No One is More Interested in Curing Your Cancer Than You

A diagnosis of cancer thrusts a, heretofore, healthy individual into the strange and unfamiliar territory of medical oncology. Many of my patients describe this transition as “entering the cancer bubble.” Suddenly, you are on the inside and everyone on the outside is talking at you about what to do, where to go, whom to see, and what treatments to receive.

From the inside of the bubble however, all of this has a hollow ring as you ponder many options, few good and some, positively frightening. Unfortunately, few patients have the time to complete a MD, or PhD, between diagnosis and the initiation of treatment. Lacking the requisite expertise, they turn to the “authorities” for advice.

Depending on which “authority” one consults, the recommendations may be colored by prejudices and biases. Some physicians adhere strictly to the National Comprehensive Cancer Network guidelines. Others insist upon accrual to Cooperative Group and Phase II trials. University-based investigators will often recommend developmental studies. And some physicians will follow the path of least resistance, examining such issues as cost, chair time and reimbursement, before considering what treatment to deliver.

It is in this milieu, that patients find themselves adrift. Who exactly should you trust? What is their motivation? To put it crassly, when they recommend a specific treatment, what’s in it for them: Cooperative Group points (provided to the most active accruers), academic accolades (the currency of junior faculty), cost containment (the purview of the managed care physicians), or finally, profit margins? Yes, there are a small number of physicians whose choices reflect their own pecuniary interests.

The antidote to all this uncertainty lies within each patient; answers to vexing questions crying out to be heard. These answers reflect the biologic features of each individual’s tumor. What pathway, what repair mechanism, what survival signal drives your tumor? No one has a perfect answer, not the genomic investigators (despite their protestations to the contrary), nor the immunohistochemists, despite the significant appeal of the platform. And not the immunologist (despite brilliant progress in this field over recent years). The closest approximation to human tumor biology is, well, human tumor biology. Using cellular constructs, in the form of native state microspheroids, we can today approximate the response profiles of patients undergoing systemic therapies. Using systems approaches to complex questions, the multitude of factors that contribute to objective response can be examined and elucidated.

No test is perfect. No patient is guaranteed a good outcome. Yet, doubling the objective response rate, and as we and others have documented, improving the time to progression and overall survival can be achieved with available methodologies that apply functional profiling to individual tumors.

No one would walk away from an investment formula that doubled the value of their portfolio. Few would turn down the opportunity to enhance their real estate positions predicated on reliable information from a realtor. Yet everyday, physicians convince patients to walk away from available, published, established methods that can improve response rates, diminish toxicities and avoid futile care. In this environment it is critical for patients to take charge of their own cancer management. Patients must not be dissuaded from seeking the best possible outcomes. Physicians, no matter how well intentioned, are human. Their opinions can be colored by misconceptions and an incomplete understanding of the questions at hand. Laboratory analysis empowers patients to make smart decisions.

In the game of cancer we need all the help we can get. After all, no one is more interested in saving your life than you.

The Unfulfilled Promise of Genomic Analysis

In the March 8 issue of the New England Journal of Medicine, investigators from London, England, reported disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of chemotherapeutic agents.

As part of an ongoing clinical trial in patients with metastatic renal cell carcinoma (the E-PREDICT) these investigators had the opportunity to conduct biopsies upon metastatic lesions and then compare their genomic profiles with those of the primary tumors. Their findings are highly instructive, though not terribly unexpected. Using exon-capture they identified numerous mutations, insertions and deletions. Sanger sequencing was used to validate mutations. When they compared biopsy specimens taken from the kidney they found significant heterogeneity from one region to the next.

Similar degrees of heterogeneity were observed when they compared these primary lesions with the metastatic sites of spread. The investigators inferred a branched evolution where tumors evolved into clones, some spreading to distant sites, while others manifested different features within the primary tumor themselves. Interestingly, when primary sites were matched with metastases that arose from that site, there was greater consanguinity between the primary and met than between one primary site and another primary site in the same kidney. Another way of looking at this is that your grandchildren look more like you, than your neighbor.

Tracking additional mutations, these investigators found unexpected changes that involved histone methyltransferase, histone d-methyltransferase and the phosphatase and tensin homolog (PTEN). These findings were perhaps among the most interesting of the entire paper for they support the principal of phenotypic convergence, whereby similar genomic changes arise by Darwinian selection. This, despite the observed phenotypes arising from precursors with different genomic heritages. This fundamental observation suggests that cancers do not arise from genetic mutation, but instead select advantageous mutations for their survival and success.

The accompanying editorial by Dr. Dan Longo makes several points worth noting.  First he states that “DNA is not the whole story.” This should be familiar to those who follow my blogs, as I have said the same on many occasions.  In his discussion, Dr Longo then references Albert Einstein, who said “Things should be made as simple as possible, but not simpler.” Touché.

I appreciate and applaud Dr. Longo’s comments for they echo our sentiments completely. This article is only the most recent example of a growing litany of observations that call into question molecular biologist’s preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer “high price” genomic analyses for the selection of chemotherapy drugs should read this and related articles carefully as these reports portend a troubling future for their current business model.

An Ounce of Prevention

Colorectal cancer is among the leading causes of cancer death in the United States. While most patients develop this disease over a period of decades, associated with an accumulation of genetic mutations (elegantly described by Burt Vogelstein, PhD at Johns Hopkins), a small percentage of patients have a genetic predisposition for this cancer. Among these are those people that carry the familial adenomatous polyp syndrome (FAPS) and those who carry mismatch repair mutations know as Lynch syndrome.

It is the latter group who are the subject of a report in the October issue of the English journal Lancet. In this study, known as the CAPP2 trial, patients with Lynch syndrome received either placebo or 600mg of aspirin per day (the equivalent of two tablets). The results reveal a statistically significant reduction of colon cancer that clearly favored the aspirin group.

To put this in perspective, this dramatic improvement in the highest risk population didn’t come about as the result of a new signal transduction inhibitor or a monoclonal antibody. Instead, it came from the simple administration of one of mankind’s earliest medicinal substances. I applaud these English investigators in conducting this study of 861 patients.

What is most laudatory is that the intervention, while highly effective, is so inexpensive. In an era of proprietary medications and the promotion of expensive new interventions, it is indeed refreshing to read the results of a well-conducted study using an intervention available to all.

Data generated more than two decades ago established the benefit of non-steroidal anti-inflammatory drugs like aspirin for the prevention of colorectal cancer. It is gratifying that this simple intervention has additional scientific support both for those with high-risk predisposition, as well as other patients at risk for this relatively common, yet potentially lethal, malignancy.

Cancer Research Becomes “Curiouser and Curiouser”

Following the Gina Kolata New York Times article on July 8, 2011, which described the failure of the Duke University gene profile program in lung cancer, a second New York Times article popped up on the radar screen.  “Cancer’s Secrets Come into Sharper Focus” by George Johnson, examined the growing complexity of cancer research.

This article explored the growing realization that human biology is not linear. Included were references to work that we have previously described in this blog, including the groundbreaking work of Pier Paolo Pandolfi. It also described the interaction between the human body and its microbial flora. We have long recognized that human health is, in part, associated with our interaction with microbes in our environment. The gastrointestinal tract has numerous species that are increasingly believed to contribute to our health. The growing field of probiotics, wherein people consume “healthy organisms,” has gone from quackery to community standard in less than a decade.

What is interesting over the past years is the growing recognition that many cancers are related to infections. Viral infections are known to be oncogenic, with the Epstein-Barr virus, HPV and other viruses now known to be causative of lymphomas, cervical, head and neck, and other cancers. The association between helicobacter and ulcers, gastric lymphoma, and esophageal malignancies are of interest both epidemiologically and therapeutically.

What is most interesting of all is the growing recognition that the cancer cell is but a small component of the cancer.

Here at Rational Therapeutics we recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to our focus on the human tumor primary culture microspheroid, which contains all of these elements. In our earlier work, we endeavored to isolate tumor cells from their benign constituents so as to study “pure” tumor cells. As time went on, however, we found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in 3-dimensional structures, lead to the realization that cancer cells inhabit a microenvironment. Our lab now studies cancer response to drugs within this microenvironment, enabling us to provide clinically relevant predictions to our patients.

It is our capacity to study human tumor microenvironments that distinguishes us from other platforms in the field. And, it is this capacity that enables us to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of notch, hedgehog and WNT, among other (Gonsalves, F, et al. (2011). An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of WNT/wingless signaling pathway. PNAS vol. 108, no. 15, pp. 5954-5963).  With this clinically validated platform we are now positioned to streamline drug development and advance experimental therapeutics.