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.

The Bad News is, You’re Going to Survive

There is a common tendency on the part of cancer patients, upon receiving their diagnosis, is to act as if their life is over and that there is nothing they do to affect it.

Given the dismal outcome for many solid tumor patients, the tendency to give up is understandable. What often happens is the patient starts bingeing, eating and drinking too much, gaining weight, and foregoing all the lifestyle changes they had worked so hard to incorporate before the diagnosis. They’ll stop exercising and continue to smoke, figuring it has no impact.

But, what if you’re not dying? What if your first anniversary passes and you’re still well? How about your second, or third?

This has been the experience of several of my patients, who jokingly now admit that they’ve never been in worse physical condition, largely due to “letting themselves go” after the diagnosis. In response, we suggest that patients maintain a normal lifestyle even in the face of the most difficult diagnoses. Appropriate nutrition, physical activity and emotional well-being all contribute to good outcomes.

Like our pancreatic cancer patient,who I need to put on a diet, many patients over indulge. In a way, this is a new wrinkle in the old adage, “If I knew I was going to live this long, I would’ve taken better care of myself.”

Melanoma, the Immune System, and Targeted Therapies

For those of you who have been following the recent news coming from the American Society of Clinical Oncology (ASCO) held in Chicago, you have heard of the breakthroughs for the treatment of malignant melanoma.

Melanoma, the most lethal form of skin cancer, arises as a pigmented lesion (mole or large freckle), generally in sun-exposed areas. Though curable in its earliest stages, once these malignancies disseminate, they can be the most aggressive and hard to treat cancers known to oncologists. That is, until recently when two important discoveries were made.

The first discovery actually dates back many years. It turns out that melanoma is one of those cancers that occasionally, spontaneously, regresses and that a subset of patients respond to interferon (an immune protein). This suggested a role for the immune system.

The next piece of evidence came from work in the 1980s, conducted by Steven Rosenberg, MD, PhD, at the National Cancer Institute. Using a genetically engineered human protein (interleukin 2-IL2), these investigators reported responses in patients with metastatic melanoma. Again, an immune component to this dreaded disease.

Fast-forward two decades. Investigators unraveling the complexities of human immunity realized that the cancer cells weren’t being recognized and effectively controlled by lymphocytes. Something was dampening the immune response. With the discovery of ipilumumab, an antibody directed against CTL4, scientists could now turn off the “off” switch, thereby turning on the immune system.

Survival advantages have been substantial. This therapy is now available to patients in need.

The second discovery represents a triumph for “targeted” therapy. As the gene BRAF, was recognized to be mutated in the majority of melanoma patients, drugs were developed to turn off this important pathway. Unfortunately, the first generation BRAF inhibitor sorafenib, could not shut down what proved to be the most common variant of the BRAF mutation, known as V600E.

To the rescue came a compound now known as vemurafenib. By turning off the V600E signal, those patients with this specific mutation (about 60 percent) responded dramatically.

While both these discoveries are meritorious, the responses in most patients unfortunately have not been very durable, with relapses generally occurring months or the first year after starting therapy. Interestingly, secondary pathways, like N-RAS and C-RAF, may step to the fore and overtake the effect of the BRAF inhibition. This offers hope that third generation small molecules will address these resistant clones.

In our laboratory, we are currently examining small molecules that inhibit the RAS and other pathways to determine whether new strategies may overcome these resistance mechanisms in melanoma. As a proof of concept, these reports from ASCO establish that the era of targeted therapy in melanoma is here.

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.

Using Function to Inform Genomics

Recently, I was asked to evaluate a charming young woman with an unusual gynecologic primary. She had received numerous forms of therapy and surgery for her low-grade carcinoma. Her most recent surgery provided tissue to our laboratory for analysis. The results were consistent with the clinical presentation, revealing relative resistance to virtually all conventional chemotherapeutic drugs, but a very striking pattern of sensitivity to three compounds associated with the insulin like growth factor signaling pathway.

As all three compounds pointed to activity in this pathway, I reasoned that the patient had a mutation upstream, as I wrote in my report to her physician. I suggested that they should investigate this pathway.

I was subsequently apprised that, upon my recommendation and at the request of patient’s husband, an analysis had been submitted to a laboratory that identified a mutation in PI3K, the very pathway that I had identified in our functional analysis. Thus, this patient’s resistance to chemotherapeutics and sensitivity to PI3K inhibitors reflected the profound survival signal provided by this mutation. Of interest, when the family originally requested a molecular profile be conducted in parallel with our functional profile, the commercial lab in Arizona did not include PI3K mutational studies. It wasn’t until the functional results pointed to the PI3K pathway that the specific mutational analysis was undertaken and found positive.

This experience is very similar to our original work with the EGFR inhibitors gefitinib and erlotinib. Several years before the EGFR mutation was identified and long before the mutational analysis was commercially available we identified activity in patients using the functional platform. Patients were then treated based upon the EVA-PCD results under protocol with every one of these patients responding, as we reported (Nagourney Proc ASCO, 2007). This speaks to the robustness of the functional platform and to its capacity to guide drug development.