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.