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.

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

Targeted Therapy and/or Immunotherapy for Cancer

Paul R. Billings MD, PhD, Internist, Clinical Geneticist, and Immunologist: Founder and Executive Chairman, PlumCare LLC; Chairman, Biological Dynamics Inc; Co-Founder and Chief Medical Officer, Omicia; Principal, Bethesda Group LLC; and Member, Board of Directors, Rennova Health Inc.

Q: Surgery and radiation treatment for many cancers are now being followed by not only adjuvant chemotherapy but also a huge panoply of targeted therapies based on precision diagnostics. In your crystal ball, how do you see immunotherapy evolving in relation to targeted therapies based on cancer genomic findings? Exclusive or sequenced or blended?
A: For decades the interplay of the neoplastic process with the immune system has been described. There are several longstanding observations that are relevant:
First, in a variety of animal models of cancer, the adaptive (cellular or humoral) and innate immune systems (natural killer cells, proteins, etc)_can be primed or manipulated to limit or eradicate tumors, or delay their development in high risk settings.
Second, patients who have inherited a defective immune system, undergone stem cell transplants, or had their immune system altered by chemotherapy have a higher than expected rate of primary or secondary neoplasms.
Third, despite apparently normal immune systems and useful cytotoxic therapies, many patients with solid tumors progress. While the therapies themselves may alter the effects of the immune system, cancers seem capable of eventually avoiding immune surveillance either by becoming less immunogenic and/or actively suppressing immunity. It may be that some cancers in early stages are effectively eliminated by our immune systems but those we detect are not.
Historically, surgery is the most effective cancer treatment. Many early stage solid tumors are cured by excision. In some cases, there is a high reoccurrence rate but this is believed to reflect a genetic predisposition or occasionally dissemination as the result of the surgical procedure. Cytotoxic chemotherapy does not usually cure cancer.
Two developments have shown promise in providing oncologists with new and effective treatments for cancers that cannot be cured by simple surgical excision. As we have improved our methods of genomic analysis of primary tumors, metastases or circulating components associated with tumors (cell free DNA or circulating tumor cells), cancer somatic mutations have been noted. Some of these affect metabolic or cellular systems that are “targetable” by small molecule or biologic pharmaceuticals. While the responses to these treatments can be small, some dramatic and effective courses have been reported. These treatments may act directly on tumor metabolism, may make the tumor more readily attacked by our immune systems or both.
A second development has been therapies that directly alter immune responsiveness. The administration of PD1 or PDL1 agents in several differing solid tumor types appears to unblock the immune system and allow it to more efficiently fight tumors. The result has been, despite some significant side effects, profound and long lasting remissions in an unexpectedly large number of patients. The best time to administer these agents and exactly which tumors are most likely to respond remains in need of further clinical investigations.
I believe that in most cases, targeted therapies should be administered early in the course of non-resectable tumors. Their side effect profile and specificity make them an improvement over standard of care cellular poisons. I also believe that once a response appears to be initiated that it should be consolidated by unleashing the patient’s immune system with current agents, vaccines or other immunostimulants. This will lead to the highest rate of cure in my opinion.
Of course, tumors will escape therapies by mutating further making their metabolism more resistant to targeted treatments and changing their “antigenic load” to avoid developing immunity or by directly suppressing the immune system. Thus, monitoring and changing both the targeted treatments and immunomodulation will eventually be necessary in effective chronic cancer care.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

A Full House for Myeloma Therapy: What’s Next in the Cards?

Robert Orlowski, MD, PhD, Florence Maude Thomas Cancer Research Professor and Professor of Medicine (Lymphoma/Myeloma) and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX

Q: Some writers have characterized 2015 as a year of great progress in the treatment of Multiple Myeloma. What advances in Myeloma treatment in 2015 do you consider to be the most important and why?
A: Five new drug approvals for patients with relapsed and/or refractory multiple myeloma mark 2015 as a year of great progress against this disease. Proteasome inhibitors were full with three new regimens:

    1. Panobinostat with bortezomib and dexamethasone
    2. Carfilzomib with lenalidomide and dexamethasone
    3. Ixazomib with lenalidomide and dexamethasone and these were complemented by a pair of antibodies:
      –Elotuzumab with lenalidomide and dexamethasone.

All of these are exciting developments that will help further improve myeloma patient outcomes. Panobinostat, an oral deacetylase inhibitor, is the first agent in its class to be approved for myeloma. It showed activity with the proteasome inhibitor bortezomib and dexamethasone in patients after at least two prior therapies, including bortezomib and an immunomodulatory agent, based on the PANORAMA-1 study. The ASPIRE trial demonstrated that proteasome inhibition with carfilzomib was safe and tolerable when added to the immunomodulatory drug lenalidomide and dexamethasone. Importantly, the three-drug regimen induced deep and durable responses, with little added toxicity. Ixazomib was found by the TOURMALINE-1 investigators to improve outcomes in combination with lenalidomide and dexamethasone for patients with at least one prior therapy. Notably, this proteasome inhibitor is orally dosed, and thereby enhances convenience and could reduce costs by avoiding the need for injections. Next, the SIRIUS study found that the anti-CD38 monoclonal antibody daratumumab was active in patients with three or more prior lines of therapy. This agent’s approval made it the first in its class, providing another new mechanism of action for our therapeutic armamentarium against myeloma. Finally, following shortly thereafter, the anti-SLAMF7 antibody elotuzumab was approved in combination with lenalidomide and dexamethasone. Supported by results from the ELOQUENT-2 study, patients with one to three prior lines of therapy can now receive this immunostimulatory combination.
Since patients with myeloma often receive several different types of therapies, additional studies will be needed to understand whether using these options in certain sequences is ideal. Also, it may be possible to identify biomarkers that could predict in advance whether some patients would most benefit from one or another of these strategies. In the meantime, patients with one prior therapy can receive either carfilzomib-, ixazomib-, or elotuzumab-based regimens, while patients who have been more heavily treated could receive these, as well as either daratumumab or panobinostat in its combination. Use of panobinostat- or antibody-based therapies could be sensible if patients have disease that is progressing through a proteasome inhibitor. Conversely, if progression has been seen on an immunomodulatory drug, therapy incorporating panobinostat or daratumumab could be reasonable. However, it is important data also show that use of sequential proteasome inhibitor- or immunomodulatory drug-based therapies can be effective in some settings, especially with addition of other, novel agents.
Moving forward, many of these drugs will be evaluated in earlier lines of therapy, including in patients with newly diagnosed disease, and it is likely that their activity in those settings will be enhanced as myeloma is then less chemoresistant. The proven track record of proteasome inhibitors make carfilzomib and ixazomib attractive candidates in this regard. While antibodies are still new kids on the block, their relative lack of added toxicity beyond first-dose infusion reactions contribute to their appeal as well. Also, it may also be possible to construct four-drug regimens with a proteasome inhibitor, immunomodulatory agent, monoclonal antibody, and corticosteroid that will achieve optimal cytoreduction. Most importantly, in playing these new therapeutic cards against myeloma, a push is no longer likely, and we are consistently getting the high hand, and coming closer to a cure for this disease.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Managing Metastatic Colorectal Cancer

Bassel El-Rayes, MD, Professor and Vice Chair for Clinical Research, Department of Hematology and Medical Oncology, Associate Director for Clinical Research, and Director of the Gastrointestinal Oncology Program Winship Cancer Institute of Emory University

Q:You have just received a new patient, referred to you from Macon, GA. She is a 52 year old white woman in good general health who is 3 months post op from a left hemi-colectomy for a grade 3 adenocarcinoma with extension through muscle but not through the serosa. Three of 15 lymph nodes were positive for cancer. She did not receive post-op radiation or chemotherapy. No molecular testing of the tumor was performed. She now presents with a single 3 cm mass in the liver discovered by CT scan. How will you manage her care?
A:This 52-year-old patient presents with a solitary liver lesion 3 months after resection of a stage III colon primary. If all her other staging is negative, my first question is do we proceed directly to surgery or should we try chemotherapy first? The short interval between the original cancer and the recurrence makes the case to use chemotherapy upfront followed by surgery. FOLFOX would be the chemotherapy of choice. The biologic agent may be influenced by the molecular profile of the tumor specifically RAS mutational status and MSI. Furthermore, knowing the BRAF mutational status may provide valuable information regarding prognosis. For these reasons, I would obtain a genomic profiling of the tumor. I would administer 2 to 3 months of chemotherapy and then obtain re-staging scans. My overall objective would be to complete roughly 6 months of therapy and follow that by surgical resection or ablation of the liver lesion.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Compassionate Use of Investigational Drugs

Arthur L Caplan, PhD Director, Division of Medical Ethics, NYU Langone Medical Center. Amrit Ray MD, MBA, Chief Medical Officer, Janssen Pharmaceutical Companies of Johnson & Johnson.

Q: What is the ethical basis for compassionate use of investigational drugs; and what are some practical considerations in making such use reality?
A: In seeking relief from the burden of disease, some patients face a lack of satisfactory treatment options from the range of available, government regulatory authority approved medicines. In these circumstances, patients often turn to investigational medicines, or “pre­approval access.” The main avenue for pre­approval access is for patients to enter clinical trials. When clinical trials (and related expanded access programs) are already fully enrolled or otherwise unavailable, individual patients – particularly those facing serious and life­ threatening conditions – may seek “compassionate use.”
Clinical trials are geared to deliver the evidence thresholds that allow regulatory approval in order that medicines can become widely available to all patients who need them, or regulatory denial where benefit­ risk is inadequate. In order not to undermine the clinical trials process and its potential to benefit all patients, individual compassionate use grants need to be evaluated using a clear process including pre­defined ethical criteria. The unbridled access to investigational drugs for all individual compassionate use requests could undermine the clinical trials process. An example would be in clinical trials where patients may feel uncomfortable with being randomized to investigational medicine or placebo, when they could instead obtain certain access to investigational medicine through compassionate use requests. An unlimited number of compassionate use grants might thus undermine the benefit to the many that comes from clinical trials supporting the approval of a new medicine. Conversely, when a potentially beneficial therapy is being studied, the absolute denial of all compassionate use requests may overlook the plight of patients in dire circumstances with no other avenue for potential relief. Therefore, a balance is needed to meet both the needs of the many awaiting new approved medicines then or in the future, and the needs of the few who are out of currently available treatment options.
In order to secure fairness, a balanced policy should lay out processes and ethical criteria that will give equitable opportunity to all patients’ requests. Further, the balance should seek to eliminate sources of bias that could result in unfairness based on morally irrelevant criteria such as celebrity or social standing.
We have proposed a mechanism to achieve this balance and are currently conducting a pilot through the use of a Compassionate Use Advisory Committee (CompAC) [The Ethical Challenges of Compassionate Use, Caplan AL, Ray, A. JAMA, 2016; 315(10): 979­-980]. The CompAC insists on anonymizing individual requests to prevent undue influences from wealth, celebrity or other similar factors. We recommend the systematic application of a number of pre­specified ethical criteria, such as do no harm and the requirement to consider current evidence with respect to benefits and risks. Further, we propose that the criteria be evaluated by an independent, objective committee that includes the voices of physicians, ethicists and patients.
The intent of these proposals is to minimize potential bias and allow the equitable consideration of each request for compassionate use. By offering clear information, a transparent request process, including pre­defined ethical criteria and an objective evaluation by those with broad expertise, we believe that the many awaiting new approved medicines and the few seeking compassionate use will each receive a fair chance at the potential benefit from the development of investigational drugs.
COI Disclosure
Caplan serves as the non­voting, unpaid Chairperson of the Compassionate Use Advisory Committee (CompAC), an external, expert panel of internationally recognized medical experts, bioethicists and patient representatives formed by NYU School of Medicine, which advises the Janssen Division of Johnson & Johnson about requests for compassionate use of some of its investigational medicines.
Ray is a full time employee of Janssen Research and Development, LLC.
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

Single Cell Biology in Cancer Research and Treatment

Gavin Gordon, PhD, Senior Director, Global Pharma & Clinical Trials Alliances, Fluidigm Corporation

Q: What do you see as the best roll for single cell biology in cancer research and treatment in the near future?
A: Supporting immuno-oncology research and development.
Single cell biology refers to the analysis of individual cells isolated from complex tissues obtained from multi-cellular organisms and can be applied to many biologically relevant areas of study. For example, the identification and characterization of various cell compartments, the study of cell fate including lineage mapping and phenotypic plasticity, and understanding mechanisms of tumorigenesis.
Why is it important to conduct single cell studies in the first place? Because biology is heterogeneous. So are complex tissues. And even among relatively homogenous tissues, morphologically speaking, it’s well understood that RNA and protein expression profiles at the whole tissue (or “bulk” level) do not correlate with those of individual cells or cell populations. The same is true for function. A biliary epithelial cell has a different purpose, and gene/protein expression pattern, than a hepatocyte. B cells function differently than T cells in mediating the body’s defense against foreign invaders. Yet both differences would be obscured simply by studying “liver” or “lymphocytes”, respectively.
What is immuno-oncology and why is it so important? Cancer as a disease is also inherently and fundamentally heterogeneous. Cancer cells proliferate and give rise to multiple generations of progeny with distinct genetic mutation profiles. These profiles relate to pathophysiological processes, like metastasis of tumor cells or tumor-induced angiogenesis, for example. This is partly why small molecule therapies that target specific tumor mutations (like BRAF and EGFR inhibitors) modestly extend the life of cancer patients and nearly always result in tumor recurrence; not every cell in the tumor contains the targeted mutation and the resulting “resistant” cells grow to repopulate the tumor post-treatment.
As with the individual cancer cells that comprise a tumor, the immunological microenvironment in which tumors grow is similarly heterogeneous and can benefit from a single cell approach to analysis. Immuno-oncology pertains to the discovery and development of therapies (“immunotherapies”) that target the body’s immune system to help fight cancer. Immunotherapy cancer treatments work in different ways. Some boost the body’s immune system in a very general way. Others help train the immune system to attack cancer cells specifically. In all cases, critical to developing effective immunotherapies is a comprehensive understanding, at a single cell level, of the cellular immune compartment associated with specific tumors.
Recent advances in cancer immunotherapies, and promise of more to come, represent the greatest leap forward for dramatically extending the life of cancer patients since the advent of chemotherapy in the middle of the previous century. While targeted therapies are associated with a modest survival benefit, immunotherapies can be associated with a more durable response in some cases. For example, approximately 25% of advanced melanoma patients receiving an early immunotherapy (the immune checkpoint inhibitor ipilumimab/Yervoy) survive 3 to 10 years post-treatment. In addition, the presence and relative abundance of various immune cell types in the tumor microenvironment may have predictive or prognostic value. These differences can only be teased out with a single cell approach. Many scientists believe that a deepening appreciation of oncology genomics and the quantity and type of antigens expressed by the tumor cells, when coupled with an analysis of the patient’s immune system, will greatly progress the field and unlock the next generation of immunotherapies, many of which no doubt will be combined with targeted therapies and conventional chemotherapy to fight cancer on multiple fronts.
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Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Initiate Treatment for Chronic Myelogenous Leukemia

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

Q: What is your basic approach to handling a middle aged adult patient in good general health who is referred to you with a new diagnosis of Chronic Myelogenous Leukemia?
A: First off, the treatment of choice for chronic phase CML is a tyrosine kinase inhibitor (TKI). Currently there are three approved TKIs in the front line setting, imatinib and the second generation TKIs, nilotinib and dasatinib. There have been three randomized trials comparing imatinib to either nilotinib or dasatinib, and all three show remarkably similar results. The second generation TKIs have better short term efficacy (cytogenetic and molecular responses at 12 months), and fewer progressions to advanced phase disease, yet surprisingly, overall survival seem similar between imatinib and the newer agents. This is especially relevant since imatinib may soon become generic.
All of the TKIs are well tolerated, and each have specific toxicities. For example, nilotinib can cause elevations in metabolic syndrome manifestations (lipids, glucose), while dasatinib can cause pleural effusions and in rare occasions, pulmonary hypertension.
In choosing a TKI, a few things are important to consider, and they revolve around the goals of therapy, which should be different for different patients. One important consideration is risk of progression at the time of diagnosis. There are several clinical prognostic scores available (Sokal, Hasford, EUTOS) that correlated with outcome. Patients with low risk disease can safely be treated with any TKI, while if a patient has a clinical presentation at high risk, it might be better to start with a more potent second generation TKI. Secondly, it is now becoming clear that some patients who achieve an outstanding disease response can discontinue therapy and not relapse. Thus, for a younger patient who might be facing decades of TKI therapy, or who may wish to have children, a second generation may be a good starting point, since the chance to achieve a complete molecular response is greater than with imatinib. However for the lion’s share of patients, starting with imatinib is a fine choice, particularly in older patients, or those with higher risk of cardiovascular complications, since imatinib seems relatively free of these complications compared to the more potent TKIs.
Lastly, if generic imatinib becomes far cheaper than other TKIs, there are some solid medical economic arguments that might compel one to start therapy with imatinib.
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

Making NGS Work for Oncologists

Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Q: Your group has recently described an Actionability Framework for designing treatment strategies for cancers that are characterized by mutations. What is the basis and rationale for such an approach?
A: As Next Generation Sequencing (NGS) is increasingly adopted into clinical practice, physicians are faced with the daunting task of identifying variants that are clinically actionable – those that can help them select potential treatment options. In oncology, NGS technologies are used to profile tumor or liquid biopsies and identify variants in cancer-related genes. Cancer gene panels range in size from a handful of genes to several hundred. Depending on the size of the panel, many variants may be observed in tumors.
Genes in cancer panels can broadly be classified into three groups. The first group includes genes (e.g. BRAF, EGFR) that are validated for use in clinical decision-making based on related drug approvals, inclusion in treatment guidelines and a large body of supporting clinical data. The second group includes genes with ‘emerging’ data supporting actionability. Lastly, the vast majority of genes in large panels have limited data supporting use in the clinic and are primarily used for research purposes.
Clinical actionability of NGS data is context-dependent. Relevant factors include diagnosis, nature of observed variants, targetability of variants by one or more drugs, strength of evidence linking variants to therapies, potential interactions between variants within a sample etc.. There is another set of considerations, having to do with the patient as an individual, that is key for clinical actionability. Even when the molecular profile of a patient’s tumor clearly identifies one or more treatment options (e.g. when observed variants are in clinically validated genes such as BRAF), acting upon these treatment options is dependent on patient physiology, disease burden, history, patient goals and wishes and many others factors. For example, inclusion of a BRAF inhibitor in the next course of treatment will be influenced by whether the patient has already been treated with one and whether they have derived or are deriving clinical benefit from it. In the case of a treatment-naive patient with a BRAF mutation, the choice between a BRAF inhibitor and an immunotherapy will likely be influenced by factors such as burden of disease. Patient context becomes even more important if observed variants are in genes in the second group, for which treatment guidelines are not established, or for which clinical data are emerging.
The goal of NGS testing is to aid oncologists choose treatments most likely to help their patients based on molecular characteristics of their tumors. However, when NGS test results are not deeply integrated with other patient information, there is a real danger that they will become just another set of data that oncologists are confronted with, and are unable to derive benefit from, in the limited time they are able to spend with each patient. This is a shame for the patient, an impediment to achieving the promise of precision oncology, and will ultimately limit adoption of this technology in the clinic.
We’ve made great strides in providing oncologists with information linking molecular information to a variety of treatment options. Now we need to equip them with tools beyond the genetic test report that will enable them to find the most appropriate treatment choices for their patient at any given time.
For reference, download the poster from the Molecular Med Tri-Con 2016:
Download PDF of Poster
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