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

Chemosensitivity Testing: Lessons Learned

Like all physicians and scientists engaged in the study of cancer biology and cancer treatment, I had accepted that cancer was a disease of abnormal cell growth. I remember reading the lead article in the New England Journal of Medicine (NEJM) that described the clonogenic assay (Salmon, S. E., Hamburger, A. W., Soehnlen, B. S., et al. 1978. Quantitation of differential sensitivity of human tumor stem cells to anticancer drugs. N Engl J Med 298:1321–1327).

I sat in a laboratory at Georgetown University reading about a lab test that could accurately predict the outcome of cancer patients, without first having to give patients toxic drugs. It seemed so logical, so elegant, so inherently attractive. Sitting there as a medical student, far removed from my formal cancer training, I thought to myself, this is a direction that I would like to pursue.

But I was only a first year student and there were miles to go before I would treat cancer patients. Nonetheless, selecting drugs based on a laboratory assay was something I definitely wanted to do. At the time I had no idea just how difficult that could prove to be.

After medical school I found myself in California. There I met an investigator from the National Cancer Institute who had recently joined the faculty at the University of California, Irvine. He too had read the NEJM paper. Being several years ahead of me in training he had applied the clonogenic technique at his laboratory at the National Cancer Institute. Upon his arrival in California, he had continued his work with the clonogenic assay.

All was going along swimmingly until the NEJM published their report documenting the results of five years experience with the clonogenic assay.  It wasn’t a good report card. In fact the clonogenic assay got an “F.”

Despite the enthusiastic reception that the assay had previously enjoyed, the hundreds of investigators around the world who had adopted it and the indefatigable defense of its merits by leading scientists, it seemed that something was very wrong with the clonogenic assay and I desperately needed to know what that was.

It so happens that in parallel to clonogenic assays, my colleague was working on a simpler, faster way to measure drug effects. Using the appearance of cells under the microscope and their staining characteristics, one could skip the weeks of growth in tissue culture and jump right to the finish line. The simple question to be answered was: Did the drugs and combinations kill cancer cells in the test tube? And if they did kill cancer cells in the test tube, would those drugs work in the patient? The answer was, “YES!”

Despite the clonogenic assay’s supporters, it turned out that killing cancer cells outright in the test tube was a much, much better way to predict patient’s outcomes. It would be years before I understood the depth of this seemingly simple observation and the historical implications it would have for cancer therapy.

FINAL book cover-lo resIn Chapter 7 of my soon-to-be-released book, Outliving Cancer I examine the impact of programmed cell death on human biology.

Platinum Resistance is in the Eye of the Beholder

I was recently apprised of an online conversation surrounding the treatment of platinum refractory and platinum resistant ovarian cancer. To clarify our terminology, platinum refractory disease refers to cancer that progresses during platinum therapy. This would be considered the most platinum resistant of the ovarian patients. The term “platinum resistant” developed over the last two decades, by Markman and others, is used to describe patients who initially respond to platinum-based chemotherapy and then relapse within six months of treatment.

While platinum refractory seems intuitively obvious, it has been suggested that platinum resistance is somewhat more arbitrary.  That is, what if one relapses one month versus five months, or seven months after treatment. In fact, studies conducted by investigators at Memorial Sloane-Kettering under Dr. David Spriggs, suggest that platinum resistance is a continuum extending from six months continuing out to 24 months and beyond. The longer the “platinum-free interval” the better the chance of response to combinations like carboplatin plus Taxol. Within the scope of this discussion I am in general agreement. However, as I describe below, this is, by far, not the whole story.

I am composing this particular blog in response to a comment that I encountered in a recent chat room discussion. The individual took an extremely strong stance stipulating that no medical oncologist should re-challenge a patient with a platinum-based regimen if they fall within the category of platinum refractory or platinum resistant. This statement is absolutely, positively WRONG.

Platinum resistance is mediated by DNA repair enzymes. These enzymes recognize and respond to platinum adducts and excise the DNA residues, replacing them with the appropriate base pairs. While this confers resistance to single agent platins, a degree of resistance which is largely is unaffected by the addition of taxanes, platinum resistance actually opens up an Achilles heel for treatment of these patients. Drugs like the antimetabolites (Gemcitabine, 5-FU), as well as the topoisomerase inhibitors become collaterally more active in those tumors with the most active DNA repair capacities. This is the reason why we have consistently observed responses in both platinum resistant and platinum refractory patients utilizing the combination of cisplatin and gemcitabine, as we reported in the original paper describing this combination in 2003 (Nagourney, R et al, Gyn Onc, 2003). Our response rate of 50 percent in heavily pre-treated and platinum resistant patients was confirmed by investigators in Ohio who reported similarly good results in patients with p-glycoprotein positive/platinum resistant disease (Rose, P, Gyn Onc 2003).  To formally test this hypothesis we conducted a national clinical trial with the GOG, which treated platinum resistant and platinum refractory patients with the combination of cisplatin plus gemcitabine. This trial provided the longest-time-to-progression for this population (six months) in the history of the GOG (Brewer et al, Gyn Onc 2006). These observations were subsequently reported in our textbook (Deoxynucleoside Analogs in Cancer Therapy, GPeters [ed] Humana Press 2006).

Similar results have been reported for Folfox in recurrent ovarian patients by Greek investigators (Pectasides, D et al, Gyn Onc 2004). To examine this phenomenon, one of the great investigators of antimetabolite chemistry, William Plunkett, conducted an instructive series of experiments in which they showed that platinum resistant ovarian cell lines expressed high levels of the DNA repair enzyme ERCC1. When these investigators blocked the ERCC1 expression with siRNA, the cell lines became resistant to the cisplatin plus gemcitabine combination, indicating beyond a shadow of a doubt, that it is the cells’ own DNA repair capacity that makes it sensitive to this drug doublet.

I write this blog because it is critically important for patients and doctors alike, to understand the chemistry of these agents and their interactions. While platinum resistance may indeed confer clinical resistance to platinum, carboplatin plus Taxol and related combinations, platinum resistant tumors may actually be more sensitive to intelligently administered drug combinations. Using our laboratory platform to measure the chemosensitivity and synergy for drug combinations we have identified numerous platinum resistant and platinum refractory patients who have had dramatic and durable response to re-challenge with platinum based therapies that employ these synergistic combinations. This is why we are extremely interested to study platinum resistant patients. After all, platinum resistance is in the eye of the beholder.

Chemosensitivity Testing – What It Is and What It Isn’t

Several weeks ago I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Our conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active “drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1.    Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.

2.    Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.

3.    Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.

4.    Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.

5.    We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.

6.    We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.

7.    Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.

8.    With chemotherapy, very often more is not better.

9.    New drugs are not always better drugs.

10.   And finally, cancer drugs do not know what diseases they were invented for.
While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

Targeted Therapies for Cancer Confronts Hurdles

The September 1 issue of the ASCO Post, a periodical published by the American Society of Clinical Oncology, features an article entitled “Research in Combining Targeted Agents Faces Numerous Challenges.” Contributors to the article by Margo J. Fromer, participated in a conference sponsored by the Institute of Medicine. These scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted agents.

One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.”

James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.” He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . .  in surrogate tissues,” and concluded “this is a huge undertaking.”

Michael T. Barrett, PhD, of TGen,  pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.”

When I read this article I dashed to my phone and waited breathlessly for these august investigators to contact me for guidance. It was obvious that they were describing precisely the work that my colleagues and I have been doing for the past two decades. Obviously, there had been an epiphany. The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms.

Eureka! Our day of vindication was at hand. The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and would, no doubt, be contacting me presently. Whole-cell experimental models had gained the hegemony they so rightly deserved. The NCI and big pharma would be beating a path to my door.

But the call never came. Perhaps they lost my number. Yes, that must be it. So let me provide it: 562.989.6455. Remember I’m on Pacific Daylight Time.

Why Some Patients Refuse Chemotherapy – And Why Some of Them Shouldn’t

In the June 13, 2011, issue of Time magazine, Ruth Davis Konigsberg described cancer patients who refuse to take potentially lifesaving therapy. Her article, titled “The Refuseniks – why some cancer patients reject their doctor’s advice,” examined the rationale applied by patients who decline chemotherapy. Many of these patients are rational, articulate, intelligent and capable individuals. While there are those who by virtue of religious belief, underlying depression, or loss of loved ones, decline interventions, many of these patients make compelling arguments in favor of their decisions.

When we examine the basis of these patients’ therapeutic nihilism, much of it reflects the uncertainty of benefit combined with the certainty of toxicity. What these patients articulate is the fundamental dilemma confronted by cancer patients, what we might describe as their logical assessment of “return on investment.”

Everything in life is based on probabilities. Will your husband or wife be true? Will you have a boy or a girl? Will you live to see retirement? Will your nest egg be adequate? Cancer medicine is no different.

Will the treatment I’m being offered extend my life long enough to be worth the short- and medium-term toxicities that I will certainly suffer?

While I cannot address this question with regard to surgery or radiation, I feel uniquely qualified to do so in the context of chemotherapy. What, after all, is a chemosensitivity assay? When correctly performed, it is a laboratory test that dichotomizes groups of patients with average likelihoods of response (e.g. 20%, 30%, 40%, etc.) into those who are more or less likely to respond based on the results. On average, a patient found sensitive in vitro has a twofold improvement in response, while those found resistant have a demonstrably lower likelihood of benefit. We have now shown this to be true in breast, ovarian, and non-small cell lung cancers, as well as melanoma, childhood and adult leukemias, and other diseases.

To address the misgivings of the Refuseniks, we might ask the following question: Would you take a treatment that provided a 30 percent likelihood of benefit? How about a 40 percent? 50 percent? 60 percent? 70 percent? Or 80 percent? While many might decline the pleasure of chemotherapy at a 20-30 percent response rate, a much larger number would look favorably upon a 70 percent response rate. On the flipside, a patient offered a treatment with a 50 percent likelihood of benefit (on average), who by virtue of a lab study realizes that their true response rate is closer to 19 percent (based on resistance in vitro), might very logically (and defensibly) decline treatment. These real life examples reflect the established performance characteristics of our laboratory tests (Nagourney, RA. Ex vivo programmed cell death and the prediction of response to chemotherapy. Current Treatment Options in Oncology 2006, 7:103-110.).

Rather than bemoan the uncertainties of treatment outcome, shouldn’t we, as clinical oncologists, be addressing these patients’ very real misgivings with data and objective information? I, for one, believe so.

The TEDx Experience

On Saturday July 16, I had the opportunity to present at the TEDxSoCal conference held here in Long Beach. The overall theme for this event was “thriving,” and appropriately, I presented in the afternoon session called, “well-being.” My lecture was entitled “The Future of Cancer Research Lies Behind Us.”

I chose this topic in light of the growing recognition that genomic analyses are not providing the therapeutic insights that our patients so desperately need. As I have written before in this blog, the Duke University lung cancer gene program, which has received much attention recently, is emblematic of the hubris associated with contemporary genomic analytic platforms.

I reviewed the contemporary experience in clinical trials, examined the potential pitfalls of gene-based analysis, and described the brilliant work conducted by biochemists and cell biologists, like Hans Krebs and Otto Warburg, who published their seminal observations decades before the discovery of the double helix structure of DNA.

I described insights gained using our ex-vivo analytic platform, that lead to treatments used today around the world, all of which were initially discovered using cell-based studies. More interesting still will be the opportunity to use these platforms to explore the next generation of cancer therapies – those treatments that influence the cell at its most fundamental level – its metabolism.

Many attendees stopped me after my lecture to thank and congratulate me for my presentation. Fearing that my topic might have been too esoteric, I was delighted by the reception and more convinced than ever that there are many enlightened individuals who thirst for new approaches to cancer treatment. It is these people who will forge the next generation of therapy.

Why I Do Chemosensitivity Testing

My earliest experience in cancer research came during my first years of medical school. Working in a pharmacology laboratory, I studied the biology and toxicity of a class of drugs known as nitrosoureas. My observations were published in a series of articles in the journal Cancer Research.

The work afforded me the opportunity to interact directly with some of the country’s leading cancer investigators. Many of the fellows with whom I worked went on to famous careers in academia and the biotech industry. I remember the rather dismal outcomes of patients treated in the early 80s; but I felt confident that there had to be a better way to treat cancer patients than just throwing drugs at them and hoping they worked.

It was then that I decided that testing cancer patients’ cell samples in the laboratory, using the drugs they might receive, could help select the most active agents. Several years later, as an oncology fellow, I had the opportunity to test this hypothesis, and it worked. I reported my first observations in leukemia patients in 1984, a successful study that proved that relapsed leukemia patients could be effectively treated when the drugs were first selected in the laboratory. (Nagourney, R et al, Accurate prediction of response to treatment in leukemia utilizing a vital dye exclusion chemosensitivity technique. Proc ASCO abs # 208, 1984)

Unfortunately, this was an era when the field of in vitro chemosensitivity testing had fallen on hard times. A negative study published in the New England Journal of Medicine, using a growth-based assay endpoint, soured the community on the concept and our cell-death based assay results fell upon deaf ears. Yet, I knew it worked. And, based upon my continued efforts in the field, I developed the EVA/PCD® platform that we use today.

With response rates two to three fold higher than national averages, and successes that include the development for the most widely used treatments for low grade lymphoma and CLL (Nagourney, R et al Br J Cancer 1993), recurrent ovarian cancer (Gyn Onc 2003) and refractory breast cancer (J Clin Oncol 2000), the question really should be why doesn’t everyone do assays for their patients?

A Pancreatic Cancer Patient – Seven Years Later

More than seven years ago, I was asked to see a patient in consultation. This vigorous 54-year-old gentleman had already undergone a Whipple procedure for the treatment of a pancreatic carcinoma. His skilled-surgeon had resected most of the tumor, but could not clear the margins. With each successive attempt, he identified additional tumor. Unable to achieve a complete surgical resection, the patient was closed, recovered and visited me for a discussion of therapeutic options.

We identified a two-drug combination to be used in conjunction with external beam radiation, a regimen that few — if any — investigators would have suggested. Adjusting the doses to achieve a tolerable schedule, he completed the entire course of therapy with acceptable toxicities. Contrary to his surgeon’s expectations, the patient achieved a complete and durable remission. He returned to his active lifestyle, remarried and became an advocate for the aggressive management of pancreatic cancer.

Now, seven and a half years later with a rising CA 19.9, he is identified to have a focus of uptake on PET CT in the body of the pancreas. A surgical exploration to remove the tumor provided adequate tissue for an EVA-PCD analysis. The patient was once again tested against the standard therapies used in this setting. Among the drugs we examined are the EGFR inhibitors, the taxanes, the combination of EGFR inhibitor + gemcitabine and the platinum + 5FU combination. Each one of these would be a reasonable choice. Indeed, FOLFOX, Tarceva + gemcitabine, the GTX regimen and — most recently — Taxol-gemcitabine based combinations, would all be favored choices for medical oncologists in the U.S. today. Yet, this patient was sensitive only to cisplatin + gemcitabine and none of the others.

Following publications from a group in Scottsdale, Arizona, many oncologists are utilizing Taxol + gemcitabine. There are proponents for Tarceva + gemcitabine, and those who prefer FOLFOX. At least for this patient, none of them would’ve been right. Interestingly, after more than seven years later the patient’s profile reflects the same combination that was used initially. It is interesting to ponder, based on this finding, whether this is a new primary or a sanctuary-site recurrence with so long a disease-free interval to remain sensitive to the platinum-based combination. We now hope to provide him seven and a half more excellent years… at the very least.

The Frustrating Reality – When a Tumor Sample isn’t Sufficient for Testing

A dying leukemia cell

A dying leukemia cell

The principles underlying the Rational Therapeutics EVA-PCD platform reflect many years of development. Recognizing the importance of cell death measures — apoptotic and non-apoptotic — our laboratory dismissed growth-based assays. The closure of Oncotech, the principal purveyor of proliferation-based assays, illustrates the demise of a failed paradigm in the study and testing of human tumor biology. A second principal of our work is the need to examine all of the operative mechanisms of cell death (autophagic, necrotic, etc.). Laboratories that measure only one mechanism of cell death (e.g. caspase activation as a measure of apoptosis) miss important cell responses that are critical to the accurate prediction of clinical response. The third principle of our work is the maintenance of cells in their native state.

These fundamentals provide the basis of our many successes, but also a constraint. Because we do not propagate, subculture or expand tissues, we can only work with the amounts of tissue provided to us by our surgeons. While some labs propagate small biopsy samples into larger populations by growth to confluence, this introduces irreconcilable artifacts, which diminish the quality of sensitivity profiles. Avoiding this pitfall, however, demands that a tissue sample be large enough (typically 1cm3) to provide an adequate number of cells for study without growth or propagation.

This is the reason our laboratory must request biopsies of adequate size. The old computer dictum of “garbage in, garbage out” is doubly true for small tissue samples. Those that contain too few tumor cells, are contaminated, fibrotic or inadequately processed will not serve the patients who are so desperately in need of therapy selection guidance. As a medical oncologist, I am deeply disappointed by every failed assay and I am more familiar than most with the implications of a patient requiring treatment predicated on little more than intuition or randomization.

We do everything within our power to provide results to our patients. This sometimes requires low yield samples be repeatedly processed. It may also set limitations on the size of the study or, in some circumstances, forces us to report a “no go” (characterized as an assay with insufficient cells or insufficient viability). Of course, it goes without saying that we would never charge a patient for a “no-go” assay beyond a minimal set up fee (if applicable). But, more to the point, we suffer the loss of an opportunity to aid a patient in need.

Cancer patients never undergo therapy without a tissue biopsy. Many have large-volume disease at presentation, so it is virtually always possible to obtain tissue for study if a dedicated team of physicians makes the effort to get it processed and submitted to our laboratory. The time and energy required to conduct an excisional biopsy pales in comparison to the time, energy and lost opportunities associated with months of ineffective, toxic therapy.