Marc B Garnick, MD, Editor in Chief, HMS Annual Report on Prostate Diseases; Gorman Professor of Medicine, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA . E. David Crawford, MD, Professor of Urology and Radiation Oncology at The University of Colorado, Anschutz Campus, Aurora, CO; Medical Advisor and Founder, 3DBiopsy, Inc., Aurora, CO

Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think?

A: The long awaited updated recommendations from the United States Preventive Services Task Force, issued at their traditional 5-year interval, got it right–Again! While the 2012 “D” recommendation from the Task Force was met with great skepticism and animosity from several groups, the change in the 2017 recommendation now emphasizes the importance of the Task Force’s continuing evaluations of new and more mature data.
In a series of four detailed, analytic and erudite publications that provide the underpinnings for their new recommendations, even the most serious students of prostate cancer and prostate cancer screening–ourselves included–can appreciate the enormous task that members of the Task Force and its sub-sections undertook. The result not only justifies the correct C recommendation for those men between ages of 55 and 69 and the unchanged D recommendation for those above 70. Moreover, the recommendation calling for the serious need for more study about the complexities facing men who are at increased risk for prostate cancer– African-American and those with a significant family history–should serve as a call to action for research agencies whose worldwide populations are affected by this common cancer. The complexities of prostate cancer biology are outlined in these accompanying publications and will undoubtedly provide avenues for productive future research programs.
The changes in the Task Force’s recommendations appropriately relied heavily on several key studies- among them, the PLCO, ERSPC and ProtecT. Of the key factors that have become available since issuance of the 2012 “D” guidelines were both the increasing utilization of active surveillance–to help address the issue of over-diagnosis and the harms of overtreatment–and the potential that the development of metastases could be decreased by treatment compared to active maintenance. This latter assessment emanated from the UK ProtecT study and its context must appreciate that many of the patients enrolled in that study who received no active treatment had cancer characteristics such as high Gleason scores that would generally have prompted interventions here in the United States.
In the end, the Task Force has in fact provided a strong rationale for what is commonly happening in practice today despite the universal 2012 “D” recommendations. Patients should consider shared decision making with their health provider about the harms and benefits of undergoing screening, and treatment if a cancer is found, and that values and preferences of the individual patient should play an important role. But, today, as was the case in 2012, the ability to show an overall survival benefit from any screening recommendation still eludes us and the cancer-specific survival benefit, if one exists at all, is at best, very modest. Hopefully, these updated screening guidelines will encourage meaningful research to enable real advances at the patient level to be achieved.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Al Musella, DPM, President, Musella Foundation For Brain Tumor Research & Information, Inc., Hewlett, NY. Marty Tenenbaum, PhD, Founder and Chair, Cancer Commons, Los Altos, CA.

Q: Your April 5, 2017 blog post that proposed a new “Conditional” category for FDA drug approval elicited a number of positive and negative responses. Please explain the proposal in more detail to enable better reader understanding.
A: In Response to “Conditional Approval: Right Solution for the Wrong Problem” by
Shannon Brownlee:
We appreciate Ms. Brownlee’s comments on our recent blog post, but think she missed our key points—perhaps we weren’t clear enough:

• Conditional approval isn’t intended for cancers that have other options—like some types of breast cancer—but rather for the invariably fatal cancers like glioblastoma multiforme (GBM), for which there aren’t any good FDA-approved options.
• Conditional approval requires not just evidence of safety, but evidence that the drug has promise, at least in some patients.
• Using the registry is just a different way of collecting the data that traditionally is collected in clinical trials. Instead of a traditional trial in which only highly selected patients participate and relatively few doctors collect the data, we will be collecting data on the entire range of patients from many doctors.

Having many doctors and patients participate removes a lot of the bias inherent in clinical trials. For example, consider a doctor using an experimental treatment on “thousands” of brain tumor patients in 100 clinical trials in which only a handful of doctors are collecting all of the data. All of the doctors involved have a major financial interest in the outcome. We still have no idea if this treatment helps or hurts—and it has been going on for 40 years. With our system, we would know in a year if it helps or hurts.
Moreover, Ms. Brownlee’s arguments extolling the virtues of randomized clinical trials (RCTs) may reflect an unfamiliarity with the cost-effectiveness of “registry trials,” especially when coupled with modern Bayesian designs.
With the traditional approach, we have been lucky to get 3 or 4 treatments approved in the last 40 years. With our approach, we can expect at least 3–6 new treatments conditionally approved each year, as the cost to get approval would be on the order of 1–2% of the cost using the current traditional approach.

• As Ms. Brownlee states, “It took more than a decade to accumulate enough patients” in an RCT to demonstrate the ineffectiveness of autologous bone marrow transplant (ABMT) in breast cancer. Further, “A few patients may actually have been helped by the Avastin, but there is no way to predict ahead of time whether patients would be helped or harmed.” These points demonstrate the limitations of classical RCTs versus Bayesian point-of-care trials that can be run on top of a registry.
• The big challenge and opportunity regarding investigational treatments that show promise in some patients is to identify and continuously refine the cohort for whom an intervention is effective, as efficiently as possible. This requires a Bayesian approach, which can rapidly replicate successes and discard failures, not accruing a large trial to test a specific hypothesis, which is likely to be wrong.
  
• A registry that captures biomarkers, treatments, and outcomes from patients undergoing a variety of interventions can provide rigorous cross-controls, which are every bit as valid as those provided by randomization.

Using Ms. Brownlee’s example of ABMT, in our system, the registry would have quickly picked up that it was not as good as standard chemotherapy. The current system allowed 41,000 women to use a treatment whose effectiveness was unknown because nobody was tracking it. An RCT took 10 years to find an answer that our registry may have had in as little as 1 year, saving many lives.
Ms. Brownlee states that the registry can’t show efficacy. We disagree. If you have the majority of patients being tracked in the registry, you can use all of the patients who are NOT taking the treatment as the control group. Comparing to the old historic control is useless for brain cancer—almost everyone died and we did not collect the necessary biomic data to correctly match them with current patients.
The comparison that needs to be made is which of many possible new treatments and combinations works the best. Some patients would probably stick with the old standard of care—we would be encouraging them to participate as well—so we can see if the current standard is better than any of the new treatments.
We are talking about using conditional approval only in cases where there really is no acceptable standard of care. And we ARE looking for new drugs and combinations that have extraordinary power to improve outcomes, not looking for something that extends life by weeks. We agree it wouldn’t make sense in a disease where the standard treatments offer hope.
In summary, our proposal is not to minimize the research, it is to maximize the amount of research done to a drug, just in a different time period—after phase 1 instead of before the end of phase 3.
As to picking up idiosyncratic reactions, by definition, these are rare and do require a large group of patients being tracked to identify how frequently they occur. With our registry, it is simple to analyze the data and get an early warning. Having the genomic data would allow us to try to figure out which patients are most likely to have such a problem. With traditional trials, which usually only allow a select population to be tested, a reaction that only occurs in the elderly or in minorities—which are underrepresented— may never be found. Once a drug is approved and underrepresented groups use it, side effects are not tracked as closely as they would be in our registry.
For more reference, please read “Rapid Learning for Precision Oncology” published in Nature on Jan 21, 2014. We include a free PDF download. Please see below for a 3-minute video showing how the Bayesian approach can be applied to medical research in a new method called Global Cumulative Treatment Analysis (GCTA).

Shannon Brownlee, MS, Senior Vice President of the Lown Institute, a think tank in Boston. She is also co-founder of the Right Care Alliance, a social movement for transforming health care.

Q: Musella and Tenenbaum recently proposed a new way, called conditional approval, for the American FDA to move potentially useful drugs to a patient market. They wrote that safety would be covered and efficacy assessed by a registry. What do you think of that idea?
A: Imagine if there were a way to speed up the discovery and testing of drugs for cancer. Al Musella and Marty Tenenbaum, founders of two cancer patient advocacy organizations, think they have just such a plan.
They have proposed giving new cancer drugs conditional approval, allowing them on the market after Phase I (safety) trials in as few as 50 patients. Patients and their doctors would be free to use the new, and unproven products, provided all patients enroll in a registry. The patient’s (de-identified) clinical information (pathology reports and biomarkers, for example) would be included in the registry. This would allow the FDA and researchers to determine, by the end of a pre-set conditional period, whether or not the drug is safe and effective when used on a larger population.
Sounds like a great idea, doesn’t it? It eliminates Phase III efficacy trials, which are slow to complete, expensive to conduct, and drive up drug prices. Musella and Tenenbaum’s plan would give patients ready access to potentially life-saving treatments, speed up approval, reduce the burden on the FDA, bring down the cost of drug development, and create a registry for cancer patients that would open up research avenues. What’s more, Japan, Canada, and South Korea have conditional pathways for new cancer treatments. Why not us?
Because it’s a bad idea that will waste a lot of money and hurt patients. Have we all forgotten the recent history of ineffective and harmful cancer treatments? Autologous bone marrow transplant, or ABMT, and Avastin (bevacizumab) are two that come to mind.
ABMT was developed in the 1980s and was used on at least 41,000 women with metastatic breast cancer. Oncologists, transplanters, and the press embraced the treatment enthusiastically on the basis of a single study comparing it to historical controls. It took more than a decade to accumulate enough patients in randomized controlled trials (RCTs), which showed in 1999 that ABMT was worse than standard chemotherapy—it killed about 10 percent of patients. Insurers paid more than $3.4 billion over the course of the decade for a treatment that actively harmed patients.
A decade after that, Avastin was approved for breast cancer on a fast track in 2008, based on “time to progression.” While there wasn’t any proof that time that progression directly affects how long patients live or their quality of life, Genentech, the manufacturer, argued that it was a good marker of improved patient outcomes. By 2010, worldwide sales of Avastin had hit $6.8 billion.
But once again, it took an RCT to show that the drug caused significant side effects and offered no survival benefit. A few patients may actually have been helped by the drug, but there is no way to predict ahead of time whether patients would be helped or harmed. The FDA withdrew Avastin’s approval for breast cancer treatment in 2011.
Imagine Avastin under a conditional approval plan. Women on the drug would have enrolled in a registry, and that registry might have turned up the side effects that emerged in the actual post-marketing trial. But it could not have shown lack of efficacy.
There are several reasons for this, the main one being that outcomes for people on a registry have to be compared to something. That something would be historical controls–similar patients who have had other treatments. The benefits of most cancer treatments are modest at best, and it’s very easy to be fooled by historical controls unless a new drug has extraordinary power to extend life or cure the disease.
There are other ways to solve the problems of high drug prices and slow development of truly innovative drugs for rare cancers, which Musella and Tenenbaum cite as their motivation for recommending conditional approval for cancer drugs. Congress could let Medicare negotiate drug prices. It could increase the FDA’s budget to speed up approvals. (FYI, the FDA already approves drugs faster than any regulator in the world.) Insurance companies could be required to cover treatment for patients in randomized controlled trials.
Even though Musella and Tenebaum’s registry is a bad replacement for RCTs, it’s still a great idea. Manufacturers can track defects in cars and toasters better than the US tracks outcomes and safety of new medical products. Registries should be required for every patient who receives an implantable device or a new drug for any condition. Let’s use registries for what they’re good at, which is spotting harms once a product is used in a large population. Don’t erode the approval process for the sake of speedy access to drugs of uncertain benefit.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

John R. Craig, MD PhD, Retired pathologist and formerly Medical Director, St. Jude Cancer Center, Fullerton, CA; Member, Board of Directors, FibroFoundation

Q: You were the lead author in a 1980 paper in Cancer that clearly delineated an unusual form of Hepatocellular Carcinoma that you termed “Fibrolamellar Carcinoma”. Now, 37 years later, what insights of importance can you share about this unique malignancy?

A: CRISPR/Cas 9 technology, fruit flies, mice and zebrafish are among the tools being used in numerous academic laboratories, encouraged by the Fibrolamellar Foundation, to determine whether the 400kb deletion found on Chromosome 19 in 90% of patients with Fibrolamellar Hepatocellular Carcinoma (S. Simon PhD, Rockefeller University) is a driver mutation.
In 1980, with renowned liver pathologist co-authors Hugh Edmondson and Robert Peters, I compiled and published the first large series of Fibrolamellar Hepatocellular Carcinoma (FL-HCC) cases in the journal Cancer.
This rare cancer has an annual detection rate of approximately 100-200 patients in the USA and occurs primarily in young adults 15-30 years of age.
After our publication, we received many consultations by pathologists who were eager to share patient information and observation. Over the next 25 years, additional publications introduced unusual findings such as increased serum vitamin B12 binding globulin and other tumor markers, such as des-carboxy prothrombin, and plasma neurotensin. Unfortunately, none of these observations advanced either the detection of the tumor or improved treatment.
Some patients are cared for at academic medical centers, but neither chemotherapy nor radiation treatment has been found to be useful. Complete surgical resection offers the best hope but is usually performed late in the course of the disease since the young patients are often thought to be in good health and have few symptoms.
In recent years, these young patients often connect by social media and have developed Facebook pages. They communicate about their disease, their suffering, treatment options, and acceptance of their disease. There is an annual fall meeting of patients and families to share their experiences.
The family of one young patient (Tucker Davis) answered the plea of their son, and in his honor, in 2008, established the Fibrolamellar Foundation with the goal of finding a cure.
The mutation described above is the result of a fusion of the first exon of DNAJB1 with exons 2-10 of PRKACA. This mutation results in a functional chimeric protein, DNAJ-PKAc, which is highly expressed in almost all FL-HCCs. Little is understood about how the mutant PKA kinase may drive cancer formation.
Numerous academic laboratories are developing models to study this genetic deletion and attempt to learn how it changes the hepatocyte and promotes metastasis. There is hope that treatment may be discovered by interrupting this mutation effect within the malignant cells.
Protein kinases are involved in complex intracellular signaling involving cell proliferation, motility, angiogenesis, anti-tumor immune reactions and other functions. There are more than 518 kinases known within the human genome but the functions of most are not understood. However, small molecule kinase inhibitors are already active in current cancer treatment for chronic myelogenous leukemia, acute lymphoblastic leukemia, and several other cancers of lung and breast. However, no kinase inhibitors are known for this mutant kinase in FL-HCC.
In our initial article, we suggested a possible etiology due to modern industrial life with pesticides or chemicals. But a recent search of old records in a large reference academic center identified some patients with this cancer long before 1940. Thus, our modern industrial contamination may not be a reason for tumorigenesis.
Similar to many other organizations representing rare diseases, the Fibrolamellar Foundation is a philanthropy that has encouraged collaboration by major academic centers and scientific research meetings bringing together diverse scientists to discuss the models and consider investigations. Ultimately, collaborative clinical trials will be necessitated since this malignancy is rare.
We believe that collaborative research with multiple experts in diverse fields who share data and concepts will be necessary in order to apply the knowledge and develop the understanding of how to connect this chimeric protein mutation and ultimately produce an effective treatment.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Srivani Ravoori, PhD, Associate Director, Science Communications; American Association for Cancer Research

Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.

In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed immunotherapy expert Elizabeth Jaffee, MD, on her views on what might develop in immunotherapy this year. Dr. Jaffee is the Dana and Albert “Cubby” Broccoli Professor of Oncology and Professor of Pathology at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. She is also the Associate Director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins. Dr. Jaffee was recently named the President-Elect of AACR for 2017-2018.

Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?

A: “The good news in the field of immunotherapy is that we are learning a lot more about the signals that tumors send to inhibit an effective immune response against them,” says Jaffee, who is a past board member of the AACR.We have already turned this knowledge into therapeutics that inhibit some of these signals (checkpoint inhibitors) so the T cells can be effective in attacking the cancer cells, and developing therapeutics that can activate certain other cells within the tumor microenvironment (checkpoint agonists) to help further activate the T cells, she says.
With these approaches, we have been able to convert some metastatic cancer patients with weeks to live into those with chronic disease living a better quality of life, Jaffee adds. In 2017, we are going to see checkpoint inhibitors being approved for more cancer types and as first-line treatment for some cancers, she notes.
The bad news, however, is that these drugs only work for about 20 to 25 percent of all cancers. Further, these drugs can unleash autoimmunity in patients who respond. The side effects can be controlled currently with steroids in some patients, but this year we will learn more about ways to deliver these drugs in a more targeted way to circumvent the toxic side effects, Jaffee says.
“In 2017, I expect to see the development of new drugs that target additional immune checkpoints,” says Jaffee. One reason why almost 70 percent of cancers do not respond to checkpoint inhibitors is that the cancer cells inhibit different pathways that affect T-cell function. Therapeutics targeting immune-evasion mechanisms other than the PD-1/PD-L1 checkpoint, such as IDO, CD40, OX40, TIM-3, LAG-3, and KIR, are already in early clinical development. We will see them progress to clinical testing, alone or in combination with PD-1/PD-L1 drugs, and some of them may be approved or may come close to approval this year, Jaffee predicts.
This year, we will also see a lot of preliminary data identifying new biomarkers of immunotherapy response, according to Jaffee.

 
Other approaches to get more patients to respond to immunotherapies include activating T cells using vaccines, radiation therapy, or different types of immune-activating chemotherapies, Jaffee says. Combining immune checkpoint inhibitors with agents that can help uncover cancer antigens, such as PARP inhibitors that can make new tumor antigens available to the T cells, or epigenetic agents that can turn on the expression of certain proteins, is another avenue. “We will start seeing results from such studies this year,” Jaffee notes.
We are likely to make more progress this year in personalizing cancer treatment with vaccines, Jaffee predicts. “We are starting to understand the importance of neoantigens for targeting by the immune system,” Jaffee notes. Tumors of many patients who respond to immunotherapy create neoantigens constantly. If we can identify them by sequencing the tumors, we can develop vaccines against them to jump-start the immune system, she says. “We are going to see several clinical trials trying this approach this year.”
“As a member of the Blue Ribbon Panel, one of the 10 areas we identified as at the point of making huge progress is basic research to better understand the mechanisms behind immunotherapy response,” says Jaffee. Answers to questions such as, “What makes a pancreatic cancer that doesn’t respond to immunotherapy different from melanoma that responds to immunotherapy?” or “Why do some tumors that have the biomarker of response not respond while some that do not have the biomarker respond?” or “How to make CAR T-cell therapy work in solid tumors?” can only be found by pursuing more basic science research, she notes.
“We have the technology to find answers to many basic research questions and there is excitement among academia, industry, and federal agencies to work together; however, we need more funding to pursue such important studies,” says Jaffee. While she is concerned about the uncertainty regarding the scientific priorities of the new administration, she is cautiously optimistic.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.