What is Personalized Cancer Therapy?

Personalized therapy is the right treatment, at the right dose for the right patient. Like the weather, however, it seems that everyone’s talking about it, but no one is doing anything about it.

In its simplest form personalized care is treatment that is designed to meet an individual’s unique biological features. Like a key in a lock, the right drug or combination opens the door to a good outcome.

When over the years I lectured on the development of the cisplatin/gemcitabine doublet, my two boys were quite young. I would show a slide depicting a doorknob with a key in the keyhole. I likened our lab’s capacity to identify sensitivity to the cisplatin/gemcitabine combination as “unlocking” an individual’s response.

At the time my wife and I would leave the key in the inside of the front door enabling us to unlock it when going out. We reasoned at the time that our 2-year-old would not be strong enough, nor tall enough to turn the key and let himself outside. We reasoned wrong, for one day our son Alex reached up, turned the key and opened the door right in front of us. Lesson learned: Given the right key, anyone can open a door.

I continued my analogy by saying that even Arnold Schwarzenegger would be unable to open a door given the wrong key, but might, if he continued trying, snap it off in the lock.

The right key is the right treatment, effortlessly unlocking a good response, while the wrong key is the wrong treatment more often than not too much, too late, akin to a solid tumor bone marrow transplant.

In recent years, personalized care has come to be considered synonymous with genomic profiling. While we applaud breakthroughs in human genomics today, there is no molecular platform that can match patients to treatments. The objective response rate of just 10 percent, almost all in breast and ovarian cancer patients in one study (Von Hoff J Clin Oncol 2010 Nov 20:28(33): 4877-83), suggests that cancer biology is demonstrably more complex than an enumeration of its constituent DNA base pairs. The unilateral focus on this area of investigation over others might be described as “the triumph of hope over experience” (James Boswell, Life of Samuel Johnson, 1791).

But hope springs eternal and with it the very real possibility of improving our patients outcomes. By accepting, even embracing, the complexity of human tumor biology we are at the crossroads of a new future in cancer medicine.

William Withering (1741-1799) the English physician and botanist credited with discovering digitalis as the therapy for dropsy, e.g. congestive heart failure (An Account of the Foxglove and some of its Medical Uses, Withering W. 1785), had absolutely no idea what a membrane ATPase was, when he made his remarkable discovery. It didn’t matter. Cardiac glycosides provided lifesaving relief to those who suffered from this malady for fully two centuries before Danish scientist, Jens Christian Skou, identified these membrane bound enzymes, for which he was awarded a Nobel Prize in 1997.

Similarly, penicillin, aspirin, and morphine were in all use for decades, centuries, even millenia before their actual modes of action were unraveled. Medical doctors must use any and all resources at their disposal to meet the needs of their patients. They do not need to know “how” something works so much as they (and their patients) need to know “that” it works.

The guiding principle of personalized medicine is to match patients to therapies. Nowhere in this directive is there a prescription of the specific platform to be used. Where genomic signatures provide useful insights for drug selection, as they do in APL (ATRA, Arsenic trioxide); NSCLC (EGFr, ROS1, ALK); CML (Imatinib, Dasatanib) then they should be used.

However, in those disease where we haven’t the luxury of known targets or established pathways, i.e. most human malignancies, then more global assessments of human tumor biology should, indeed must, be used if we are to meet the needs of our patients. Primary culture analyses like the EVA-PCD® provide a window onto human tumor biology. They are vehicles for therapy improvement and conduits for drug discovery. Scientists and clinicians alike need to apply any and all available methodologies to advance their art. The dawn of personalized medicine will indeed be bright if we use all the arrows in our quiver to advance clinical therapeutics and basic research.

Reposted from May 2012

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.

Cancer Patients Need Answers Now!

I read a sad editorial in the Los Angeles Times written by Laurie Becklund, former LA Times journalist. It is, in essence, a self-written obituary as the patient describes her saga beginning almost 19 years earlier, when she detected a lump in her breast. With stage I breast cancer she underwent standard therapy and remained well for 13 years until recurrence was heralded by disease in bone, liver, lung and brain. Given a dire prognosis she became a self-made expert, conducting research, attending conferences, and joining on-line forums under the name “Won’t Die of Ignorance.” Despite her heroic effort Ms. Becklund succumbed to her illness on February 8. She was 66.

Ms. Becklund experienced the anguish that every patient feels when his or her own individual and highly personal needs simply aren’t being addressed. She opines that entities like the Susan G. Komen Fund, which has raised over $2.5 billion in the last 20 years, “channels only a fraction of those funds into research or assistance to help those who are already seriously sick.” She continues, “We need people, patients, doctors, scientists, politicians, industry and families to make a fresh start.” Her frustration is palpable as she states her outcome seemed to be based on the roll of the dice, like playing “Chutes and Ladders.”

The author’s plight is shared by the millions of patients who are confronting advanced cancers. They are not interested in “why” or “how” their cancers came to be. They can no longer benefit from early detection or cancer awareness campaigns. They need practical, actionable, clinical answers today.

Ms. Becklund’s commentary resonates with me and with everyone who has cancer or knows someone who does. As an oncology fellow at Georgetown, I found myself losing patient after patient to toxic and largely ineffective treatments, all despite my best efforts. I described this in my book “Outliving Cancer.” It was then that I decided that I would dedicate myself to meeting the individual needs of each of my patients and I have used a laboratory platform (EVA-PCD) to do so. I have encountered surprising resistance from clinicians and researchers who seem to prefer the glacial pace of incremental advancement found in population studies over individual solutions found in the study of each patient’s unique biology. Ms. Becklund correctly points out that every treatment must meet each individual’s need.

The role of the scientist is to answer a question (treatment A vs. treatment B) while that of the clinical physician must be to save a life. Every patient is an experiment in real time. It may well be that no two cancer patients are the same. Indeed, the complexity of carcinogenesis makes it very possible that every patient’s cancer is an entirely new disease, never before encountered. Although cancers may look alike, they may be biologically quite distinct. Meaningful advances in cancer will only occur when we learn to apply all available technologies to treat patients as the individuals that they are. Let us hope that Ms. Becklund’ s final essay does not fall upon deaf ears.

Truly Personalized Cancer Care

In the mid 1980s, it became apparent to me that cancer did not result from uncontrolled cell proliferation, but instead from the lack of cell death. Yet, cancer research labored for almost a century under the erroneous belief that cancer represented dysregulation of cell proliferation. Today, we confront another falsehood: the complexities and redundancies of human tumor biology can be easily characterized based on genomic analyses.

The process of carcinogenesis reflects the accumulation of cellular changes that provide a selective survival advantage to transformed cells.  However, the intricate circuitry that provide these survival advantages, reflect harmonic osolations between DNA, RNA and protein. Put simply, Genotype does not equal Phenotype. It is the phenotype that determines biological behavior and clinical response in cancer. Thus, it is overly simplistic to imagine that a DNA profile by itself can provide more than a fraction of the information required to make individual patient treatment decisions.

Colon cancer

When therapies are based on genomic analysis, only a portion of the patient’s profile is taken into consideration. These analyses disregard the environmental, epigenetic and proteomic factors that make each of us individuals. Though useful prognostically and applicable in select circumstances where a unique genetic perturbation leads to a clinical response (c-ABL and Imatinib response in CML), genomic analyses provide only a veneer of information.

The Rational Therapeutics Ex Vivo Analysis – Programmed Cell Death™ (EVA-PCD) assay focuses upon the complexity of human tumors by measuring cell death, the end result of all cellular mechanisms of response and resistance acting in concert. By incorporating cell-cell, vascular, stromal and inflammatory elements into the tumor response assessment, the EVA-PCD platform provides a robust surrogate for human tumor response. While much of modern cancer research pursues the question of “Why” cancer arises, the clinical oncologist must confront the more practical question of “How” the best outcome can be achieved.

Assay-directed therapy is truly personalized cancer care providing treatments unique to the individual.

 

Reblogged from February 2010.

Cancer Patient’s Need to Know – Whose Avatar is it?

The 1984 celebrated case of Baby Fae described the efforts of intrepid investigators at Loma Linda University in California to save the life of an infant born with a hypoplastic heart (the left side of the heart was severely underdeveloped). To salvage this unfortunate child, the heart of a baboon was transplanted into her chest, which successfully maintained her cardiac function. Unfortunately, the child died 21 days later after rejecting the heart.

The experience nonetheless spawned a lively discussion of ethics in human experimentation and the lengths to which we will go to save a life. A friend residing in New York contacted me shortly thereafter. Knowing that I was in medical training in California, he was intrigued by this report and posed the question. “What is the fastest animal in the world?” When I suggested a cheetah or African gazelle, he answered “No, a baboon running past Loma Linda Medical Center.”

I am reminded of this quip following a news report about Champions Oncology. This biotech company located in Hackensack, NJ, founded by investigators from Johns Hopkins University has developed a technique to transplant human tumors into immunocompromised (known as nude for their loss of hair) mice to test drugs and combinations. They use the term “avatar” to describe these human-tumor-bearing mice and like their video-game counterparts these mice serve as surrogates for their patient “users.” It takes 20 to 30 mice to complete the analyses for each patient. Although the work is based on sound science, the practicality, predictive validity and ultimate utility of this approach has yet to be established. This has not dampened the enthusiasm of desperate cancer patients who have proven willing to spend tens of thousands of dollars to undergo a Champion analysis.

So what are the upsides of the avatar model? For one, this is a living organism with a functioning blood supply, liver, kidneys and the capability of metabolizing pro-drugs (precursor) into active species. The process utilizes cell clusters, not individual single cells in their analysis. Responses are ultimately “phenotypic” in as much as they reflect cellular responses to injury and not genotypic profiles. Finally, toxicities can also be assessed by measuring the animal’s tolerance of the drug or combination administered.

But let’s drill down for a moment and take a closer look. The avatar approach requires months of preparation, the operation of a vivarium (animal zoo) and several mice for every single drug or combination tested. It requires prolonged (many months) maintenance of the animals with highly unpredictable engraftment of the transplanted tumors. Furthermore, significant time, energy and skill are needed to maintain these in-vivo systems.

Ultimately, only a handful of drugs can be examined, lest the number of mice required becomes unmanageable. At the end of the day these investigators are making a valiant effort to approximate work that we, and our colleagues, have successfully conducted for more than two decades – the accurate selection of chemotherapies and drug combinations for individual patients.

If we allow for the obvious downsides of expense, difficulty, time, limited sample size, low efficiency and resource intensity required to conduct even a single patient’s study there are more daunting concerns.

First, these cells are not actually in their “native state.” Over a period of time the tumors will no longer be host to human immune cells, nor will they be exposed to human cytokines and VEGF. The observed growth of the implanted tumors in the mice-avatars may, in part, reflect an ingrowth of mouse-derived fibroblasts and blood vessels, which have distinctly different biology from those of a human host.

Even if we accept the expense and difficultly of avatars, there is no clear evidence on an individual patient basis, that this approach holds any advantage over the much simpler and direct evaluation of human primary culture microspheroids. That is, the avatar approach appears to be a difficult, cumbersome, inefficient and a very expensive way to do something that we can already do inexpensively, rapidly and efficiently. Further, the purported advantages of in vivo-avatar system are actually less than meets the eye.

After all, most clinical drugs have “active” derivatives that can be utilized for testing in short-term culture without the need for a mouse liver. Our careful calibration of in vitro drug exposures against actual patient responses (P < 0.001) has established the predictive validity of these culture conditions. Finally, the toxicities of virtually all clinically relevant drugs that patients would request for testing (and likely receive) are already well-known to clinicians from existing Phase I and Phase II clinical data sets.

Human tumor sensitivity to chemotherapy (or targeted agents) is driven by what might be described as “response elements.” These unique features of each patient’s tumor can be accurately probed at the phenotypic level through the use of simple assays conducted in short-term culture. Our microspheroid model has proven highly predictive of clinical outcome in virtually every tumor type ever tested.

Our analyses are conducted in seven days, with samples that are the same size or smaller than those required for avatar generation. Furthermore, short-term platforms can analyze dozens of drugs and combinations at a price that is far less expensive. While it might be argued that avatars, once established, can be used as repositories for future research, that is small comfort to patients in need of immediate answers who find themselves paying handsomely for a service that will not be available in a timely manner, e.g. that which can help them in their need for immediate drug selection.

It seems that the medical science community is less interested in results than process. The fact that short-term cultures are predictive of clinical outcome seems less important than the provocative scientific results that these avatar models can provide Avatars enable scientists to interrogate cancer cells for genomic and proteomic signals, offering the opportunity to conduct interesting science. But has that science become more important than the clinical utility of the tests that were purportedly developed (and sold) to improve patient outcomes?

Patients who are considering spending tens of thousands of dollars for these glorified chemosensitivity tests would do themselves a service to first carefully examine the predictive validity, breadth of data, cost and turn-around-time of short-term culture methods, like the EVA-PCD® assay before they commit their precious time and resources to so “interesting” an endeavor as an avatar analysis. After all, it is the patient and their good outcome that should be at the top of the list when the advantages of any system or method are being weighed. Truly personalized cancer care should be just that – personalized.

With the rise of avatars it may be timely to re-examine the original question and wonder whether the fastest animal in the world will soon be a nude mouse running past Johns Hopkins University.

Why Do Cancer Surgeons Cure More Patients Than Medical Oncologists?

Surgery remains the most curative form of cancer treatment. While the reasons for this are many, the most obvious being earlier stage of disease and the better performance status of the patients, there are other factors at work. Surgeons tend to be rugged individualists, prepared to make life and death decisions at a moment’s notice. The surgeon who enters the pelvis expecting an ovarian cyst only to find disseminated ovarian cancer must be prepared to conduct a total hysterectomy and bilateral ovary removal if he/she is to save the patient’s life. It is these types of aggressive interventions that have that revolutionized the treatment of advanced ovarian cancer.

What of the medical oncologists who, with the exception of leukemia and some lymphomas, confront diseases that are difficult to eradicate and for which treatments can be toxic? Trained as incrementalists, they do not expect cures so much as palliation. Their role is not to make hard decisions, but instead to rely upon precedence. Educated in the school of small advances, these physicians are not rewarded for individual successes but they are harshly criticized for any departures from community standards.

Deprived of the opportunity to make bold decisions, medical oncologists follow opinion leaders who instruct them to accrue to standardized protocols. As meaningful advances are few and far between, enormous numbers of patients must be accrued to provide sample sizes with any hope of achieving statistical significance. Among the most disturbing examples of this approach was a trial reported in patients with inoperable pancreatic cancer. The study compared single agent gemcitabine to gemcitabine plus erlotinib. The trial achieved an improvement in survival that led the FDA to approve the two-drug combination. Yet, the actual improvement in median survival was a mere 10 days. The authors beamed, “To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine.” (Moore, MJ et al J Clin Oncol, 2007). To the average observer however, a clinical trial that required 569 patients to improve median survival from 5.91 months to 6.24 months (10 days) would hardly seem cause for celebration.

Medical oncologists have become so accustomed to these marginal advances that they are unmoved to depart from standard protocols lest they be accused of breeching guidelines. This might be acceptable if chemotherapy provided meaningful benefits, but the extremely modest advantages provided by even the best clinical trials scream for medical oncologists to think, well, more like surgeons.

While community oncologists think it heresy to step around a National Comprehensive Cancer Network (NCCN) guideline, investigators at the best institutions, the opinion leaders, have begun to question the merit of blind protocol accrual and come to recognize that many critical questions cannot be easily answered through the current trial process. Questions such as the role of liver resection for colon cancer patients with disease spread to the liver or the role of additional chemotherapy after that liver surgery, simply may not lend themselves to randomized trials. In a review of the topic by one of the leading investigators in the field, Dr. Nancy Kemeny from Memorial Sloan-Kettering in New York examined this dilemma, “The management plan for each patient should be decided by a multidisciplinary team, it may not be possible or ethically defensible to perform large randomized adjuvant trials comparing chemotherapy with surgery alone or comparing modern chemotherapy with older regimens. It may be reasonable to extrapolate from adjuvant trials and meta-analyses showing predominantly disease-free survival benefit. Each decision on postoperative chemotherapy should be viewed in context of prior treatment, surgical preference and individual patient characteristics.”

How refreshing. Finally a clinical investigator has recognized that patients must be managed on an “individual basis” regardless of what the clinical trial data does or does not support.

The concept of personalized medicine flies in the face of contemporary guideline driven treatment. Individualized care is on a collision course with the NCCN. It is time for medical oncologists to reclaim the high ground in doing what is right for patients, using resources that enable them to make smart decisions and to eschew standardized care. In cancer, the dictum “one size fits all” is more accurately “one size fits none.”

Cancer Patients Take Heart: The Power of Public Opinion

A January 27, 2014, report on National Public Radio brought recent discussions into sharper focus. Though the story was unrelated to cancer, the lessons learned provide a road map for cancer patients in their pursuit of the most effective, least toxic treatments.

The condition known as “clubfoot” (talipes equinovarus) is a congenital deformity that afflicts one of every 1,000 births in the US. The abnormal internal rotation of the ankle is highly debilitating if not corrected shortly after birth. For decades, orthopedic surgeons used complex surgical procedures that disrupted the ankle structure and realigned the bones. Despite numerous surgeries, this rarely corrected the deformity resulting in chronic arthritis and gait disturbances. The costs were significant and the loss of productivity for those afflicted even greater, yet the dilemma remained unresolved.

Into the fray came Dr. Ignacio Ponseti. Ponseti, the son of a Spanish watchmaker, had gained a unique perspective on structural integrity working in his father’s shop. Fleeing the Spanish Civil War he came to the US to practice orthopedic surgery at the University of Iowa. Recognizing the poor outcomes for clubfoot surgery, he took it upon himself to rethink the problem. After all, newborns have flexible ligaments. These ligaments, he reasoned, could be re-trained through a series of casts that were replaced serially over months after birth. Once the foot was in better alignment, the children were placed in a boot to retrain the joint into its normal alignment. Not surprisingly, this simple, noninvasive, inexpensive method was eschewed by the orthopedic professionals. Undaunted, he continued to practice his art, with excellent results year after year. Dr. John Herzenberg, a Baltimore-based practitioner of the Ponseti method was quoted: “People were falling over themselves to do fancy invasive surgery, and this one strange old guy, who speaks softly with a Spanish accent in Iowa, was getting sort of ignored by the drumbeat of people who were in favor of surgery.” Despite its obvious appeal and its manifest successes, this technique remained largely in Iowa for 50 years.

And then came the Internet. When a child born with clubfoot in 2000 was recommended for standard surgery, her mother went online to examine all the options and came across Dr. Ponseti. She traveled to Iowa for an opinion. Convinced that Dr. Ponseti’s approach was superior, this brave mother took the leap and undertook the Ponseti method. Dr. Ponseti completely corrected the child’s foot. Horrified that her daughter would have suffered a life of misery without this brilliant breakthrough, this young mother took it upon herself to get the word out. Using the Internet, she created a Yahoo Support Group called “No Surgery 4 Clubfoot.”  Families with afflicted children could now find out about this technique and identify practitioners who used it.

Voting with their feet, parents took their children to centers that applied this simple, relatively noninvasive approach. Over time, the academic community and their adherents to invasive surgery found themselves on the wrong side of patient referrals. Demanding better outcomes for their children, parents charted a new course for their medical care and forced their doctors to agree or be left behind. With a 97% success rate today, virtually every orthopedic surgeon in America practices the Ponseti method. Indeed, it is now recommended by the American Academy of Orthopedic Surgeons.

I relate this story to cancer patients as they confront similar resistance. While marginally effective therapies are promoted by many academic centers, simple, comparatively easy techniques are available that can empower patients in treatment selection. Just like the clubfoot parents, cancer patients must demand access to treatment options and explore every lead.

The Internet has offered an entirely new platform for cancer patients to communicate their experiences, recommend physicians, educate friends and family members and change referral patterns. The power to change the way cancer is treated in America today is within the grasp of the patients themselves. Just like Dr. Ponseti, who knew that his method worked and just like his patients who avoided the pain and suffering they would have otherwise endured, patients enlightened about better ways to treat cancer need to communicate and take charge of their disease.

Gastric Cancer: A Call for Patient Selection

Gastric cancer is the fourth most common cancer worldwide with more than 930,000 diagnoses and 800,000 deaths attributed to this disease each year. Although relatively uncommon in the U.S., constituting only 2 percent of new cancers, in countries like Korea it makes up 20 percent of all new malignancies.

Among the causes are Helicobacter pylori infection, diets rich in smoked food, a high intake of nitrates and nitrites and cigarette smoking. A rare but aggressive form of the disease is associated with a gene mutation known as CDH1. The high frequency of metastatic disease at the time of initial diagnosis often precludes surgery, leaving systemic chemotherapy as the principal treatment option.

A recent report in The Annals of Oncology (No improvement in median survival for patients with metastatic gastric cancer despite increased use of chemotherapy: Bernards N. et al, Annals of Oncology. November, 2013) describes a retrospective analysis by Dutch investigators who examined the use of chemotherapy in patients with inoperable gastric cancer.

In total, 4,797 cases were examined from 1990 to 2011. Over this time, the proportion of patients presenting with metastatic disease increased from 24 percent in 1990 to 44 percent in 2011. At the same time, palliative chemotherapy use increased from 5 percent to 36 percent. Younger patients and those of higher socioeconomic status had the largest increase in chemotherapy use, while older patients, those with linitis plastica and those with multiple metastases had lower chemotherapy use. Despite the significant increase in the use of chemotherapy, the median survival for patients was unchanged at 15 weeks in 1990 and 17 weeks in 2011 (P = 0.1).

Over this period, early treatment regimens like 5-fluorouracil (5FU) and FAM were largely replaced by combinations like Docetaxel/Cisplatin/5-FU (DCF), Cisplatin/Irinotecan, Epirubicin/Oxaliplatin/Capecitabine (EOX) and Carboplatin/Taxol. While response rates and palliative benefits have continued to improve, this has not translated into improved overall survival. This reflects a dilemma that has confronted medical oncologists for decades.

For many years, clinical trialists have held that one cannot assess the benefit of a treatment by comparing responders to non-responders. That is, time to progression and survival must compare all patients on a given treatment arm to those on the control arm. Their rationale was that “one must treat all patients to obtain the benefit seen in some.”  Put differently you cannot “cherry pick” your winners and losers. It was said that this proscription was needed to avoid selection bias. But as any medical or nonmedical person would recognize, people who respond to treatment do better than those who do not. Lacking the ability to identify responders upfront, these trialists have insisted upon a one-size-fits-all approach to the detriment of clinical therapeutics and drug development.

With the dawn of the molecular era we see chinks in the armor of these trial designs as investigators now question why everyone should receive a treatment if only a small percentage will benefit. In gastric cancer, HER2 over-expression, found in 20-25 percent of patients, is now routinely used to identify patients who will respond to trastuzumab. But what of the other 75-80 percent of patients who do not carry HER2 and for whom there are no widely used determinants of clinical response? Do the results of Bernard article suggest that these patients should not receive therapy?

The Bernard article offers an interesting insight into what may be the future of medical oncology. As cancer therapy is increasingly scrutinized, not only for response or palliation but also for overall survival, patients may soon be denied treatments unless the results of the therapy rise to this, the highest level of evidence, for the entire population of treated patients.

Would it not be preferable to use laboratory analyses, like the EVA-PCD®, to select among treatment candidates before subjecting all patients to the risk and expense of toxic chemotherapy? In this regard, the author’s comments are poignant: “Identification of the subgroup of patients which benefit from palliative chemotherapy is of the utmost importance to avoid unnecessary treatment.” As a laboratory investigator engaged in the field of drug selection science (functional profiling), I couldn’t agree more.

ASCO Update: Personalized Cancer Care – Our Contributions

As part of our ongoing blog postings we like to include recent presentations and publications. On July 9, I described our ASCO presentation exploring crizotinib, “Functional Profiling Leads to Identification of Accurate Genomic Findings.”

To conclude the review of our other presentations from that meeting, here is a brief summary of our work.

The first of the two was our international collaboration in personalized medicine for the treatment of advanced and drug-refractory cancers: “Clinical application of human tumor primary culture analyses.” The study reviewed the results of 67 patients from institutions across Brazil.

Tumor samples were transported by overnight courier to California for drug response profiling. A broad array of tumors were included. The overall success rate provided actionable results in 62 of 67 patients (92 percent). More than 75 percent of the studies provided results for between 8 and 16 drugs and combinations with a median of 12 reported. Several strikingly good responses were observed, including novel combinations identified in the laboratory. This study confirms the feasibility of international collaboration and reflects the globalization of medical care delivery.

The final study published by ASCO was also a collaborative effort with SageMedic of Larkspur, CA, The Ludwig Maximilians University Munich, Germany and the Weisenthal Cancer Group. The study was a meta-analyses that examined the sensitivity and specificity of human tumor primary culture studies and the efficacy of drug therapies selected, based on laboratory findings. In aggregate there were 28 retrospective and 15 prospective trials included.

The overall sensitivity was 0.92 (95 percent C.I. 0.89 – 0.95), and specificity of 0.72 (95 percent C.I. 0.67 – 0.77) with an area under the curve for the ROC of 0.893 (SE = 0.023, p < 0.001). When clinical outcomes were examined, it revealed a two-fold improvement for assay-guided therapy for standard of care (odds ratio 2.04, 95 percent C.I. 1.62 – 2.57, p <  0.001). Finally, the one-year survival rate for assay-guided therapy proved superior (OR 1.44, 95% C.I. 1.06 – 1.95, p= 0.02).

As can be seen from this well conducted meta-analysis, there is a wealth of evidence to support the use of human tumor primary cultures for the selection of chemotherapy.

The Human Micro Biome

There is a growing recognition that we as a species, humans that is, are not a single organism but a community of organisms living in synchrony. As scientists have recognized for many years, the human gut, skin, and digestive tract are colonized by trillions of bacteria, fungi and other microbes. What we did not realize until recently, was how important these organisms are to our health and well-being

The microenvironment of the human gastrointestinal tract reflects the interplay between bacteria, our diet, intestinal digestive enzymes, lipids, polysaccharides, amino acids, and the by-products of metabolism. The specific make-up of each individual reflects their environment, diet, and family heritage. Indeed, our bacterial flora are transmitted to us by our mothers, who prior to the advent of pasteurized baby-foods, pre-chewed their infant’s food.

More to the point, we now realize that bacterial infections and exposures to foreign antigens early in life protect and prepare us for a healthy adult life. Many modern maladies, such as asthma, diabetes, hypertension, even possibly autism and schizophrenia, may reflect infections, immune responses and the timing thereof. It has been suggested that infections with parasites modulate our immune response. In our increasingly clean environment, devoid of hookworms, tapeworms, and the like, our overactive immune system creates autoimmunity in the form of rheumatoid arthritis, systemic lupus and other maladies.

This reflects the growing recognition that human biology is in fact human ecology. The importance of this cannot be overstated when we examine human tumor biology. We are continually bombarded by the teachings of a cadre of scientists who believe whole heartedly that they can answer the puzzle of human cancer by examining the intricacies of individual human cancer cells, primarily at the level of DNA.  Nothing could be further from the truth.

Take for example just one of the myriad of signaling pathways. Beta catenin is among the most potent tumor promoters. The deranged function of beta-catenin has been identified in several human tumors including prostate, lung and colon. Its closest association being that with colon cancer, wherein the loss of the APC protein (adenomatous polyposis coli), results in a particularly aggressive form of the disease.  The APC protein normally combines with axin and glycogen synthase kinase 3 beta (GSK3B) which all together function to regulate beta-catenin. It is the loss of APC that releases Beta-catenin and drives polyps to become cancerous.

However, upstream of this triumvirate of regulatory proteins are the integrin-ca cadherin proteins that communicate across the cell membrane. By changing the environment of the colon itself, we can influence the integrins, which regulate the cadherins. This in turn regulates beta catenin.  Thus, colon cancer may not arise from changes in our genetic makeup but instead may be driven by micro-environmental changes in the colonic milieu that alter cellular behavior and drive malignant transformation.

Again and again, we are forced to recognize the complexity of human biology. Now we realize that it is not just the genome to the transcriptome to the proteome, but indeed the micro biome.