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.
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

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.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

How to 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
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

Treating Metastatic Malignant Melanoma

Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital.

Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:

  1. Brain MRI
  2. Serum LDH
  3. V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
  4. Presence or absence of disease-related symptoms
  5. Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression.

The factors above go into determining disease burden and pace of disease progression. Presence of brain metastases does not necessarily impact choice of first-line systemic therapy, but certainly informs the need for resection (for single large metastases) or stereotactic radiation for one or several small metastases in parallel with pursuing systemic therapy. The presence of numerous brain metastases would push me to select BRAF/MEK combination therapy if a V600 BRAF mutation were found. Elevated serum LDH, the presence of disease-related symptoms, or evidence of rapid disease progression each push me toward considering of BRAF/MEK combination therapy (presuming BRAF mutant), and certainly two or three of these three factors would force that decision. In the absence of any of these factors, first-line immunotherapy is generally my approach. For most patients that means single-agent PD-1 antibody therapy. But, for young patients who are not deterred by a high rate of severe toxicity and for patients with any of the three “aggressive’ disease warning signs indicated above, I would favor combined CTLA-4/PD-1 antibody therapy. This is based on the higher initial response-rate and short-term ability to control the disease with the combination compared to PD-1 antibody monotherapy. We do not yet know that this combination improves overall survival compared to sequential therapy with PD-1, CTLA-4 and/or BRAF/MEK inhibition. In the absence of that data, I favor PD-1 monotherapy first-line for most patients. If a patient progresses on first-line PD-1 antibody therapy, then I reassess the same warning sign factors as above, now informed by the rate of progression evident on follow-up scans. Modest evidence of progression pushes me to consider CTLA-4 antibody therapy as the second-line approach versus BRAF/MEK combination therapy for more aggressive evidence of disease progression. Recent evidence that the same strategy will soon be an option with MEK inhibitor monotherapy in NRAS mutant melanoma patients. These decision points for selecting first, second and even third line therapy are currently informed by clinical factors. However, we know that each treatment approach can produce years-long remissions as first-line treatment. Thus, it is imperative that we continue to conduct clinical research to develop additional diagnostic methods for identifying those patients predicted to achieve long-term benefit from each of therapies and relay on these for navigating among these multiple treatment options.
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

Introducing a New CollabRx Blog

George D Lundberg, MD, Editor in Chief and Chief Medical Officer & Denise Bartolome, Managing Editor and Webmaster

Q: Why are we starting The CollabRx Blog?
A: With our new blog, we intend to provide a vehicle to communicate timely information of importance about cancer to a broad audience. Our Editorial Board members come from hospitals, cancer research centers, government, academia, industry, and other organizations, invited guest experts, and the CollabRx staff.
Our goal is to teach about the use of genomic (and other -omic) data in cancer diagnosis, prognosis, therapy selection, and clinical trials, as well as payer attitudes, policies, ethics, and economics; and focus, filter, and distill pointed and clear understanding selected from an abundance of very complicated and often confusing source data.
The CollabRx Blog will be a regular recurring journalism column about cancer in blog format with a link on the home page of the corporate website It begins today, Wednesday, March 2, 2016. Our primary audience will be physicians (especially oncologists, pathologists, radiologists and surgeons) plus basic and clinical scientists. We welcome the viewpoints of other health care professionals, students, foundations, pharmaceutical, biotech and device company workers, hospital employees, investors, NGOs, government, public media, payers, purchasers, cancer patients and their families
We will publish weekly at 12 noon PT each Wednesday. The posts will be about 500 words or less. Our blog will be in a Q&A format with specific questions from the CollabRx Editor in Chief to invited experts who respond with answers. Each posting will eventually have an open-ended discussion forum.
Our blog will abide by the Creative Commons rules for open access.
Our posts will be found on Social Media Platforms such as Twitter, LinkedIn, and Facebook in the near future.
Thank you for looking and for reading. We hope to provide regular information of value so as to merit your frequent return.