Why do People get Cancer?

While there are a lot of reasons why people develop cancer, there is a growing recognition that a subset of patients carries genetic predispositions for the disease. Some of these genetic syndromes result in childhood cancers like the retinoblastoma gene or mutations in P53. These abnormalities are so profound that virtually all patients develop aggressive cancers at an early age. However, there is a second group of genetically driven cancers that are being encountered in young and middle aged adult patients. One of the best described is the ovarian/breast cancer syndrome associated with the BRCA 1 and 2 genes. Another group of patients carry a DNA repair deficiency known as mismatch repair or Lynch Syndrome.

Not unlike the BRCA patients, people with mismatch repair have an inability to respond to DNA damage. This failure leads to mutational events that, over the course of a lifetime, can result in cancer. We now know that the BRCA genes may provide therapeutic opportunities as the new class of drugs known as PARP inhibitors can target them. What we are now learning is that the Lynch Syndrome patients may have a similar attribute that can, in some circumstances, render them “hypersensitive” to chemotherapeutics. One such patient has been under my care for the last two years.

This charming 43-year-old patient presented with cancer of the uterus. She was managed by a gynecologic oncology service and received a combination of surgery, radiation and chemotherapy. One year later, she revealed recurrent disease in the right, lower abdomen with involvement in the liver. Impending bowel obstruction lead to surgical exploration, providing my laboratory with tissue for analysis. When I first received the tissue specimen, I was expecting recurrent uterine cancer, the same diagnosis for which she had been treated the year earlier. But, to my surprise, the patient was actually diagnosed with colon cancer. This triggered an analysis of her mismatch repair gene and provided confirmation of Lynch Syndrome.

What I found amazing was that this patient’s colon cancer was sensitive to a two-drug combination that I had never in my career administered for colon cancer. Indeed, in my published work I had consistently identified colon cancer as a bad target for this doublet. Yet, this patient’s tumor was unequivocally sensitive to the combination. Her response was as prompt as it was dramatic — a complete remission within a scant few months. And then, in follow up, her PET/CT revealed a small focus of abnormality, seemingly associated with the colon. With a negative colonoscopy, we waited an additional several months and repeated the study. This time, it was even more evident; there was clearly an abnormality in the left pelvis.

A biopsy provided an unexpected finding. It was cancer, but it wasn’t colon cancer. The patient’s original uterine cancer from two years earlier had recurred, most likely as a residual vestige of tumor from an incomplete resection two years before. The drug response profile was distinctly different, but highly consistent with a profile one might find in a patient with mismatch repair. As we prepared to treat the patient, she developed gastrointestinal bleeding, a workup for which confirmed erosion by the uterine cancer into the bowel wall. We decided to use our findings to treat the patient and initiated a three-drug combination. The patient’s tolerance was excellent and gastrointestinal bleeding stopped immediately.

She is now receiving additional courses of therapy and will be evaluated for response in the coming months. While it is too early to know how well she’ll respond, we are optimistic regarding her outcome. Among the most interesting feature of this and related cases is the fact that the genetic mutation that caused her cancer may be the same genetic mutation that makes it possible for us to treat her.

Disrupting Cancer’s Circuitry – an Electrician’s View of Oncology

In many ways, cancer can be viewed like an integrated circuit. On-off switches and back up switches constitute the controls. When one of these switches stops working and a cell “short circuits,” cancer is the result. As we become more sophisticated in our understanding of cancer biology, we begin to create drugs that specifically target these short circuits.

On April 3, 2011, I will be reporting our most recent findings on novel compounds that target two parallel circuits in cancer cells. These compounds, or small molecules, disrupt the signal that drives cancer cell survival and proliferation. While the profiles of each drug alone are of interest, the profiles of the drugs in combination are better still. The phenomenon of cross talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When we as therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what we have observed with these duel inhibitor combinations.

What is interesting is the fact that the activities cut across tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths. Once again, we find that cancer biology is non-linear. Moreover, cancers share pathways across tumor types, pathways that might not intuitively seem related. This is the beauty of our platform — for it allows us to explore drugs and combinations that most people wouldn’t think of. It is these counterintuitive explorations that will likely lead to meaningful advances.

There is More to Gastrointestinal Cancer Management Than FOLFOX

Several months ago, I was introduced to a 58-year-old gentleman with a very bad diagnosis — a bout of gastrointestinal bleeding that had lead to an upper GI endoscopy. It wasn’t an ulcer, or even gastric cancer, but a very rare form of cancer arising in the duodenum. Adenocarcinoma of the duodenum is very uncommon.

This patient was in trouble.

In addition to the bleeding, he had lost a substantial amount of weight, was in pain and had a very large tumor that was nearly obstructing his upper GI tract. After getting the patient stabilized in September 2010, he was referred to a surgeon who conducted an aggressive surgical resection. The recovery was difficult, prolonged and accompanied by additional GI bleeding. By the time the patient had recovered adequately enough to consider additional therapy, his PET scan revealed extensive re-growth.

If you were to ask medical oncologists in the United States what to give such a patient, 99 percent would recommend FOLFOX or some variation thereof. But, FOLFOX wasn’t the right treatment for this patient. Instead, he had a strong signal for Irinotecan, which was further enhanced by the addition of an EGFR inhibitor. Based on this, I elected to treat the patient with Erbitux + Irinotecan. Before starting therapy, his CA 19-9 was 354. Although his signal for the EGFr inhibitor was very favorable in our analysis, I screened him for K-ras mutation. It seemed evident from his dose response curves and clear synergy between Irinotecan and the EGFR inhibitors that he would be K-ras wild type, but in this era of evidenced-based medicine one must be politically correct.

Indeed, he was K-ras wild type and we started treatment with Erbitux + Irinotecan. Other than the rash associated with the Erbitux, the tolerance was good. The bleeding stopped immediately, the CA plummeted with the first dose to 71 and the patient then returned every other week for therapy.

On February 11, 2011, three cycles later, we repeated the PET/CT. The phrase “marked interval regression” of measurable disease caught my eye. I also noted the normalization of his CA 19-9. The patient had gained weight and returned to normal activities. With the exception of a small and diminishing rash, he looks quite normal. In fact, with the rather modest dose of Irinotecan used in his schedule, he hasn’t even suffered any hair loss. What I find most interesting about this patient is that FOLFOX, the most widely used regimen in this setting, wasn’t anywhere on the radar screen. It wasn’t active, it wasn’t recommended and I feel confident it wouldn’t have worked. However popular FOLFOX may have come to be in patients like this, it doesn’t fit everyone.

The Pot Calling the Kettle Black

The January issue of the Journal of the National Comprehensive Cancer Network features a point-counterpoint on the topic of the validity of chemosensitivity assays for drug selection in recurrent ovarian cancer. Having conducted a similar exercise with Maurie Markman, MD, as a part of a special symposium at the Society of Gynecologic Oncology in New Orleans in February 2003 — attended by hundreds of gynecologic oncologists — I was surprised on several levels.

First, (and perhaps, in this case, to his credit) Dr. Markman’s position hadn’t changed whatsoever in eight years — one could virtually excerpt his commentary, verbatim from the discussion that we had almost a decade ago. His references and scientific arguments strike me as no more convincing today than they did then, but at least they are consistent.

Second, that the authors arguing in the affirmative neglected to mention seminal influences in the field. Strikingly, Dr. Larry Wiesenthal, a pioneer and mentor, was never mentioned. Of all the modern-day investigators in this field, Dr. Wiesenthal’s contributions should certainly have been referenced. Despite this, these authors do repeatedly cite the marginal contributions of other platforms.

Third, these investigators who claim that there are no published prospective clinical correlations in ovarian cancer, appear to not read their own literature. In a paper that I authored with the chairman of the Gynecologic Oncology Group (Dr. Philip DiSaia) we provided unequivocal, statistically significant evidence in a blinded prospective analysis that assay sensitivity correlated with response (P = 0.035) and time to progression (P = 0.022). (Nagourney RA., Brewer, CA., Redecki S., et al. Gynecologic Oncology ADA 35-39. 2003.)

At least in our neck of the woods, that’s called significant.

What is perhaps the most surprising aspect of these articles is the sudden, newfound interest in this field on the part of these investigators. After a decade of efforts on my and other investigator’s parts to incorporate these methods into GOG trials fell upon deaf ears, it’s surprising to me that these arguments are finally being heard. Maybe my voice, or that of pioneers like Dr. Wiesenthal, has gotten louder? I hadn’t noticed.

In the scientific literature we use statistical tools like analysis of variance (ANOVA) to discern trends and explore new findings. When I examine these two manuscripts for new insights, I find that Dr Markman’s position, to his credit, hasn’t changed; that the statistical significance of our response and survival data also hasn’t changed; that the well documented scientific basis of our work hasn’t changed. But, I do identify one new correlate associated with this sudden enthusiasm for the field. A small (but potentially loud) line found at bottom of the first page “receives research support from…”

A New Wrinkle on an Old Remedy

For many years, naturopaths and health-conscious individuals have recommended the consumption of grape seed extracts. Chemical analyses of grape seeds have provided a treasure trove of active ingredients including resveratrol, anthocyanins, pro-anthocyanins, and numerous terpenes. Many of these substances are potent antioxidants and there is reason to believe that they may have meaningful health benefits.

As one of the editors of the Journal of Medicinal Food, I was asked to review an article on the chemical activities of grape seed extracts. I then wrote an editorial describing the interesting findings in this study and their biological relevance. The most interesting aspect of this well-conducted analysis was the description of a wholly new mechanism of action for the substances found in grape seeds. What the authors found was that the chemical species in grape seed extracts influence gene expression through a process knows as histone acetylation. What makes this so interesting is the fact the histone acetylation is one of the fundamental regulators of genetic expression and a critical part of the new field of science known as epigenetics.

Epigenetics is the field of study that examines heritable attributes that are not incorporated into DNA sequence. These epi-phenomena take existing genes and determine whether or not they will actually be expressed. The reason that this is so important is that it shines a very bright light on the limitations of genomic analyses (studies that examine the DNA sequence in tissues). Clearly, if the consumption of foodstuffs (like grape seed) can alter gene expression then the use of genomic profiles to predict cellular behavior can only be viewed as highly simplistic.

We are continually impressed by the complexity of biology and are humbled when we consider the intersecting pathways that take us from gene to function.