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

Sun Exposure and Skin Cancer Risk

David Polsky, MD, PhD, Professor of Dermatology and Pathology;
Alfred W. Kopf, MD, Professor of Dermatologic Oncology; Director, Pigmented Lesion Section; The Ronald O. Perelman Dept of Dermatology; New York University School of Medicine; NYU Langone Medical Center

Q: Summer sun season is upon us. What role, if any, does sun exposure have in the causation of cutaneous: 1) Actinic keratosis? 2) Squamous cell carcinoma? 3) Basal cell carcinoma? 4) Malignant melanoma? How completely should humans try to eliminate sun exposure lifelong?
A: The potential health effects (both benefits and harms) of sun exposure have been the subject of much controversy over the last 100 years. In the early 20th century when dietary sources of vitamin D were more limited, sun exposure was thought to promote both bone health and optimal health overall. Early epidemiologic studies, and later laboratory investigations demonstrated a definitive causal link between ultraviolet light exposure (i.e. the damaging wavelengths from sunlight) and skin tumors. Unfortunately, the genie was out of the bottle, and everybody wanted to be tan due to the mistaken belief that it was a sign of good health.
Interestingly, the contribution of sun exposure in different skin cancers varies.
Actinic keratosis: These extremely common skin growths are potentially pre-cancerous pre-cursors of squamous cell carcinoma. They occur on the same skin sites as squamous cell carcinoma (described below) and have a high rate of ultraviolet light-induced mutations.
Squamous cell carcinoma: This malignant tumor has the most direct relationship between sunlight and cancer. These growths occur on the face, arms and hands; skin sites that have received high cumulative levels of sun exposure. In addition, epidemiologic studies found a strong association of squamous cell carcinoma and outdoor occupations. Ultraviolet light-induced mutations are seen in more than 80% to 90% of these growths.
Basal Cell Carcinoma: This skin cancer is also linked to sun exposure, but not as directly as squamous cell carcinoma. The rate of ultraviolet light-induced mutations is lower in basal cell carcinoma than squamous cell carcinoma, and some studies suggest that skin cells’ ability to repair ultraviolet light-induced DNA damage is critical in preventing basal cell carcinoma. In contrast to squamous cell carcinoma, intensive sun exposure in childhood and adolescence may play an important role in basal cell carcinoma.
Cutaneous melanoma: While most cases are clearly caused by sunlight, melanoma is a heterogeneous disease. Some forms are associated with long-term chronic sun exposure; the more common form is associated with indoor occupations and intermittent, intense sun exposure (i.e. sunburns) in childhood and/or adulthood. Rare forms that occur on mucosal surfaces and the palms and soles are unlikely to be associated with sun exposure. Besides sun exposure related risk factors, having a large number of moles and/or atypical/dysplastic moles/nevi is even more important in identifying individuals with an increased chance of developing melanoma.
So how completely should humans try to eliminate sun exposure lifelong, and what are the most effective methods? Clearly sun exposure contributes to all forms of skin cancer so individuals, especially those with fair skin should protect themselves. Patients with light skin and hair color have higher risks because they have relatively low levels of the skin pigment melanin that protects skin cells from sun-induced DNA damage. Patients with lower levels of melanin sustain more DNA damage per minute of sun exposure than darker skinned individuals. To reduce skin damage caused by ultraviolet light, protective clothing should be the major strategy (e.g. long sleeves, long pants, hat, etc.). Nowadays, specialized lightweight sun protective clothing is available for different types of activities (e.g. water sports, golf, hiking, etc.). For skin that cannot be covered by clothing, use a high SPF, broad-spectrum sunscreen. SPF means sun protection factor, a measure of how well a sunscreen blocks ultraviolet B radiation, the wavelengths that cause sun burn. While SPF numbers roughly translate into how many times longer you can stay in the sun without burning, most people apply less than half the amount used to develop the numbers. Also sunscreens may lose effectiveness throughout the day. Experts typically recommend an SPF of at least 30 to insure a minimal level of protection. ‘Broad spectrum’ sunscreens have ingredients that also block ultraviolet A radiation which contributes to skin cancer and photoaging but doesn’t cause sunburns. Apply sunscreen generously in the morning and at midday to insure adequate sun protection throughout the day. Finally, planning outdoor activities to avoid the midday sun between 10AM and 4PM, is an effective strategy but may be impractical.
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

Is there a Better Descriptive Name than Personalized Medicine?

Jerald P. Radich, MD, Director of the Molecular Oncology Lab at the Fred Hutchinson Cancer Research Center, and Professor of Medicine at the University of Washington School of Medicine, Seattle, Washington.

Q: What’s in a name? Should “it” be “Personalized Medicine,” “Precision Medicine,” or perhaps, “Accurate Medicine”?
A: Much of what we do in my laboratory at the Fred Hutchinson Cancer Research Center revolves around the genetics of response and relapse in leukemia. I often describe this as the biology of luck. Why do some good risk patients fail to respond to therapy, while some patients with characteristics of very poor risk nevertheless respond well? This phenomenon is often ascribed to deity, diet, or luck.
One must hope that there is some biology behind the differential response we see in patients. This then is the heart of “personalized” or “precision” medicine. Words matter, however, and in this case, neither of these trendy phrases passes muster. The term “personalized medicine” suggests that prior to the current revolutionary approach, we did not consider our patients to be unique. This is both wrong and insulting. I cannot remember a time where personal features like age, physical condition, comorbidities, and social elements were not as much a part of treatment considerations as were leukemia cell type and cytogenetic findings. A quote ascribed to both Hippocrates (400 BCE) and/or Caleb Parry (18th century) says it well: “It is much more important to know what kind of patient has a disease than to know what kind of disease a patient has.”
”Precision medicine” is a misnomer. If you imagine a target, precision means how tightly the arrows are clustered, whereas accuracy describes the proximity of the arrows to the bull’s eye. Therefore, you could have a very precise diagnostic assay but not be anywhere near the target (truth).
Thus a byline slogan for precision medicine could be “We’re reproducible wrong!” Famed British economist John Maynard Keynes once keenly observed, “I’d rather be vaguely right than precisely wrong.” Other terms that might be considered for this field of contemporary medicine and that are improvements include “accurate medicine” (though admittedly, that doesn’t sound very snappy), “bespoke medicine” (imagine a stylish and perfectly tailored suit), or perhaps simply modernmedicine or good medicine.
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

Seeing the Forest for the Trees: How Cancer Evolution Affects Treatment

Lisandra E. West, PhD, Senior Scientific Knowledge Engineer, CollabRx.

Q: How might current thinking on tumor evolution/heterogeneity and sequential mutational profiling inform optimal therapy selection?
A: I’d like to share some learnings from ASCO, 2016:
To help think about tumor evolution over the course of time and treatment of cancer, I’m a fan of the palm tree analogy (made by Charles Swanton, ASCO 2016). Early genetic alterations that occur in the developing tumor are “trunk” genetic events that are present in every cancer cell in the tumor. Trunk driver mutations may be predictive of drug sensitivity or intrinsic resistance. As the tumor continues to grow some cells will develop additional mutations that will be shared by their progeny cells within the tumor. To continue the palm tree analogy, this results in a branching effect, with each branch representing a sub-clonal population of tumor cells that have new acquired mutations not shared with the original trunk cells or cells in branches that evolved earlier. Swanton cites an earlier study (Landau et al, Cell, 2013) that demonstrated that acquisition of subclonal driver mutations (occurring in the tree branches) results in significantly reduced survival over time as compared to patients whose tumors lack subclonal drivers.
How does subclonal heterogeneity (many tree branches) affect response to targeted therapy? Swanton cited a study (Pearson et al, Cancer Discovery, (2016)) that showed that the best response to FGFR inhibitor therapy occurred in patients whose tumors were homogenous (having few or no branches) for FGFR amplification. Non-responding tumors had sub-clonal heterogeneous FGFR amplification AND presence of FGFR non-amplified tumor cells. This work indicates that targeting trunk or early clonal events is important because response to targeted therapy is better when a greater proportion of cancer cells in the patient share genetic alterations. Interestingly, the overlap of mutations from two different metastatic sites biopsied from the same patient showed that percentage of mutations shared between sites decreases after therapy (venn diagrams presented by Alexandra Snyder, MD, at ASCO 2016). That is to say, there is higher diversity in mutational profiles from different metastatic sites after treatment. This indicates cancer evolution over the course of treatment(s), and leads to questions about whether molecular data from a single biopsy site can be sufficient to inform treatment decision making as cancer progresses.
Thus, therapy drives tumor heterogeneity, which then fosters polyclonal cancer therapy resistance. In a study of patients with metastatic CRC treated with EGFR antibodies, liquid biopsy and sequencing demonstrated that KRAS, NRAS, BRAF, and EGFR mutations were present in post-treatment circulating tumor DNA, whereas they had been absent in pretreatment cfDNA (Bettegowda et al, Science Translational Medicine (2014)). Treatment with a PI3K inhibitor has been shown to select for sub-clones that harbor inactivating PTEN mutations which confer resistance to PIK3CA inhibitor treatment (Juric et al, Nature (2013)). Chemotherapy damages DNA and causes mutations in tumor cells that persist after treatment. These cells go on to form sub-clonal populations that are resistant to drug treatment. In a heterogeneous tumor, drug resistant subclones take over and become the dominant cancer clones that ultimately cause cancer recurrence. Quite remarkably (at least to me), Swanton suggested consideration of treating a patient to stable disease, versus maximal tumor response, based on the idea that treating to maximal tumor response may provoke the rise of a resistant and untreatable subclonal cancer cell population – to the detriment of the patient.
An emerging mechanism fueling tumor diversity and subclonal evolution is genomic DNA cytosine deamination catalyzed by members of the AID/APOBEC family of DNA deaminases which induce genomic damage through their DNA deaminating activity. Deregulation of APOBEC enzymes causes a general mutator phenotype that gives rise to the non-random somatic mutations observed in cancer, ultimately manifesting as diverse and heterogeneous tumor subclones (Mcgranahan et al, Science Translational Medicine (2015); De Bruin et al, Science (2014)). Systemic drug treatment provides selective pressure that gives clones harboring resistance-conferring mutations a competitive growth advantage. We are beginning to understand that it will be necessary to predict and target tumor evolution over the course of treatment. This will require measuring (through ongoing liquid biopsies?) cancer’s subclonal structure that mitigates drug resistance.
Importantly we are beginning to find evidence that lots of mutations in cancer (mutational load/burden) or heterogeneity itself may represent an “Achilles heel” in cancer (Charles Swanton, ASCO 2016). Mutational burden is emerging as a predictive biomarker for sensitivity to checkpoint inhibitor immunotherapy in several cancer types including non-small cell lung cancer and melanoma. Detecting mutational burden, monitoring tumor evolution, and timing and sequencing of immunotherapy with targeted therapies seem likely to be areas of intense investigation moving forward in cancer research.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Multiple Sequential Biopsies now Standard of Care in NSCLC

Gregory Otterson, MD, Professor of Internal Medicine; Interim Division Director of Medical Oncology; Co-Director, Thoracic Oncology Program; Program Director, Hematology & Medical Oncology Fellowship Program; The Ohio State University Wexner Medical Center.

Q: How has the introduction of molecular testing of non small cell lung cancer (NSCLC) altered therapy and outcomes?
A: The understanding of lung cancer as a genetic disease has been developing over at least 30 years. The technology (and cost of this technology) to utilize this understanding has only been developed over the last 10 years, and importantly, along with the technical ability to test for molecular/genetic abnormalities has been the development of a new generation of targeted agents that can specifically target these abnormalities.
In 2004, several groups described mutations with the epidermal growth factor receptor (EGFR) in patients who had sustained substantial responses to EGFR targeted tyrosine kinase inhibitors (TKIs). At this time, a number of TKIs had been approved for treatment of non-small cell lung cancer without respect to mutations. Over the next months and years, clinicians started to understand the frequency and clinical characteristics of these mutations – seen in adenocarcinomas from patients with a light or never smoking history, and especially those from East Asia. The concept of “clinical selection” of patients most likely to benefit from these agents developed between 2004 and 2009. This strategy changed forever however in 2009 with the publication of the IPASS (Iressa Pan Asia Study) which compared gefitinib (Iressa®) to standard platinum based chemotherapy in patients with a light or never smoking lung adenocarcinoma. This study demonstrated conclusively that clinical selection was inadequate – patients with the sensitizing EGFR mutations had profound benefit from the TKI, while those with the same clinical features, but lacking the mutation, had essentially no benefit from the TKI. Multiple subsequent studies have confirmed the benefit from EGFR TKI treatment in patients with molecular selection.
More recently, the development of additional TKIs against the anaplastic lymphoma kinase (ALK) and ROS1 genes have been developed SOLELY in patients who express the molecular abnormality – i.e. the drug and the molecular test have been developed concurrently. The co-development of drug and diagnostic test has revolutionized the diagnostic evaluation of patients with lung cancer because the benefit seen in patients with the abnormality (compared with those without the abnormality) is profoundly different. We expect a response rate exceeding 60% in patients treated with the matched TKI, while those without the molecular abnormality can expect little more than placebo effect benefit, and the standard treatment ought to be cytotoxic chemotherapy. More important than the response rate, the DURATION of response and the overall survival is substantially improved (at least double) in patients matched with the appropriate drug for the defined molecular abnormality (compared with patients not bearing the mutation or treated with the targeted agent).
In the last 2-3 years, several major developments have “moved the goalpost;” the development of second (and third) generation TKIs that are targeted to specific resistance mutations, and the ability to perform sequencing from cell free DNA in blood and other biological samples. Interestingly, while the responsiveness of tumors with specific molecular abnormalities to agents targeted to these abnormalities is profound, the duration of these responses is, on average, less than a year. Essentially all tumors will eventually develop resistance. The mechanism(s) of resistance are profoundly different depending upon the specific targeted gene – for example resistance to EGFR TKIs is most commonly (approximately 60% of the time) via a secondary EGFR mutation (T790M) which acts as a “gatekeeper” mutation preventing binding of the 1st/2nd generation TKI from accessing their binding pocket. Osimertinib (Tagrisso®) is an interesting EGFR TKI with the interesting property of being specific for mutant EGFR proteins (including T790M) and was recently approved by virtue of its ability to “rescue” patients who have progressed after initial responsiveness to the first generation TKI. Importantly, the approval (and insurance coverage) for this agent is dependent upon the demonstration of the presence of this mutation – meaning that, unlike the situation 10+ years ago, it is now considered the STANDARD OF CARE to biopsy patients at multiple time points during the course of their disease.
The second important recent development has been the ability to detect miniscule amounts of tumor DNA (and the corresponding mutation spectrum) from non-tumor tissue (most commonly blood, but also urine and other more accessible bio-specimens). The ability to detect mutations in cell free DNA samples provides an easier and safer mechanism to monitor patients and to detect resistance mutations.
The future of molecular analysis of tumors, and the integration of this technology with the other major treatment revolution in the last 10 years (immunotherapy/checkpoint inhibitors) is a story that remains to be told. Molecular analysis of NSCLC is undoubtedly only going to grow in importance.
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

Use CUREUS to Build Rapid Learning Communities

John R. Adler, Jr., MD, CEO & Editor-in-Chief;
Dorothy & TK Chan Professor, Emeritus, Stanford University

Q: CollabRx, and its “sister” not for profit organization “Cancer Commons”, are dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. The National Academy of Medicine has called for the building of rapid learning communities. How can your company and journal “CUREUS” help facilitate these efforts?
A: CollabRx is dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. But where does one find such evidence? Meanwhile, the National Academy of Medicine has called for the building of rapid learning communities. Yet what is the vehicle for such physician interaction? The answer to both of the above questions is peer-reviewed journals, which are the foundation for most scientific communication. Unfortunately the processes inherent to traditional medical journals undermine these very objectives, i.e. the “rapid” dissemination and “rapid” learning of critical knowledge. I would like to argue here that our reflexive reverence for conventional processes for curating peer reviewed knowledge can and is holding back better cancer treatment.
Modern medicine prides itself for being grounded in the scientific method, and looks to science as the only credible mechanism for improving cancer care. However, it is also important to remind our collective selves that the first step in the scientific method starts with observation, and in the case of cancer, much of this is clinical observation. Because most clinicians are ill equipped to take “bedside” observations and turn them into practical new cancer therapies, (a complex task often requiring lots of money and the backing of large organizations), it is essential that these “in-the-trenches” physicians be able to clearly communicate their discoveries to big cancer research institutions and Pharma. Traditionally this communication happened through peer-reviewed journals, whose review processes function as a safe guard against the publication and dissemination into the mainstream of fallacious science. I would like to suggest that something new, and better, might be afoot.
Burdened by their long legacies as vehicles for academic promotion and tenure, most journals subject observational clinical science to almost the same level of scientific, statistical and documentary scrutiny as that of very complex and socially highly consequential research. Yearning for the fame that comes with publishing big scientific studies, few such “luxury” journals (as nicknamed by Nobel Laureate Barry Schekman) truly value humble clinical observations, or “small science”, as I like to term it. This innate bias represents a hurdle to the documentation and dissemination of clinical science within oncology, and by virtue of such, it undermines the advancement of cancer care itself. Recognizing this impediment to scientific communication, Cureus, a new generation medical journal was created 4 years ago which seeks to blend the traditions of peer reviewed journalism with many contemporary tools that have recently emerged from within the consumer internet. By virtue of design, technology and philosophy, Cureus has sought to streamline the publication of small science without compromising scientific quality. It accomplishes this goal by combining accelerated prepublication peer review with a never-ending “exhaustive” post publication “crowd sourced” peer review, a process referred to as SIQ (Scholarly Impact Quotient) “scoring”. To further break down barriers to the documentation of innovative clinical science, Cureus service is free for both authors and readers, many of which find the increasingly cost of subscription or publishing fees prohibitive. Just maybe, future “cures” for cancer will be reported and authenticated in Cureus, thereby helping CollabRx and the National Library of Medicine to better live up to their own missions.
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

Should All Potentially Lethal Tumors Be Sequenced?

Lisandra E. West, PhD, Senior Scientific Knowledge Engineer, CollabRx.

Q: Is there enough benefit to justify sequencing all patients’ tumors? – Perspective from a scientific knowledge engineer.
A: As a scientist working as a scientific knowledge engineer in molecular oncology, part of my job is to collect, organize, and deliver data that correspond to aberrations present in cancer that could inform clinical decision making.
I recently read with great interest, the opposing viewpoints on “Is there enough benefit to justify sequencing all patients tumors?”, published in JAMA Oncology (April 14, 2016). From the Yes side: sequencing technology provides invaluable intelligence to diagnose, treat, and defeat cancer (Universal Genomic Testing Needed to Win the War Against Cancer by Razelle Kurzrock, MD, and Vivek Subbiah, MD). From the No side: rigorously tested superiority and outcome data are lacking and the cost to patients is still prohibitive (No Solid Evidence, Only Hollow Argument for Universal Tumor Sequencing by Howard Jack West, MD). Both of these are compelling arguments, in spite of their contradictory nature, that deserve ongoing consideration in the oncology community. What we are increasingly coming to understand is that beyond a relatively small set of driver aberrations, whose testing and treatment are specified in standard treatment guidelines, there are a wealth of other molecular abnormalities in cancer that may be highly useful in informing clinical decision making. A few examples to illustrate the point:
1) Biomarker overexpression suggests selection of one targeted therapy drug may be superior to the other targeted drugs recommended for the diagnosis in treatment guidelines (example: high AXL expression in EGFR-mutated NSCLC is associated with acquired and de novo resistance to first generation EGFR inhibitors).
2) Identification of an oncogenic fusion responsive to one class of targeted therapy approved for a cancer and resistant to another (example: BRAF fusions in pan-negative melanoma are responsive to MEK inhibitors, but resistant to BRAF inhibitors).
3) Biomarker loss of expression is predictive of poor prognosis suggesting more intensive therapy is needed (example: loss of expression of MET and RON receptor tyrosine kinases is an independent prognostic factor in DLBCL patients receiving R-CHOP).
4) Gene amplification is predictive of clinical benefit from targeted therapy suggesting the patient may want to consider joining a clinical trial (example: CDK4 amplification in liposarcoma is associated with favorable progression-free survival for liposarcoma patients treated with a CDK4/6 inhibitor).
Before the cost of genetic testing for all patients’ tumors becomes universally accessible thanks to increased affordability, how can we unite the best quality emerging data with each physician-patient pair at the crucial treatment decision points? One piece of the solution may lie in development of focused, cancer specific panels that include the highest strength of evidence markers. These markers will likely span biomarker modalities, including not just sequence variants (detected by NGS), but also protein expression (IHC), copy number variation (FISH), and gene fusions (FISH). Strength of evidence and frequency of occurrence in respective cancers may inform aberration selection for such panels. Physician demand could drive both panel creation and availability, while the evidence for treatment optimization and patient benefit could provide justification for insurance reimbursement to help cover the cost for patients. I hope such advancements in panel design are not too far in the future.
Meanwhile, to the extent that molecular testing is currently available today, how can physicians, and patients, access the highest value evidence that can guide clinical decision making over the course of cancer treatment and tumor evolution? Every physician should have easy access to the highest quality data in a digestible format. Every patient has the right to know, not just what the options are, but that they have been considered by both their personal oncologist, and expert physicians in the community. To me, these are at least in part, problems of knowledge engineering, and thus problems that I would like to work on solving. To this end, I hope to collaborate with some of you on tools and solutions to enable this process in the near future.
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

Use of Circulating Tumor Cells (CTCs) in Detection and Management of Lung Cancer

Ruth L. Katz, MD, Professor of Pathology, Director Image Analysis Lab; Chief research Cytopathology, University of Texas, MD Anderson Cancer center, Houston, Texas.

Q: Liquid biopsy is “all the rage” in the cancer diagnostic space these days. You have worked with Circulating Tumor Cells (CTCs) for quite some time. Beyond R and D, is there a practical clinical usefulness for CTC at this time, what is it and how does one go about using it well?
A: Yes, I believe there are several important practical clinical applications for CTCs beyond R&D, including the early diagnosis of lethal cancers, such as lung cancer. If discovered at an early stage in the disease and treated appropriately with video-assisted transthoracic resection or stereotactic body radiation therapy (SBRT), the early diagnosis of lung cancer would result in a much improved survival rate. If there is a sensitive and specific CTC test for lung cancer, that can be performed as an adjunct to an indeterminate nodule on spiral CT scan or as a primary screening test in high risk individuals and that can be validated and replicated in laboratories worldwide, it would have a major impact on the devastating morbidity and mortality that lung cancer currently wreaks.
Unfortunately, while CTCs are a subject of intense interest to the scientific community, and a current avid pursuit of many researchers, with thousands of publications appearing in the last few years, there is still a state of confusion regarding their reliability as a biomarker for the presence of early cancers, as well as to what constitutes the best platform for the isolation and enumeration of CTCs. Numerous techniques to detect CTCs have been described ranging from different EpCAM capture antibody methods via magnetic beads, with subsequent positive staining for Cytokeratin’s (CK8,CK18, CK19) and negative staining for CD45, to filter methods that rely on isolation of CTCs by size and morphology. Other methods include negative selection of CTCs by depletion of leukocytes from the blood stream. All the aforementioned methods have their pros and cons, with lack of sensitivity being the most prominent disadvantage, as early in dissemination CTCs adopt an EMT phenotype and most cells will escape detection via EPCAM. At MD Anderson Cancer Center, our lab has devised a sensitive and specific CTC test for lung cancer, that relies on a gradient enrichment step, followed by a multi-probe DNA FISH test that has been designed to detect genetic aberrations common in lung cancers irrespective of histologic subtype, including small cell and non-small cell lung cancers. The objective of CTC detection is for an unambiguous test that is specific for rare CTC detection, without inadvertent detection of accompanying background lymphocytes and mononuclear cells. Using a method known as FICTION, in which we perform dual staining for combinations of cytokeratin, SNAIL1, ALDH1 and CD45 followed by FISH for multiple different DNA probes, we have shown that genetically abnormal cells undergo a constant phenotypic evolution or lineage plasticity throughout different time points after tumor resection. In addition there is also genetic heterogeneity amongst the CTCs. Therefore to overcome this phenotypic variance, we have focused on an antigen independent or label-free assay, in which only aneuploid cells with gains of extra genetic material can be scored as CTCs. We have defined a threshold of CTCs, above which a sample can be called positive, and in this way we have been able to detect needle biopsy confirmed lung cancer < 1 cm on spiral CTC scan We also demonstrate that CTCs disappear over time in patients undergoing removal of their tumors either by surgery or by SBRT.
Other important applications involve detecting CTCs that carry ligands which can be targeted by specific antibodies that are conjugated to deliver a lethal dose of the conjugate. For example, in small cell lung cancer (SCLC) an antibody drug- conjugate targeted to a novel protein called delta-like protein 3 (DLL3) (Rovalpituzumab tesirine (Rova-T),Stemcentrx) may bind selectively to the CTCs of SCLC and deliver a drug that kills these cells, while not affecting the normal blood cells. Although not yet approved as a companion diagnostic for CTCs, it would seem that the next logical step for exploiting the presence CTCs would be making drugs of this class that would be effective in fighting both small cell and non-small cell lung cancer. This would take CTCs into the realm of application.
In summation, I would say that CTCs may imminently be used in practical application both in the early detection of lethal cancers as well as the creation of drugs targeting CTCs themselves. There is still work to be done, and we should bear in mind that in order to be acceptable to laboratory professionals, as well as useful to the general public, tests for CTCs for lung cancer should be fairly easy to perform and replicate, and should be validated in a CLIA approved laboratory. We are on the cusp of an exciting new phase in oncology and precision medicine.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Can Precision Oncology Develop Despite Pharmaphobia?

Thomas P. Stossel, MD, American Cancer Society Professor of Medicine, Harvard Medical School; Senior Physician, Hematology Division,
Brigham & Women’s Hospital, Boston, MA; Visiting Scholar, American Enterprise Institute; Secretary, Options for Children in Zambia

Q: Your recent book “Pharmaphobia:—–” about conflict of interest “Myths” drew great attention to what you and David Shaywitz earlier called the “Pharmascolds” hazard. How do you see that phenomenon impacting the current national movement toward “Precision Oncology”?
A: The public’s dread of cancer engenders electric excitement every time something new comes along to combat the disease. The latest example of such a development is “precision oncology:” using the specific genetic makeup of a patient’s malignancy to target therapy against it or else engineering a subject’s immune system to recognize and destroy tumors based on their unique composition.
Over my five decades in health care new anti-cancer strategies have, for the most part, incrementally brought cancer mortality to its all-time low. Therefore, in theory the public’s enthusiasm for these novel approaches ought to be justifiable.
But one serious impediment threatens to squelch such optimism. I call this obstacle “pharmaphobia”: demonization of the industries that produce medications and medical devices. The current political fallout of this attitude is to demand drug price controls.
Underlying pharmaphobia is profound ignorance of fundamental facts. One is that the maligned industry is responsible for healthcare — including cancer treatment — being far better today than in the past.
Another is that developing new drugs is incredibly difficult and expensive. An FDA drug approval costs eighty times more today compared to 50 years ago. It’s because even small increases in testing stringency the FDA imposes on drug development disproportionately exacerbate a high disappointment rate: nine out of ten drugs that seem promising in test tubes and animal studies crash in clinical trials. Therefore, every drug brought to market has to pay for the nine that fail. In no other enterprise does the cost of developing a product bear so little relationship to its present value or production costs. Only profitability addresses the long odds by enabling taking more chances.
What motivates pharmaphobes? Academics gain promotions by attacking industry. Lawyers profit by teaching regulatory compliance – so the more regulations the better. The media attracts readership by ginning up faux scandals, and demagogue politicians garner attention. Medical journals demonize industry marketing to brand themselves as fonts of “trustworthy” information. But the truth is practicing physicians get far more accurate practical information from FDA-regulated company marketing than from unregulated medical journal articles or health center propaganda.
But what about those huge fines medical products’ companies pay for alleged misconduct? These penalties are not smoking guns for corruption but rather manifestations of a federal extortion racket. Physicians often and rightly prescribe FDA approved products “off-label” for unapproved indications. Prosecutors twist the definition of a “false claim” — billing the government for unperformed services – to allege that devious corporate marketing that physicians can’t resist coerced them to prescribe off-label. These cases never go to trial, because conviction for one indictment confers a penalty called “debarment.” A debarred company cannot sell to the government, the major purchaser of its products. To avoid this draconian punishment, companies always settle.
Pharmaphobia has slowed or prevented research relationships, limited or eliminated worthwhile activities (such as providing product samples to patients) and compromised medical training. Most importantly, it diverts scarce resources from medical innovation and education. Unchecked, pharmaphobia will sabotage the promise of precision oncology.
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 do Phase 1 Clinical Trials for Cancer Drugs Work?

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: How is it determined that an investigational cancer drug is ready for entrance into Phase 1 clinical trials? And, how is that transition accomplished?
A: Phase 1 oncology studies encompass clinical trials wherein a new drug or combination of drugs is given to patients for the first time. These studies may include: (i) new combinations of FDA-approved or investigational drugs; and (ii) a first-in-human drug.
For this commentary, I will concentrate on first-in-human phase 1 studies. The main objectives of first-in-human studies include elucidating: (i) safety/toxicity; (ii) pharmacokinetics; (iii) optimal dose; and (iv) response signals.
These studies are designed with dose-escalation steps. The most efficient and, hence, most popular design is termed 3 + 3. Three patients are entered on a dose level, and depending on the side effects or lack thereof, the next cohort receives a higher dose (if there is no toxicity greater than grade 2) or there is an expansion of the current dose (if there is > grade 3 toxicity). The degree to which the doses are escalated can be predetermined by a variety of mathematical schemes.
How is a drug readied for Phase 1? It must go through multiple steps (outlined below) that often take 7 to 8 years. Once the steps are complete, the drug can be granted an Investigational New Drug (IND) by the FDA and given to humans.
The process starts with target discovery and then documenting in vitro and in vivo efficacy. But there is much more. Here are a few examples of the studies that must be done.

  • Formulation/drug stability
  • Pharmacology/pharmacokinetic in animals
  • ADME (absorption, distribution, metabolism, excretion)
  • P450 inhibition or induction
  • Short and long-term safety—often in 2 species
    • Single dose toxicity
    • Repeat dose toxicity
  • Teratogenicity in animals
  • Carcinogenicity in animals
  • Establish manufacturing processes meeting FDA guidelines

A key step is determining the starting dose for the first patient. While a primary concern is prevention of toxicity, an initial dose that is too conservative is also undesirable and can lead to a large proportion of patients being treated at sub-therapeutic doses.
Measures such as the no-observed-adverse-effect-level (NOAEL), maximum tolerated dose and lethal dose (LD) are determined in animals. Well-established algorithms convert these numbers to a suggested safe dose in humans. Sometimes a measure such as 10% of the LD10 (one tenth of the lethal dose to 10% of mice) is used, especially for cytotoxics, to define the first dose in humans. There is abundant evidence that Phase 1 oncology trials are exceedingly safe, with deaths that are even possibly due to drug being in the 1.5 % range. In contrast, ~50% of patients with cancer who enroll on Phase 1 trials will have succumbed to their disease by nine months.
Developing a new drug, from target discovery through preclinical to clinical testing and then to FDA approval, costs about one billion dollars and takes 10 to 15 years. For every 5,000 to 10,000 compounds that enter the pipeline, only one receives approval. And even drugs that reach clinical trials have only about a 15% chance of being approved. Drug development is a long and expensive process.


Dr. Kurzrock has research funding from Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, and Guardant, as well as consultant fees from Sequenom and Actuate Therapeutics and an ownership interest in Novena, Inc. and Curematch, Inc.
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 and the Prevention of Cancer

Erica Frank, MD, MPH, Professor and Canada Research Chair, University of British Columbia; Founder and President,; Founding Member, CollabRx Editorial Advisory Board

Q: What is Next Gen U and how does it approach the prevention of cancer?
A: is essentially the world’s first free university; uniquely global for credit, for free. Founded in 2001 with a focus in the health sciences, NextGenU’s accredited courses span from college-level pre-health sciences and community health worker training through medical and public health graduate training, residency programs, and continuing medical education.  The courses are competency-based, and include online knowledge transfer, a web-based global peer community of practice, and local and remote skills-based mentorships. Our accredited partners, North American universities that are outstanding in each particular course topic, give individual learners credit for this training (or institutions can adopt them and use them with their students). We collaborate with leading universities, professional societies, and government organizations including the American College of Preventive Medicine, CDC, Grand Challenges, Harvard Institute for Lifestyle Medicine, NATO Science for Peace, and WHO.
We now have more than 3,000 registered users in over 130 countries, and expect to achieve our ultimate outcome this year:  the world’s first free degree, a Master’s in Public Health.  We globally launched our first full course in March 2012, Emergency Medicine (EM) for Senior Medical Students, in partnership with Emory University’s WHO Center for Injury Control, the International Federation of EM, and the Society of Academic EM — with this and other NextGenU courses now demonstrated to imbue students in North America and beyond with as much knowledge gain and greater satisfaction than with traditional courses.  NextGenU’s educational system will soon span from expert-created competencies, through learning resources and activities, and multiple choice and mentor, peer, and self assessments, to recommending Continuing Medical Education based on the outcomes of trainees’ patients’, and will encompass a community of practice of former trainees who have learned to interact globally and meaningfully.
What do we offer that is specifically useful to CollabRx Curious Dr. George readers and their colleagues and constituents? We produce courses with components that can help with broadly ranging aspects of cancer prevention, diagnosis, and treatment, including:

  • Alcohol, Tobacco, and other Substance Use Disorders in Primary Care
  • Alcohol, Tobacco, and other Substance Use Disorder Screening (for community health workers)
  • Community-Oriented Primary Care
  • Emergency Medicine
  • Environmental Health (the MPH core course)
  • War and Health

In addition, we will soon be launching these cancer-relevant trainings:

  • All Core MPH courses
  • Breastfeeding
  • Family Medicine Residency
  • Oral Public Health
  • Pediatrics Residency
  • Public Health Nutrition
  • Practice Support
  • Prevention and Treatment of Alcohol Use Disorders
  • Prevention and Treatment of Tobacco Use
  • Preventive Medicine Residency

And one last piece to offer — we would love to work with volunteers (from medical and graduate students through residents, practitioners, and professors emeriti) to co-create further cancer-related trainings, and organizations with which we could co-sponsor these educational offerings globally.
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.