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

Weathering the Perfect Storm of the Vaping Threat

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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

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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.

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

Emphasizing Oncogeriatrics

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A Q&A with Nicolò Matteo Luca Battisti, MD, Medical Oncologist at The Royal Marsden NHS Foundation Trust, London, United Kingdom, and Chair of the Young Interest Group of the International Society of Geriatric Oncology (SIOG); nicolo.battisti@gmail.com

Q: Everyone knows that the practice of pediatric oncology is very different from adult oncology. How does the growing field of oncogeriatrics differ from usual adult oncology?

A: In my opinion geriatric oncology is a large part of the routine oncology practice, and every oncologist is a geriatric oncologist. Cancer is a disease of older adults, and currently, approximately 50 percent of all cases and 70 percent of related deaths occur in adults aged 65 or older. In the context of ongoing demographic changes, with average life expectancy increasing worldwide, the incidence of cancer in older adults is obviously expected to increase.

Moreover, older adults have always been underrepresented in clinical trials investigating the management of cancer and which have defined the current standard of care. Older patients are more frequently excluded due to strict inclusion and exclusion criteria that are very difficult for them to match, logistical barriers that sometimes make enrollment quite challenging for this age group, and concerns and misconceptions of treating physicians. This limits the external validity of the evidence base that currently guides management of cancer in older patients.

Older adults are a very heterogeneous patient population due to a number of challenges unique to this age group. First, we observe a gradual decline in function and reserve of organs—including the liver, the kidneys, bone marrow, the heart, and muscle—which may affect the pharmacokinetics of drugs and increase the risk of complications for systemic and local anticancer treatments. Second, an increased burden of comorbidities may affect the life expectancy of these patients and again affect treatment outcomes. In this age group, polypharmacy is a common issue that makes patients particularly prone to the risk of drug interactions. Functional impairment is also prevalent in this cohort and may increase the risk of adverse events independently of other factors, including comorbidities. Older adults also tend to value quality of life over “quantity of life,” which may make decision-making in this age group even more complicated. Further issues may also involve psychological and social aspects, financial toxicity, and the presence and role of caregivers.

All these factors make the management of cancer in older adults particularly challenging, as oncologists are not able to simply apply guidelines and consensus in this age group. A comprehensive geriatric assessment should always guide decision-making in this population.

On the other hand, this increased complexity makes the field particularly rewarding, since these challenges provide oncologists a unique opportunity to aim for a truly personalised approach. This does not necessarily involve only new biomarkers and fancy new systemic treatments, but also a more holistic approach which should take into consideration all the aspects that I briefly mentioned here in order to recommend the most appropriate treatment plan in the context of life expectancy and our patients’ preferences.

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

Fixed and Variable Factors that Impact a Brain Tumor Patient’s Prognosis

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A Q&A with Burt Nabors, MD, Professor and Director of the Division of Neuro-oncology at the University of Alabama, Birmingham, and a member of the Cancer Commons Brain Tumor Advisory Board; bnabors@uabmc.edu

Q: Primary brain gliomas can be devastating, often deadly, malignancies. Obvious prognostic factors include whether they are grade 1, 2, 3, or 4; their extent of growth prior to diagnosis (stage); and their location, such as in the brain stem. What are other key factors that affect prognosis? Some say that the skill of the original surgeon is the most important prognostic factor. Others suggest that the size (case volume) of the initial treating institution is most important. What do you think?

A: An excellent question and one I may try to answer in two ways. The first are the known and well-quantified prognostic factors. The two most powerful are the patient’s age and their performance status. Age is a pretty clear factor and one we cannot alter. We in the neuro-oncology community are seeing increased attention to treatment recommendations based on age, both at the young and older ends of the spectrum. These efforts do appear to provide brain tumor patients in those spaces improved outcomes. However, as a modifiable prognostic factor, age is not one.

A patient’s performance status is, at the core, a measure of how well they retain their station in life and can manage their activities of daily living independently. It most likely reflects the summation of several other factors, such as the location of the tumor, the grade, and the ability of the neurosurgeon to safely resect (remove) tumor. When looking simply at tumor location, we do see improved outcomes for tumors in the non-dominant hemisphere or in more silent regions, such as the frontal or anterior temporal lobes compared to more eloquent or vulnerable brain regions. However, again, the location of the tumor is not modifiable by the individual patient. It is where it is.

As you suggest, another—and modifiable—way to consider this question is to focus on the experience and skill of the neurosurgeon. I would submit the factors that have the greatest impact here are the training environment for the neurosurgeon, the experience and interest of the neurosurgeon in brain cancer, and the volume of the treatment facility. Surgery at centers involved in high volumes of brain tumor surgery with neurosurgeons who are dedicated to advancing the practice of surgical intervention is an important consideration.

The current practice of the neurosurgeon also has a significant impact on patient outcomes. This has been well quantified and published, clearly for high-grade glial tumors such as glioblastoma, but also for lower-grade tumors such as astrocytoma and oligodendroglioma WHO II. This need for a dedicated practice is typically seen in environments that offer pre-operative neurological function mapping, advanced imaging modalities, and intraoperative awake craniotomy with cortical mapping. When this degree of neurosurgical sophistication is available, it is often in settings with multidisciplinary groups, including a research base with an intense interest and focus on brain cancers.

An unfortunate current reality is that, most often, settings with this degree of sophistication are in our larger urban centers, where ease of access for patients living and presenting in a more rural environment can be quite a challenge. Creating opportunities to provide access and equal care to all remains a significant part of the neuro-oncology mission and challenge.

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

How to Treat Uveal Melanoma that Recurs in the Liver?

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A Q&A with Emma Shtivelman, PhD, Chief Scientist at Cancer Commons; emma@cancercommons.org

Q: Malignant melanoma may arise from multiple sites, including the eye.

What would you recommend be done for a 50-year-old man in the San Francisco Bay Area who was entirely well for nine years after undergoing enucleation surgery for a large uveal melanoma, but has now been informed by his physician that he may have a mass in his liver?

A: Uveal melanoma (UM), sometimes called ocular melanoma, is a rare type of cancer, and there are no definitive guidelines for its treatment once it spreads to other organs. Because of the location of the tumor and interference with vision, most patients are diagnosed when there are no metastases. However, many patients (up to 50%) who have successful surgery and/or radiation for the primary tumor will develop metastases, which occur most often (in almost 90% of cases) in the liver.

The mutational landscape of UM is well described, but this has not translated into effective targeted treatments, in spite of clinical research efforts that have tested potentially relevant drugs. The treatment options for metastatic UM (mUM) are not many, and none are endorsed by clinical guidelines nor approved by the U.S. Food and Drug Administration (FDA), underscoring the lack of progress in treatment of mUM.

For the patient with late recurrence of UM described in your question, my first recommendation would be to seek a clinical trial. The main reasons for this are:

  1. No chemotherapy regimen is effective in mUM.
  2. While the treatment landscape of cutaneous melanoma was transformed by the introduction of BRAF/MEK-targeting drugs and by immune checkpoint blockade (ICB), this transformation has not extended to UM. BRAF mutations are practically non-existent in UM, and so far, responses to ICB have been less than spectacular. Only a low percentage of patients respond to monotherapy with anti-PD-1 or anti-CTLA4 drugs.
  3. The combination of nivolumab and ipilimumab reported an overall response rate of 16% and disease stabilization in 47%. There is an obvious need to improve the response rate, not to mention the fact that this combination is not FDA-approved for mUM, and may not be available to some mUM patients.

Liver-directed treatments present a currently available option for liver-dominant disease, and are available in a number of larger cancer clinics. They usually involve liver embolization (chemo, radio, immune) or percutaneous hepatic infusion. Precision radiation—and, less frequently, radiofrequency or cryoablation—and surgery can be used as well. Liver-directed treatments translate most often into prolongation of progression-free survival (PFS), sometimes offering a significant survival benefit. Systemic treatment (for now, most likely dual ICB) should be considered alongside or after liver-directed interventions. Recent reports based on treatment of a small number of patients indicate better PFS and overall survival (OS) in patients who received liver radioembolization with Yittrium-90 and ICB, or chemoembolization and ICB.

So, my advice to the 50-year-old patient with mUM would be, first, to biopsy the liver tumor to confirm the diagnosis and to perform mutational testing. Mutational testing can test for possible predictors of the patient’s response to combined ICB and for the slim possibility that a targetable mutation is present.

For liver-dominant disease, liver embolization should be considered as the first line of treatment, and/or enrollment in one of several ongoing clinical trials.

The current clinical trial landscape includes:

  1. ICB combined with liver embolization (Y90 SIR-Spheres or immunoembolization)
  2. Tebentafusp(IMCgp100), a bispecific antibody bridging CD3 on T cells and gp100 on melanoma cells. Tebentafusp has received the FDA fact-track designation for uveal melanoma, based on the results of a small clinical trial in which OS at 1 year was 74%. It is available in one trial only, and that trial is unfortunately randomized to investigator’s choice of dacarbazine or a single immune checkpoint drug. Moreover, it is only relevant to patients who have a certain HLA type: HLA-A*0201 (found in 44% of the population in general).
  3. A virus-based drug: oncolytic VSV-IFNbetaTYRP1 (vesicular stomatitis virus expressing IFNbeta and tyrosinase), which is designed to replicate in and induce cytolysis of cancer cells specifically, and instigate an immune response.
  4. If a BAP1 mutation is present (and most often it is in mUM), it is possible that treatment with a PARP inhibitor will have a desired effect.
  5. Cell-based treatments. These include a CAR T-cell approach with T cells modified to target the protein SLC45A2, which is often present on uveal melanoma, and tumor-infiltrating lymphocytes (TILs).

The last three trial options are new, and have not reported even preliminary results. Liver embolization (if not offered in the trial) could be considered first to reduce the tumor burden and thus hopefully increase the possible efficacy of investigational approaches.

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

The Importance of Brain Tumor-Initiating Cells in Glioblastoma

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A Q&A with Anita Hjelmeland, PhD, Associate Professor of Cell, Developmental and Integrative Biology at the University of Alabama Birmingham School of Medicine

Q: The inner workings of malignant gliomas are mysterious to many of us. Why does the prognosis of patients with these tumors remain poor?

A: Glioblastoma is a primary brain tumor that is treated with surgery, radiation, and chemotherapy. While surgical removal of glioblastoma is a goal, glioblastoma cells move into the normal brain where they cannot be removed and where many chemical therapies do not reach. The latter is due to a special wall of blood vessels called the blood-brain barrier that protects the brain from toxins. To overcome these obstacles, researchers are developing ways to identify tumor cells during surgery and break down the blood brain barrier for short periods of time.

Another reason that glioblastoma is difficult to treat involves the body’s defense against invaders—the immune system. The immune system usually will not attack cells it recognizes as “self” (if it does, autoimmune diseases will develop), but special immune cells can recognize and destroy infected self cells that have different proteins on the cell surface than do normal cells. Glioblastoma cells also have different-from-normal proteins that could be targeted by drugs, but glioblastoma cells often block the activity of immune cells. To improve the treatment of glioblastoma, there are clinical trials testing the effects of drugs or viruses that are designed to activate the immune system.

A final reason that glioblastoma cures remain elusive is that tumor cells are not all the same. There are different genetic or mutational features that could lead to resistance to any one targeted therapy. Glioblastoma cells also behave differently depending on their environment: for example, lower oxygen levels can promote resistance to radiation. Furthermore, glioblastoma cells can resemble specialized cells in the brain to differing degrees, reflecting a difference in stem-cell state. To improve our ability to target all tumor cells, researchers seek to identify ways to prevent therapeutic resistance and combine therapies to try to make them more effective.

Q: Your research delves seriously into the role of brain tumor-initiating cells (BTICs). What are BTICs, what do they do, and how might an understanding of them lead to improved therapies? 

A: Glioblastoma cells can look and act more or less like normal stem cells in the brain, the neural stem cells. Neural stem cells are important during development and in brain diseases because they remake themselves, a process called self-renewal, and make specialized (differentiated) brain cells like neurons. Neural stem cells and differentiated brain cells can be distinguished by levels of different proteins called markers, which can also be expressed by glioblastoma cells. Glioblastoma cells with neural stem cell markers and the ability to self-renew or differentiate are called cancer stem cells or glioblastoma stem cells. Human glioblastoma stem cells have a greater capacity to cause tumors to initiate or grow in mice without an immune system: this tumor-initiating ability has led to the alternative name of BTICs.

BTICs can comprise only a small portion of the overall number of tumor cells present but could be especially important to eradicate. BTICs better survive chemo- and radiotherapy, and can live in environments where therapies are less effective. BTICs possess a high capacity to invade and readily move into the normal brain. Therefore, BTICs are believed to be the cells that remain after surgery, radiation or chemotherapy. Any such cells that remain after treatment, as their name denotes, can stimulate glioblastoma to grow anew. Thus, it is imperative that we make strong efforts to understand how to eradicate BTICs along with the more differentiated tumor cells in the hope of extending patient survival. Our ability to ever cure glioblastoma could rest upon that success.

It is important to note that glioblastoma is not alone in harboring tumor-initiating cells. By studying ways to combat BTICs in glioblastoma, progress is likely to be made towards understanding better therapies for other malignancies with such a capacity for therapeutic resistance and recurrence.

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

Navigating Pancreatic Cancer—The Basics

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A Q&A with Lola Rahib, PhD, Lead Scientist, Pancreas Cancer, at Cancer Commons, Los Altos, CA

Q: Navigating a pancreatic cancer diagnosis can be overwhelming and confusing for patients and their loved ones. How can patients and their caregivers ensure having the knowledge, support, and plan they need to be able to navigate treatment options and other aspects of the disease?

A: Patients and caregivers can regain control of a chaotic and anxiety-inducing process by making sure they maintain and organize detailed medical records and information about diagnosis, treatments, and options. As a patient it is critical to advocate for yourself and your needs. If this is not possible, ensure a designated family member or caretaker can advocate on your behalf.

Q: What are the specific aspects of the disease that are most important to navigate?

A: A little over ten years ago, Dr. Brown began a series of preclinical studies to test the possibility that an important contributor to the recurrence of malignant brain tumors after radiation therapy was reconstitution of the tumor vasculature. Specifically, he hypothesized that this reconstitution stemmed at least in part from circulating pro-angiogenic cells not in the tumor at the time of radiation—a phenomenon known as “vasculogenesis.” In agreement with this concept, a finding common to all of the tumor models he tested was a major influx into the irradiated tumors of bone marrow-derived cells, most of which were macrophages, that correlated with when tumors began to grow two to three weeks after completion of radiation. Further, he demonstrated that the mechanism for this influx was a radiation-induced hypoxia that triggered a cascade that led to the secretion of stromal cell-derived factor-1 (SDF-1), which was instrumental in attracting these cells. The apparent importance of excluding these cells’ entry into tumors post-irradiation suggests a new treatment strategy, which we call macrophage exclusion radiation therapy (MERT).

In August of 2014, based on these strong preclinical data, we launched a phase I/II clinical trial of MERT. This study examined the effects of administering a four-week continuous infusion of plerixafor (Mozibil)—the only commercially available agent that blocked the SDF-1 binding receptor CXCR4—at the end of irradiation to newly diagnosed GBM patients (NCT01977677). We enrolled 29 patients and established in phase 1 that the treatment was well tolerated at a dose that resulted in plerixafor serum values being maintained above the threshold level for CXCR4 blockade.

Two findings in phase II of this trial were particularly noteworthy: (i) a persistently lower relative cerebral blood volume within the irradiated field, and (ii) a much-improved control of the cancer in the treated field.

The noted overall median survival of nearly 22 months compared favorably with the best results obtained in other studies of GBM. However, it fell short of the dramatic improvements in survival noted in our preclinical studies, which utilized whole-brain irradiation (WBRT). WBRT was abandoned by clinicians in the early 1990s as a treatment for GBM because the high rate of local recurrence did not seem to justify the associated potential treatment-related issues of irradiating the entire brain (i.e., cognitive decline). However, we have shown that MERT is actually radioprotective for cognitive decline in rats given WBRT, consistent with the fact that tissue inflammation after radiation is related in large part to macrophage entry. Therefore, we have opened a new trial (currently open to accrual)using the same basic strategy in which a modest dose of WBRT has been added. Our expectation is that the widened radiation fields will further patient survival without excessive toxicity.

It is also important to note that the MERT strategy can be applied to any solid tumor in which local control using radiation is challenging. Further study of this strategy can therefore be of benefit to a wide spectrum of cancer patients.

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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

Serious Caveats in Screening for Pancreatic Cancer

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A Q&A with Rama Gullapalli, MD, PhD; a a physician-scientist in the departments of Pathology, Chemical and Biological Engineering at the University of New Mexico. His research lab focuses on the role of the environment in hepatobiliary cancers. He is also a practicing molecular pathologist with an interest in emerging molecular diagnostics, next generation sequencing and bioinformatics. Email: rgullapalli@salud.unm.edu 
Q: A recent New York Times op-ed piece from an NYU Langone Health professor urged an aggressive approach to screening for early-stage pancreatic cancer. Despite optimism, the history of cancer screening is rife with trouble, the harms often exceeding the benefits. What do you think is the best way to proceed?
A: Imagine a scenario.
A new cancer test hits the market with some impressive characteristics: a detection sensitivity of 95% and a specificity of an equally impressive 95%. If you were asked the question, “Given a positive test result, what are your chances of actually having cancer?” and you guessed a number of 80 or 90%, you would not be alone. But you’d be wrong.
The key missing information necessary to answer this question is the disease probability among the general population. The number of new cases of cancer detected every year in the U.S. is about 462 cases per 100,000 people. This means that the probability of a new cancer being detected in a member of the U.S. population annually is roughly 0.00462%. Incorporating this information leads to only an 8.1% chance of having cancer for a test that is positive! This is what is called an inverse probability problem.
Puzzled? Let me explain it in a different way. Statistics show that, in the U.S., about 462 people are newly diagnosed with cancer for every 100,000 people among the general population each year. The new test will correctly pick up 95% of these new cancer patients (i.e., about 439 patients). Of the remaining 99,538 people who do not have cancer, the test will incorrectly diagnose cancer in about 4,977 individuals! This is what pathologists would refer to as a “false-positive” diagnosis. The key point to remember is that cancer is a relatively rare disease. This basic fact enormously influences the value of any given cancer-screening test available in the market.
There has been much optimism and hype associated with cancer screening. Some cancer screening tests, such as tests for colorectal cancer or cervical cancer, have indeed made a dent in our ability to detect and treat the disease at an earlier stage. But in other cancers, such as breast cancer and prostate cancer, the results have been a mixed bag. For instance, screening for cancer in hard-to-access organs, such as ovarian cancer, led to an increase in complications due to surgery with no difference in the cancer outcomes.
A screening test with an increased false-positive rate (think of the 4,977 people in our imagined scenario who had a false-positive test result, but no real cancer), results in unnecessary and invasive testing that is ultimately of no clinical value. However, the societal costs of following up false-positive test results are enormous and include increased downstream testing and increased patient interventions. For patients, an enormous amount of anxiety and stress is expended in resolving false-positive screening test outcomes.
A recent New York Times op-ed piece discussed the issue of cancer screening in one such hard-to-treat disease: pancreatic cancer. In response to beloved TV host Alex Trebek’s diagnosis of stage 4 pancreatic cancer, author Diane Simeone, MD, suggests DNA testing as a first step to identify high-risk BRCA gene mutations in potential pancreatic cancer patients. BRCA gene mutations are associated with a higher risk of some types of cancer, including breast, ovarian, and pancreatic cancers. In her op-ed, Dr. Simeone reports that her clinic identified BRCA gene mutations in roughly 15% of the pancreatic cancer patients treated there. The key point is that these mutations were detected in patients who already had pancreatic cancer.
The op-ed piece correctly states the importance of identifying individuals at a higher risk for pancreatic cancer. While it is indeed optimal to screen for these high-risk pancreatic cancer patients, the means by which we can identify these patients beforehand is unresolved and very much a work in progress. One must be especially careful in the context of hard-to-diagnose and hard-to-treat diseases, such as pancreatic, liver, and ovarian cancers.
With the dramatically falling costs of DNA testing, one may be tempted to view it as the silver bullet for early cancer detection. However, the utility of DNA testing for screening purposes in different cancers is unproven currently and needs further research. Patients and physicians must be fully aware of the potential harms of unnecessary downstream testing due to the false positive outcomes of DNA testing. DNA testing may be cheap, but the consequences of DNA testing may prove to be very costly.
Caveat emptor!
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Encouraging and Paying for Clinical Trials, Right to Try, and Expanded Access: Part Three

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A Q&A with Mark Shapiro, PhD,Vice President of Clinical Development at xCures, Inc., Partner at Pharma Initiatives; mshapiro@xcures.com. This is the final installment in a three-part series in which Dr. Shapiro has shared his thoughts on the question below. Read part 1 and part 2.
Q: Treatment of Americans with advanced cancer is complex and challenging and can be very expensive. Many urge greater participation of such patients in clinical trials. In general, who pays the expenses of clinical trials? And, specifically, how are the costs for Right to Try and expanded-access approaches reimbursed?
A: In clinical research, agreements between the research sponsor and the treating institution define what aspects of a study protocol are charged as research or related administrative costs, and what items are considered standard-of-care; that is, eligible for billing to insurance. This is made by a coverage review at the institution. While the sponsors provide the study drug freely to the site and patients, they expect to receive valuable data in exchange. In expanded access, which is treatment rather than research—but stills follows a protocol approved by the U.S. Food and Drug Administration (FDA)— sponsors pay the required administrative costs and the free provision of the investigational drug. The drugs are expensive, and the sponsor incurs additional compliance costs when they make an investigational drug available. So, expanded access is largely a charitable act on behalf of the sponsor. While there are regulations allowing sponsors to recoup their costs under expanded access, these are rarely used. Most sponsors, especially larger companies, deliberately plan for expanded access when planning manufacturing campaigns during oncology drug development. In fact, large sponsors report that they approve about 95% of the expanded-access requests that they receive.
Recently, the FDA commissioned a study by McKinsey & Company on their processes for expanded access and has been busy implementing several recommendations to streamline the administrative barriers. In that report, it was estimated that it takes a physician and their support staff an average of 30 hours to prepare a single-patient expanded-access request, so the FDA introduced a plan to prepare the requisite forms for single-patient expanded-access requests for doctors who request it. The cost of expanded access then is partly borne by the patient’s doctor, who must invest significant extra time to request the drug and comply with the additional responsibilities associated with using it.
These programs are for the primary purpose of treatment, not research. Nonetheless, ethicists have made it clear that there is an ethical imperative to learn from treatment provided under expanded access. Therefore, at xCures we try to learn as much as we can in the least burdensome way possible while helping to meet regulatory requirements for reporting on safety and patient outcome by using real-world data to further reduce the administrative burden for sponsors and physicians participating in expanded-access programs.
Under the Right to Try Act, the patient does not have a “right to try,” but they do have a “right to ask.” Specifically, they can ask their doctor, who, if suitably licensed to practice medicine, can ask a sponsor to make an experimental drug available. That is no different than expanded access—there is a right to ask. In both cases, the sponsor is under no obligation to provide the drug. The difference is that with Right to Try, a health insurer is not required to pay for care associated with the treatment, which contrasts with the coverage determination for clinical trials, including expanded access, conducted under an Investigational New Drug authorization.
The law does provide clarification about liability, which is another aspect of medical costs. The physician, their institution, and manufacturer are explicitly shielded from liability related to a drug administered under Right to Try for anything other than reckless or willful misconduct, gross negligence, or an intentional tort. I think this may reduce barriers to access, but in my experience, expanded access is not typically inhibited by insurance coverage, and only rarely does language around indemnification in compassionate use agreements become a contentious point of negotiation between sponsors and hospitals. In clinical trials, the consent must disclose who is responsible for costs in the event of a trial-related injury. Often that risk is insurable since adverse experiences that occur during a clinical trial are treated and billed normally. Under Right to Try, the costs of treating any adverse drug effects are likely to be billed entirely to the patient.
So, under Right to Try, the patient will bear the costs of medical care, and unlike an insurer with market power to negotiate discounted rates, they will likely pay the chargemaster rates. They may end up paying for the cost of the drug as well, since the Right to Try Act waives the application of sections in 505 and 351 prohibiting commercialization of unapproved drugs. Only those who are wealthy enough to completely self-pay their healthcare could reasonably access treatments under Right to Try, which could easily run into the hundreds of thousands of dollars (perhaps more). With expanded access, the cost is spread across the sponsor, insurer, institution, and patient, making it more accessible for now.
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