Rare Tumors – Challenges and Triumphs

When I am asked how our EVA-PCD laboratory platform might best be applied, I have several responses.

On the one hand, there is my catchphrase, “we cure the curable, treat the treatable and avoid futile care.” What I mean by this is that patients with potentially curable malignancies, e.g., small cell lung cancer, previously untreated ovarian, non-Hodgkin lymphoma, and some leukemias should receive the most effective treatment first line, in order to enhance the likelihood of a cure.

The majority of our patients fall into the second category, those whose tumors can be treated but are less likely to be cured. They include recurrent breast, newly diagnosed lung or pancreas, and colorectal cancer among others.

Finally, in those patients for whom very few options exist, it is arguable that they are best served, when found drug resistant, by avoiding the toxicity of ineffective therapy, or what is known as futile care.

The other way I describe our platform is to explain its capacity to explore treatment options where no reliable guidelines exist. These rare malignancies offer the opportunity to examine a broad array of treatment options, including signal transduction inhibitors in pursuit of heretofore-unrecognized therapeutic directions. Just such a case was submitted to our laboratory this spring

The patient, a 56-year old woman from Brazil, presented in February with a large mass in the left axilla. Biopsy confirmed for an ER, PR and HER2 negative (triple negative) epithelial neoplasm with a proliferative index of 80 percent. The only positive findings were p63 antigen and cytokeratins. Work-up revealed extensive metastatic disease but no other primary could be identified.

The patient underwent surgery followed by aggressive multi-agent chemotherapy. The disease rapidly progressed. Second line therapy proved ineffective. At this point a tissue sample was submitted to our lab. The EVA-PCD analysis revealed an unusual profile with a high degree of activity for sorafenib combinations.  Sorefenib was originally developed as BRAF inhibitor and ultimately received FDA approval for the treatment of advanced kidney and liver tumors, associated with the drugs cross reactivity as a VEGF inhibitor. The patient’s study also revealed persistent activity for the beta tublin inhibitors vinorelbine and paclitaxel. The treating physician used our profile to create a novel combination of vinorelbine, paclitaxel combined with sorafenib.

The pretreatment PET CT obtained in June, revealed complete replacement of the liver and extensive soft tissue and nodal metastasis to the lungs, mediastinum, retroperitoneum, as well as innumerable boney metastasis. After failing the previous chemotherapies the patient began this novel drug combination in mid June.

When I arrived in my office this week, I was met with an email that had as an attachment a slide set from a tumor board presentation that described this patient. The introductory slide was, “Tumores Raros.”(Portuguese for Rare Tumors)  Included in the presentation was the patient’s history, pathology, immunohistochemistry, treatment overview and serial CT/PET scans. The final slide compared June 2013 PET CT (taken before she began our combination) with an August 2013, (taken after 2 cycles of therapy). The results could not have been more different.  The patient had achieved a complete remission. Gone was the extensive hepatic disease. Gone were the boney metastasis. Gone were the dark nodal mets that had scattered across her torso and abdomen like shotgun pellets on an x-ray image. Contrary to every expectation this patient had responded to a drug combination that no one had ever heard of.  No one including her treating physician and me.

These experiences remind us that every patient is a unique story, unfolding in real time. This is a stellar example of personalized cancer care, a gleaming testament to the laboratory’s capabilities and even more so to the dedication of the treating physician who broke with all tradition to treat this patient correctly. I am honored to work with this courageous colleague and delighted by this spectacular outcome.

Does Chemotherapy Work? Yes and No.

A doctor goes through many stages in the course of his or her career. Like Jacques’ famous soliloquy in Shakespeare’s “As you Like It,” the “Seven Ages of Man,” there are similar stages in oncologic practice.

In the beginning, fresh out of fellowship, you are sure that your treatments will have an important impact on every patient’s life. As you mature, you must accept the failures as you cling to your successes. Later still, even some of your best successes become failures. That is, patients who achieve complete remissions and return year after year for follow-up with no evidence of disease, suddenly present with, a pleural effusion, an enlarged liver or a new mass in their breast and the whole process begins again.

I met with just such a patient this week. Indeed when she arrived for an appointment, I only vaguely remembered her name. After all, it had been 13 years since we met. When she reintroduced herself I realized that I had studied her breast cancer and had found a very favorable profile for several chemotherapy drugs. As the patient resided in Orange County, CA, she went on to receive our recommended treatment under the care of one of my close colleagues, achieving an excellent response to neo-adjuvant therapy, followed by surgery, additional adjuvant chemotherapy, and radiation. Her decade long remission reflected the accuracy of the assay drug selection. She was a success story, just not a perfect success story. After all, her large tumor had melted away using the drugs we recommended and her 10 year disease-free interval was a victory for such an aggressive cancer.

A dying leukemia cell

A dying leukemia cell

So what went wrong? Nothing, or more likely, everything. Cancer chemotherapy drugs were designed to do one thing very well, stop cancer cells from dividing. They target DNA synthesis and utilization, damage the double helix or disrupt cell division at the level of mitosis. All of these assaults upon normal cellular physiology target proliferation. Our century long belief that cancer was a disease of cell growth had provided us a wealth of growth-inhibiting drugs. However, in the context of our modern understanding of cancer as a disease of abnormal cell survival (and the need to kill cells outright to achieve remissions), the fact that these drugs worked at all can now be viewed as little more than an accident. Despite chemotherapy’s impact on cell division, it is these drugs unintended capacity to injure cells in ways they cannot easily repair, (resulting in programmed cell death) that correlates with response. Cancer, as a disease, is relatively impervious to growth inhibition, but can in select patients be quite sensitive to lethal injury. While cancer drugs may have been devised as birth control devices, they work, when they do work at all, as bullets.

There is an old joke about aspirin for birth control. It seems that aspirin is an effective contraceptive. When you ask how this simple headache remedy might serve the purpose, the explanation is that an aspirin tablet held firmly between the knees of a young woman can prevent conception. The joke is emblematic of chemotherapy’s effect on cancer as a drug designed for one purpose, but can prove effective through some other unanticipated mechanism.

Chemotherapy does work. It just does not work in a manner reflective of its conceptualization or design. Not surprisingly it does not work very well and rarely provides curative outcomes. Furthermore, its efficacy comes at a high price in toxicity with that toxicity reflecting exactly what the chemotherapy drugs were designed to do; stop cells from growing.  It seems that the hair follicles, bone marrow, immune system, gastrointestinal mucosa and reproductive tissues are all highly proliferative cells in their own right. Not surprisingly, chemotherapy extracts a heavy price on these normal (proliferative) tissues. It is the cancer cells, relatively quiescent throughout much of their lives that escape the harmful effects.

As a medical oncologist in the modern era, I have recognized only too well the shortcomings of conventional cytotoxic drugs. It is for this reason that I use a laboratory platform to select the most effective drugs from among the many badly designed agents. Culling from the herd those few good drugs capable of inducing lethal injury these are the ones that the EVA-PCD assay selects for our patients. Applying this approach, we have doubled responses and prolonged survivals.

Over the past decade we have focused increasingly on the new signal transduction inhibitors and growth factor down regulators. If we can double the response rates and improve survivals using our laboratory assay to select among bad drugs, just imagine what our response rates will be when we apply this approach to good drugs.