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

Preventing Hair Loss from Cancer Chemotherapy

Richard B. Schwab, MD. Associate Clinical Professor of Medicine, Moores Cancer Center, University of California, San Diego, School of Medicine

Q: Loss of hair is a predictable adverse effect of much chemotherapy. Although “only cosmetic” this can be a troubling event for some patients. What is your opinion about the new devices or methods available to diminish chemotherapy-induced alopecia?
A: Scalp cooling to reduce chemotherapy-induced alopecia has been available for many years. This approach is effective for taxane-based chemotherapy regimens and, in my experience, can have benefit even with anthracycline-based regimens. There is good safety data for acute toxicity (for example frostbite hasn’t been an issue) but there is no good data on how exclusion of chemotherapy from the scalp might affect the risk of recurrence in this area of the body. Fortunately scalp recurrences are extremely rare, which is the major reason why data on scalp recurrence risk with cooling is not likely to ever be available. Regardless, I always educate my patients about this hypothetical risk. Given that the benefit of adjuvant chemotherapy for some breast cancer patients can be modest, this approach to reduce toxicity is quite reasonable.
In the past Penguin Cold Caps were used by some of my patients, under their own arrangements. This approach is quite burdensome requiring patients to bring in caps on dry ice and have an assistant with them to exchange these caps frequently during the infusion, and for some hours after as well. The total duration of recommended use varies with chemotherapy regimen but is about 5-6 hours per treatment. More recently Dignitana has obtained FDA approval for their system. The advantage of their system is that cap exchanges are not needed. A disadvantage is that centers offering this system need to lease a machine and thereby become involved in the business of scalp cooling. Given that insurance rarely reimburses any costs associated with the treatment of chemotherapy-induced alopecia this is a significant issue. Patients can expect to pay approximate $500 per treatment so a typical course of chemotherapy, with 4 treatments, scalp cooling will cost an additional $2000.
Now centers must consider how to handle scalp cooling. If a center leases a Dignitana system there will be a financial incentive for utilization. Additionally centers will need to consider how to handle this for patients that cannot afford the added cost. Is reduction of hair loss a good use of limited charity resources? Additionally logistical issues could develop. Each system can only accommodate 2 users at a time so patients using this system will face additional scheduling limitations. Is waiting to start chemotherapy at a time when scalp cooling is available acceptable or will additional systems need to be leased to prevent delays in therapy?
Obviously numerous additional questions will arise if scalp cooling becomes more popular. For now, it seems to me that this is a good thing for our patients. Fortunately cure rates for breast cancer patients are relatively high and are rising. This gives us the luxury to focus more and more on reducing the toxicity of breast cancer treatment. Scalp cooling is undoubtedly an effective way to reduce one of the most troubling toxicities of chemotherapy for our patients.
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

Mutational Oncology: The Basics

Vivian B. Douglas, PhD. Associate Knowledge Engineer, CollabRx San Francisco, California

Q: Many mature clinicians find “Mutational Oncology” to be a bit mysterious. Please help them understand. As they pertain to cancer, what are somatic (as opposed to germ line) mutations, transitions, transversions, “point”, “missense”, “nonsense”, insertion, deletion, and copy numbers and why does it matter?
A: With the plethora of molecular alterations that commonly occur in cancer, it can be confusing to understand what causes them and how these alterations affect the proteins that these genes encode. To begin, in cancer a somatic alteration refers to a non-inherited molecular alteration, which can occur spontaneously during replication or may be due to DNA damage or mistakes during DNA damage repair, and is only detectable in the tumor. These mutations are not passed to offspring. In contrast, a germ line mutation is heritable and detectable in nearly all tissues.
Many types of alterations occur in cancer. For example, a point mutation is the modification of a single base in a DNA coding sequence. A point mutation may be a transversion (replacement of a purine base with a pyrimidine and vice versa) or more commonly, a transition (replacement of a purine with a purine or pyrimidine with a pyrimidine). These single-base modifications can have several different effects. One common type of mutation is a missense mutation, in which the resulting base substitution changes the coding sequence for one amino acid to another. Another type of single base substitution may lead to a change from a coding amino acid to a termination codon, resulting in premature truncation of the protein. A point mutation may also result in the insertion or deletion of a base resulting in a change of the reading frame (a frameshift mutation) during protein translation. Finally, a single base substitution may not have an effect and will code for the same amino acid; this effect is known as a silent mutation.
These seemingly simple changes in DNA coding sequences can have profound effects on protein function. If the coding sequence of a protein is altered, this can lead to a number of different altered behaviors including inactivation or activation, mislocalization, or altered transcription (which can affect mRNA and protein expression). For example, the well-known missense mutations BRAF V600E and EGFR T790M mutations change these proteins from their normal functioning state to a hyperactive state. In the case of a truncating or frameshift mutations, this can result in the loss of key portions of the protein that are critical to its function. For example, a truncating mutation that results in the loss of a kinase domain in a tyrosine kinase protein will completely abrogate that function of the protein. It is these functional characterizations that lead to the classification of variants as deleterious/pathogenic or benign.
Knowing the tumor profile of a patient can aid in treatment decisions, aid in the identification of potential targeted therapies that may be beneficial, and identify clinical trials that can be beneficial to the patient. Additionally, genetic testing for certain germline mutations can identify patients that have an increased risk for developing certain cancers, a well-known example being BRCA testing for breast cancer risk. Another perhaps more critical role in personalized medicine that genetic profiling of patient tumors plays is the guidance on treatments that should not be used for a particular patient. In particular, some mutations can render a tumor resistant to certain drugs and others can lead to acquired resistance after an initial response. In the era of personalized medicine, determination of mutation type and the effect of that mutation on protein function can be a critical part of cancer 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

The Most Relied Upon Journals in Precision Oncology

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: The medical world is running amuck with new information, some credible, some not. What are the most reliable sources of information in Precision Oncology?

A: “Half of knowledge is knowing where to find knowledge”.
No one knows how many medical journals/periodicals there are in the world. Estimates range from 20,000 to 40,000.
Many are general medical journals; many more are specialty or sub-specialty journals. Their foci may be scientific, clinical, or even marketing. A few are strictly on paper; most also have an internet version, either a replicate of the print version, or a hybrid; some are exclusively electronic.
There are many parameters used to evaluate medical journals: exclusionary indexing systems, circulation, readership, revenue, advertising, paid subscription or open access, author fees, profitability, volume of information, frequency of publication, speed to publication, reference citation scores and indices, open and click through rates, page views, library catalogs, public media attention, owner/publisher status, primary language, location, tradition, brand name recognition, and others.
Of course the internet “changed everything “ so now there are “legitimate” as well as “predatory” online-only, open access journals.
CollabRx works in the field of Precision Oncology. We rely heavily on availability and veracity of the published literature. CollabRx enjoys the voluntary contributions of scores of unpaid editorial board members.
So, in 2016, I made the following request of sixty-six (66) of our editorial board members, paid staff and a few other esteemed experts:
Twenty nine individuals (44%) responded. A total of 70 journals were named. ONLY 10 journals had 10 or more advocates. This was a single pass survey.
The top 10 are:
New England Journal of Medicine-28;
Journal of Clinical Oncology- 27;
Lancet Oncology- 15;
Cancer Clinical Research-15;
Cancer Research-13;
Nature Medicine-12;
Cancer Discovery-12;
Journal of the American Medical Association- 11;
JAMA Oncology-10.
Eight (8) journals drew 5-9 advocates.
Science-9; Blood-9; Science Translational Medicine -8; Cancer Cell-7; Oncotarget-7; Journal of the National Cancer Institute – 7; Molecular Cancer Therapeutics-7; Cell-6.
Sixteen (16) publications enjoyed 2-4 advocates.
Cancer-4; Cell Reports; Breast Cancer Research; British Journal of Cancer; Annals of Internal Medicine; Nature Review Clinical Oncology-3 each; these attracted 2 each: European Urology; Clinical Cancer Research; Annals of Hematology/Oncology; Proceedings of the National Academy of Sciences; PLoS ONE; PLoS; Journal of Precision Medicine; Journal of Thoracic Oncology; Nature Genetics; New York Times.
The remainder (36) were named by a single advocate.
AJCP; AACR; Annals of Oncology; Arch Path Lab Med; BMC Cancer; Brit J Urol; Cancer Genetics; Cancer Immunology and Immunotherapy; Cancer Science; Clin Adc in Hem and Onc; Euro J Cancer; HemOnc Today; Haematologica; Immunity; Int J of Cancer; JCI; J Comm and Supportive Oncology; JID; J of Onco Pract; JNCCN; J or Urol; Leukemia; Mayo Cl Proc; Molecular Cancer Research; Molecular Cell; Molecular Oncology; Nature Biotech; Nature Cancer Biology; Nature Review Drug Discovery; Nature Methods; Oncogene; Oncologist; Pig Cell Mel Res; PLoS Genetics; Urology; Prostate Diseases; WSJ.
The data source is: EXPERT OPINION. This may be as good a way as any to evaluate a medical publication, as long as you can engage “the best experts”. Was your favorite source included or missing?
Write to me at to add other favorites or to argue that some that are included here are unfairly ranked or should be delisted.
Medical and Scientific Journalology is a big deal. Once scientific work has been accomplished, unless it is written about, no one else will ever learn from it. The economics and sociology of medical publishing are also big deals, and are very much in flux. This blog may address other publishing issues as time goes by, especially topics like “paywalls” for readers and publication costs borne by the authors.
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

Length and Quality of Life in Cancer Patient Treatment

Professor Michael Baum, Professor Emeritus of Surgery & Visiting Professor of Medical Humanities. University College, London, UK.

Q: Although you have practiced as a surgeon in the British National Health Service (NHS) for most of your career, how is it that you’ve been such an outspoken critic of the “21st C cures act” that was passed through congress last year? What possible relevance might this have for your NHS?
A: All first year medical students should be taught the raison d’être for the practice of their chosen profession. Simply stated this distills down to three principles: the maintenance of health (well-being) for those who are free of disease and, for those with life threatening disease, the improvement of quality of life (QoL) and length of life (LoL). Therefore for patients diagnosed with cancer, QoL and LoL should be the primary outcome measures for all randomized clinical trials (RCTs) of innovative treatment. All other outcome measures have to be considered surrogates that may or may not translate into improvements in the primary outcomes. These may be used for legitimate reasons, such as aborting a trial early if surrogates all point in the wrong direction, but more often than not these surrogates are used to replace the primary outcome measures in order to fast track the adoption of what look like “promising” new interventions.
At its best, even significant improvements in cancer specific mortality might be abrogated by deaths directly related to the toxicities of treatment. At its worst is the assumption that some third or fourth level indices of “activity” of the novel treatment are accepted as evidence sufficiently compelling to bring the treatment to market.
In a recent JAMA Internal Medicine study, Prasad et al used meta-analysis to study the association of surrogate end points and overall survival in oncology. In 52% of examined studies the correlation was low; 25% showed medium correlation: only 23% showed a high level. Well over half the time surrogate end points failed to impact the gold standard of overall survival. This disconnect will have profound influences on safety, efficacy, and cost of oncology drugs that is already reaching fever pitch after the passing of the U.S. Congressional “21st Century Cures” bill last year.
In an accompanying JAMA Internal Medicine editor’s note, Rita F. Redberg MD MSc commented, “We must reduce drug approvals based on unreliable surrogates and change practice when critical studies show no survival benefit… In our rush to find new effective treatments, we should not harm our patients with ineffective toxic ones.”
We recognize that surrogate end points continue to figure prominently in oncology studies, usually promoted as meaningful outcomes in desperate situations where it is better to have cancers respond than not respond, and it is better to live progression-free than with progression. But without QoL measures to account for the offsetting toxicity of such gains, and without financial data to account for the cost, we really don’t know what has been achieved for patients who ended up surviving for identical amounts of time.
As someone who has practised in the British NHS all his professional life why should that worry me? Sadly ill-considered lunacies from the USA often follow the prevailing winds to our shores. Last year Lord Saatchi tried to drive through the House of Lords a “Medical Innovations” bill that was considered a “Quacks Charter”, based on the same fundamental misconceptions. It was a close call but fortunately it came to nothing.
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

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.