What Can You Do to Improve Your Odds Against Cancer?

I sometimes joke with my patients that a new diagnosis of cancer rarely provides them enough time to get an MD or PhD. Yet it is that level of preparation that may be required to answer the myriad questions that lie ahead.

Although it’s a joke, it is only partly in jest. Unlike buying a house or a car for which one’s life experiences can prepare you, medicine is opaque, complicated and ever changing. At the bleeding edge of medical complexity sits medical oncology and its dizzying array of genomics, transcriptomics, proteomics, epigenomics and metabolomics. Not only is it difficult for patients to keep up with all the changes, it is increasingly beyond the ken of their doctors who have spent entire careers training in the specialty, many of whom may have an MD and a PhD.

So how can patients improve their odds when the obstacles seem so daunting?

My first recommendation is that you develop a personal diary or record book of the procedures, staging studies, pathologic diagnosis, tumor markers, and physician recommendations. This can be accomplished by requesting that your doctors provide either electronic or physical copies of CT scans, pathology reports, blood tests and other clinically relevant information. While there has been some controversy surrounding their overuse, I am a believer in the simple blood tests used as barometers of your cancer with names like CEA, CA19.9, CA125, CA27.29, and CA 15.3. Although they are not perfect, they are easy to obtain, relatively inexpensive and can be repeated regularly to assess progress with therapy.

The second thing that I recommend is that you gain a working knowledge of your diagnosis. While there are no perfect sources of information, the internet can provide useful basic information as a starting point. Begin by obtaining from your doctor the most accurate definition of the cancer. If it is breast cancer, is it infiltrating ductal or lobular? Are you ER positive? Is your tumor HER-2 positive? If it is stomach cancer, is it intestinal type or diffuse, etc? This will facilitate your searches, as well as your future conversations with consultants.

Once you know what you’ve got, the next thing you will need to know is where it is. That is what is known as your stage. The older classification used Roman Numerals I-IV with local disease (early) as stage I and metastatic (disseminated) as stage IV. The more modern system is known as TNM, where T stands for tumor size (1-4), N stands for lymph involvement(1-3), and M stands for metastatic involvement (0 or 1). Most contemporary pathology reports include TNM staging. With the diagnosis and stage established, you now know what you have and where it is.

This is where it gets interesting. Now, what do you do about it?

It is at this point that therapeutic choices must be made. Most physicians will rely upon standard established guidelines. Among the most widely used guidelines are those published by the National Comprehensive Cancer Network known as NCCN. While these guidelines can be useful, they can also be stultifying, limiting patients to what might be considered the lowest common denominator of care. While they may be better than haphazard treatment selection, they may very much miss the mark for your unique needs.

Here the process degenerates into a plethora of confusing choices.

Should you have genomic profiling? If so, should it be based on a tissue biopsy, circulating cell free tumor analysis, or even the newer urine tests that measure the presence or absence of abnormal genes? All of these technologies have merit and over the coming years the best ones will shake out. Despite these tests being widely touted (and profitable for the purveyors), none of these test have been put to formal trials that establish their capacity to influence survival. This is interesting because many of these tests have obtained insurance and Medicare coverage without even remotely rising to this standard. Nonetheless, these tests can be used for specific diseases like lung and leukemia where actionable targets are known to exist. Beyond that, caveat emptor (buyer beware).

One of the problems with genomic profiles is that they do very good job of telling you what the problem may be, but a very bad job at telling you the solution. It is a rare genomic mutation that comes with a drug to treat it. Most of the findings wind up asking more questions rather than providing more answers.

With the diagnosis established, the stage known and in certain circumstances molecular profiles complete, it is time for you to choose treatments and the centers that will provide them. Many seek the care of academic centers. These centers may offer clinical trials as a first line therapy for those who meet criteria.

It should be remembered that clinical trials are conducted in three principal formats. Phase I trials examine brand new drugs. These trials determine the safety of the drugs at different dose schedules. Phase II trials take the established safe doses and develop experience in each type of disease, e.g. lung versus colon versus breast. Phase III trials then compare the new drugs with existing treatments to see if there is any real improvement.

It is critical to recognize the functions of these different types of trials. Phase I studies classically have no therapeutic intent (your benefit is secondary to their measurement of your ability to tolerate the drug).

Phase II trials seek evidence of clinical activity by disease, but your specific disease may not be right for that drug.

Finally, Phase III allows a comparison of standard treatment to the new one. Many of these drugs do not make the grade and fall off the development wagon. In addition, you must be willing to be randomly assigned.

It is here that my approach diverges from those outlined. I have long maintained that each patient is unique and that their cancers must be treated individually. Recognizing that no genomic, proteomic or transcriptomic platform can answer the very complex questions of therapeutic response, we at Rational Therapeutics have developed functional analyses through the use of the EVA-PCA assay, which studies each patient’s tumor by exposing it to the drugs of interest. The most active, least toxic combinations are then recommended. In a report at the American Society of Clinical Oncology meeting of 2013, we showed a 2.02 higher response rate (P < 0.001) and a 1.44 improvement in one year survival (P < 0.02) for patients who received assay-guided therapy. This established the predicative validity of the functional approach.

It is important for patients to realize that cancer is an unbalanced system, not just an abnormal cell. Cancer as a disease goes beyond the cell or even the tumor to affect the body itself. Alterations in immunity, metabolism and physiology contribute to the good or bad outcomes of every patient. Patients should seek to normalize their lifestyle, improve their diets, maintain an active exercise program, reduce their weight to lean body weight, and may in some circumstances consider nutritional supplements and/or appropriately selected natural products that may augment their wellbeing.

The human body is a complicated machine and each part resonates with every other part. A good diet, a good night’s sleep and avoidance of an unhealthy lifestyle, as much as they may sound like your mother’s advice, is indeed very good advice.

Every cancer patient has the right to get better. As a patient, you should take charge of your cancer and make smart decisions. Afterall, no one is more interested in saving your life than you.

Practicing Clinical Oncologists to the Rescue

Cancer patients and their physicians can find themselves at the wrong end of many scientific discoveries. For example, the drug capecitabine, sold commercially as Xeloda, was originally marketed at a daily dose of 2500 mg/m2 given for two weeks.

This schedule developed by the pharmaceutical investigators, is known as the maximum tolerated dose (MTD) and it performed well against other regimens for breast and colon cancer. With an FDA approval in hand, oncologists began administering the drug on the recommended schedule.

It did not take long before physicians and their patients realized that 2500 mg/m2/day was more than many patients could tolerate. Hand-foot Syndrome (an inflammation of the skin of palms and soles), mucositis (oral ulcers) myelosuppression (lowered blood counts) and diarrhea were all observed. Immediately clinical physicians began to dose de-escalate. Soon these astute practitioners established more appropriate dose schedules and the drug found its rightful place as a useful therapeutic in many diseases.

What was interesting was that activity continued to be observed. It appeared that the high dose schedule was simply toxic and that lower doses worked fine, with fewer side effects.

Modern targeted agents have been introduced over recent years with dose schedules reminiscent of capecitabine. The drug sunitinib, approved for the treatment of renal cell carcinoma, is given at 50 mg daily for four weeks in a row, followed by a two week rest. Despite good activity, toxicities like mucositis and skin rash often set in by the third week. What remained unclear was whether these schedules were warranted. A recent report in the Annals of Oncology examined this very question. In a retrospective analysis of patients with kidney cancer the physicians found that lowering the dose of sunitinib preserved activity but reduced toxicity.

As a practitioner, I have long reduced my patient’s schedule of sunitinib to two weeks on, one week off or even 11 days on, 10 days off. In one patient that I treated for a gastrointestinal stromal tumor (GIST), I achieved a durable complete remission with just 25 mg/day, given seven days each month, a remission that persists to this day, seven years on.

We are in a new world of targeted therapy, one in which very few people understand the kinetics, pharmacodynamics and response profiles of patients for novel drugs. In our laboratory, favorable dose response curves often suggest that many agents could be administered at lower doses. More interestingly, some patients who do not carry the “targets” for these drugs nonetheless respond. This has broad implications for multi-targeted inhibitors like sunitinib that can influence multiple targets simultaneously.

As so often happens, it is the nimble clinical physicians with their feet on the ground, confronting the very real needs of their patients who can outmaneuver and outthink their academic colleagues. The trend toward consolidation in medicine and the absorption of clinical practices into hospital groups all using standardized algorithms has the risk of stifling the very independence and creativity of practicing oncologists that has proven both effective and cost-effective for our patients and our medical system at large.

Of Cells, Proteins and Cancer Drug Development

Our recent presentation at the American Association for Cancer Research meeting reported our work with a novel class of compounds known as the HSP90 inhibitors. AACR 2015-HSP90 Abstract

The field began decades earlier when it was found that certain proteins in cells were required to protect the function of other newly formed proteins hormone receptors and signaling molecules. Estrogen and androgen receptors, among others, require careful attention following their manufacture or they will find themselves in the cellular waste bin.

As each new protein is formed it risks digestion at the hands of a garbage disposal-like device known as a proteasome (named for its protein digesting capabilities). To the rescue comes HSP90 that chaperones these newly created proteins through the cell and protects them until they can assume their important roles in cell function and survival.

Recognizing that these proteins were critical for cell viability, investigators at Sloan-Kettering and others developed a number of molecules to block HSP90. The original compounds known as ansamycins underwent clinical trials with evidence of activity in some breast cancers. The next generation of compounds was tested in other diseases. Though the clinical results have been mixed, the concept remains attractive.

We compared two drugs of this type and showed that they shared similar function but had different chemical properties and that the concentrations required to kill cells differed. What is interesting is the activity of these drugs seems to be patient-specific. That is, each patient, whether they had breast or lung cancer, showed a unique profile that was not directly connected to the type of cancer they had. This has important implications.

Today, pharmaceutical companies develop drugs by disease type. Compounds enter Phase II trials with 30 to 50 lung cancer patients treated, then 30 to 50 breast cancer patients treated and so on. This continues until (it is hoped) one of the diseases provides a favorable profile and the data is submitted to the FDA for a disease-specific approval. As home runs are rare, most drugs never see the light of day failing to provide sufficient response in any disease to warrant the enormous expense of bringing them to market.

What we found with the HSP90 inhibitors is that some breast cancers are extremely sensitive while others are not. Similarly some lung cancers are extremely sensitive while others are resistant. This forces us once again to confront the fact that cancer patients are unique.

Pharmaceutical companies exploring the role of targeted agents like the HSP90 inhibitors must learn to incorporate patient individuality into the drug development process. Failing to do so not only risks the loss of billions of dollars but more importantly denies patients access to active novel agents.

The future of drug development can be bright if the pharmaceutical industry embraces the concept that each patient’s profile of response is unique and that these responses reflect patient-specific, not diagnosis-based drivers. Clinical trials must incorporate individual patient profiles. Drugs could be made more available once Phase I studies were complete by using biomarkers for response, such as the EVA-PCD assay, which has the capacity to enhance access and streamline drug development.

Cancer Research Moves Forward by Fits and Starts

I recently returned from the American Association for Cancer Research (AACR) meeting held in Philadelphia. AACR is attended by basic researchers focused on the molecular basis of oncology. Many of the concepts reported will percolate to the clinical literature over the coming years.

There were many themes including the revolution in immunologic therapy that took center stage, as James Allison, PhD, received the Pezcoller Prize for his groundbreaking work in targeting immune checkpoints. The Princess Takamatsu Award given to Dr. Lewis Cantley, recognized his seminal contribution to our understanding of signal transduction at the level of PI3K. A series of very informative lectures were provided on “liquid biopsies” that examine blood, serum and other bodily fluids to characterize the process of carcinogenesis. These technologies have the potential to revolutionize the diagnosis and monitoring of cancers.

The first symposium I attended described the phenomenon of chromothripsis. This represents a catastrophic cellular trauma that results in the simultaneous fragmentation of chromosomal regions, allowing for rejoining of disparate chromosome components, often leading to malignancy and other diseases. I find the concept intriguing, as it reflects the intersection of oncology with evolutionary developmental biology, reminiscent of the outstanding work of Stephen Jay Gould. His theory of punctuated equilibrium, from 1972, challenged many long held beliefs in the study of evolution.

Since the time of Charles Darwin, we believed that evolution was slow and continual.  New attributes were selected under environmental pressure and the population carried those characteristics forward toward higher complexity. Gould and his associate, Niles Eldredge, stated that evolution was anything but gradual. Indeed, according to their hypothesis, evolution occurred as a state of relative stability, followed by brief episodes of disruption. This came to mind as I contemplated the implications of chromothripsis.

Licensed under CC BY-SA 3.0 via Wikimedia Commons

According to the new thinking (chromothripsis and its related fields), cancer may arise as a single cell forced to recover from what would otherwise be catastrophic injury. The reconfiguring of genetic elements scrambled together to avoid apoptosis (programmed cell death) provides an entirely new biology that can progress to full-blown malignancy.

By this reasoning, each patient’s cancer is unique. The results of damage control whereby chromosomal material is rejoined haphazardly would be largely unpredictable. These cancers would have a fingerprint all their own, depending on which chromosome was disrupted.

As high throughput technologies and next generation sequences continue to unravel the complexity of human cancer, we seem to be more and more like those who practice stone rubbing to create facsimiles of reality from the “surface” of our genetic information. Like stone rubbing, practitioners do not create the images, but simply borrow from them.

With each symposium, we learn that cancer biology does not come to be, but is. Grasping the complexity of cancer requires the next level of depth. That level of depth is slowly being recognized by investigators from Harvard University to Vanderbilt as the measurement of humor tumor phenotypes.

Cancer is phenotypic and human biology is phenotypic. Laboratory analyses that allow us to measure, grasp, and manipulate phenotypes are those that will provide the best outcomes for patients. Laboratory analyses like the EVA-PCD.