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

Canadian/American Cancer

Cynthia Martin, MA is a freelance/ghost writer (who tried to write a serious piece).

Q: As a journalist, you are a savvy native Canadian consumer/patient who also knows a lot about the United States. What do you see as the main similarities and differences between cancer prevention and care in the US and Canada?
A: Writing a 500-word answer to this is like trying to boil down 40 gallons of sap collected amid a chilly stand of trees to make 1 gallon of maple syrup. If all goes well, you get a dreamy confection where waffles are merely a delivery system. If not, you get a soggy gooey mess leaving you with sticky pails and spouts, a burnt-out fire, cranky people who remind you they could have spent the day elsewhere, an awful friggin’ lot of cleaning up and a spike in wine sales at my closest store.
I started in healthcare in 1985; written and ghosted a whack of health material including on cancer, volunteered and taken care of friends including my best friend who died partially from sheer weariness and partially because a doctor missed his calling as a government clerk. I read, I nod, I empathize, I sympathize and I get mad. Then I forget until a fresh sad story comes along; so I’ll first address the main difference. With the US a market-driven system – which is very bad for healthcare – your cancer services are slick and self-serving, like a smarmy blind date who shows up perfectly groomed with an IQ of 49 who mowed down the uninsured and underinsured to get to me. Under that difference is that Canadian parents don’t have to mortgage houses to pay for a child’s cancer care, Canada doesn’t have the many hundreds of insurance companies as in the US; with overhead and administrative costs dramatically reduced if rolled into a single-payer system the US would see enough savings to cover every citizen.
Turning to similarities between the two countries, my overarching thought is we should all be ashamed. Ashamed, as Brian Klepper wrote on this blog, “Cancer care is such lucrative business that more than one in four health systems is now building a cancer center.” Ashamed, that since Richard Nixon declared a war on cancer in 1971, cancer became the disease dominating the zeitgeist of the past 45 years (!!!!) Whether another touching tribute in an father’s obituary who “fought valiantly” or sister who “battled bravely” – I’m sure that’s not what Nixon meant. You bet cancer is lucrative: with more than 56,400 clinical trials listed it’s not disappearing soon.
Another similarity is urban and rural cancer services; both the US and Canada are large landmasses which make comprehensive services impossible. This makes me want to run screaming off the end of my closest wharf since I do indeed live in a semi-rural area and if I got cancer, would be screwed in the bad kind of way (oh really, I’m the one not taking cancer seriously?).
Also similar: prevention is largely an afterthought, like no-name condiment packages stuck at the back of a drawer (“Right, we have some of that somewhere…”). In 2015, it was estimated that in the US 1,658,370 new cancer cases would be diagnosed with 589,430 cancer deaths; and 196,900 Canadians would develop cancer and 78,000 die of cancer. If extrapolated into deaths from plane crashes – say Boeing’s 737-800, likely the most common large aircraft–that’s some 43 planes full of individuals a day. I know those stats can’t be compared but think of each person as a mother, lover, child –losses impossible to calculate correctly. In a small sign of related prevention, consider Mexico, which applied an 8% tax on “non-essential” food in January 2014, seeing junk food sales drop 5.1%, while our governments dilly-dally. The only two jurisdictions: Berkeley California’s health tax on sugar-laden drinks (must be the dreamcatcher earrings) while Philadelphia’s recent vote for its sugary-drinks tax was approved precisely because it was pitched as a tax measure for city revenue. That the beverage industry spent $10.6 million to thwart Philadelphia’s tax is obscene, like opposition (in large part by US health insurance companies) to 1993’s US Health Security Act and recently Obamacare – your two-party feuds are emblematic, wasting so much energy and time, being infinitely more precious than jettisoning partisan vested interests for the good of your citizens.
Soon after she was appointed the 18th US Surgeon General, I interviewed Dr. Regina Benjamin. She seemed she’d bring spunk and honesty to the role, especially when she said disco dancing was exercise (be still my heart). But the PR gauntlet I had to negotiate told me not to put that in (it’s an article pull quote). One of Dr. Benjamin’s hopes was to see a “smoke-free world,” but…poof she resigned. I’m thinking since she was muzzled on disco dancing even whispering “Let’s address tobacco use” would have been like a scene from a mob movie, her being bundled out her office rolled up in a carpet. People have completely lost their minds and souls and misdirected their talents since Nixon’s proclamation. So very much has been and is still written and discussed and debated, so very many trial balloons sent up by politicians as to which policies incur less wrath and fewer lost votes, so many millions of people needlessly suffering and ever lost to us – because the will is not strong enough to shut down tobacco and change taxing policies, corral lobbyists and target chemicals, take less from whatever payment system because – oh, it’s great going to conferences (saying the same things said for decades). Although I deeply adore Obama and Biden, now there’s a Cancer MoonShot, as American as the war on cancer.
No cancer isn’t funny, not even the black humour wit needed to work in healthcare, nor are greeting cards now cheerily saying “Cancer Sucks!” instead of “Get Well.” I’m trying not to mention pink ribbon marketing so here’s a musical interlude. The lead singer of an iconic Canadian band has glioblastoma winding up their supposed last tour, every station playing their music ad nauseum as media, the public (many of whom never paid attention to the band prior) and medical community fawned over his “bravery” – as if he is the only patient in their waiting room, as if he is the only person to ever have cancer and be prescribed its itchy coat of hope – as if he is the ONLY one who will die. Meanwhile, funds roll in to cancer research and – of course – the band. Not so for the lead singer of another Canadian band, who has early Alzheimers and wound up his tour quietly–so Canadian-like – but then Alzheimers isn’t as sexy. The twin brother of a British guitarist, not parlaying cancer into sales, just announced his twin’s death at 28, while yet a member of another iconic Canadian band – who’s going to die somehow not raking in teary-eyed royalties – quit to work at a library. This is all so very very – to use a scientific term – nuts.
I hope I can hear keyboards stirring to action…not to flame me for opinions on this soggy gooey mess (don’t shoot the messenger), but in a universal demand for an end to cancer, mad enough to bite down hard, not just nibble away ad nauseum at its margins.
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

Conflict of Interest in Cancer Clinical Trials

Kevin B. Knopf, MD MPH, Medical Director, Cancer Commons
San Francisco, California

Q: Clinical trials are the lifeblood of continuing drug development in the US. Yet they are often undersubscribed. What do you see as key conflicts of interest in recruiting for patients in the academic medical center, the hospital, and the private oncologists’ practice?
A: Recently readers of this blog engaged in a spirited debate about conflict of interest in cancer clinical trials. The issue was divided as to whether or not the treating oncologist was the best person to offer a patient a clinical trial. I might suggest that the question can not be reduced to an “either or” answer – but is best understood as an asset allocation problem – the result of increasing financial pressures on cancer care due to trends over the past several decades.
The patient’s interest is in finding the best possible treatment for their cancer – on or off a clinical trial. The provider wants the patient to achieve the best possible outcome for their cancer and has an altruistic motivation to find better treatments for other patients. At the same time any provider stands to gain financially or secondarily (publication, promotion) from their involvement with a clinical trial. PHARMA has vested interests in finding new drugs that will provide return on investment and wisely invests heavily in clinical trials.
The American oncology enterprise is adopting to thinner profit margins. There is less profit from chemotherapy and radiotherapy reimbursement, and funding by the NCI for research is at a 20 year low. Thus the necessity of running clinical trials as a “revenue surplus” has risen – particularly in academic medical centers. At the same time clinical trials are the main engine that drives progress in cancer care.
I believe a partial solution is to reallocate assets in cancer care to ease some of the financial stress felt by academic medical centers and community based practices. When we stop paying so much for things that don’t help our patients we have more financial assets to investigate trials of drugs that can actually help them. For example, overly aggressive oncologic care at the end of a patients’ life with prolonged (and expensive) stays in the Intensive Care Unit rather than a timely referral to hospice are unlikely to help as many patients as discovering a novel therapy might. Reduplication of imaging studies at multiple institutions if they don’t add to patient outcome is a second. The ASCO “choosing wisely” campaign, if followed fully, would be cost-effective for the cancer care system. This will reduce some of the financial pressure that might drive patients into clinical trials for reasons other than purely altruistic ones.
Health economics – the fuel for the engine that drives cancer care in the United States – is a zero sum game. With the declining funding rate from the NIH funding for clinical trials is dependent on honest and moral relationships with PHARMA. The cooperative group trials from the NIH are financial “loss leaders”. At a time when funding for cancer research from the NCI is diminishing and we have a record number of new cancer drugs approved we are now dependent on industry sponsored trials to keep the research endeavor going. Value based cancer care seems to be the catchphrase as we struggle with rising costs of treatment. What may help us ultimately are a series of real world clinical trials with economic endpoints to find cost-effective opportunities for cancer treatment. We should redouble our efforts to curb endeavors that seem purely destined to bring “economic friction” in cancer care. A wiser approach to economic asset allocation in cancer care could free up the financial pressures at the heart of this conflict of interest and start to minimize – but never completely erase – this conflict.
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

Can Preclinical Data Guide Clinical Cancer Therapy?

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

Q: Under what circumstances and to what extent are you willing to take clinical actions on a cancer patient based primarily on preclinical data?
A: There are two scenarios that come to mind when thinking about reliance on preclinical data for treatment decision-making: (1) use of an agent that is an established treatment for a noncancer indication and (2) use of an established cancer therapy outside of the context(s) for which there is known clinical efficacy.
In the first scenario, I am essentially NEVER willing to accept a preclinical finding that suggests efficacy as a basis for prescribing use of such an agent. This perspective comes from a career focused on performing early phase clinical trials with agents that demonstrated promising in vitro and in vivo effects that failed to exert any discernible effect in cancer patients.
The explanations for these failures are numerous, but the most common explanations are inability to achieve the drug concentrations/exposures needed to match those used in preclinical experiments and lack of fidelity of the preclinical model systems for predicting outcomes in patients.
This second category remains a major challenge for many cancer therapeutics in that we simply do not have a repertoire of ex vivo or in vivo model systems that fully recapitulate the complexity of human cancer with regard to the molecular features of the cancer cells themselves, the tumor microenvironment, and an intact immune system. This is a greater or lesser liability for certain classes of cancer therapeutics, but we generally cannot be dogmatic about which mechanisms of action will translate across preclinical and clinical settings.
Regarding the scenario of using a cancer therapy with known efficacy in some context for an off label indication based on preclinical data, I am generally more willing to consider this possibility, though it is infrequent in clinical practice that such an approach trumps direct clinical evidence for a repertoire of therapies in a given cancer indication.
When thinking about specific types of systemic cancer therapy (conventional cytotoxic chemotherapy, oncogene targeted therapy, and immunotherapy) there are very real differences in cancer biology that relate to variable efficacy for each across Cancer types. Several years ago, we had hoped that this would not be true for the activated oncogenes for which molecular targeted therapies have been established as effective and at least one contact. BRAF mutations are, perhaps, one of the best examples here. We know that BRAF mutations are found across the majority of cancer types, though at very low rates in many of them. Going into the first clinical trials with selective BRAF inhibitors, we were equally optimistic regarding potential efficacy in melanoma and colorectal cancer, but came away with enormous enthusiasm in melanoma and essentially no efficacy in colorectal cancer.
Extensive laboratory research subsequently help to explain the relative resistance of BRAF mutant colorectal cancer, but it was not a phenomenon predicted by preclinical models prospectively. In fact, it is this type of example that motivated the NCI MATCH trial which is broadly exploring molecular targeted therapies in cancer patients where the molecular features are the basis for inclusion in a given therapeutic arm, not cancer type.
In other words, we take it as conventional wisdom currently that we do not have a basis for predicting efficacy when exploring these types of approaches across the spectrum of cancer types.
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

Circadian Cancer Therapy

William Hrushesky, MD FACP, Founder and Chief Scientific Officer Rythmalytics LLC (Cicada Circadian Coach), West Orange NJ; Chief Medical Officer Ambulatory Monitoring Inc., Ardsley, NY

Q: Are there meaningful advantages to show for optimizing and specifying time of day treatments for cancer?
A: Everyone knows: GEICO can save you 15%. Everyone knows “Timing is everything”. Almost no one knows: the time of day cancer therapy is given determines the severity of its toxicities, its anti-cancer efficacy and the likelihood of five year advanced cancer patient survival (four fold).
Some 25 years ago, a physicist and engineer, since friend and research collaborator, read of our circadian cancer therapy work in “Science” and came to visit me.
He had just had a colon cancer resected. This cancer was very mean and aggressive under the microscope and involved many lymph nodes. He had been told that he should undergo multi-agent chemotherapy. He was also told his cancer would probably recur and kill him within a few months or years, despite this highly toxic chemotherapy. Mike is a compulsive bike rider & athlete and had read about our work, creating, programmable continuous infusion pump based regimens with little or no toxicity and greater efficacy in metastatic colorectal cancer when given by continuous infusion, mostly at the right time of each day. I told him that such data were solid but that we had not done post surgical adjuvant (after surgery to increase cure) studies.
He and I created an adjuvant regimen which provided the vast majority of each day’s continuous 24 hour infusion in the night time hours, when in the day our clinical studies demonstrated unequivocally the patient would be spared the most damaging ill effects. Within six months this 24 hour continuous personalized timed chemotherapy regimen devolved into a night time only regimen with weekend breaks. We repeatedly found no evidence for cancer recurrence. Mike had NO side effects and continued to ride his bike 50 miles each day. After close to two years of this completely benign timed infusional therapy, I asked Mike whether he wished to stop. He did. That was more than two decades ago.
Mike now studies the metastatic process and interrupting it. We have written some thirty papers together, have earned two grants to support this work and are working on a third.
The five billion years of life on this planet, characterized by the continuous rhythmic dynamic dance of earth and sun have endowed each earthborn life form with hierarchies of circadian clocks. Molecular clocks inhabit and beat within each cell. A range of neurologic (SCN and retinal) and neuro-endocrine (pineal) physiologic clocks, time each and every life event optimally within each day. The blue wavelength (dawn & dusk) sensitive retinal ganglia clocks connect the brain, pineal and cellular clocks directly to the sun each and every day. Cancer cells maintain this coordinated daily biology.
Nearly every useful anti-cancer agent targets aspects of highly coordinated circadian organized cellular proliferation. Human beings living in a single time zone share time of day, intimately, providing potential temporal personalized synchrony.
In cancer therapy timing is “everything”. Forty years of work and thousands of peer reviewed publications back this up and await immediate application.
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

Generic Drugs vs. Biosimilar Biologics

Y. Tony Yang, ScD, LLM, MPH., Associate Professor, Department of Health Administration and Policy, George Mason University, Fairfax, Virginia. Charles Bennett, MD, PhD, M.P.P., Smart State and Frank P and Jose M Fletcher Chair, Medication Safety and Efficacy, Smart State Center of Economic Excellence, University of South Carolina and the Hollings National Cancer Institute Designated Cancer Center of the Medical University of South Carolina, Charleston, South Carolina.

Q: Are biosimilars the same as generic versions of biologics? Will they be approved by the FDA? Are they safe? Are they cheaper? What about the intellectual property rights of the manufacturer of the reference biologics? If they are only slightly less expensive than the reference biologics, why would anyone prescribe them- particularly if we are not certain that they are as safe as the reference biologic?
A: Biosimilars are NOT generic versions of biologics. Biosimilars are HIGHLY SIMILAR to the reference product they were compared to, but have allowable non-clinical differences. Differently, generic drugs are copies of brand-name drugs, have the identical active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Biosimilars are produced from a living organism; therefore, it is impossible to produce an exact copy of the reference biologic. Two biosimilars are approved in the U.S. as of July 2016: one is marketed (Zarxio, a Neupogen biosimilar) and the other is involved with patent litigation (a Remicaide biosimilar approved in April). A third and fourth biosimilar received unanimous votes in July of support from FDA’s Arthritis Advisory Committee (a Humira and an Enbrel biosimilar) although patent litigation may occur before marketing is allowed to begin.
For years, biosimilars have been approved and safely used by patients in Europe, Japan, Australia and other countries. While the regulations for approval are similar internationally, Europe has been way out in front on approving biosimilars and the U.S. is just entering this market. The biosimilar approval in developed countries relies on each country’s regulatory agency’s previous findings that the agency-approved reference biologic is safe and effective.
Although biosimilars in the U.S. are not expected to provide the 70-80 percent savings we have seen with traditional generics, biosimilars have historically cost at least 20-30 percent less than the reference product, which can cost over $100,000 per year. Zarxio came to market in the U.S. at a 15 percent lower cost than its reference biologic. That implies the price differential between a biologic and its biosimilar is more likely to approximate the competition in a multi-brand category of drugs rather than between a reference drug and its generic. Nevertheless, these cost savings from biologics help give patients access to these complex drugs. By improving access to biologics through biosimilars, more patients have the potential to receive life-changing treatments. The reduced cost of biosimilars will also lead to substantial cost-savings in the broader healthcare market. Although it remains to be seen as the biosimilar pipeline continues to mature in the U.S., it is estimated that the U.S. health care system has the potential to save up to $250 billion by 2024. These savings create resources to enable access to other innovative treatments, improving the lives of all patients.
Biosimilars were first allowed under the Biologics Price Competition and Innovation Act (BCPIA), a section of the sweeping 2010 Affordable Care Act. The BPCIA acknowledges the significance of promoting innovation, but it also provides a pathway for competition once monopoly protection ends. Biologics can acquire patent protection, which lasts for 20 years from the date the patent application is filed. The BPCIA stipulates a 12-year market exclusivity and a 4-year data exclusivity beginning when the biologic drug secures FDA marketing approval. Each exclusivity can be extended 6 months for pediatric applications. A biosimilar cannot be marketed until the 12-year exclusivity expires. These exclusivity protections are designated to stimulate biologic research and development. However, if the politically controversial Trans-Pacific Partnership between the U.S. and 11 other Asia-Pacific countries is approved, exclusivity could drop to 5 years. Stay tuned and the next few years should be exciting times for biosimilar approvals and uptake in the U.S.
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

Driver and Passenger Mutations in Cancer Cell Genes

Michelle Turski, PhD, Senior Scientific Knowledge Engineer, CollabRx

Q: What are the similarities and differences between “driver” mutations and “passenger” mutations and in what common malignancies is that distinction most important?
A: The commonly accepted definition of a driver mutation is a mutation within a gene that confers a selective growth advantage (thus promoting cancer development), while passenger mutations are those that do not provide a growth advantage. Independent of context, the type of mutation observed is not a factor in differentiating between a driver versus a passenger mutation. However depending upon whether the driver gene is classified as an oncogene or tumor suppressor, the type of mutation observed can play a role in determining whether it is a driver or passenger. For instance, driver mutations in oncogenes tend to be missense mutations at specific codons or focal amplifications, while nonsense or frameshift mutations or focal deletions are often the hallmark driver mutation type in tumor suppressors. Driver mutations have a tendency to occur in protein-coding regions of genes and within important functional domains of the protein, although it’s increasingly being recognized that non-coding mutations, like splice-site or promoter mutations, can also be driver mutations. Thus, using mutation location as a discriminatory factor may be becoming a less reliable indicator of whether a mutation is a driver or passenger. Additionally, driver mutations are often somatic in origin, with germline mutations often fast-tracked to the passenger bucket; however, a cautionary note should be inserted here as there are very clear examples of where germline mutations are driver mutations (e.g. BRCA1/2 in familial breast and ovarian cancer or TP53 mutations in Li-Fraumeni syndrome).
In terms of the ‘how’, there are generally two methods or approaches to classifying a mutation as a driver or passenger: 1) by frequency (driver mutations should be mutated in a greater proportion of cancer samples than would be expected from the background mutation rate) and/or 2) by prediction of functional impact (either via in-silico algorithms or cell/model-based assays). Each method is fraught with caveats and disadvantages or challenges, however the gold standard of evidence that a mutation is a driver is experimental evidence demonstrating that the mutation produces a cellular phenotype that provides a selective growth advantage to the cell. Thus, importantly, bioinformatic methods cannot provide definitive classification of mutations as either driver or passenger but can be a means by which to prioritize mutations for functional testing.
Because driver mutations are by definition those resulting in cancer initiation and/or progression, they are seen as the ‘achilles’ heel’ of tumors, sought after as targets for drugs, and used in making therapeutic decisions. Thus, being able to make distinctions about whether a mutation is driver or passenger is important for any malignancy. However, being able to make this distinction is harder in some cancer types than others. For example, lung cancer has a much higher mutational burden than acute myeloid leukemia (AML), which makes the identification of driver mutations in lung cancer more difficult than in AML. Passenger mutations perhaps shouldn’t be dismissed entirely, as emerging data and theories suggest that passenger mutations can transform into driver mutations (so-called “latent drivers” or “mini-drivers”, amongst other proposed terms), especially within the context of resistant and/or recurrent disease. However given the high number of passenger mutations usually present in tumors, it will be hard to discriminate between those passengers likely to ‘stay put’ and those with hidden driver potential, requiring more investigative studies.
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

Patients and Physicians Should Share Decisions in Oncology

Brian Klepper, PhD, CEO and Founding Principal of Health Value Direct

Q: Many of us have been touched by the publication of your sensitive but serious criticism of your wife’s care once her ultimately lethal peritoneal cancer had spread. How do you propose that oncologists, patients and their families should best practice “shared decision making”?
A: Sad but true, most cancer patients today unknowingly enter highly conflicted treatment environments where, as a practical matter, the ideal of shared decision making may run counter to the provider organization’s interests. Cancer care is such lucrative business that more than one in four health systems is now building a cancer center. Physicians or the health systems they work for typically profit from the drugs they prescribe, which often lack evidence of efficacy. These vectors often result in care decisions that accrue more to the health system’s than the patient’s benefit.
Patients should assume that their physicians have their best interests at heart but, in complicated, unfamiliar territory, insist on asking hard questions. Doctors are increasingly aware that their role includes making patients aware of their options, but they, like all of us, may also have inherent biases that manifest in what treatments they urge for their patients.
Physicians can be optimistic about outcomes and patients may be unreasonably hopeful, so an honest evidence-based assessment of current realities is critical. What benefits will the treatment realistically buy the patient and how much of an ordeal will it induce? What are the odds of success and what, exactly, is the definition of success in each case? The goal is to arrive at care decisions based not just on abstract notions of what works better, but on results that will be meaningful to the patient’s and family’s lives.
Treatments that buy a few extra days or months may not be worth it if adverse effects make that additional life miserable. And palliative care data over the past few years has shown that stopping after failed 1st or 2nd line chemotherapy often lengthens life by 2-3 months and improves quality of life over conventional therapy.
It would be particularly useful to know whether the vast majority of cancer patients who have gone through aggressive therapy and are about to die believe in hindsight that it was worth it. That voice of experience would be critical new information for patients, and validate or counter many physicians’ arguments that they prescribe all-but-hopeless treatments because many patients demand any chance. Of course, studies are less fundable when they aspire to less treatment and are not in the care community’s financial interests.
In Being Mortal, Atul Gawande MD’s profound and wonderful book, he presents 5 questions for patients at the end of life, developed by Susan Block, a palliative care physician at the Dana Farber Cancer Institute in Boston.

  1. What is your understanding of where you are and of your illness?
  2. What are your fears about what is to come?
  3. What are your goals as time runs out?
  4. What tradeoffs are you willing to make?
  5. What would a good day look like?

The beauty of these questions is their deep humanity. They clarify the patients’ understanding, worries and priorities for the patient and family, and help clinicians know what matters most to them. My wife Elaine referred to them as “perfect questions.”
In British Medical Journal, Richard Lehman MD sums up the shared decision making problem this way. “We urgently need every paper about a new oncology drug trial to incorporate a comparative infographic, compiled by an independent author from the individual patient data. This could probably be done for the same cost as a single course of the treatment.”
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 for Waldenstrom’s Macroglobulinemia

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

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

Using Patient Navigators to Improve Cancer Care

Valerie Fraser Cancer Research Advocate/­Patient Navigator;
Inflammatory Breast Cancer International Consortium (IBC-IC)
Huntington Woods, Michigan

Q: What are Patient Navigators and why are they sometimes necessary for some cancer patients. How do the best programs work?
A: As precision medicine, information technology and an increasingly savvy internet society merge, there will be a greater expectation that patients be involved, informed and engaged with their healthcare team. Navigators will be pivotal in this process, both those that are within the healthcare system and increasingly those that are lay navigators outside of the system. Lay navigators are often resourceful survivors or caregivers themselves, experienced in research and the health care process, with critical skills, resources and most importantly the “heart connection” that patients will need throughout their cancer experience.
Accessing resources and seeking quality care for those diagnosed with cancer is a demanding and complicated process. A patient’s survival can be impacted by critical decisions, so there’s the pressure to get it right. The reality of receiving a cancer diagnosis begins with an avalanche of emotion, anxiety and uncertainty both for the patient and their family. Many patients will inevitably encounter barriers along the way and face important crossroads critical to their care. Often they will feel buried and paralyzed under the weight of a system focused on time and process and may feel uncomfortable with their ability to question or evaluate the process. With multiple experts and treatments involved, it is often difficult to transition levels of care. Many also experience long term side effects following treatment, impacting their transition from patient to survivor.
Patient navigators are resourceful problem solvers there to guide patients through a difficult experience often never encountered before. They help to prevent and eliminate barriers to quality care and treatment, locate resources and often act as a communication liaison between the patient and the care team. A navigator can help support patient satisfaction through their compassionate guidance, often having first hand experience as a cancer patient themselves, resulting in improved quality of care and overall outcomes. Navigators are also self-advocacy educators and encourage patient empowerment improving a patient’s overall outlook, engagement and quality of life. Studies have shown this is often a win-win for the patient, their care team and their treating institutions.
The best navigation programs are those that are resource and information rich and designed from a patient perspective. A navigation program must be adaptable and broad so as to provide the best information, resources and guidance while at the same time engage and empower patients in the process. Personalized needs assessment and evaluation of patient satisfaction throughout the navigation intervention supports optimal outcomes. As addressed in the landmark 2005 IOM report “From Cancer Patient to Cancer Survivor: Lost in Transition” the key components of delivering high quality cancer care must include patient needs, values, preferences and engagement with the care process.
Cancer is unwanted, unplanned, unscheduled and a very personal experience for those diagnosed. Patients are faced with critical decisions while dealing with overwhelming stress. A navigation plan must be designed around the individual and their unique needs. The best programs will be focused on clearing away barriers and uncertainty while rebuilding a pathway to patient empowerment and survivorship.
Patient Navigation is a rapidly growing and evolving industry especially in cancer care. A patient navigation requirement is now part of the Commission on Cancer institutional accreditation to ensure patient-centered care. Health care institutions and cancer centers developing their programs, often assign nurses to fill these positions who focus on patients at that particular institution. Salaries for Oncology Nurse Navigators can average anywhere from $67,000+ annually . Private/Professional Patient Navigators work independently as consultants with various organizations and individually one-on-one with patients. Their fees are often hourly and can vary based upon the scope of their services, demographics, background and experience, etc..
Patient Navigators are filling important roles in an increasingly complex cancer health care system. Their involvement in patient-centered care will undoubtedly continue to grow and add value to a health care system striving to better serve their cancer patients. However, their real impact will be in the immeasurable value they provide to patients and families on the receiving end of a life threatening cancer diagnosis often overwhelmed and lost in the maze of the cancer experience and process.
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

CollabRx and the 2016 Cancer Moonshot

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, 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.
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.