what clinical trial participation can do for your own prostate cancer journey.

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How did you become involved with prostate cancer advocacy and the Prostate Cancer Foundation (PCF)?

Dr. Jonathan Simons: When I joined the Johns Hopkins faculty in 1993 as a young assistant professor, perhaps six laboratories in the world had prostate oncologists trained in molecular biology. Johns Hopkins did not have even one clinical trial in advanced prostate cancer using a medicine actually designed to fight the disease.

Then I met Mike Milken. He’d been diagnosed with advanced prostate cancer and was seeking third and fourth opinions—not only about his own case, but the state of prostate cancer research in general. Mike wasn’t new to medical philanthropy; he’d been funding a broad range of research for decades before his diagnosis. But he was new to prostate cancer, so it was encouraging when he left our meeting saying there would be an infusion of research funds and a foundation to make progress against this disease. My mentor and research director at Johns Hopkins, Dr. Donald Coffey, told me, “If anyone’s going to change this field, he’s the guy. I didn’t realize that later I’d end up being PCF’s CEO and President.

You were quite young.

Dr. Simons: I was an Assistant Professor eight months on the Johns Hopkins faculty, and I had a six-year-old and a four-year-old son running around in my office with coloring books on weekends while we set up experiments in my small laboratory. Back then, I was funded by PCF from across the hallway. They were within shouting distance. I have now a 30-year-old and a 28-year-old who do not use crayons.

What year did you officially join PCF?

Dr. Simons: I was there at the beginning in 1993 and was invited to the inaugural celebration of the founding in Washington, DC. Early funding from PCF allowed me as a physician-scientist to train in my laboratory another generation of young investigators who have gone on to become chairpersons and full professors at leading cancer institutions. Today they work toward better precision treatments and cures for prostate cancer in fields ranging from molecular biology to drug development, early clinical trials and nanotechnology. In 2007, I was recruited from the Emory University Cancer Center as its Founding Director and appointed CEO and President of the Foundation. I feel an awesome responsibility and the privilege to continue to serve the field in this way.

PCF funds quite a bit of research, both in United States and abroad. Is there a theme behind the kind of research you fund? What is your overall strategy?

Dr. Simons: The overall strategy is to fund the world’s best, most innovative ideas early enough to reduce deaths from prostate cancer, reduce suffering from prostate cancer, and ultimately eliminate prostate cancer as a plague on humanity. What that means, though, is that we fund mostly laboratory-to-clinic, game-changing, early-stage research in university and cancer center laboratories. We find partners to leverage this funding with additional government or biopharma support. We also fund research to help guide those therapies into the clinic to test whether they are successful or not.

If the treatment shows promise, we try to leverage further the tens of millions of philanthropic dollars that we put in at the beginning with hundreds of millions more from Department of Defense, National Cancer Institute, Stand Up 2 Cancer, the V Foundation, and private foundations. About 80% of what we fund is precision treatment science, 10% basic biology, and perhaps 10% prostate cancer prevention including precision nutrition research.

Additionally, PCF was established with more in mind than accelerating cure for prostate cancer. From the beginning, we aspired to change the face of cancer research and to produce results that could help people suffering from a broad range of serious diseases. We never saw the process as a zero-sum game where increased funding for one disease diminished support for others. Rather, it has always been one of our key goals to increase the size of the research pie in ways that would benefit the greatest number of people.

Your organization funds the beginning idea—sparking research—and then other organizations like pharmaceutical companies or research institutes take the ball and run with it?

Dr. Simons: That’s exactly so. Spark, instigate, cultivate scientific proof-of-concept, and convene stakeholders to ensure there is a strong ecosystem to take those concepts forward for patients.

You partner with pharmaceutical companies. You partner with medical institutions and the United States government. What about other countries? Do you work with groups in other countries?

Dr. Simons: We fund research in 21 countries. We have working partnerships with five foundations. We usually lead invest, but we are delighted to co-invest in research, particularly new kinds of treatment. We should really be called the Global Prostate Cancer Foundation.

It has been difficult for researchers to get patients to enroll in clinical trials. Why do you think that is? What has been the obstacle to getting men to participate?

Dr. Simons: It is complex. I wish I knew all the answers. I think one reason is that patients feel fear about receiving a placebo and about being a guinea pig. That almost never happens in the kind of treatment research that we fund.

But I also think there is a lack of access to information about trial availability. I still think patients aren’t empowered to ask which clinical trials could help them have a better outcome and also help others. I don’t think the system is proactive. (Crate and Barrel bothers me a lot more about their products than the National Cancer Institute bothers patients about whether or not they might be eligible for a precision medicine trial.)

We’re trying to increase awareness of these newer precision medicine clinical trials that have a much higher probability that the drug will work because the target gene is expressed or mutated. Basically: your tumor is vulnerable now and we’re getting access to it, so the investigational drugs have a real chance of getting you back into remission. I think those are the major challenges.

Another issue is distance and travel time and associated costs. Clinical trial participation goes way down if it takes the patient more significant time to get to the hospital. If you are enrolled in a clinical trial, you have to go back and forth more often to see the doctor and nurses monitoring you. With a longer commute, participation rates fall. We’re therefore very interested in telemedicine, or using the internet, so patients don’t have to drive as much. That’s still experimental. Dr. Matthew Galsky, from Mount Sinai, is working on that problem.

Using telemedicine in clinical trials?

Dr. Simons: Yes. Most everything in the clinical trials world is still analog, and yet we live in this extraordinarily digital age. I’m talking to you on my phone—a piece of glass with some metal off ultra high frequency radio waves. Right before this call I was looking at an MRI scan on my iPhone. I can do that, but we still make patients drive 90 minutes to see a doctor when we could probably use a smartphone.

There are a lot of ways we could very reliably take care of patients in an outpatient fashion. We just haven’t fully digitized clinical trials, particularly for patients at a distance. There are a lot of ways to innovate around digital healthcare that would help make clinical trials easier for prostate cancer patients.

I think some men assume that a clinical trial might not be an option until their cancer has advanced. They wait until things have gotten really bad and then they look for a trial. I don’t get the impression that many people think about trials when they’re first diagnosed.

Dr. Simons: No.

But there are trials for the newly diagnosed, aren’t there?

Dr. Simons: Absolutely. And a lot of them offer the possibility of much greater longevity and survival. Your instinct should be: where is the right clinical trial? But you’re still processing, thinking, “My God, I have cancer!” We could do a much better job of educating patients.

How do most people find out about clinical trials? Just waiting for your doctor to say that she has found a trial you might want to consider? Or is the burden on the patient to find the trial?

Dr. Simons: Most of the time, if your physician isn’t a real champion, it’s just not a part of the consultation. Most clinical trial enrollment happens because you have a urological oncologist who believes in putting patients on clinical trials and is probably participating in one. We’d like patients at every stage in their journey to look for a clinical trial with the idea that it might offer a better plan of care than they would otherwise have. We could also do a better job of encouraging nurses to talk with patients about clinical trials.

How would you suggest men look for trials?

Dr. Simons: The site http://www.clinicaltrials.gov is an excellent place to look. I think www.PCF.org is an excellent place to look as well. Making a habit of asking your doctor if there are any new clinical trials for where you are is also a great idea. Create the expectation that your doctor has to pay attention to potential trials.

The site http://www.clinicaltrials.gov tends to be a little bit technical. I would think it might be difficult for the average person to sort through.

Dr. Simons: You can always just ask your nurse or doctor about it. But I agree. We put more than 82 cents on the dollar into our research mission every year. But we wish we had the resources to create an incredibly patient-friendly, readable, real-time, digital website for clinical trials. Until somebody does that, clinicaltrials.gov and pcf.org are good places to find the really important trials.

I suppose you could always come up with a list of trials and then bring it to you doctor and ask if any are appropriate for you.

Dr. Simons: Yes. For right now, that is the best thing to do. The first thousand men cured of advanced metastatic prostate cancer will all be on a clinical trial. That’s a true thing. This is how we talk to lymphoma patients. It’s just more and more possible to talk about it for prostate cancer.

Prostate cancer is undergoing a revolution that other cancers have already gone through?

Dr. Simons: We’ve cut the death rate down by 52%. That’s incredible. For the last 48%, we’re going to need clinical trials. We need patients on clinical trials to take the death rate to zero. Sometimes prostate cancer, unfortunately, escapes surgery or radiation and comes back. While we’ve significantly increased the overall survival rate, we’re not yet able to cure the majority of men. We think we can. We know we can, but we have more work to do.

What does the financial end of clinical trial participation look like? Do men have to pay a fee for the therapies?

Dr. Simons: In clinical trials, research drugs are always free. Medical care is always free. The inconvenience is what is costly. Some employers are very difficult about you missing work for a clinical trial. There is a lot of going back and forth. They call it wage and financial toxicity. One of the effects of the experimental drug is toxic to job security. (It’s hard enough when you’re a cancer patient and worried about your employer.) But the drugs, the pharmacy, the medical care, and the scans are all free.

Is there anything else you think patients might want to know about clinical trials?

Dr. Simons: The misperception is that patients will be treated like guinea pigs. But the first thousand patients cured of prostate cancer will all be on a clinical trial. Every major clinical trial is changing prostate cancer patient survival.

For example, in the SPARTAN trial for Erleada (apalutamide), the drug was so effective that within two weeks of presenting the results, it was FDA-approved. That’s a record. Data was presented showing that 800 patients were benefitting from the drug, and then it was approved.

The only drug that gained approval that quickly in all of oncology was Soltamox (tamoxifen) for breast cancer. We think this is going to happen all the time now.

The SPARTAN Trial focused on patients for whom previously there were no treatments. They saw their PSAs going up, but they were not metastatic. There was really nothing for them to do except wait until we started seeing metastases.

Now, with Erleada (apalutamide) there is a chance that they’re not going to see metastases for years. They’ve got hope. For that first group of men, all of this is possible because they found that clinical trial. Hundreds of men who participated in the SPARTAN trial are going to have a prolonged time without metastases.

Would you encourage newly diagnosed men to seek out clinical trials, even if their cancer is under control?

Dr. Simons: Yes. I encourage every patient to think about joining a clinical trial. It’s not an easy message, but there are many studies showing that you get better nursing just by being on a clinical trial. You just get more attention. You can be there for the cure.

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