Will Advanced Computing Help Eradicate Cancer?
November 30, 2016
Q: Computers and artificial intelligence show both great progress and great promise in many fields. Can “Big Data”, A.I., and the Watson ilk devise a way to end cancer?
A: In 2011, a young and emotionless Watson grabbed the tech industry’s attention by dominating Jeopardy’s two greatest champions. That night, the show was not at all about the $1 million prize. Instead all eyes were on the one-of-a kind contestant: Watson, IBM’s supercomputer. Watson had just proved that intelligent machines can understand, process, and respond to questions posed in human language.
A few years later, artificial intelligence (AI) exploded into many information-intensive industries with its market expected to reach $47 billion by 2020. But young Watson had one main career in mind since its inception: healthcare. It entered medical school in 2011 and graduated in 2 years.
So how can AI change the oncology field? According to a paper published by Michael Schatz in the journal PLoS Biology, genomic data is likely to generate the most raw data in the next ten years–data which holds answers to many health questions. While understanding and finding patterns in this enormous amount of data might seem impossible for the human brain, cognitive computing capable of ingesting data that analyzes and self-learns without forgetting might hold the key to uncovering the answers.
AI can therefore revolutionize oncology care, save doctors time, and save patients’ lives. Because supercomputers store millions of oncological records which they can rapidly analyze and cross-reference, their deep learning ability has the potential to…
The Essential Value of ICMJE
(International Committee of Medical Journal Editors)
November 23, 2016
Q: The internet has produced mass democratization of information provision and access with little quality control. You represented JAMA at the International Committee of Medical Journal Editors (ICMJE) for over 10 years. How important is the ICMJE in protecting quality and ethics?
A: Since 1978, when a group of high impact medical journal editors representing several countries first met, the ICMJE has played a major role in setting standards for the ethics, preparation, and formatting of biomedical manuscripts. The current membership consists of thirteen medical journal editors and representatives of selected related organizations including the National Library of Science and the World Association of Medical Editors (WAME). These individuals work together to improve the quality of medical science and the reporting of such science.
The ICMJE publishes recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. These guidelines, primarily for authors, reviewers and editors, are available on line for anyone. ICMJE developed these recommendations to review best practices and ethical standards for the conduct and reporting of research and other material published in medical journals. The recommendations also help authors, editors, and others involved in peer review and biomedical publishing create and distribute accurate, clear, reproducible, and unbiased medical journal articles. These guidelines have also provided useful insights into the medical editing and publishing process for the media, patients and their families, and general readers.
One example of the important role the ICMJE has played in helping to assure the ethical publication of sound research occurred in September 2004 when the editors published a joint editorial regarding the registration of randomized clinical trials. At that time the law in the United States required that all clinical trials be registered in clinicaltrials.gov as soon as the first patient was enrolled. Very few such trials were registered because no one enforced the law. This put editors in a quandary because they had no idea if the submission of a manuscript that described a trial accounted for…
Making Cancer Care Great Again
November 16, 2016
Q: Donald Trump’s campaign for the presidency included a promise to repeal “Obamacare” in its entirety. If he succeeds in fulfilling that promise, what impact can we expect on American cancer prevention and cancer treatment?
A: Donald Trump, emboldened by eliminating ISIS, ending illegal immigration and energizing the economy, will eradicate cancer. Or at the very least, I predict, he will append it to his list of promised achievements as president.
Our current chief executive, dubbed “No Drama Obama” by his staff during the 2008 campaign, couldn’t resist the heady promise of a cancer “moonshot.” Trump, who’s declared, “I will take care of ISIS,” “close up those borders” and “jump-start America,” will likely rev up the rhetoric back to Nixonian “War on Cancer” levels.
A candidate whose campaign centered on his personal pledge to “make America great again” will surely be galvanized by the chance to make cancer care “great,” too.
The current Cancer Moonshot initiative, featured in President Barack Obama’s last State of the Union Address, is codified in a presidential memorandum of Jan. 28, 2016 and placed within the Office of the Vice President. While fighting cancer was of deep personal interest to Vice President Joe Biden, Vice President-elect Mike Pence was governor of Indiana, where pharmaceutical giant Eli Lilly has a major portfolio of oncology products…
How to Control American Drug Costs
November 9, 2016
Q: Many newer (as well as many older) drugs are of great value in treating many diseases. But the prices charged seem very high and rising, causing serious concern for many. Is there anything the United States can do to control these costs?
A: We can do a lot to control drug costs, but success will take the cooperation of Congress and the legislatures, which are fundamentally in the drug industry’s pocket.
The industry lavishes money on Congress to buy that favor. Open Secrets data show that the pharmaceutical/health products sector, the most politically influential industry, gave Congress $3.3 billion in campaign contributions between 1997-2015. That largess averages out to $183 million annually over that 18-year period, or a stunning $343,000 per legislator per year. Within these dynamics, every relevant law and rule is spun to favor the interests of the drug industry over those of the American people.
In an excellent recent JAMA article on the sources of US drug pricing, Kesselheim et al. point out that influence over policy has translated into two core problems: “granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits.”
Consider Congress’ prohibition against Medicare negotiating drug prices. Millions of patients’ medications are subsidized by Medicare, which pays whatever price is demanded. It’s hard to imagine a better deal than the purchaser allowing the manufacturer to set any price, with the guarantee that the bill will be paid.
These dynamics translate to harsh realities…
Expanded-Compassionate Use of an Investigational Drug
November 2, 2016
Q: You have exhausted surgical, radiation, and standard chemotherapy options for a patient with an advanced epithelial malignancy. Yet the patient has a strong will to live and to advance science during palliative care. No active clinical trial is available. How would you evaluate pre-clinical data to try to identify an investigational drug for “expanded-compassionate” use?
A: Thank you for the question. This is a challenging situation. It is subjective and complex.
My answer – “it depends”. Let me give you 2 scenarios.
Scenario A: A 30-year-old surgeon, recently married with the love of his life who has just graduated from a neurosurgery residency, is expecting his first child and diagnosed with Stage IV non-small cell lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. Has a strong will to live.
Scenario B: An 85-year-old man, who has a wife in the nursing home and a son in California and another son in Australia has been diagnosed with Stage IV non-small lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. He lives alone and has a declining PS with multiple co-morbid conditions.
In the first case, yes, as an experimental investigator I would go to any lengths to try to provide investigational drug for expanded-compassionate use.
In the second case, I would likely arrange a family meeting to discuss the reality and lean towards providing best supportive palliative care.
Breakthroughs in oncology or any other field infers that successful outcome in the face of what was considered impossible. We all live in the future. If we do not take risky experiments, breakthroughs cannot be made. It could be argued…
The “Hutch” and Improving Baseball: World Series Edition
October 26, 2016
Q: You are known to be good at clever solutions to daunting problems, and a baseball fan to boot. What should we do about the conflicted designated hitter (DH)?
A: The last six months have been contentious across our land, with anger and hostility replacing civility and tolerance. Families and friends are pitted against each other. Religions and cultures are torn apart.
Can we save our nation from the additional conflict at World Series time, the designator hitter (DH) divide?
As the World Series is upon us, the wound will continue to fester.
Here is a solution that will both satisfy baseball “purists” (National League) and “progressives.” There are four easy steps.
- Make the DH available and optional for all games, all season long, in both leagues.
- Before each game, a designated specific team decides whether or not the DH will be used in that game.
- Which team gets to choose will always be the same, but is based on an anticipated upcoming decision by Major League Baseball (MLB). If MLB wants to soften home field advantage…
- Panobinostat with bortezomib and dexamethasone
- Carfilzomib with lenalidomide and dexamethasone
- Ixazomib with lenalidomide and dexamethasone and these were complemented by a pair of antibodies:
- –Elotuzumab with lenalidomide and dexamethasone.
- Brain MRI
- Serum LDH
- V600 BRAF mutation status (younger patients are significantly more likely than older patients to have a V600 BRAF mutation), so it’s likely that this patient has one
- Presence or absence of disease-related symptoms
- Prior scans that might allow the pace of disease progression to be ascertained (not always possible in a very recently diagnosed patient; but even if 4-6 weeks have passed since the first assessment prior to me seeing the patient, I’ll consider repeating imaging of the lungs and liver to glean the pace of progression…
How to Decide to Offer a New Lab Test
October 19, 2016
Q: Pathologists are faced with the need to set up additional lab tests routinely. Immunotherapy for cancer is the current rage. How does a pathologist decide whether and how to offer a new test such as PD-L1 Expression Testing?
A: The decision to introduce a new test or remove an old test is not as easy as one would think. There are many variables that must be taken into consideration. Concerning your question i.e. when to introduce a “new” test that may be used to direct therapy in a patient with cancer is an especially important task for the pathologist.
In my own experience using your example the subject would probably arise at a tumor board or multidisciplinary conference. This is setting where pathologists, oncologists, radiologists, surgeons and other medical specialists discuss possible or already identified cancer patients for input and recommendations on evaluation, more specific diagnostic information, treatment options and follow-up plans.
Today with the rapidly expanding complexities resulting from the introduction and availability of new biomarkers be they genomic, proteomic etc. that aid in diagnostic, prognostic and/or therapeutic decisions the burden of proof to introduce a test into your lab is very high. The more so if the “claims” being made are the specific biomarker results which are important and maybe critical in enhancing patient outcomes. The point is that the initial but critical decision of whether a new test should be available and introduced into your lab will be a team effort with input from users of test (the utility) and those responsible for ensuring the test can in fact be performed accurately in your specific lab environment (your validation).
The FDA has already approved PD-LD1. Its value is backed up by…
Preventing Hair Loss from Cancer Chemotherapy
October 12, 2016
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…
Mutational Oncology: The Basics
October 5, 2016
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…
The Most Relied Upon Journals in Precision Oncology
September 28, 2016
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:
“PLEASE PROVIDE FOR ME A LIST OF THE TOP 10 (OR SO) JOURNALS THAT YOU MOST RELY UPON TO INFORM PRECISION ONCOLOGY. NO PARTICULAR ORDER.
Twenty nine individuals (44%) responded. A total of 70 journals were named. ONLY 10 journals had 10 or more advocates…
Length and Quality of Life in Cancer Patient Treatment
September 21, 2016
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…
September 14, 2016
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…
Conflict of Interest in Cancer Clinical Trials
September 7, 2016
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…
Can Preclinical Data Guide Clinical Cancer Therapy?
August 31, 2016
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…
Circadian Cancer Therapy
August 24, 2016
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…
Generic Drugs vs. Biosimilar Biologics
August 17, 2016
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…
Driver and Passenger Mutations in Cancer Cell Genes
August 10, 2016
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…
Patients and Physicians Should Share Decisions in Oncology
August 3, 2016
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…
Targeted Therapy for Waldenstrom’s Macroglobulinemia
July 27, 2016
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…
How Are Cancer Mutations Like Palm Trees?
July 20, 2016
Q: How might current thinking on tumor evolution/heterogeneity and sequential mutational profiling inform optimal therapy selection?
A: I’d like to share some learnings from ASCO, 2016:
To help think about tumor evolution over the course of time and treatment of cancer, I’m a fan of the palm tree analogy (made by Charles Swanton, ASCO 2016). Early genetic alterations that occur in the developing tumor are “trunk” genetic events that are present in every cancer cell in the tumor. Trunk driver mutations may be predictive of drug sensitivity or intrinsic resistance. As the tumor continues to grow some cells will develop additional mutations that will be shared by their progeny cells within the tumor. To continue the palm tree analogy, this results in a branching effect, with each branch representing a sub-clonal population of tumor cells that have new acquired mutations not shared with the original trunk cells or cells in branches that evolved earlier. Swanton cites an earlier study (Landau et al, Cell, 2013) that demonstrated that acquisition of subclonal driver mutations (occurring in the tree branches) results in significantly reduced survival over time as compared to patients whose tumors lack…
Using Patient Navigators to Improve Cancer Care
July 13, 2016
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…
CollabRx and the 2016 Cancer Moonshot
July 6, 2016
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…
Sun Exposure and Skin Cancer Risk
June 29, 2016
Q: Summer sun season is upon us. What role, if any, does sun exposure have in the causation of cutaneous: 1) Actinic keratosis? 2) Squamous cell carcinoma? 3) Basal cell carcinoma? 4) Malignant melanoma? How completely should humans try to eliminate sun exposure lifelong?
A: The potential health effects (both benefits and harms) of sun exposure have been the subject of much controversy over the last 100 years. In the early 20th century when dietary sources of vitamin D were more limited, sun exposure was thought to promote both bone health and optimal health overall. Early epidemiologic studies, and later laboratory investigations demonstrated a definitive causal link between ultraviolet light exposure (i.e. the damaging wavelengths from sunlight) and skin tumors. Unfortunately, the genie was out of the bottle, and everybody wanted to be tan due to the mistaken belief that it was a sign of good health.
Interestingly, the contribution of sun exposure in different skin cancers varies.
Actinic keratosis: These extremely common skin growths are potentially pre-cancerous pre-cursors of squamous cell carcinoma. They occur on the same skin sites as squamous cell carcinoma (described below) and have a high rate of ultraviolet light-induced mutations.
Squamous cell carcinoma: This malignant tumor has the most direct relationship between sunlight and cancer. These growths occur on the face, arms and hands; skin sites that have received high cumulative levels of sun exposure. In addition, epidemiologic studies found a strong association of squamous cell carcinoma and outdoor occupations. Ultraviolet light-induced mutations are seen in more than 80% to 90% of these growths…
Is there a Better Descriptive Name than Personalized Medicine?
June 22, 2016
Q: What’s in a name? Should “it” be “Personalized Medicine,” “Precision Medicine,” or perhaps, “Accurate Medicine”?
A: Much of what we do in my laboratory at the Fred Hutchinson Cancer Research Center revolves around the genetics of response and relapse in leukemia. I often describe this as the biology of luck. Why do some good risk patients fail to respond to therapy, while some patients with characteristics of very poor risk nevertheless respond well? This phenomenon is often ascribed to deity, diet, or luck.
One must hope that there is some biology behind the differential response we see in patients. This then is the heart of “personalized” or “precision” medicine. Words matter, however, and in this case, neither of these trendy phrases passes muster. The term “personalized medicine” suggests…
Multiple Sequential Biopsies now Standard of Care in NSCLC
June 15, 2016
Q: How has the introduction of molecular testing of non small cell lung cancer (NSCLC) altered therapy and outcomes?
A: The understanding of lung cancer as a genetic disease has been developing over at least 30 years. The technology (and cost of this technology) to utilize this understanding has only been developed over the last 10 years, and importantly, along with the technical ability to test for molecular/genetic abnormalities has been the development of a new generation of targeted agents that can specifically target these abnormalities.
In 2004, several groups described mutations with the epidermal growth factor receptor (EGFR) in patients who had sustained substantial responses to EGFR targeted tyrosine kinase inhibitors (TKIs). At this time, a number of TKIs had been approved for treatment of non-small cell lung cancer without respect to mutations. Over the next months and years, clinicians started to understand the frequency and clinical characteristics of these mutations – seen in adenocarcinomas from patients with a light or never smoking history, and especially those from East Asia. The concept of “clinical selection” of patients most likely to benefit from these agents developed between 2004 and 2009. This strategy changed forever however in 2009 with the publication of the IPASS (Iressa Pan Asia Study) which compared gefitinib (Iressa®) to standard platinum based chemotherapy in patients with a light or never smoking lung adenocarcinoma. This study demonstrated conclusively that clinical selection was inadequate – patients with the sensitizing EGFR mutations had profound benefit from the TKI, while those with the same clinical features, but lacking the mutation, had essentially no benefit from the TKI. Multiple subsequent studies have confirmed the benefit from EGFR TKI treatment in patients with molecular selection.
More recently, the development of additional TKIs against the anaplastic lymphoma kinase (ALK) and ROS1 genes have been developed SOLELY in patients who express the molecular abnormality – i.e. the drug and the molecular test have been developed concurrently…
Use CUREUS to Build Rapid Learning Communities
June 8, 2016
Q: CollabRx, and its “sister” not for profit organization “Cancer Commons,” are dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. The National Academy of Medicine has called for the building of rapid learning communities. How can your company and journal “CUREUS” help facilitate these efforts?
A: CollabRx is dedicated to rapid dissemination and implementation of the best evidence to improve cancer care. But where does one find such evidence? Meanwhile, the National Academy of Medicine has called for the building of rapid learning communities. Yet what is the vehicle for such physician interaction? The answer to both of the above questions is peer-reviewed journals, which are the foundation for most scientific communication. Unfortunately the processes inherent to traditional medical journals undermine these very objectives, i.e. the “rapid” dissemination and “rapid” learning of critical knowledge. I would like to argue here that our reflexive reverence for conventional processes for curating peer reviewed knowledge can and is holding back better cancer treatment…
Should All Potentially Lethal Tumors Be Sequenced?
June 1, 2016
Q: Is there enough benefit to justify sequencing all patients’ tumors? – Perspective from a scientific knowledge engineer.
A: As a scientist working as a scientific knowledge engineer in molecular oncology, part of my job is to collect, organize, and deliver data that correspond to aberrations present in cancer that could inform clinical decision making.
I recently read with great interest, the opposing viewpoints on “Is there enough benefit to justify sequencing all patients tumors?”, published in JAMA Oncology (April 14, 2016). From the Yes side: sequencing technology provides invaluable intelligence to diagnose, treat, and defeat cancer (Universal Genomic Testing Needed to Win the War Against Cancer by Razelle Kurzrock, MD, and Vivek Subbiah, MD). From the No side: rigorously tested superiority and outcome data are lacking and the cost to patients is still prohibitive (No Solid Evidence, Only Hollow Argument for Universal Tumor Sequencing by Howard Jack West, MD). Both of these are compelling arguments, in spite of their contradictory nature, that deserve ongoing consideration in the oncology community. What we are increasingly coming to understand is that beyond a relatively small set of driver aberrations, whose testing and treatment are specified in standard treatment guidelines, there are a wealth of other molecular abnormalities in cancer that may be highly useful in informing clinical decision making. A few examples to illustrate the point:
1) Biomarker overexpression suggests selection of one targeted therapy drug may be superior to the other targeted drugs recommended for the diagnosis in treatment guidelines (example: high AXL expression in EGFR-mutated NSCLC is associated with acquired and de novo resistance to first generation EGFR inhibitors)…
Use of Circulating Tumor Cells (CTCs) in Detection and Management of Lung Cancer
May 25, 2016
Q: Liquid biopsy is “all the rage” in the cancer diagnostic space these days. You have worked with Circulating Tumor Cells (CTCs) for quite some time. Beyond R and D, is there a practical clinical usefulness for CTC at this time, what is it and how does one go about using it well?
A: Yes, I believe there are several important practical clinical applications for CTCs beyond R&D, including the early diagnosis of lethal cancers, such as lung cancer. If discovered at an early stage in the disease and treated appropriately with video-assisted transthoracic resection or stereotactic body radiation therapy (SBRT), the early diagnosis of lung cancer would result in a much improved survival rate. If there is a sensitive and specific CTC test for lung cancer, that can be performed as an adjunct to an indeterminate nodule on spiral CT scan or as a primary screening test in high risk individuals and that can be validated and replicated in laboratories worldwide, it would have a major impact on the devastating morbidity and mortality that lung cancer currently wreaks…
Can Precision Oncology Develop Despite Pharmaphobia?
May 18, 2016
Q: Your recent book “Pharmaphobia:—–” about conflict of interest “Myths” drew great attention to what you and David Shaywitz earlier called the “Pharmascolds” hazard. How do you see that phenomenon impacting the current national movement toward “Precision Oncology”?
A: The public’s dread of cancer engenders electric excitement every time something new comes along to combat the disease. The latest example of such a development is “precision oncology:” using the specific genetic makeup of a patient’s malignancy to target therapy against it or else engineering a subject’s immune system to recognize and destroy tumors based on their unique composition…
How do Phase 1 Clinical Trials for Cancer Drugs Work?
May 11, 2016
Q: How is it determined that an investigational cancer drug is ready for entrance into Phase 1 clinical trials. And, how is that transition accomplished?
A: Phase 1 oncology studies encompass clinical trials wherein a new drug or combination of drugs is given to patients for the first time. These studies may include: (i) new combinations of FDA-approved or investigational drugs; and (ii) a first-in-human drug.
For this commentary, I will concentrate on first-in-human phase 1 studies. The main objectives of first-in-human studies include elucidating: (i) safety/toxicity; (ii) pharmacokinetics; (iii) optimal dose; and (iv) response signals…
NextGenU.org and the Prevention of Cancer
May 4, 2016
Q: What is Next Gen U and how does it approach the prevention of cancer?
A: NextGenU.org is essentially the world’s first free university; uniquely global for credit, for free. Founded in 2001 with a focus in the health sciences, NextGenU’s accredited courses span from college-level pre-health sciences and community health worker training through medical and public health graduate training, residency programs, and continuing medical education. The courses are competency-based, and include online knowledge transfer, a web-based global peer community of practice, and local and remote skills-based mentorships. Our accredited partners, North American universities that are outstanding in each particular course topic, give individual learners credit for this training (or institutions can adopt them and use them with their students). We collaborate with leading universities, professional societies, and government organizations including the American College of Preventive Medicine, CDC, Grand Challenges, Harvard Institute for Lifestyle Medicine, NATO Science for Peace, and WHO…
Targeted Therapy and/or Immunotherapy for Cancer
April 27, 2016
Q: Surgery and radiation treatment for many cancers are now being followed by not only adjuvant chemotherapy but also a huge panoply of targeted therapies based on precision diagnostics. In your crystal ball, how do you see immunotherapy evolving in relation to targeted therapies based on cancer genomic findings? Exclusive or sequenced or blended?
A: For decades the interplay of the neoplastic process with the immune system has been described. There are several longstanding observations that are relevant:
First, in a variety of animal models of cancer, the adaptive (cellular or humoral) and innate immune systems (natural killer cells, proteins, etc)_can be primed or manipulated to limit or eradicate tumors, or delay their development in high risk settings…
A Full House for Myeloma Therapy: What’s Next in the Cards?
April 20, 2016
Q: Some writers have characterized 2015 as a year of great progress in the treatment of Multiple Myeloma. What advances in Myeloma treatment in 2015 do you consider to be the most important and why?
A: Five new drug approvals for patients with relapsed and/or refractory multiple myeloma mark 2015 as a year of great progress against this disease. Proteasome inhibitors were full with three new regimens:
All of these are exciting developments that will help further improve myeloma patient outcomes. Panobinostat, an oral deacetylase inhibitor, is the first agent in its class to be approved for myeloma…
Managing Metastatic Colorectal Cancer
April 13, 2016
Q:You have just received a new patient, referred to you from Macon, GA. She is a 52 year old white woman in good general health who is 3 months post op from a left hemi-colectomy for a grade 3 adenocarcinoma with extension through muscle but not through the serosa. Three of 15 lymph nodes were positive for cancer. She did not receive post-op radiation or chemotherapy. No molecular testing of the tumor was performed. She now presents with a single 3 cm mass in the liver discovered by CT scan. How will you manage her care?
A: This 52-year-old patient presents with a solitary liver lesion 3 months after resection of a stage III colon primary. If all her other staging is negative, my first question is do we proceed directly to surgery or should we try chemotherapy first? The short interval between the original cancer and the recurrence makes the case to use chemotherapy upfront followed by surgery…
Compassionate Use of Investigational Drugs
April 6, 2016
Q: What is the ethical basis for compassionate use of investigational drugs; and what are some practical considerations in making such use reality?
A: In seeking relief from the burden of disease, some patients face a lack of satisfactory treatment options from the range of available, government regulatory authority approved medicines. In these circumstances, patients often turn to investigational medicines, or “preapproval access.” The main avenue for preapproval access is for patients to enter clinical trials…
Single Cell Biology in Cancer Research and Treatment
March 30, 2016
Q: What do you see as the best roll for single cell biology in cancer research and treatment in the near future?
A: Supporting immuno-oncology research and development.
Single cell biology refers to the analysis of individual cells isolated from complex tissues obtained from multi-cellular organisms and can be applied to many biologically relevant areas of study. For example, the identification and characterization of various cell compartments, the study of cell fate including lineage mapping and phenotypic plasticity, and understanding mechanisms of tumorigenesis…
How to Initiate Treatment for Chronic Myelogenous Leukemia
March 23, 2016
Q: What is your basic approach to handling a middle aged adult patient in good general health who is referred to you with a new diagnosis of Chronic Myelogenous Leukemia?
A: First off, the treatment of choice for chronic phase CML is a tyrosine kinase inhibitor (TKI). Currently there are three approved TKIs in the front line setting, imatinib and the second generation TKIs, nilotinib and dasatinib. There have been three randomized trials comparing imatinib to either nilotinib or dasatinib, and all three show remarkably similar results…
Making NGS Work for Oncologists
March 16, 2016
Q: Your group has recently described an Actionability Framework for designing treatment strategies for cancers that are characterized by mutations. What is the basis and rationale for such an approach?
A: As Next Generation Sequencing (NGS) is increasingly adopted into clinical practice, physicians are faced with the daunting task of identifying variants that are clinically actionable – those that can help them select potential treatment options. In oncology, NGS technologies are used to profile tumor or liquid biopsies and identify variants in cancer-related genes. Cancer gene panels range in size from a handful of genes to several hundred. Depending on the size of the panel, many variants may be observed in tumors…
Treating Metastatic Malignant Melanoma
March 9, 2016
Q: What is your basic approach to handling a new young adult patient in good general health who is referred to you with a diagnosis of Malignant Melanoma, metastatic to liver or lung? The primary cutaneous melanoma, 1.5 mm in thickness, was diagnosed in Maine 5 years ago and was of skin on the forearm; treated there by wide resection with clear margins and no lymph node dissection. There was no molecular/genomic testing of the primary.
A: In a case like this, there are a few additional elements of data that I always try to obtain:
Introducing a New CollabRx Blog
March 2, 2016
Q: Why are we starting The CollabRx Blog?
A: With our new blog, we intend to provide a vehicle to communicate timely information of importance about cancer to a broad audience. Our Editorial Board members come from hospitals, cancer research centers, government, academia, industry, and other organizations, invited guest experts, and the CollabRx staff.
Our goal is to teach about the use of genomic (and other -omic) data in cancer diagnosis, prognosis, therapy selection, and clinical trials, as well as payer attitudes, policies, ethics, and economics; and focus, filter, and distill pointed and clear understanding selected from an abundance of very complicated and often confusing source data.
The CollabRx Blog will be a regular recurring journalism column about cancer in blog format with a link on the home page of the corporate website www.collabrx.com. It begins today, Wednesday, March 2, 2016. Our primary audience will be physicians (especially oncologists, pathologists, radiologists and surgeons) plus basic and clinical scientists. We welcome the viewpoints of other health care professionals, students, foundations, pharmaceutical, biotech and device company workers, hospital employees, investors, NGOs, government, public media, payers, purchasers, cancer patients and their families
We will publish weekly at 12 noon PT each Wednesday. The posts will be about 500 words or less. Our blog will be in a Q&A format with specific questions from the CollabRx Editor in Chief to invited experts who respond with answers. Each posting will eventually have an open-ended discussion forum.
Our blog will abide by the Creative Commons rules for open access.
Our posts will be found on Social Media Platforms such as Twitter, LinkedIn, and Facebook in the near future.
Thank you for looking and for reading. We hope to provide regular information of value so as to merit your frequent return.