Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Next Steps for Improving Clinical Evidence and Consistency of Payment for Precision Oncology

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Kathryn A. Phillips, PhD, Professor of Health Economics and Health Services Research; Founding Director UCSF Center for Translational and Policy Research on Personalized Medicine; Dept. of Clinical Pharmacy; Institute for Health Policy Studies; Comprehensive Cancer Center
University of California, San Francisco

Q: Adoption and insurer coverage for precision oncology may require evidence that it can improve patient outcomes. The current situation is confusing for many. What are some practical next steps that workers in the field can take to improve clinical evidence and consistency of payment?

A: It’s been said that the greatest challenges facing genomic medicine are not scientific, but economic. Much has been written about the need for improved clinical evidence and consistent reimbursement policies, but there have been relatively few studies that illuminate what steps can be taken to address them. Two new studies from the University of California San Francisco Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) address these questions.
A newly published study in Genetics in Medicine combines insights from TRANSPERS collaborators and leading genomic medicine experts to identify evidence gaps in genomic medicine that comparative effectiveness research can address, with direct relevance to precision oncology. For genomic/precision medicine to fulfill its potential, it must be (1) evidence-based and (2) consider a full range of patient outcomes. Does the literature to date suggest that these objectives have been met? TRANSPERS and experts from multiple institutions addressed this question. This is the first study that uses a systematic structured literature review (combined with expert input) to provide an overarching assessment of comparative effectiveness research for genomic medicine. We found that all included reviews (N=21) identified potentially important clinical applications of the genomic medicine interventions. Most had significant methodological weaknesses and there were few studies of conditions other than cancer. There were only a few analyses examining a broad range of patient-centered outcomes. Our findings provide next steps about where to focus future research activities and policy initiatives by identifying conditions, tests, and interventions where comparative effectiveness questions may be appropriate for study. We also discuss the limitations of prior research and how they could be addressed.
Specifically for precision oncology, we found that studies are needed to measure whether tumor sequencing tests lead to better clinical outcomes than alternative prognostic methods in different stages of common cancers. Additionally, studies are needed for cancer risk assessment panels that examine the consequences of testing for individuals and families including acceptability to patients, adherence to screening, delivery of genomic testing, and models to estimate the incremental net benefit of testing and optimal testing intervals.
Another recent publication from TRANSPERS identifies opportunities to resolve reimbursement challenges of genetic panel tests for cancer risk assessment. This study, published in the Journal of the National Comprehensive Cancer Network used data from payers themselves to address not only reimbursement challenges but also opportunities for resolving those challenges. Hereditary cancer panels – testing for multiple genes and syndromes – are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. Our study of private payers found a number of barriers to coverage for hereditary cancer panels including poor fit with coverage frameworks, insufficient evidence, and departure from pedigree/family history-based testing toward population-based genetic screening. Opportunities for addressing these challenges includes refining target populations, developing evidence of actionability and pathogenicity/penetrance, and creating infrastructure and standards for informing and re-contacting patients. We also need to separate research from clinical use in the hybrid clinical research setting and adjust coverage frameworks. Our findings have particular relevance to the NIH’s Precision Medicine Initiative, which will assemble and study an unprecedented cohort of one million or more volunteers who will contribute genomic, clinical and lifestyle data to accelerate genetic science.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Conditional Approval: Right Solution for the Wrong Problem

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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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

In Memorium: Richard E. Horowitz, M.D.

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by Dr. George Lundberg

Searching for Truth in Cancer Clinical Trials

Richard E. Horowitz, MD, Clinical Professor of Pathology, Keck School of Medicine at USC; Emeritus Professor of Pathology, UCLA School of Medicine; Consulting Pathologist, Los Angeles Veteran’s Affairs Medical Center

Q: Who has been among the strongest supporters and most constructive critics of CollabRx (since 2010) and Curious Dr. George (since 2016)?
A: American pathology lost one of its greatest leaders (and I lost one of my best friends) when Richard Horowitz died on March 15, 2017 in Los Angeles, California. Still of sharp mind and keen humor, he died with dignity and grace, in a manner of his own choice during home hospice care, of metastatic non-small-cell adenocarcinoma of the lung.
Richard and I met across an autopsy table at the old LA County General Hospital in summer 1967. We bonded and remained colleagues and friends who shared many professional beliefs based on personal experiences for 50 years.
Richard was born in Vienna, Austria on May 17, 1931. He left Austria with his parents to flee Hitler’s scourge in 1939.
His college was UCLA, medical school UCSF, internship at Los Angeles County General Hospital, and pathology training (after 2 years in the US Army at Walter Reed doing germfree research) at Mount Sinai in New York. Richard was one of those rare individuals who could keep one foot in academia and one foot in private practice in perpetuity and perform brilliantly in both.
Richard’s “real world” pathology practice management writings and teachings exerted wide influence. But his “tour de force” was always the irreplaceable medical learning uniquely gleaned from his legendary “Organ Recitals” at USC, UCLA, and especially the Wadsworth Veterans Administration Hospital.
Richard achieved many positions in organized pathology, wrote numerous articles, chapters and books, and received many awards.
Family life was very important to Richard; he leaves his lovely and dedicated wife Nona, 3 daughters, and 4 grandchildren.
Richard’s total course of illness after initial diagnosis (malignant pleural effusion discovered at a routine annual medical checkup with established widespread metastases) was 9 months. He tried “Precision Oncology”; his cancer was found to harbor an EGFR mutation, so he was begun on erlotinib. He experienced adverse effects of such severity that he decided to decline further “curative” therapy of any sort and quickly moved into palliative home-hospice care.
Richard’s last publication in a primary source medical journal was in February 2017 in the Archives of Pathology and Laboratory Medicine. Co-authored with Dr. Sarah Bean, it was entitled “Pathology’s Stepchild”, all about the dilemma of Clinical Chemistry and what to do about it.
His final (of many) contributions to the CollabRx discussion group posted on February 25, 2017. It reads:
Sirs & Madams:
You are making pronouncements and decisions based on insufficient knowledge.  Until the use of autopsies becomes the standard of whether the new therapy worked or how the new therapy’s side effects caused the death, we do not have adequate data.  I previously sent the following:

  1. A letter sent to the Wall Street Journal (Published on Sep 23, 2016)
    . . . The autopsy is credible outcome measure; nothing else can attest as convincingly to the accuracy of a diagnosis or the efficacy of a therapy.  Few, if any, clinical trials utilize the autopsy to test their hypotheses . . . .
  2. A short composite of the many autopsies I have personally done:
    The patient has Stage IV lung cancer; all standard therapy has failed.  The patient is coerced into treatment, first with targeted therapy and later, with immunotherapy.  Soon he experienced diarrhea – the oncologist “handles” that with loperamide which results in annoying constipation. Then after a few days, there is marked increase in dyspnea – is it a progression of the disease, perhaps carcinomatous pneumonia or therapy related (auto-immune) interstitial pneumonitis? Well, that can certainly be treated with steroids.  Oh, the oncologist forgot to tell the patient that he needs CNS radiation because of brain metastases.  So the patient is given a course of radiation therapy – unfortunately, there is significant cerebral edema.  Again the oncologist ameliorates that with steroids, however, the cognitive impairment and confusion persist.  About the same time there are some cardiac arrhythmias – are they due to metastases to the heart or due to “auto-immune” myocarditis?  No worry, add some more steroids.   Regrettably a mixed bacterial and fungal pneumonia develops and that, of course, is treated with powerful antibiotics.  Within a brief period of time another bout of diarrhea, this time due to C.difficile, develops and progresses into a dire megacolon that appears about to perforate.  The patient is taken to surgery, the colon has, in fact, perforated and a segment is resected.  In the surgical ICU the early signs of sepsis appear, soon septic shock ensues and the patient dies after prolonged intensive, but futile, care.  The surgeon requests an autopsy, the oncologist does not attend the autopsy and does not answer the call when informed of the Cause of Death.

In September 2015 the National Academy of Sciences/IOM released their Report “Improving Diagnosis in Health Care”. The report listed eight Goals and multiple recommendations. Goal 4 was to develop and deploy approaches to identify, learn from, and reduce diagnostic errors and near misses in clinical practice and Recommendation 4C was that HHS should provide funding…to conduct routine postmortem examinations on a representative sample of patient deaths. It is incumbent on oncologists to obtain autopsies – then they will know if their “magic bullet” worked or killed.
R.E. Horowitz, MD
George Lundberg, MD
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Fibrolamellar Hepatocellular Carcinoma: Still Rare but Deadly

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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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

A Proposed New FDA Drug Approval Pathway: “Conditional”

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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: The delay time from discovery/observation, through validation to approval and distribution/use of new cancer treatments remains excessive. With promising experimental treatments, advanced computer technology and biostatistics, creative alternatives to traditional randomized clinical trials, and a government seeking efficiencies, might it now be time for the FDA to issue: “Conditional Approvals”?
A: The first advances in oncology occurred at a time when there were no regulations. Doctors had ideas, and put them to work immediately. They adjusted and combined treatments as needed until they were optimized and became standard treatments. Many types of cancer were cured by this work.
Unfortunately, for patients, with glioblastoma, pancreatic cancer and other rarer cancers, the prognosis remains dire: average survival with currently approved treatments is less than 2 years. These patients can’t afford to wait a decade or more for new drugs to be approved.
The good news is that the oncology drug development pipeline is full of promising targeted- and immuno-therapies that have already demonstrated safety and at least some evidence of effectiveness. However, under current regulations, it will take years before the average patient can get access to these potentially life-saving treatments. Moreover, it is likely that a cure will involve intelligent combinations of treatments. Under current regulations, combination testing cannot even begin until these drugs are approved. And what if a new treatment was not effective as a monotherapy, but could be an essential component of a multi-drug cocktail, say to block a resistance pathway. Catch 22. Under current regulations, many good ideas will never get to patients, and those that do get approved have to be priced so high that many patients cannot afford them.
We would like to propose a new pathway to FDA approval – the “Conditional Approval” – that addresses these issues. It would allow the FDA to approve a treatment that shows safety and a biological effect in a small group of patients. (Click HERE for more details). The twist is that it would require patients using these drugs to participate in a registry where their doctors submit details on the treatments they use, side effects and outcomes.
Conditional approval would be granted to treatments that have been proven safe in a clinical trial(s) with at least 25 patients, and have demonstrated biologic activity: an improvement in a biomarker, brain scan, progression free survival or overall survival.
Once approved, the treatment could be offered as if it had a standard approval, and could not be denied by insurance as being “experimental”. However, all patients who use a conditional treatment would be required to participate in a registry for the duration of the conditional approval period, and to sign a consent form acknowledging and agreeing to the risks inherent in undergoing a treatment whose safety and efficacy have not been fully tested.
The FDA would conduct periodic reviews of this registry data, with three possible determinations: 1) If the safety is questionable or if the results look worse than the standard treatments, conditional approval would be withdrawn, and the manufacturer could continue on the standard paths of approval. However, the FDA could not use these results against the standard approval tracks, as the patient population was not controlled and patients were combining other treatments with it; 2) If the results look at least 20% better than the standard treatments, in the first 50 patients over a predetermined period of time, full approval is granted; or 3) If the results are similar to standard treatments, the conditional approval is maintained until the review shows either the treatment is good enough for full approval or bad enough to withdraw approval.
The decision to try a conditionally approved drug, alone or in combination, would be up to treating physicians, who could consult with peers through a network linked to the registry or use a decision support app that exploits the registry as a database (e.g., show me all treatments and combinations that have been tried on similar patients, sorted by most effective, most cost effective, best risk / benefit ratio, cost, or least side effects.) Such apps could also support low cost point-of-care ‘registry trials,’ whereby patients are dynamically assigned to treatment arms based on expert recommendations and clinical outcomes for similar patients.
It is painfully obvious that the way to cure our currently incurable cancers is to use a combinational approach. We may well have the necessary tools available today—but we are not allowed to use them. When faced with certain death, we believe it is acceptable to not have 100% proven safety and efficacy. We will be approaching the FDA with a request to pilot conditional approval in brain cancer – because life and death decisions should not be made based on regulations – they should be based on what is best for the patient, as determined by the patient and his/her doctors.
We have been working on this plan for a while, but we think now is the time for it to actually be approved. Everything is coming together – like the perfect storm:

  1. We finally have a few experimental treatments in the pipeline that look really good.
  2. The new President is slashing regulations and calling for faster FDA approvals and for slashing drug prices.
  3. Computer technology and biostatistics have reached the point where our plan for a registry trial can be just as reliable as traditional phase 3 trials – maybe more so.

IF this proposal is put into effect, it could lead to rapid advances in the treatment of brain tumors, and the possibility of a breakthrough cure in a few years, instead of the decades it would take on the current path.
We need your support and will be reaching out in a few weeks for help with writing letters and making phone calls. Meanwhile, we welcome your thoughts.
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.
 

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

AACR: Advances in Immunotherapy to Continue

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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.

AACR Immunotherapy 2017 What Advances Can We Expect

 
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

A Fully Integrated Histo-Molecular Pathology Report

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Margaret L. Gulley, MD, Professor of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill

Q: The CAP, ASCO, ASCP and AMP have developed guidelines for interpretation and reporting of NGS variants in cancers. These analyses are performed in a wide range of types of labs and involve professionals from many disciplines. The reports should take into consideration the bioinformatics, molecular data, source of specimen, age, gender, and location of patient, treatment background, morphologic diagnosis, immunohistochemical tumor profile, and special stains. Who is the best qualified and positioned person to consolidate all of this information and produce a final integrated pathology report and how should this be accomplished?

A: Pathologists are the best professionals to synthesize data from all the tests done on a given tumor specimen via an integrated report that is actionable for downstream medical decision-making.
Hematopathologists enthusiastically embrace new technologies and they are the role models for data integration and analysis of microscopy, flow cytometry, histochemistry (IHC, ISH, FISH), karyotype, PCR, or sequencing.
College of American Pathologists guidance for reporting molecular test results suggests that all results on a given tissue be synthesized by one pathologist, typically the histopathologist although increasingly the molecular pathologist who performs ancillary genomic testing. Since molecular results are best interpreted in the context of histomorphology of input tissue (e.g. percent malignant cells), and in the context of the clinical dilemma to be solved by the test, good communication is essential to assuring that professionals selecting the tissue block, doing the test, and interpreting results provide answers to pertinent medical questions. Access to patient medical records promotes high quality interpretation of histo-molecular findings.
Pathologists are in the best position to allocate precious (often small) specimens and to prioritize which ancillary tests are most critical in a given clinical scenario. Certain tests are feasible only on selected specimen preparations (e.g. karyotype requires fresh tissue), and the pathologist is vital to assuring that tissue is processed in a manner that maximizes success.
In many cases, ancillary tests are ordered by the surgical pathologist who feels comfortable synthesizing results of the test with histomorphology, even if different professionals (e.g. cytogeneticists, molecular pathologists) performed and interpreted raw data. What about ancillary tests ordered by clinicians, sometimes months or years after the microscopist issued their histopathologic interpretation? Specimen requirements must be considered (e.g. fixative type, size, % malignant cells) along with whether to test primary vs metastasis, recent biopsy vs an older or larger resection, in situ vs invasive components, etc. There needs to be better compensation for the expert work of the surgical pathologist to understand the clinician request in order to retrieve and select the best archival tissue portion for the test. Compensation is also needed for the resources required to incorporate test findings into a revised integrated report.
Ancillary tests have benefits and limitations that are best understood by the testing laboratory, so it may be realistic for the testing laboratory to synthesize data from the surgical pathology report, rather than expecting the surgical pathologist to integrate lab data. When a histopathologist feels uncomfortable performing an integrative interpretation of lab data, the histopathologist should at least make it clear in their (addendum) pathology report what test(s) were ordered on which block in order to facilitate work by another professional in synthesizing findings and minimizing accidental repeat testing.
The criteria pathologists use for tumor diagnosis and classification are evidence-based and are updated periodically by various professional groups. Increasingly, ancillary tests are value-added components of standard-of-care surgical pathology workups. Since every patient is different and every tumor is different, pathologists should be valued for their expert judgment and for taking responsibility for translating histo-chemical findings into expert consultations.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Paying for Precision Oncology – Who Decides?

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Patricia Deverka, Principal Researcher, Health Care Group
American Institutes for Research, Chapel Hill, NC; Adjunct Associate Professor, Center for Pharmacogenomics & Individualized Therapy, University of North Carolina at Chapel Hill

Q: Paying for Precision Oncology – Who Decides?
A: There is tremendous enthusiasm for the scientific rationale and clinical promise of precision oncology amongst researchers, oncologists, industry and subgroups of cancer patients. Nearly three-quarters of the compounds in the oncology pipeline have the potential to become personalized medicines and over 90% of the $25 billion personalized medicine market in 2015 came from the sale of oncology drugs that required use of a companion diagnostic, such as Herceptin and Her2 testing. The typical companion diagnostic analyzes single gene mutations or abnormal gene expression profiles, in contrast to next generation tumor sequencing (NGTS), which assays genomic alterations in tens to hundreds of genes simultaneously. Tumor profiling using NGTS now occurs frequently at major cancer centers across the U.S., however reimbursement for both the test and the off-label use of targeted therapies is unpredictable and challenging for most molecular tumor board staff, oncologists and their patients. Without coverage by either private or public insurers, most patients will not have access to NGTS tests and targeted therapies.
Payers typically use a stepwise approach for coverage decision-making when evaluating the evidence supporting the technical and clinical aspects of new molecular diagnostic tests. Based on published studies, technology assessments and professional guidelines, payers assess:
1) analytic validity – whether a new test is accurate and reliable,
2) clinical validity – if the result is medically meaningful, and
3) clinical utility of the test – whether results affect clinical decisions and improve health outcomes.
Payers are one of key stakeholder groups that require evidence of clinical utility for decision-making, however clinical utility cannot be demonstrated until analytic and clinical validity are established. As compared to “ single test/single result” assays, each of the two validation steps are inherently more difficult for payers to assess with NGTS tests, due to the complexity of the technology, as well as variation in informatics analyses and procedures for interpretation and reporting of sequence variants. Economic considerations such as whether use of the test will lead to cost offsets (e.g., reductions in hospitalizations) are potential factors in test evaluations, but they also depend on evidence of clinical utility since changes in resource utilization must be linked to an alteration in patient outcomes, such as improved response or avoidance of side effects compared to an alternative approach.
When determining medical policy for an insured group, assessment of the evidence base typically leads to a determination of whether a test is “medically necessary” and therefore covered, or “experimental/investigational” and not covered. NGTS tests create particular challenges for payers given that they include both established and novel targets and test results are used to guide the use of off-label therapy, thereby challenging the standard approach to evidence evaluations. There is growing recognition that the traditional reliance on randomized controlled trials to demonstrate clinical utility is not feasible and that use of basket trials, observational studies, registries, n-of-1 studies and modeling may be required. These study methods are less familiar to payers and will require education and published examples. Nevertheless, more payers are acknowledging that flexibility in evidence requirements is required and oncology is one of the most likely areas for innovation.
However while many payers view NGTS clinical applications as a reasonable hypothesis, they still consider this approach to be investigational. What is needed now is stronger evidence to support the proof of concept of using NGTS to guide treatment decisions. One example is the National Cancer Institute’s basket trial, Molecular Analysis for Therapy Choice (NCI-MATCH), which pairs patients’ genomically profiled tumors with a treatment regardless of anatomical location. The study has recently expanded the number of targeted therapy treatment arms and is actively enrolling patients. In the meantime, the current model of health care delivery encourages standardization and use of treatment pathways as a mechanism to promote quality of care and reduce unnecessary costs. Thus the purported advantages of NGTS tests such as individual patient customization run counter to current system incentives.
Without convincing evidence that NGTS tests lead to better outcomes through better decision-making, payers will continue to struggle in the near-term to develop transparent, evidence-based affirmative coverage decisions. One example of how the Blue Cross Blue Shield Association is addressing the problem is a new subscription service called Evidence Street. Researchers in this group conduct technology assessments of new drugs, devices and tests, including molecular diagnostics. They work with test developers, commercial laboratories, drug companies and professional societies to ensure more consistent and transparent evidence standards for their technology assessments. Evidence Street does not make coverage decisions, but provides evidence to support Blues plans in their technology evaluations throughout the country.
So what is the path forward? There needs to be a combination of efforts from all stakeholders. Researchers in both for-profit and academic settings need to design and publish context-specific NGTS clinical utility studies, using a variety of appropriate methods. They should involve patients, caregivers and payers in study planning to ensure relevancy of results and use a range of outcome measures, including those developed by various research groups supported by NHGRI, such as the Clinical Sequencing Exploratory Network (CSER). Whenever possible studies should be conducted in practice-based research networks to reduce data collection costs and reflect usual care.
There are efforts underway to collect test use and patient outcomes data more systematically as part of multi-stakeholder supported registries (ASCO’s Targeted Agent and Profiling Utilization Registry; Molecular Evidence Development Consortium) and through third party oncology data aggregators (Syapse, Flatiron). Medicare’s MolDX (molecular diagnostics) program administered by Palmetto GBA allows the option of provisional coverage for tests under its Coverage with Data Development program which is used for promising tests that meet evidence standards for analytic and clinical validity but lack sufficient proof of clinical utility.
While NGTS tests are potentially disruptive technologies, if they are to be widely covered by private and public payers, stakeholders will need to demonstrate evidence of test accuracy, medical relevancy and ability to improve the process and/or outcomes of care. Assessment of clinical utility answers practical questions such as “Can and will we take action on the NGTS test results?” and “Does the outcome change in a way in which patients and other stakeholders find value relative to the outcome without the test?” Given the opportunity costs for patients, families and the health care system, we must work together to answer these questions.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

A Plea for Gold Standards in Precision Oncology

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George Lundberg, MS, MD, ScD, MASCP, FCAP, Chief Medical Officer and Editor in Chief, CollabRx, a Rennova Health Company; Editor at Large, Medscape; Executive Adviser, Cureus; Consulting Professor of Pathology and Health Research and Policy, Stanford University; President and Chair, The Lundberg Institute; @glundberg

Q: Is Precision Oncology Accurate?
A: Precision oncology in 2017 is neither accurate nor precise.
From my clinical pathology background, accurate means correct, as close to a “Gold Standard” as you can get, regarding sensitivity and specificity. Precise means reproducible. Prasad and Galehave recently demonstrated that not even the use of the term “precision oncology” is precise. It has changed often and dramatically.
We need to determine current (they would float with new information) “Gold Standards” for every step (and many sub-steps) in the Brain to Brain loop of molecular testing and clinical actions in oncology.
For example:
WHICH cancers should be subjected to some sort of molecular analysis? All, or all except non-melanoma skin cancers? Only those cancers for which there are FDA approved therapies matched by molecular definition? Cancers for which there are open relevant clinical trials?
WHEN should NGS be performed on a cancer? At initial diagnosis, or not until after spread, or both, or after other treatment failures, or depends on histopathologic diagnosis?
WHERE to sample the tumor? Primary, and/or one or many metastatic sites, or depends on tumor diagnosis?
Should SAMPLE be liquid biopsy and/or solid tumor biopsy or fine needle aspiration cytology or whole tumor segments after surgical removal, or paraffin block, or perhaps other sources?
WHERE should testing be done: local pathology lab, regional reference lab, nearest academic or comprehensive cancer center, or large commercial lab company? Perhaps this should in part depend on lab accreditation, TAT, and price.
HOW TO CALL the variants consistently via bioinformatics and experienced professional judgment, reproducible from lab to lab.
HOW is the mutation(s) identified? As a passenger or driver? Relevant or irrelevant?
DOES a particular mutation, CNV or fusion confer “actionability”?
Would ACTIONABILITY include a clinical trial match as a criterion?
WHAT FDA-approved, or investigational, single drug or combination of drugs, concurrently or in sequence, would be the best choices?
WHEN/WHETHER should clinical trials be large and randomized, or at the level of an n-of-1 after a fully informed consent and expanded access (compassionate use)?
WHO/WHAT should pay for the costs? Patient, insurance company, government, drug company, medical laboratory, or medical treating institution?
HOW MUCH COST for the NGS testing and for the drug (which can cost $100,000- 200,000 or more per drug, per patient/cancer) can be justified by QALY or research?
WHAT THERAPEUTIC STRATEGY might make scientific sense for that patient’s cancer?
WHETHER there is ANY currently available drug that is a reasonable choice (estimated 10% of cancers).
HOW to ascertain and how to report frequency and severity of unanticipated adverse clinical effects?
WHAT outcome can be anticipated and communicated to the patient? Is there a possible cure? A few weeks or months of average/median extended life seems to me a low “bar” to affirm cost-effective “success.”
Acceptable QUALITY OF LIFE during treatment? Meaningful? Useful? Worthwhile? Pain free? Pain tolerable? Desired? Comfortable? Connected? Freely chosen?
Roughly 1.7 million Americans a year are diagnosed with potentially lethal malignancies. About 600,000 die. Establishing GOLD STANDARDS, consistent with current knowledge, is really important for many patients, the field, the public health and many micro-economies.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Precision Oncology: Requirements for the Next Leap Forward

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Razelle Kurzrock, MD, Chief, Division of Hematology and Oncology, UCSD School of Medicine; Senior Deputy Director, Clinical Science; Director, Center for Personalized Cancer Therapy; Director, Clinical Trials Office, UCSD Moores Cancer Center, San Diego, California

Q: Some workers in the field of precision oncology are growing despondent because of observed limitations of therapeutic effectiveness. What do you believe are now the best approaches to consider in order to move towards potential cures?
A: The pillars of precision oncology are genomically-targeted and immune-targeted therapies. Of interest, the fields of immunotherapy and genomics, often considered to be separate, are actually married to each other. Inhibiting checkpoints exploited by the tumor to shield itself from the immune machinery can reactivate the immune system. But, once reactivated, the immune system must be able to differentiate tumor cells from normal elements. The mutanome produces neo-antigens that permit this differentiation—and the more genomically aberrant the cancer, the more likely that the reactivated immune system will eradicate it. In contrast, with genomically-targeted therapies, the fewer the aberrations, the less likely that resistance will occur.
Yet, in treating patients, we are using old clinical trial paradigms rather than adjusting to the realities unveiled by genomic interrogation.
For instance, we administer genomically targeted therapies, mainly as monotherapy, to patients with heavily-pretreated, advanced metastatic disease—ie., the equivalent of heavily-pretreated chronic myelogenous leukemia (CML) blast crisis (where the response rate to imatinib is vanishingly low) (see Table). These patients have highly complex molecular portfolios and we should not expect that genomically targeted monotherapies will be curative.
We should not be then wringing our hands and talking about the limitations of our therapy–but rather the limitations of our approach.
The real eye opener is that so many patients with such late-stage disease respond at all.  The response rate of metastatic solid tumors to genomically targeted agents is actually much higher than that for imatinib in late-stage CML (see Table). Yet, CML is considered the poster child for successful genomically-targeted therapy, with the median survival increasing from about 4-5 years to a near normal life expectancy.
The key ingredients for transforming CML included:

  1. Identifying the driver (Bcr-Abl)
  2. Identifying matched targeted therapy (imatinib)
  3. Moving from late-stage disease (blast crisis—the biologic equivalent of metastatic solid tumors) to newly diagnosed disease.

In solid tumors, as in CML, the cancer evolves with time and becomes more genomically complex. If we therefore want to use genomically targeted treatments to cure more patients with solid tumors, we need to fundamentally change our approach:

  1. Move to newly diagnosed disease
  2. Use customized combinations rather than monotherapy or random combinations for metastatic disease, which inevitably harbors complicated molecular alterations that differ from patient to patient.

Intriguingly, for patients whose tumors have highly chaotic genomes, immunotherapy is most effective. Indeed, in diseases such as melanoma, characterized by high tumor mutational burden, the long-term disease-free survival with immunotherapy may now be about 50%–an incredible improvement over the ~18% two-year survival seen with traditional chemotherapy.
In summary, we should be elated with the results yielded to date by precision oncology. If we, however, want to leap from improvements to cures, we need to stop relying on age-old clinical trial designs and adjust our strategy to the biology of each patient’s cancer.
 

Table: Precision Treatments and Response Rates

(All solid tumor results were obtained in late-stage, metastatic disease analogous to heavily-pretreated blast crisis of CML)

 

Cancer diagnoses Precision Treatments Biomarkers Response rates (%)
CML (newly diagnosed)CML (heavily-pretreated blast crisis) Imatinib BCR/ABL ~100%~0-10%
Colorectal cancer Pembrolizumab Mismatch repair deficiency ~70-80%
Gastrointestinal stromal tumors Imatinib KIT ~50-80%
Hodgkin lymphoma (refractory) Nivolumab
Pembrolizumab		 PD-L1/PD-L2 amplification ~65-87%
Melanoma Dabrafenib plus
Trametinib		 BRAF V600E ~50-60%
Non-small cell lung cancer Crizotinib
Vemurafenb
Erlotinib
Osimertinib (T790M)		 ALK, ROS1
BRAF
EGFR
EGFR T790M		 ~60-70%
~40%
~70%
~70%
Ovarian cancer Olaparib BRCA ~50%
Prostate cancer Olaparib BRCA ~86%

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.