Javier Munoz MD, FACP, Hematologist/Oncologist at Banner MD Anderson Cancer Center in Gilbert, AZ and Hematology-Oncology Adjunct Assistant Professor at the University of Texas MD Anderson Cancer Center in Houston TX

Q: A 76-year-old male is referred to you. His labs at presentation showed anemia and elevated immunoglobulin M. A bone marrow biopsy showed lymphoplasmacytic lymphoma with MYD88 gene mutation. He received a rituximab-based chemotherapy regimen frontline although his disease relapsed with worsening anemia and increased Ig M levels. The patient has no siblings. How do you manage his care?
A: My recommendation at this point would be to prescribe the Bruton tyrosine inhibitor (BTK) ibrutinib. The U.S. Food and Drug Administration granted accelerated approval to ibrutinib (420 mg daily) for patients with lymphoplasmacytic lymphoma in 2015. Clinical response correlates with the presence of mutations in the MYD88 and CXCR4 genes which are commonly seen in this hematologic condition.
What is the difference between Waldenström’s macroglobulinemia (WM) and lymphoplasmacytic lymphoma?
There are some differences even though the terms are used interchangeably by some. Lymphoplasmacytic lymphoma is a neoplasm of small B lymphocytes, plasmacytoid lymphocytes, and plasma cells that usually involve the bone marrow. Waldenström’s macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and monoclonal immunoglobulin M of any concentration. This particular case is better defined as WM.
What is the molecular basis for using ibrutinib in WM?
Whole genome sequencing has revealed highly prevalent somatic mutations in WM. MYD88 L265P is highly present in patients with WM and supports malignant growth via signaling involving BTK. Ibrutinib inhibits BTK and induces apoptosis of WM cells bearing MYD88. WHIM-like mutations in CXCR4 are also present in patients with WM, and their expression induces BTK activity and confers decreased sensitivity to ibrutinib.
What is the expected clinical response to ibrutinib in patients with WM?
The overall response rate was 90% in the original paper by Treon et al; and the highest responses were seen in patients with MYD88 mutation (100%). It is expected the hemoglobin will increase and the immunoglobulin M will decrease in this patient after exposure to ibrutinib.
Do you see any novel possibilities for targeted therapy in hematologic diseases?
We have been trying hard to emulate the imatinib story in CML that would work just as well in other malignancies but it has been very difficult to do so. There are case reports and some ongoing clinical trials trying to match a medication to a particular mutation in hematologic diseases. BRAF mutations have been reported in patients with lymphoma, leukemia, and multiple myeloma. Particularly, BRAF mutations are extremely frequent in patients with Hairy cell leukemia and we may have a therapeutic signal with BRAF inhibitors in such condition with clinical trials underway. MYD88 mutations have been reported in patients with lymphoproliferative disorders as lymphoplasmacytic lymphoma and Diffuse Large B-Cell Lymphoma (particularly the activated B-cell subtype). Some medications, as the BTK inhibitor ibrutinib, seem to work better in patients with WM that carry MYD88 mutations as explained above. Immunotherapy is currently stealing the show across the board in multiple malignancies but responses are not necessarily ever-lasting. Immunotherapy as checkpoint inhibitors have been said to “release the brakes” of the immune system. We need to support rationally-designed trials to overcome resistance to single-agent therapy so perhaps combination studies of immunotherapy plus targeted agents may be a possible avenue for progress in this field.
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George Lundberg, MS, MD, ScD, MASCP, FCAP, Chief Medical Officer and Editor in Chief, CollabRx, a Rennova Health Company; Editor at Large, Medscape; Executive Adviser, Cureus; Consulting Professor of Pathology and Health Research and Policy, Stanford University; President and Chair, The Lundberg Institute; @glundberg

Q: Did the CollabRx vision of 2008-2010 foretell the 2016 Cancer Moonshot?
A: True history is difficult to confirm. Its representation depends in large part on who recorded “his-story.” Even Socrates, who, amazingly, did not himself write, is known mostly because of the extensive writings by his students.
Did Richard Nixon, in declaring “War on Cancer” in 1972, calling for vast research to find a cancer cure foretell the Obama-Biden 2016 “Moonshot”? Perhaps, since it also was a presidential decree.
It takes many threads to weave a tapestry.
Jay Martin (Marty) Tenenbaum PhD, himself both a former Stanford professor and pioneering internet entrepreneur as well as a metastatic melanoma survivor, founded CollabRx as a privately held, for profit company in 2008.
When Marty conceived CollabRx, he envisioned breaking down the silos of process that inhibited movement of positive research results from “the bench to the bedside” to enable a far shorter time than the extant 16 years. Blending-merging the wonders of advanced information technology and the Internet with the increasing wonders of molecular oncology was to be the method.
The goal was always to “defeat cancer, one patient at a time.”
Jeff Shrager, PhD (still with Cancer Commons) and Smruti Vidwans, PhD (still Chief Science Officer of CollabRx) were early hires.
John Wilbanks (an initial CollabRx Editorial Advisory Board member) is credited with founding “Science Commons” in 2006, as a part of the Creative Commons concept.
Wilbanks and Tenenbaum announced/described “Health Commons” in June 2008.
John Niederhuber, MD, Director of the National Cancer Institute, in the March 17, 2010 issue of JAMA, published “Translating Discovery to Patient Care”, nicely summarizing many of these cancer issues and opportunities. He left the NCI Directorship in July 2010.
From 2004-2011 caBIG was an NCI program that was envisioned to accomplish many of the goals described by Niederhuber and envisioned by Tenenbaum. But after spending >$350 000 000 with little to show for the money, caBIG was replaced.
I joined CollabRx on March 2, 2010.
On April 1, 2010, I participated in an Institute of Medicine program in Washington, DC on “The Learning Healthcare System in 2010 and Beyond”. I mentioned the CollabRx and Cancer Commons concept in my lecture and many people expressed interest.
Tenenbaum, Shrager and I announced Cancer Commons in MedPage Today on July 12, 2010. “The goal of Cancer Commons is to provide patients and physicians with the latest information, tools and resources they need to obtain the best possible outcome and to capture and aggregate the results over all studied patients to improve cancer treatment generally.”
The first real product of CollabRx (in addition to appointing dozens of stellar collaborating editorial board members) was the PLOS ONE paper “A Melanoma Molecular Disease Model” (MDM) on March 30, 2011. This paper portrayed a model describing how to envision cancer by genomes, mutations, and pathways. Harvard’s Keith Flaherty and David Fisher teamed with Smruti Vidwans and other CollabRx authors in this groundbreaking effort.
In order to enable utilization of the new MDM, we harked back to the May 5, 1975 beginning of The JAMA series called “Toward Optimal Laboratory Use” (TOLU) which introduced the concept of algorithms and decision trees and tables to physicians that truly did foretell CollabRx “Therapy Finders.”
Following the TOLU model, CollabRx invented “User Guides” for physicians and patients to use as open access interactive web apps at www.collabrx.com, subset Melanoma Therapy Finder
intended to facilitate shared decision making by patients and physicians together at this most difficult time, dealing with advanced cancer. Lung cancer, colorectal cancer and breast cancer web apps followed. The CollabRx Therapy Finder concept incorporated the new biomarkers, recognized practical therapeutic onco-genomics and was based upon cancer site/organ of origin.
On April 1, 2011, The Scientist Magazine (Sarah Green editor) published my “Thought Experiment” called “Medical Publishing for an N of One.” I, an aficionado of large-scale clinical trials as the gold standard for evidence in medicine, had completely acquiesced to the notion that cancer is thousands of different possibly unique diseases with mutational and other …omic designators.
Parallel to these developments, CollabRx science, led by Vidwans, also invented and built a complex, deep, up to date and highly automated Genetic Variant Annotation (GVA) Service that can be agnostic to organ of cancer origin and utilized a “Pan-Cancer” genomic approach, with a different kind of editorial board called “Pan Cancer” headed by Razelle Kurzrock. The GVA is intended to bridge the interpretation-action gap between the NGS laboratory findings and the practicing physician.
In 2012 CollabRx was acquired by Tegal (which adopted the CollabRx name) and moved to San Francisco. New CEO Thomas R. Mika. Cancer Commons by this time had transitioned from a not for profit initiative into a 501c3 corporation and remained in Palo Alto with Tenenbaum.
By 2014, CollabRx announced a new product, CancerRx, as a mobile app extension of the previously exclusively web-based Therapy Finder apps.
There can be little doubt but that the well funded and widely publicized ASCO product called CancerLinQ formally launched in 2016 after years of planning draws heavily in concept from the early thinking of Cancer Commons.
Listening in person to Vice President Joe Biden exhort the ASCO membership in June 2016 to cooperate, collaborate, break down the silos, share, place beating cancer ahead of promoting your institution, company, career, financial gain, etc. sounded a great deal like Marty and me exhorting the IT planning leaders of ASCO in Alexandria, VA in April 2010, and others subsequently, to help us bring the CollabRx and Cancer Commons visions to reality.
We can all hope that the upshot of the Joe and Jill Biden call to double the rate of progress in the fight against cancer (10 years compressed into 5) has a better outcome for many cancer patients, and not only for the American Cancer Industrial Complex, than did the war declared by Richard Nixon in 1971.
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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.
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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.
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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.
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