Gee (G719X) Whiz: Novel Mutations and Response to Targeted Therapies

In a recent online forum a patient described her experience using Tarceva as a therapy for an EGFR mutation negative lung cancer. For those of you familiar with the literature you will know that Lynch and Paez both described the sensitizing mutations that allow patients with certain adenocarcinoma to respond beautifully to the small molecule inhibitors.  The majority of these mutations are found in Exon 19 and Exon 21, within the EGFR domain. Response rates for the EGFR-TKI (gefitinib and erlotinib) clearly favor mutation positive patients. Depending upon the study, mutation positive patients have response rates from 53 – 100 percent, generally around 70 percent, while mutation negative response patients have a response rate of 0 – 25 percent, generally about 10 percent.

So why don’t all the mutation positive patients respond and conversely why do some mutation negative patients respond?

The story outlined in this online forum gives some insight. The individual in question carried a rare, and only recently recognized, Exon 18 mutation known as a G719X. This uncommon form of mutation had previously been unknown and few laboratories knew to test for it. Nonetheless, G719X positive patients respond to erlotinib and related agents. Indeed, there may be reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-272, may be even more selective for this point mutation.

The excellent and durable response described by this individual, would not have been possible had the patient’s first physician followed the rules. That is, had her physician refused to give erlotinib to an (putatively) EGFR mutation negative patient she might well not be here to tell her story. More to the point, her good response (a clinical observation) led to the next level of investigation, namely the identification of this specific EGFR variant

The lessons from this experience are numerous. The first is that cancer biology is complex and, to paraphrase E.O. Wilson, was not put on earth for us to necessarily figure it out. The second, is that molecular biologists can only seek and identify that which they know about apriori.  To wit, if you don’t know about it (G719X) and you don’t have a test for it, and you don’t know to look for it, then it’s a virtual certainty that you aren’t going to find it.

The premise of our work at Rational Therapeutics is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Crizotinib was originally developed as a clinical therapy for patients who carried the CMET mutation. Serendipity led to the recognition that the responding subpopulation was actually carrying a heretofore-unrecognized ALK gene rearrangement. Sorafenib was originally evaluated for the treatment of BRAF mutation positive diseases. Yet it was the drug’s cross-reactivity with the VGEF tyrosine kinases that lead to its broad clinical applications. Each of these phenomena represents accidental successes. Were it not for the clinical observation of response in patients, the investigators conducting these trials would have been unlikely to make the discoveries that today provide such good clinical responses in others.

To put it quite simply, these patients and their disease entities educated the molecular biologists.

When we first identified lung cancer as a target for gefitinib, and began to administer the closely related erlotinib to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that we observed. It didn’t matter why it worked, but that it worked.  While the EGFR story has now been well-described, might we not use functional analytical platforms (functional profiling) to gain insights into the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc., etc., etc. . . .

Cancer Medicine – A Humbling Experience

In his brilliant 1998 book, Consilience, Edward O. Wilson, notes: “The cost of scientific advance is the humbling recognition that reality was not constructed to be easily grasped by the human mind.”

This sententious point has remained a guiding principle in my thinking about human cancer. It is critically important for scientific investigators to be humble. We are explorers in a field more complex than any man-made system. We must be instructed by biology – as biological events will always find a way to outsmart our best efforts to explain them.

I was reminded of E.O. Wilson, when a colleague forwarded a recent publication from Molecular Cancer Therapy, “Molecular Profiling of Patient with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials,” Dienstmann, R. et al MOL CANCER THER Sept 2012. The study conducted by the Molecular Therapeutics Research Unit at Vall d’Hebron Institute of Oncology in Barcelona, Spain, evaluated 254 patients for evidence of specific genetic aberrations. Their genomic analyses included, KRAS, BRAF, PIK3CA, PTEN, and pMET. Patients were then provided clinical therapy trials that matched the targeted agents (drugs with activity against the specific mutation) with their individual mutation profiles

In all, 68 patients received treatment constituting a total of 82 different molecularly targeted therapies. The clinical response rate for this population of patients who received molecularly selected therapy was 1.2%. No that isn’t a typo; it was really one point two percent.

While I applaud the scientific concept of this trial and must admit that I might have expected a somewhat higher response rate, I am not surprised by the result. In keeping with E. O. Wilson’s quote, human biology is not a puzzle designed to be solved by humans; it is instead the complex product of a billion years of evolution. Rather than demanding that cancer patients respond to those treatments we have selected for them based on genetic information, we should be instructed by the tumor’s behavior of each patient and use those insights to select amongst active drugs, whatever genetic elements they may have been originally designed to target. In my lectures, I describe this approach as the wisdom of whole cell experimental models.

I am continually humbled by the complexity of human tumor biology and delighted to have the insights that my patient’s cancer cells provide through the functional profile created by our EVA-PCD assay. Not only do I gain exciting scientific knowledge, but my patients have very good responses to the drugs we select. Not a bad day’s work.

Outliving Cancer: Surviving Even the Deadliest Forms of Cancer

FINAL book cover-lo resMy book of the same title (Outliving Cancer, Basic Health 2013) is an exploration of cancer biology through the lens of individual patients.

The conceptual framework within which my laboratory operates, reflects the basic premise that cancer doesn’t grow too much it dies too little. Thus, effective cancer therapy (regardless of contemporary wisdom) provides benefit only when the drugs induce cell death. While the forms of cell death may vary from necrotic, to apoptotic, autophagic and others, it is, in the end, the death of the cell that heralds a successful outcome.

We, along with a small group of collaborators, have pioneered the concept of individualized cancer care using each patient’s tumor as the study model. Fresh biopsies exposed to chemotherapies and signal transduction inhibitors, live or die depending upon their relative sensitivity to the drugs in question.

The simple elegance of our platform has provided immense insight into cancer biology, insights we describe in the book, which may ultimately lead to a greater understanding of all human diseases.

Having successfully applied this approach in many diseases, we have published findings in leukemia, breast, ovarian, and most recently, in lung cancers. We are now very excited by observations in one of the most difficult cancers – pancreatic. Ongoing work in this disease will be the subject of upcoming clinical trials.

One patient with pancreatic cancer comes to mind. Steve Lockwood presented to medical attention in the Spring of 2010 with weight loss, abdominal pain, and unrelenting low back pain. He was seen by a local medical oncologist after a CT scan revealed a large mass in the pancreas, extensive liver metastases and disease throughout the abdomen. He then sought the opinion of UCLA and the City of Hope.  Neither institution could offer any solutions. Luckily his wife, a nurse, had heard about our work and brought him to Rational Therapeutics.

His tumor markers were doubling every week. He couldn’t eat and required daily intravenous hydration, as well as high dose narcotics to get through each day. He was deteriorating so rapidly that I had concerns that he might be too ill for me to help. We decided to conduct an open liver biopsy. As his tumor markers, CA19.9, climbed into the multiple thousands, we found a three-drug combination to be the most active for his tumor.

Within a week, the pain began to subside. After two weeks, it was demonstrably better. By the time we began treatment cycle two, he had begun to gain weight and came off pain medications entirely.

Two cycles later, his tumor markers were normal and his PET CT remarkably improved. An additional cycle later, his PET CT was normal.

While there are many difficult cancers, metastatic pancreatic cancer figures among the worst. The fact that we could find a treatment was cause for celebration. The fact that Steven now remains in remission, after three years, is nothing short of a miracle. As I have written before, there are two kinds of cancer patients: those we can treat and those we can’t. Steve Lockwood turned out to be one of those patients we could.

Like Niebuhr’s Serenity prayer, oncologists need the serenity to accept the cancers they cannot treat, the courage to treat those that they can, and the wisdom to know the difference. It is our use of laboratory assays to select treatments that provides us with that particular form of wisdom.

HER2 Two

I met a charming patient in my office this week. A gentleman with advanced gastric cancer. Upon further examination of his cancer, the adenocarcinoma cells were found to be strongly positive for human epidermal growth factor receptor 2 (HER2).

Many of my readers are familiar with this surface receptor, a member of the epidermal growth factor family. It’s discovery, and the subsequent development of treatments directed toward this target, are well described in the literature. While most people are familiar with this protein in breast cancer, it is only in the last several years that we have recognized the importance of HER2 expression in diseases like gastric and esophageal cancer.

Discussing the implications with the patient and his sons, I realized that this attractive therapeutic target might not be available for use due to the patient’s underlying heart disease. One of the toxicities of HER2-targeted therapies is congestive heart failure. As I pondered the dilemma, I was reminded of one of my patients from 16 years earlier.

At that time, a strapping 69-year-old woman arrived in my office with a large, high-grade breast cancer and 13 positive lymph nodes. She was also HER2 positive. The problem was that in 1997, the drug trastuzumab was not widely available and never (not ever), used in the adjuvant setting. With that as a backdrop, I treated the patient based on laboratory analysis using the best combinations I could identify. Now, 16 years later, still free of disease, she represents a rare success for someone afflicted with such aggressive (and yes, HER2-positive) disease.

The reason this former patient came to mind was that her excellent success 16 years earlier had not required the use of HER2-directed therapy. Ingrid Ottesen had done very well using assay-directed therapy chemotherapy without the addition of trastuzumab.  All we needed for Ingrid was the best use of available drugs. Despite the possible contraindication for trastuzumab in this gentleman’s case, we can still hope for a good outcome if we use the available drugs that best meet his need. After all, it worked perfectly for Ingrid.

You can read about Ingrid in Chapter 14 in Outliving Cancer, to be released later this month.FINAL book cover-lo res