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

How I Cope with the Tsunami of Cancer and COVID-19 Info

Kevin Knopf, MD

Oncologists worldwide face the challenge of staying on top of the latest treatments, research findings, and other information that could help them treat their patients more effectively. Now, they must do so in the context of COVID-19. Here, our Curious Dr. George asks Kevin Knopf, MD, MPH, Division Chief of Hematology/Oncology at Highland Hospital/Alameda Health Systems in Oakland, California, how he keeps up.

Dr. Knopf can be reached at kevinbknopf@gmail.com. Or follow him on Twitter: @drkevinknopf

Curious Dr. George: Even without COVID-19, the field of clinical oncology is changing so rapidly. How do you, as a practicing oncologist, keep up with new information about cancer and COVID-19? On a day-to-day basis, do you mostly rely on the best medical journals, emails from medical associations, government agencies, press releases, actual or virtual medical meetings, hospital conferences, mainstream media, social media, or what?

Kevin Knopf, MD, MPH: There are three key journals I read regularly: two weeklies—The New England Journal of Medicine and Blood (the journal of the American Society of Hematology)—and the thrice-monthly Journal of Clinical Oncology (American Society of Clinical Oncology or ASCO). They all have excellent updated guidelines on cancer care, including during COVID-19. Medscape Hematology – Oncology is a fourth online publication that I read daily. There are several other fine journals in oncology* that I read, but their web presentations are not quite as robust. Together, these four periodicals have done an outstanding job of curating scientific and clinical information about COVID-19 and publishing it quickly online prior to print publication.

As Division Chief of Hematology/Oncology, I must also set guidelines and policy that affect our entire hospital and health care system. We were quick to adapt our chemotherapy infusion suite for COVID-19 safety based in part on shared information. Triage of outpatients has been an ongoing challenge and an iterative process. ASCO guidelines and rapid publication of information have been key in my ability to care for our patients.

I’ve also discovered another fascinating development on keeping up with cancer care during COVID-19. I registered on the Twitter-based community #MEDTWITTER in 2013 to follow what was happening in academic oncology, see new clinical developments, and learn and interact with colleagues. On Twitter, we debate the latest findings in hematology/oncology and share articles with each other. For the record, I think one of the first physicians to predict the magnitude of the COVID-19 tragedy is Christos Argyropoulos, MD, (@ChristosArgyrop), a brilliant nephrologist and researcher in New Mexico who pondered the epidemiology of COVID-19 well before the first case in the United States. My friend Dan Goldstein, MD (@drdgoldstein), retweeted a video featuring Italian pulmonologist’s experience treating COVID-19 in Italy on March 10—the day things really sank in for me. A video on Twitter can be worth more than 1,000 words. Now, I follow the Twitter accounts of several epidemiologists and molecular biologists engaged in COVID-19 research.

While rapid information has been brought to bear on COVID-19 during this time of crisis, many shoddy and methodologically flawed scientific “studies” have been rushed to publication. For instance, recent discussion has focused on the retraction of some highly flawed publications on hydroxychloroquine. Journalists Jeanne Lenzer and Shannon Brownlee have written eloquently about these problems.

An illustrative and highly pertinent ongoing issue is whether we should change our clinical approach to treating COVID-19 patients who have acute blood clotting disorders—strokes, pulmonary embolism, and the like—who often die, even of disseminated intravascular coagulation. This question touches on not just the biology but the nature of clinical research; it is now known that patients in the intensive care unit with COVID-19 have a high incidence of thrombotic (clotting) complications, but whether and how to intervene is being debated.

In clinical medicine, when possible, we conduct prospective randomized controlled trials to minimize confounding and bias in order to get closer to the truth of whether an intervention helps or harms a patient. The principle is that while retrospective trials are hypothesis generating, prospective trials help to prove or disprove a hypothesis. In this context, several institutions have been interpreting the retrospective data to recommend more aggressive anticoagulation for patients with COVID-19. I’ve had to sit tight and believe what I believed before—that this doesn’t make sense. On Twitter this has been debated extensively, even with a picture of a patient who died from a bleed into the brain caused by excessive anticoagulation (arguing against this practice). For my institution, I have not recommended changing our approach of not anticoagulating COVID-19 patients, but I am monitoring the evidence daily.

So much is changing in our communication about cancer care as a result of COVID-19. I gave my first online lecture to an international conference on March 9. And, our usual ASCO meeting of 60,000 people in Chicago was instead held completely online while (coincidentally) peaceful protests and violence in the streets erupted over George Floyd’s death. The convention center for this meeting had been converted into a COVID-19 hospital in anticipation of a tsunami of cases in Chicago. Interestingly, the academic oncologists on Twitter are mostly commenting about how nice it is to not have to travel for a meeting; the only part we seem to miss are the social interactions with each other.

The internet has dramatically improved how we practice medicine and share knowledge in cancer care. Now, COVID-19 is another jolt to the system that will change how medical information is generated and disseminated. As a physician practicing at a county “safety net” hospital, I predict dramatic changes in cancer care as more than 27 million Americans have already lost their health insurance due to the pandemic. This erosion of coverage may herald a sea change towards more value-based cancer care as the finances of cancer care in 2020 and beyond are challenged.

*Additional important journals for hematologists/oncologists include The BMJ, The Lancet, The Lancet Oncology, JAMA Oncology, The Oncologist, Clinical Advances in Hematology & Oncology.

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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

How the Coronavirus Pandemic Impacts Cancer Care: Our Survey Results

Lola Rahib, PhD

The ongoing COVID-19 pandemic presents unprecedented challenges to cancer patients. Many have experienced changes to their care, and some face increased risk of infection or worse prognosis if they are infected. In partnership with the company xCures, Cancer Commons is studying how COVID-19 impacts cancer patients.

Here, our Curious Dr. George asks Cancer Commons Director of Scientific and Clinical Affairs Lola Rahib, PhD, about our findings so far. Dr. Rahib can be reached at lola.rahib@cancercommons.org.

Curious Dr. GeorgeCancer is listed as one of the preexisting conditions that may result in increased susceptibility to the harm caused by COVID-19. In addition, the mass shutdown of many of society’s activities intended to mitigate the pandemic has major impacts on functions of medical care.

Cancer Commons has launched an FAQ page to inform cancer patients of these many interactions. In addition, you have performed a survey of cancer patients to identify their experiences during this pandemic. What are some of your main findings?

Lola Rahib, PhD: Our goal was to understand the impact of COVID-19 on cancer patients through a questionnaire completed by them or their caregiver. A total of 112 patients or caregivers completed the questionnaire from March 24 to April 15. Ninety of those who completed the survey had previously registered for Cancer Commons’ services and received the survey by email. The remaining 22 patients completed the survey through social media platforms.

Of the 112 patients and caregivers who completed the survey, 78 (70%) reported that they or the patient they care for was currently receiving cancer treatment. Canceled or postponed appointments due to COVID-19 were reported by 32 (29%) participants. Thirteen (12%) reported treatment delay because of COVID-19.

Six patients (5%) were newly diagnosed and had to make a treatment decision about a new cancer diagnosis during the COVID-19 pandemic. Twenty-one (19%) patients had to make a decision about a treatment change.

Eighty-three reported on whether COVID-19 affected any treatment decisions they had to make. Of these 83, 24 (29%) reported that COVID-19 affected their treatment decision, and 23 gave an explanation. The most common explanations of how COVID-19 affected treatment decisions were “changes to travel for treatment/change in place of treatment,” “changes in travel/living situations/other personal changes,” “changes to surveillance,” “changes, delays, or not receiving treatment to decrease risk of COVID-19 infection,” “continued on treatment that is not working,” and “did not continue to pursue a clinical trial.”

Symptoms of COVID-19 (coughing, fever, shortness of breath) were reported by 16 (14%) patients and caregivers. Six (5%) patients had COVID-19 testing, with one patient still awaiting results, and all of the other five tested negative. Increased anxiety about cancer treatment due to COVID-19 was reported by 72 (64%) participants.

Most of those who completed the survey were the patients themselves (72%), 13% were caregivers, and 15% did not report whether they were a patient or caregiver or played another role. Fourteen percent of the patients were 49 years old or younger (7% younger than 40), 48% were between the ages of 50 and 69, 13% were 70 to 79, 3% were 80 or older, and for 22% of the patients, their age was unknown. Most patients were female (66, or 59%), 30 (27%) were male, and for 14%, the sex was unknown. Thirteen types of cancers were reported, the most common cancer types being breast, lung, and colorectal cancer. Most of the participants were from the U.S. (70%) with 12 countries represented including Italy (7%), Canada (4%), Australia (3%), and the U.K. (3%).

To conclude, changes to appointments, treatment delays, and the impact of COVID-19 on treatment decisions were reported by patients and caregivers. The majority of patients (64%) reported increased anxiety about their cancer treatment during the COVID-19 pandemic.

Cancer Commons remains dedicated to helping patients and caregivers navigate their cancer journey and ensure they are able to access the best possible care. Get help now.

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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

The Challenges of Using Artificial Intelligence to Improve Cancer Treatment

Razelle Kurzrock, MD, and Jeff Shrager, PhD

In a previous post, CureMatch co-founder Razelle Kurzrock, MD, told us all about her company’s artificial intelligence (AI) platform that matches patients with treatments based on their cancer’s molecular profile. Here, AI expert Jeff Shrager, PhD, responds, and Kurzrock offers a rebuttal.

Shrager is Co-Founder and Director of Research at xCures, and was formerly Director of Research at Cancer Commons. He is also an Adjunct Professor of the Symbolic Systems Program at Stanford University. Email: jshrager@stanford.edu.

Kurzrock is Director of the Center for Personalized Cancer Therapy and the Rare Tumor Clinic at U.C. San Diego, and Co-Founder and Board Member of CureMatch, Inc. Email: razelle@curematch.com.

Shrager: Whereas I applaud Dr. Kurzrock and CureMatch for their efforts to apply machine learning in precision oncology, I want to offer a bit of a heads-up.

Whereas it is certainly true that “we live in the ‘big data’ generation,” two senses of that term are often conflated. Google and Facebook have enormous datasets with many independent observations across relatively few features. Medical data, especially at the molecular level, is exactly the opposite, having relatively few independent observations across an enormous feature space. Moreover, the settings in which modern AI (i.e., machine learning) has seen successes are those where there are either existence proofs of a solution, which can be drawn upon as a teacher, (e.g., self-driving cars, where even 16-year-olds drive cars adequately well), in closed systems for which we have excellent simulators (e.g., astrophysics), domains in which the roles are static (e.g., games), or in which experiments are basically free (games again, or any domain with a good simulator).

Medicine is completely different: We have essentially no simulations, medical experiments are extremely costly, we lack good treatments (which is why we’re bothering with this at all), and the treatment space changes rapidly. You can’t just teach your robot doctor to cure cancer by observing good doctors curing cancer, because there are no such doctors and cures—there may be some better and some worse doctors, but as far as I know, there isn’t one that can cure cancer “adequately well” who you can use as a guide; indeed, there may be no cure for cancer at all.

Heads up! Machine-learning applications in domains like medicine, where there are small numbers of samples that range over very high dimensionality feature spaces, and with the above-enumerated limitations, are exceedingly prone to getting stuck in non-optimal minima, preferring solutions that work well enough, over exploring solutions that might work better than the ones that have been observed or tried. The way out of this problem is active learning: Rather than taking the apparently best action in all cases, one must balance the strength of belief in one’s rankings against the information gain of trying something new. Doing this requires having a global view of the whole medical (or at least oncological) space, and working out some very difficult “statistico-ethical” questions. Indeed, this is what the clinical trial system is striving to do, although it is doing so horribly inefficiently, and will basically never get there. We can solve this problem, but it requires a much broader AI approach than simply treating each patient in accord with a locally-optimal solution.

(This commentary abbreviates the argument made in much greater detail in a paper I wrote with my colleagues at xCures last year for The Journal of Law, Medicine & Ethics: Is Cancer Solvable? Towards Efficient and Ethical Biomedical Science.) 

Kurzrock: I would like to thank Dr. Shrager for highlighting two excellent points pertaining to the use of AI in routine oncology practice and the inefficiency of clinical trials—I fully agree with him. Allow me to provide some brief comments.

First, I concur that current AI-containing software platforms are certainly not sophisticated enough to be “robot doctors” that could treat cancer. Indeed, decision-support platforms like CureMatch’s BionovTM are not here to replace oncologists. They are necessary tools that help oncologists process immensely complicated data, such as that revealed by next-generation sequencing of tumors. Decision-support platforms are rule-based systems that enable evaluation of complex information by utilizing prior knowledge, akin to the dimensional origami model Dr. Shrager referenced in his earlier work.

Moreover, some of the work that lends confidence to the decision-support platforms are clinical trials. I agree with Dr. Shrager’s point regarding clinical trials’ extreme inefficiency, the fact that they are indispensable to clinical oncology research, and the concept that new clinical strategies are needed, especially to address the questions raised by today’s precision medicine that utilizes complex molecular diagnostics. For example, the prospective cross-institutional I-PREDICT study demonstrated the value of customized, matched combination therapies (rather than scripted monotherapies) and of a matching score similar to that used by BionovTM. Other efforts, such as obtaining real-world data via a Master Observational Trial are also unique approaches that enhance the clinical trial process.

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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

How to Beat COVID-19 with Real-Time, Real-World Data

As the COVID-19 pandemic continues, researchers around the world are working quickly to develop strategies to treat and prevent this disease. In partnership with the company xCures, Cancer Commons is studying how COVID-19 impacts cancer patients. Meanwhile, xCures has launched larger initiative, BEAT19, to gather information from everyone and anyone who wishes to participate—whether they’ve had cancer, COVID-19, or neither.

Here, our Curious Dr. George asks xCures’ Vice President of Clinical Development Mark Shapiro, PhD, about BEAT19. Shapiro is Principal Investigator of the BEAT19 registry (Behavior, Environment and Treatments for COVID19) and can be reached at mshapiro@xcures.com.

Q: In 2000, we said that “the internet changes everything,” and it did. In 2020, we can say that “COVID-19 changes everything,” and it will. The good news is that the internet allows a whole new approach to studying the coronavirus that causes COVID-19 using clinical trials to produce real world evidence (RWE). How might RWE be applied now to study COVID-19, using innovative methods?

Mark Shapiro, PhD: I certainly agree that everything has changed. This pandemic has moved much faster than biomedical science is generally designed to move. It is also a stark reminder of the connectedness of people, not just online but in real life. There is an information vacuum, and if we as scientists don’t fill it with accurate information, it will get filled with half-truths and speculation. The internet spreads information quickly, but it doesn’t discriminate.

I’ve been amazed by the efforts to publish so many small studies about COVID-19 in days or weeks, but they often raise as many questions as they answer. Having communicated frequently with friends in Italy, Singapore, and Hong Kong since January, I had the feeling that it would be increasingly difficult to run traditional clinical trials if a great many of the people experiencing this illness would be in isolation at home.

So, a small group at xCures worked tirelessly to launch an electronic registry, BEAT19, for daily symptom tracking with the ability to go back to later link up to medical records. We had some sense of the symptoms and have deployed patient-reported outcomes in our other work. Of course, there isn’t a validated SARS-CoV-2 symptom questionnaire, so we tried to adapt various questions that could characterize the natural time course of symptoms. The goal was to generate data that would help collective understanding the disease in an empirical way.

With BEAT19, we are trying to observe the symptom trajectory of COVID-19 and measure endpoints, such as seeking testing or hospitalization. The natural experiment investigates how the trajectory or endpoints differ between similar patients on different anti-hypertensives. I’m sure you saw yesterday’s report in the New England Journal of Medicine; the hypothesis around angiotensin signaling has been around for weeks. Similar questions have been posed about classes of diuretics and more generally about corticosteroids. While a vaccine is urgent, in the short term, answering these questions about how medical management could reduce the risk or severity of infection can have a major impact.

For a few weeks, we have also been aware of people taking hydroxychloroquine or lopinavir/ritonavir, so any evidence people on those medications have different risk or disease severity than similar people is valuable, for example in forming a strategy to protect front-line healthcare workers.

We are committed to running BEAT19 as a public service and have already received offers of collaboration from dozens of people in industry, academia, and government. A number of them have suggested important hypotheses to test, so we’re organizing working groups to formulate and design the analyses.

Thank you for your question, George. Please let your readers know that they can learn more or sign up at BEAT19.org.

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

What Sets Cancer Commons Apart?

Erika Vial Monteverdi, Executive Director of Cancer Commons

Cancer Commons is a patient-centric, nonprofit network of patients, physicians, and scientists that helps identify the best options for treating an individual’s cancer. Here, our Curious Dr. George asks executive director Erika Vial Monteverdi what sets Cancer Commons apart.

Q: As the Executive Director of Cancer Commons, how do you consider our approach to be uniquely different from that of many other organizations working to change the paradigm of cancer treatment?

A: Cancer Commons’ approach arises from the simple yet powerful fact that no two patients and their cancers are exactly alike. Supercomputers and “big data” present promising possibilities to advance cancer treatment. However, we believe that such efforts will fall short without also improving the use of existing information, coupled with expert doctors’ insights.

More to the point, every doctor would agree that, when it comes to making treatment decisions for very sick, one-of-a kind patients, the judgment of the best experts in the world coupled with existing data would be more convincing than existing data alone. In fact, we have seen that doctors will accept the judgments of experts when that judgment differs from their own, and are less likely to change their treatment plan based upon data alone.

Cancer Commons and our team of experts focus on advanced cancer patients for whom the treatment data are particularly thin, the treatment cost is particularly high, and the treatment success rate is particularly low. Our mission is to be the preeminent resource for advanced cancer patients by breaking down knowledge barriers to save lives.

In a currently fragmented U.S. healthcare system—with variation and disparity in cancer care, as well as a lack of information and resources for patients—Cancer Commons is especially important for those with hard-to-treat cancers who have exhausted standard-of-care options and often feel left alone to navigate next steps. These are the patients who are asking, what now?

We connect patients and their families to our Nurse Navigators and PhD Scientists, who combine a compassionate approach with deep scientific knowledge of cancer to help advanced cancer patients understand their disease and identify and access the best personalized tests, clinical trials, and treatments.

Our solution enables a patient-centric network of patients, nurse navigators, scientists, physicians and national experts to collectively reason and deliver a plan to patients. We elevate the patient to equal status of other industry stakeholders by cutting across organizational and information barriers and combining available knowledge with clinical experience to focus on what is best for each individual. We then apply those learnings to help the next similar patient.

Cancer Commons differentiates itself from all other cancer organizations through our transformative process, which aims to continuously learn from the experiences of all patients, on all treatments, all the time.

For anyone who is wondering, “what now?” for themselves or for a loved one with cancer, I encourage you to register now to get support from Cancer Commons.

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

Facilitating Access to Treatment for Children with Brain Cancer

Leslie Jared, RN, MSN

A Q&A with Leslie Jared, RN, MSN, Nurse Navigator at Cancer Commons. Email: leslie.jared@cancercommons.org

Q: A midline glioma is a type of brain tumor that is particularly dangerous because of its nature and its location in the brain. It often afflicts children. An investigational drug called ONC201 has shown early promise in some patients whose tumors have a specific genetic mutation called H3 K27M. At Cancer Commons, in collaboration with xCures and Oncoceutics (the developers of ONC201), we are helping patients who cannot participate in ongoing clinical trials with ONC201 to gain access to the investigational therapy. You work directly with some of the patients in this program. Can you update our readers on its progress?

A: Oncoceutics has several clinical trials in progress to evaluate ONC201 in high-grade glioma, in particular for patients with H3 K27M-mutant glioma. The expanded access program currently allows the treatment of patients in the U.S. with recurrent/progressive H3 K27M-mutant and/or midline high-grade gliomas that are not otherwise eligible to participate in these trials. This includes patients with diffuse intrinsic pontine glioma (DIPG).

Under expanded access, patients with life-threatening illnesses who are not eligible for clinical trials may access treatments that are still under investigation and have not yet been approved by the FDA. Access to investigational treatments does require review and authorization by the FDA, but more importantly, in order to be successful, it requires the active involvement and cooperation of drug companies, health care providers, and patient advocacy groups.

ONC201 is a highly selective antagonist of the dopamine receptor D2 (DRD2) and has shown the ability to cross the blood-brain-barrier. DRD2 is overexpressed in some forms of cancer, including brain tumors that possess the H3 K27M mutation. ONC201 has been shown to kill cancer cells via activation of an integrated stress response, inactivation of Ras signaling, and apoptosis (death of cells). Clinical trials have shown that ONC201 may benefit some patients with DIPG- and midline-glioma patients who exhibit the H3 K27M mutation.

H3 K27M-mutant glioma patients, including those with DIPG, who do not qualify for the currently enrolling ONC201 clinical trials can consider the ONC201 intermediate-sized expanded access program as an additional option. Unlike single-patient Compassionate Use protocols, the intermediate-sized Expanded Access Program allows the treatment of multiple patients under one protocol.

Oncoceutics opened the current Expanded Access Program in January 2019 under collaboration with xCures, The Al Musella Foundation, The Cure Starts Now and DefeatDIPG. Many physicians/institutions have been able to open the program and treat patients at their U.S.-based sites. The real-world safety and outcomes data for these expanded access patients is being collected in a clinical database and will be used in an effort to speed up the development process and provide broader learning on who can benefit from ONC201.

If you are interested in the ONC201 expanded access protocol for yourself or a loved one, I encourage you to register with Cancer Commons as a new patient. Once you complete the registration process, I will help guide you through the evaluation process to determine whether you or your loved one qualifies for the protocol.

Please note: Oncoceutics does not currently distribute ONC201 outside of the United States.

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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.

Leslie Jared, RN, MSN

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

Using Artificial Intelligence to Match Combination Targeted Therapies in Oncology

A Q&A with Razelle Kurzrock, MD, Director of the Center for Personalized Cancer Therapy and the Rare Tumor Clinic at U.C. San Diego, and Co-Founder and Board Member of CureMatch, Inc. Email: razelle@curematch.com

Q: The new understanding of many cancers brought about by molecular testing has led to a whole new field: precision oncology, which emphasizes targeted and immunotherapy. While promising, and sometimes spectacularly successful, targeted monotherapy has limitations. The evolution of targeted and immunotherapy by combinations of drugs offers new scientific options for cancer patients. But there are so many new molecular findings, so many new investigational drugs or drugs newly approved by the U.S. Food and Drug Administration (FDA), and so few appropriate patients, that matching patients to best drug combinations can be a mathematical nightmare. What have you and your company CureMatch to offer to help with this dilemma?

A: Thank you for this excellent question. As you correctly noted, tumors, even those that share the same histologic origin, are highly heterogenous and unique at the molecular level. Therefore, the existing paradigm of treating all cancer patients based on their tumor’s tissue of origin, even by adding minimal biomarker stratification criteria, has proven largely inadequate. The advent of molecular diagnostics allows for improved patient stratification during therapy selection; however, most patients are still treated with monotherapies, which ultimately perform poorly.

Early data show that individualized matched combination therapies targeting most of a patient’s druggable aberrations are associated with improved outcome. However, selecting the “right” combination in routine oncology practice could be challenging. The average oncologist is pressed for time, seeing approximately 350 new patients annually and up to 100 patients per week. To complicate matters, even if an oncologist wanted to rationally combine only the approximately 300 FDA-approved “oncology-specific” drugs, there would be estimated 45,000 possible two-drug and approximately 4.5M three-drug combinations. Even molecular tumor boards found in some academic centers rely largely upon expert knowledge and experience to tailor personalized combination treatment strategies for hundreds of patients with unique molecular profiles. Clearly, the drug selection process is rapidly outpacing human capabilities, and software tools are needed to help with data analytics.

Bionov™, a rule-based artificial intelligence platform developed by CureMatch, utilizes the latest data available on targeted, immuno-oncology, hormone therapy, and cytotoxic agents. Bionov™ employs an algorithm that matches patients with monotherapy and multidrug regimens based on their available tumor “omic” profile. Drug regimens provided in the Bionov™ report are ranked using a predictive “Bionov™ score” that reflects the degree to which a given regimen matches the patient’s molecular profile.

To generate our database, we curated all FDA-approved drugs relevant to oncology for their biological impact on their targets. Recently, we added oncology drugs that have been approved by the European Medicines Agency (EMA) to our database, and FDA/EMA-approved drugs are kept up-to-date based on their respective labeling changes. Further, we researched and curated preclinical and clinical literature pertaining to the efficacy of these drugs, including drug toxicities and contraindications. The CureMatch scientific team conducts literature reviews on a routine basis to ensure drug efficacy is kept current.

Our methodology has been validated in several studies, and I will highlight two of them here. First, in a retrospective meta-analysis of 70 exceptional responders for whom molecular profiling data was available, Bionov™ correctly ranked the response to all treatment regimens (including failed regimens) with 84% sensitivity and 77% specificity. This analysis demonstrates how the Bionov™ algorithm is able to discriminate, solely on the basis of the molecular fingerprints of a patient’s cancer, treatment regimens that favor a positive outcome from those that are more likely to be associated with an unsuccessful response. The second study I want to highlight is a prospective clinical trial: our group found that a higher matching score (similar to the Bionov™ score) was an independent predictor of increased disease control rate, prolonged progression-free (PFS), and overall survival rates. Furthermore, PFS was significantly improved in 75% of patients treated with combination therapies based on high matching scores.

We live in the “big data” generation. As the patient progresses through their treatment journey, massive amounts of actionable molecular information are generated, and clinical oncologists may not be entirely prepared to effectively utilize it. We believe that predictive analytics models—such as Bionov™—can provide an alternative framework for modern clinical practice, collaborating with and empowering oncologists in their decision-making process.

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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

Comprehensive Molecular Testing Needed for Stage IV Lung Cancer

A Q&A with David Spigel, MD, Chief Scientific Officer, Director of the Lung Cancer Research Program, and Principal Investigator at Sarah Cannon Research Institute. Email: dspigel@tnonc.com

Q: You are an expert medical oncologist with particular interest in lung cancer. The various forms of lung cancer are serious diagnoses, all potentially lethal malignancies. There are theoretical, investigational, and clinical justifications to perform molecular testing of these tumors. In your opinion, should such testing target specific mutations, panels of genes, or use next-generation sequencing (NGS) for whole-exome or genome analysis? At what point in a patient’s disease should molecular testing be performed?

A: Caring for patients with lung cancer today requires broad NGS at diagnosis for stage IV disease. There are multiple potential targets, and spot testing for individual mutations is simply inefficient in my view. We need to test for mutations in EGFR, ROS, ALK, MET, and BRAF—and also TRK and PD-L1. HER2 is nearing similar importance, and others are not far behind. I need to know about mutations in these genes as soon as possible to make treatment decisions, not the least of which is deciding whether a patient will qualify for a clinical trial.

Q: What challenges do you and other oncologists face in getting the molecular tests you need?

A: It’s a bit ridiculous that we have local and “send out” testing, and each can be imperfect if the labs are not using NGS. Currently, blood has become the easiest for me to get the day I meet a patient, and it takes five to eight days for results. It gets the ball rolling so to speak. I have tissue tested by commercial vendors, but those results can take three to four weeks—and that’s simply too long to make treatment decisions for a lot of folks (and me).

In the future, we will need a one-stop shop that offers the best-in-class technology in the shortest amount of time with the least amount of material. I bet that will be blood. And lung cancer is just the first malignancy that makes the strongest case for broad upfront testing; there’s no reason this won’t be also true for every cancer we treat one day.

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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

Weathering the Perfect Storm of the Vaping Threat

A Q&A with Alan Blum, MD, who founded the Center for the Study of Tobacco and Society in 1999 at The University of Alabama, where he serves as Professor and Gerald Leon Wallace, MD, Endowed Chair in Family Medicine. Email: ablum@ua.edu

Q: Inhalation of carcinogens and other harmful chemicals in tobacco smoke is responsible for more American deaths—especially from cancer—than any other one factor. Nicotine addiction is central to that pathologic process. The relatively recent invention of the e-cigarette seemed to offer great hope as an alternative nicotine-delivery device that most likely did not cause cancer, and could prevent nicotine addicts from having to smoke. Yet, the “unintended” consequence of masses of new young nicotine addicts produced by unregulated for-profit vaping companies has created a new public health disaster. How might the U.S. Congress and the U.S. Food and Drug Administration (FDA) have better managed this threat?

A: In 2009, Congress passed a bill giving the FDA the authority to regulate tobacco products. When the treacly named Family Smoking Prevention and Tobacco Control Act was signed by President Obama, the bill’s proponents—notably, the Washington lobbying group Campaign for Tobacco-Free Kids—touted it as a long-awaited defeat for Big Tobacco. When it was revealed that the Campaign had secretly co-written the bill with Altria, maker of the top-selling cigarette Marlboro, we realized that the brand’s iconic cowboy wouldn’t be riding off into the sunset just yet.

But few could have predicted that the efforts to protect Americans from the harmfulness of tobacco would become more confused and convoluted by adding it to the FDA’s portfolio.

Because the FDA is the nation’s watchdog over medications and medical devices, a provision in the 2009 bill distinguishes drugs and devices from tobacco products, in order to prevent duplicative regulation by different centers within the FDA. And therein lies the origin of the unfettered explosion of vaping—the inhaling of a heated, flavored nicotine solution from an e-cigarette or other device: in their eagerness to get the FDA bill passed, Senate Democrats rejected a Republican amendment to regulate e-cigarettes as tobacco products and deliberately left them out of the bill. After all, proponents reasoned, e-cigarettes were new and expensive, and they were manufactured by just a handful of companies. The proponents also counted on using a provision of the bill in which the FDA could “deem” as tobacco products both e-cigarettes as well as future nicotine-containing products that regulators couldn’t yet envision.

But a not-so-funny thing happened. While the FDA hemmed and hawed about these new-fangled electronic nicotine delivery systems (now called ENDS), hundreds of manufacturers entered the market, costs dramatically dropped, and e-cigarettes could be purchased at any convenience store for the price of a pack of Marlboros.

Finally, in 2016, the FDA issued its deeming rule that included e-cigarettes as tobacco products subject to the agency’s regulatory authority. In July 2019, a U.S. District Court in Maryland upheld the FDA’s rule. Meanwhile, products such as the Juul e-cigarette, craftily designed to resemble a USB drive and promoted through social media to the wired generation, became an essential accoutrement of high school and college students. That Juul was also engineered to deliver nicotine more rapidly than any previous e-cigarette—and came in appealing flavors such as mango and mint—contributed to its capturing 75% of the e-cigarette market just three years after it was introduced in 2014.

In December 2018, Altria paid $12.8 billion for a 35% stake in Juul Labs, Inc. At the same time, the vape shop industry burgeoned, as did online sellers of e-liquids and paraphernalia aimed at a counter-culture that rejected commercial products. The legalization and commercialization of marijuana by several states also led to the proliferation of e-cannabis with THC-containing e-liquids. This in turn has resulted in an outbreak of vaping-related pulmonary illness in 2019, causing more than 40 deaths and sickening more than 2100 users of electronic vaping devices.

Thus, the FDA lost a full decade in which it could have required manufacturer registration and ingredient-reporting, inspected e-liquid-making facilities, and acted against adulterated or misbranded products. Lost, too, was the opportunity to slow the introduction of e-cigarettes, to temper so-called harm reduction health claims about these products compared to cigarettes, to verify their value in smoking cessation, and to thwart their marketing to young people.

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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

Using Molecular Testing to Guide Treatment for Advanced Colorectal Cancer

A Q&A with Kalpana Kannan, PhD, former Scientist at Cancer Commons

Q: Colorectal cancer is common, and although many cases in earlier stages are cured by surgery alone or with adjuvant chemotherapy, it is still a lethal threat for many patients. Nonetheless, several new targeted and immunotherapeutic agents are now available. When should patients receive molecular testing for their colorectal cancer, what information should especially be sought, and which therapeutic agents are likely to be effective?

A: For every patient who is diagnosed with stage IV colorectal cancer (mCRC), complete molecular profiling of their tumor is highly recommended. It is important for patients to know their microsatellite status, RAS (KRAS and NRAS) and BRAF mutations, and HER2 amplification status at a minimum. Depending on these molecular profiling results, targeted therapy or immunotherapy may be applicable.

Microsatellite status refers to the status of short tandem repeats of DNA that are present throughout the human genome. Since microsatellites have a repetitive sequence, they are prone to mutations. These mutations are usually corrected by the DNA mismatch repair (dMMR) system. Tumors with a defective dMMR system that cannot adequately repair the mutations have microsatellites of different lengths than would be found in the germline DNA. This molecular phenotype is called microsatellite instability (MSI). Tumors are generally categorized as MSI-high (MSI-H), MSI-low, or microsatellite stable (MSS).

MSI-H or dMMR tumors are very sensitive to immune checkpoint blockade. The U.S. Food and Drug Administration has approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of patients with MSI-H/dMMR mCRC following progression with chemotherapy. Recently, the immunotherapy combination of nivolumab and ipilimumab showed an overall response rate of 60% in the front-line setting (before any chemotherapy) in a clinical trial with 45 patients. So, immunotherapy has an important role in the treatment of this population of patients who seem to not benefit as much with conventional chemotherapy.

For most other patients, in fact 95% of mCRC patients whose tumors are MSS or MMR-proficient, single-agent immune checkpoint inhibitors are not advisable. Combination treatments of checkpoint inhibitors with kinase inhibitors (such as regorafenib) and VEGF-targeting agents (bevacizumab) are currently being evaluated in clinical trials and are showing some promising results. In a phase 1b trial of the combination of regorafenib and nivolumab, an overall response rate of 33% was observed in patients with MSS tumors. While this is promising, it is important to focus on targeting the other alterations that may be present in these patients’ tumors.

Most often, these are KRAS mutations, which are present in about 30–50% of CRCs. The most frequent mutations in the KRAS gene are in codons 12 and 13, namely, KRAS G12V, G12C, G13D, and others. Mutations at these positions result in the activation of RAS. Considered to be undruggable for a long time, only recently have efforts to target KRAS paid off. AMG 510 is an oral inhibitor of KRAS G12C. Clinical trial results with this agent in CRC indicate a disease control rate of 92% (1 partial response and 10 stable disease among 29 patients).

Various other strategies to target RAS mutations are currently in trials. These include targeting of EGFR; targeting of the downstream effectors RAF, MEK, and ERK; and targeting of synthetic lethal interactions with CDK4, SHP2, and PLK1.

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.