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.

Highly Productive Targeted Therapies

The introduction of targeted therapies now provides select patients the opportunity to receive first-line therapies with these new classes of drugs. The recognition that epidermal growth factor tyrosine kinase inhibitors are most effective in patients with EGFr mutations (codons 19-21) has enabled us to apply the EGFr mutation analysis as a biomarker for response. Despite the high response rates (up to 70% in mutation positive patients), approximately 30% of patients with the appropriate biomarker do not respond. In addition, patients who do not carry EGFr mutations can nonetheless respond to these classes of drugs. This reflects the complexity, redundancy and promiscuity of signal pathways, such that, pathway cross talk has the capacity to salvage cancer cells from the lethal effects of these inhibitors. The EVA-PCD™ platform has the unique capacity to identify all of the operative mechanisms of response and resistance by gauging the result of drug exposure at its most important level: cell death. Our earliest work, gefitinib conducted in 2001, identified non-small lung cancer as an important target disease. As we continued this work with gefitinib (Iressa) and erlotinib (Tarceva), we have had the opportunity (under IRB-approved protocol) to treat patients with first line Tarceva. To date, we are tracking a 100% response rate to Tarceva in the select populations; even patients who have not been found to carry recognized mutations. More interesting, patients not expected to respond such as one multiply recurrent male, smoker has remained in a 4 year remission on Tarceva as a third line therapy. As predicted by EVA/PCD analysis, the emerging study of combined signal inhibitors provides the opportunity to examine favorable combinations for effect and synergy. The rational combination of signal inhibitors is a highly productive avenue of research under investigations in many centers, including our laboratory. Consistent with our presentation at the recent meeting at the American Association for Cancer Research (Nagourney, R. et. al, Horizontal and vertical signal pathway inhibition in human tumor primary culture micro-spheroids. Abstract 1764, proceedings AACR 2010), the dual inhibition of the PI3k and EGFr pathways may prove highly productive. This work is ongoing at our center.