Chemosensitivity Testing Captures Attention of “Nature Biotechnology”

An interesting editorial appeared in the February 2013 issue of Nature Biotechnology titled “Dishing out cancer treatment.” The lead line reads, “Despite their limitations, in-vitro assays are a simple means for assessing the drug sensitivity of a patient’s cancer . . . we think assays deserve a second look.”

The author describes the unequivocal appeal of laboratory analyses that are capable of selecting drugs and combinations for individual patients. At a time when 100’s of new drugs are in development, drug discovery platforms that can mimic human tumor response in the laboratory are becoming increasingly attractive to patients and the pharmaceutical industry. While the author, rooted in contemporary molecular biology, examines the field through the lens of genomic, transcriptomic, proteomic and metabolomic profiling, he recognizes that these analyte-based approaches cannot capture the tumor in its microenvironment, yet we now recognize that these micro-environmental influences are critical to accurate response prediction.

As one reads this piece, it is instructive to remember that no other platform can examine the dynamic interaction between cells and their microenvironment. No other platform can examine drug synergy. And no other platform can examine drug sequence.

It is these complexities however, that will guide the next generation of drug tests and ultimately the process of drug discovery. Even the most ardent adherents to genomic profiling must ultimately recognize that genotype does not equal phenotype. Yet, it is the tumor phenotype that we must study.

I am gratified that the editors of so august a journal as Nature Biotechnology have taken the time to reexamine this important field. Perhaps, if our most scientific colleagues are beginning to recognize the importance of functional analyses, it may be only a matter of time before the clinical oncology community follows suit.

The editor’s final line is poignant, “After years spent on the sidelines, perhaps in-vitro screening methods deserve another look.” We couldn’t agree more.

What Goes Around Comes Around

On a recent morning, I found myself listening to an analysis of the public defender program in America. It seems that defendants who are provided with publically funded lawyers are almost uniformly advised to submit pleas. Regardless of the strength of their cases or their apparent innocence, plea bargains have become the preferred legal defense.

As I listened, the reason became increasingly apparent. It seems that in many states, legal fees paid to public defenders are bundled into a single, one-time payment. Lawyers are provided the same amount of money whether the client is convicted or found innocent. If the lawyers choose to vigorously defend their clients and prove their innocence, they receive precisely the same amount of money that they would receive if the accused pleaded guilty on the spot. It has not taken long for the legal community to figure out that plea bargains are good for business.

As a physician, I found this analysis of more than passing interest. After all, the movement toward managed care and the DRG (diagnosis-related groups) system make lump sum payments for medical care the norm. Using arbitrary metrics like per member/per month, physicians receive the same amount of the money whether they save your life or not. The defenders of this approach explain that it was designed to limit the profit motive and curtail physician avarice. What it has succeeded in doing however, is to incentivize physicians to give up. If there is no return on investment, then there will be no investment of time, energy, skill or ability. If physicians receive no more payment, accolades, or recognition for good outcomes than for bad ones, how long can we realistically expect good outcomes to continue?

The district attorneys, who were interviewed for the piece on public defenders, pointed out, in their defense, that this has succeeded in “clearing the dockets” of backlogged court cases. However, if we were to extend that line of reasoning into the realm of medical care delivery, we would need to confront a number of distinctly unappealing ramifications.

The corporatization of medicine, expanding regulation, creation and promotion of the HMO model, and recent legislation are all the products of legal minds. While NCCN cancer therapy guidelines are increasingly employed, not as guidelines, but instead as dictates to limit the ability of well-trained, sophisticated oncologists to practice their art; a recent article in the New England Journal of Medicine on bending the healthcare curve had the “underutilization” of hospice care as a principal focus. It is interesting to observe how lawyers, faced with “lump sum” payments, are responding. Is the reported deterioration of legal representation, especially for the under privileged in America, the jurisprudence counterpart to policies already underway in the medical system? Will the same disincentives in place for physicians now come home to roost for lawyers?

Cancer Gets Personal

Early in the morning of Nov 21, I suffered the loss of my father. However prepared one might be for this eventuality, there is nothing that can really prepare you.

At 95 years of age, he had lived longer than many. I had cared for my father as a patient since 1974, when he was first diagnosed with inoperable prostate cancer. I remember the day I received notification of the diagnosis. I felt a sense of deep sorrow that my father at 74 would soon die of high-grade locally advanced prostate carcinoma. As a member of the generation that forgot to have children, I was saddened that my father would not live to see grandchildren.

I remember traveling to Connecticut for his initial evaluation and then scouring the literature for the best possible options. Fortunately, despite the aggressiveness of the disease it had not metastasized.

I arranged for my father to travel to California where I then oversaw his care in collaboration with Dr. A.M. Nisar Syed in radiation oncology. There is a well-known dictum in medicine that only doctors and their families suffer unexpected complications. In my father’s case it certainly rang true. First, the radiation implants did not penetrate the tumor and needed to be removed and replaced. As a result of this double procedure, he then developed bleeding that required emergency hospitalization several days later.

Despite these hiccups, the combination of implant and external beam radiation provided excellent control. With a full recovery my father returned to his normal activities.

As so often happens in medicine a personal experience provides a focused interest. I delved into the prostate cancer literature and became increasingly interested in the biology of this disease. One area of particular interest was the role of hormonal therapy. When? How much? How long?

When my father’s PSA began to rise the second year, I had a unique opportunity to examine these questions at a very personal level. Would the early institution of androgen blockade induce the hormone refractory state? Was there a “trigger” value of the PSA that dictated the institution of the therapy? I remember discussing these questions with a prostate cancer expert and chairman of the ECOG committee, Dr. Basil Kasimis, whom I had had the pleasure of working with several years earlier. I agonized over starting hormonal therapy as my father’s PSA rose from 4 to 10, to 25, to 54, and up to 150. Despite these frightening PSA values, there was no evidence of metastatic disease on serial bone scans, which I performed religiously every six to 12 months.

Almost a decade passed but there was still no metastatic disease. And then my father developed severe coronary artery disease in his early 80s. Coronary artery bypass graft was the only option. To avoid the possibility of seeding the sternal wound, I bit the bullet and treated him with hormonal suppression – immediately driving the PSA to nearly 0.

With his coronary artery bypass surgery a success, he came off hormonal therapy and I let his PSA drift upward again.

As he had returned to Connecticut, his urologist became increasingly concerned by the rising PSA, and, without my knowledge, decided to rechallenge him with hormonal ablation. While I understood the motivation for this intervention, I didn’t agree and took him off all hormones for a prolonged period of time. Over the subsequent years, I would intervene occasionally to shepherd my father through pneumonia, a broken hip, a bleeding ulcer, and a variety of other maladies so common in patients who transition from their 80s to their 90s. On several occasions, we gave brief courses of hormonal ablation to suppress the PSA, when the steepness of the rise gave concern. Twenty-one years after his diagnosis my father died of natural causes, with no evidence of metastatic prostate cancer.

The experience was instructive on many levels. First, I realized how important it is to treat all patients as if they are a member of your own family. Second, it takes a lot of guts to step outside the normal guidelines and to do what you believe to be best. Third, I realize that in medical oncology it is the most “aggressive” physician who has the courage not to treat.

So often in this field doctors institute treatment, not because it is needed, nor because it will work, but because by doing so they have “done their job,” the rest is no longer their responsibility.

But “doing your job” as a physician, particularly in medical oncology may demand that you step outside of the NCCN guidelines, however uncomfortable it may make you, to do the right thing. Virtually every urologist or oncologist in America would have treated my father for his rising PSA 20 years ago. While I cannot say with certainty, I feel fairly confident that he lived the past 21 years in part because I didn’t treat him. Every patient needs an advocate. I feel a sense of personal satisfaction that I was there to be my father’s. He lived a long and productive life, I hope and believe that I helped him to do so.

Every experience, even traumatic ones, can have a silver lining. My father’s diagnosis lead me to develop a combined modality approach for locally advanced prostate cancer that has provided among the best biochemical relapse-free survival rates ever observed in this disease. Had I known then what I know today, I would have certainly treated my father with this approach.

Secondly, my interest in prostate cancer lead me to examine the lifestyle, nutritional, and micro-nutritional aspects of this disease – knowledge that I apply to this day. This lead to my analysis of an herbal remedy for prostate cancer that unfortunately uncovered the adulteration of an herbal mixture as we reported. (Herbal Composition PC-SPES for Management of Prostate Cancer: Identification of Active Principles: Journal of National Center Institute, Vol. 94, No. 17, September 4, 2002.) Despite our disappointment at the discovery, it lead me to reexamine the use of estrogenic substances as therapies in this disease, insights that have provided benefit to many of my patients ever since.

In retrospect, it may have been my father’s natural inquisitiveness (that he imparted to me) that leads to my pursuit of these lines of investigation. And for that I will always be grateful.

To read more about Alphonse Nagourney, click here.

So What Happened to the PARP Inhibitors in Breast Cancer Anyway? ASCO 2011

Many of you may recall that we described our studies with the small molecules BSI201 (iniparib) and AZD2281 (olaparib) (Nagourney, et al. ASCO 2011). Based upon the exciting Phase II data reported by Dr. Joyce O’Shaughnessy, first at the ASCO meeting, then in the NEJM, describing the remarkable efficacy of BSI201 (iniparib) combined with carboplatin and gemcitabine in triple negative breast cancer (TNBC), we initiated a study of both iniparib and olaparib in human breast cancer specimens. Our results were reported at the American Society of Clinical Oncology meeting.

Despite the enthusiasm that surrounded Dr. O’Shaughnessy’s initial observations, the confirmatory clinical trial using iniparib combined with carboplatin and gemcitabine, then compared with carboplatin and gemcitabine did not achieve statistical significance. That is, the trial was negative and the combo of inabirib with carboplatin plus gemcitabine was not proven superior.

So, what happened? Quite a few things.

It turned out that BSI201, a member of the benzamine chemical family, at physiological concentrations achievable in humans is not a PARP inhibitor. This, in retrospect, should have been obvious because a full-dose PARP inhibitor, plus a potent combination of carboplatin plus gemcitabine would not likely be tolerable if PARP inhibition were achieved.

Second, the patients receiving the drug are probably not a homogeneous population. That is, some TNBC patients may be similar to the BRCA patients, while others may not have the DNA repair deficiencies associated with PARP inhibitor response.

Finally, it was our group that originally reported the carboplatin plus gemcitabine combination in breast cancer, as a split-dose doublet in 2008 (Nagourney, Clin Breast Cancer Research, 2008). We observed, in that original clinical trial, that even a lower starting dose of gemcitabine (i.e. 800mg/ml2 vs. the O’Shaughnessy 1000 mg/m2) resulted in significant toxicity and in our concluding comments in that paper, we suggested 600mg/ml2. At 1000 mg/m2, Dr. O’Shaughnessy’s trial nearly doubled our recommended dose in this patient population.

While our abstract did not receive the fanfare of the clinical trial, it was, in fact, remarkably prescient. We, like other investigators, entered into our original studies of these molecules believing iniparib to be a PARP inhibitor. To our surprise, and, in retrospect, to our credit, a direct comparison of olaparib (AZD2281) to inapaprib (BSI201) revealed no correlation. We described this in our abstract, “Of interest, BSI201 & AZD2281 activity did not correlate in parallel analyses (R = 0.07, P > 0.5).”  Thus, our human tumor primary culture analysis scooped the ASCO investigators. Unfortunately, it appears they weren’t listening.

So, what have we learned? First, we’ve learned that iniparib is not a true PARP inhibitor.

Second, we learned that the combination of platins plus gemcitabine in breast cancer is synergistic, highly active and can be toxic (particularly at the doses chosen for this trial).

Finally, we learned that TNBC, indeed all breast cancers, even more to the point, all cancers in general, are heterogeneous. That is precisely why the use of human tumor primary culture analyses are so instructive and should be incorporated into clinical trials for these and other targeted agents.

Cell Phones and Cancer Causation

The World Health Organization has now come out labeling mobile phones as a carcinogenic hazard. In a report made public Tuesday, May 31, a team of scientists reported that the cumulative data supports this new designation of “hazard.”

Many may remember that the University of Pittsburgh released a memo requesting that employees guard themselves against excessive cell phone usage. Much of that work reflected the efforts of Devra Lee Davis, PhD, who has worked tirelessly to promote this area of investigation. Indeed, Dr. Davis, who was at the University of Pittsburgh, spearheaded that effort as well.

The science of cancer causation associated with cell phones and related electromagnetic fields is still maturing. One fascinating presentation by investigators at Harvard and New Mexico suggested piezoelectric rectification as the mechanism. When collagen and other biological tissues respond to these resonant frequencies, heat is released. Yet, the piezoelectric effect is a non-thermal energy effect that might better explain the carcinogenesis.

Examinations of cell phone electromagnetic fields suggest the penetration of the signal several centimeters into the brain. While this is a real concern in adults, it becomes a frightening concern in young children, one of the largest growth segments in cell phone sales.

It may not be surprising to realize that sources of electromagnetic radiation can have serious consequences on our health. Life as we know it is dependent upon chemical energy. Influencing the charge and polarity of cells may adversely affect normal metabolism and signal transduction. The take-home message is that cell phones do pose a risk, that the risk can be minimized by limiting exposure and that those strategies that put distance between the cell phone and the user’s ear are the safest. Speakerphones make more and more sense and the use of small earpieces would also be supported, for the field they generate is demonstrably smaller. Finally, it would seem advisable to limit children’s use of cell phones to a minimum.

When it Works, it Works

Despite the toxicities and haphazard administration schedules associated with many chemotherapy combinations, some patients have dramatic responses to therapy. One such patient was seen in consultation today. In September 2009, this 46-year-old gentleman presented with bilateral plural effusions associated with bilateral pulmonary infiltrates, mediastinal adenopathy, ascite, and respiratory failure. He was immediately intubated and stabilized.

His condition was so grave that no one wished to give him any therapy. A medical oncologist consulted and examined the patient’s extremely poor performance status. I was then asked to provide a second opinion. After discussing the findings with the primary oncologist, we agreed to try empiric chemotherapy with a combo known as folfox. Our reasoning was that this young man with adenocarcinoma would stand the greatest chance of benefit from platinum based therapy and that 5FU — though not often used in lung — would have activity both in thoracic and gastrointestinal primaries. This highly undifferentiated neoplasm could not be better characterized to identify a likely site of origin.

Contrary to everyone’s expectations, the patient had a dramatic recovery. He was first weaned off the respirator, then transferred to physical therapy and, finally, discharged for follow up and out patient chemotherapy. Now, seven months later, the patient is back to normal activities. In my discussions with this patient, I suggested he remain on therapy and I made no recommendation that changes or biopsies be considered. It is my belief that this patient is a biological responder. His underlying disease retains the capacity to respond to therapy. For this reason, I encourage the patient to follow up if he shows signs of progression. It is very possible that other classes of drugs can yet provide benefit when necessary. My reasoning is that the patient has a tumor that retains programmed cell death capacity. The selection of therapies in the future may well continue his excellent response. Nonetheless, I would not intervene at this time based on the old saying that “if it isn’t broken, don’t fix it.” My final point in this patient, despite my misgivings about randomly administering therapies, is that cancer therapies can be extremely effective and well tolerated. Our job is to match the most active, least toxic drugs for each patient.

Emerging Therapies in Breast Cancer: a Focus on Triple Negative Disease

As our understanding of breast cancer biology continues to advance, this disease has come to be understood as many different diseases. Original categorizations based on histology lead to lobular versus ductal subtypes. Thereafter, recognition of estrogen and progesterone status, and finally HER2 status provided further subcategorizations. Over the past decade, molecular subtypes have characterized this disease into a series of signatures characterized by luminal, basal and other groupings with distinct prognoses. Within the context of these categories, the triple negative breast cancers have emerged as an important target. These patients whose tumors do not mark for estrogen, progesterone, or HER2 on immunohistochemical or FISH analyses, appear to carry features that segregate them into a BRCA1-like biology. This is of great interest clinically for it offers the opportunity to treat these patients with drugs found active in the BRCA mutant populations. Among the most active drugs in these patients are the PARP inhibitors. The excellent results with PARP inhibitors and BRCA mutants have been followed by striking response and survival data combining PARP inhibitors with carbo-platinum and gemcitabine. PARP inhibitors by inhibiting DNA damage response can enhance the effects of ionizing radiation, mustard alkylators, topoisomerase inhibitors, platins, and intercalating agents. We have explored the biology of PARP inhibitors in breast and other cancers. In these investigations, our lab to applies the EVA-PCD™ platform to understand how PARP inhibitors enhance the effects of drugs and drug combinations. To date, we have observed good activity for the PARP inhibitors as single agents in BRCA1 positive patients, and in some triple negative patients. More interesting, will be the results combining the PARP inhibitors with mustard alkylators, platins, and drug combinations to optimize PARP inhibitor combinations. This work is ongoing in triple negative and BRCA positive patients as well as other tumor types where the PARP inhibitors may prove useful in the future.

New Drugs Are Not Always Better Drugs

The most common form of renal carcinoma is the clear cell variant. These tumors are driven by mutations in the VHL gene and are associated with hyper-vascularity. Understanding the pathogenesis of this disease has enabled researchers to develop new classes of drugs that target VEGF, both at the protein level (Bevacizumab) and at the tyrosine kinase level (sorafenib, sunitinib, etc.). An additional class of drugs targets the intracellular metabolic pathway known as mTOR. Patients newly diagnosed with renal cell carcinoma of the clear cell type are treated with drugs that target these pathways. However, responses occur in the minority of patients. It is unclear why some patients respond to these interventions while others fail.

The EVA-PCD™ analysis is equally applicable to classic cytotoxic drugs and the newer classes of targeted agents, which include Sunitinib and Sorafenib and the rapalogs like Everolimus and Temsirolimus. This enables our lab to explore whether renal cell carcinoma patients are likely to respond to vascular or mTOR targeting classes of drugs. Interestingly, patients who do not respond to these classes of drugs may nonetheless have sensitivity to cytotoxic chemotherapeutic agents. One example currently undergoing therapy is a 51 year old male who was presented in February 2009 with widely metastatic renal cell carcinoma, and a destructive lesion of the right femur requiring open surgical stabilization. Tissue removed from the patient’s femur at the time of the orthopedic surgery was submitted for an EVA-PCD™ analysis. The results were highly instructive, indicating clear resistance to the VEGF targeting agents and the rapalogs but substantial sensitivity to a novel combination of cytotoxic drugs. The patient received an opinion from a renowned renal cell expert who immediately placed him on sunitinib (Sutent™). When he failed sunitinib he was then placed upon Everolimus (Afinitor). Again the patient failed to respond. Progression of his disease was heralded by brain metastases that required both neurosurgery and cranial irradiation. He then revealed rapidly progressive pulmonary metastases as well as large painful bilateral axillary lymphadenopathy and large painful subcutaneous lesions. In light of the patient’s failure of targeted agents, he was treated with a three-drug combination identified to be active in the EVA-PCD™ analysis. The response to date has been dramatic, with complete resolution of subcutaneous lesions and lymph nodes , and objective improvement in the pulmonary metastases by CT scan. The patient remains on therapy, with continued excellent response.

This is but one example of an unexpectedly good response to classic cytotoxic drugs following a failure to respond to the newest classes of targeted agents. These experiences reinforce the need for cancer therapies to be individualized. They also remind us, as physicians, that it is the good outcome of the patient not the therapy applied that constitute successful application of the healing arts.