Role of Ras Inhibitors in the Management of Breast Cancer
Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Last Modified: November 7, 2005
Presenter: Joseph A. Sparano, MD Presenter's Affiliation: Albert Einstein Cancer Center, Bronx, New York Type of Session: Scientific
G proteins are a superfamily of >100 proteins which are widely distributed in mammalian cells.
They regulate a variety of cellular functions, and are classified into 5 families.
The names of the 5 different families of G proteins are: Ras, Rho , Rab, Sar1/Art, and Ran.
Ras proteins are important in gene expression and controlling growth and development.
Ras proteins are key intermediates in signal transduction and cycle between an inactive, GDP- bound form and an active, GTP-bound form.
When active, they induce proliferative signals from upstream elements.
These proteins need to localize to the inner surface of the cell membranes in order to perform their actions.
In order for the G proteins to localize to the cell membrane, they have to undergo post-translational modification.
Ras is secreted as a biologically inactive protein, and is then modified by a process known as farnesylation, whereby a long-chain lipid tail is added which will allow it into the inner surface of the cell membrane.
Many tumors have mutations in the Ras proteins that cause Ras to always remain activated in the GTP- bound state.
Mutations in this gene are seen in about 30% of all human cancers, especially in gastrointestinal cancers.
However, Ras mutations are quite uncommon in breast cancer, occurring in <2% of all cases.
Ras can be overxpressed as a late event in breast cancer, and may occur through signaling abnormalities with EGFR or Her2.
One of the inhibitors of farnesylation is a drug called Tipifarnib (Zarnestra, R115777).
Tipifarnib has inhibitory activity in many different cell lines, and it has been shown to have anti-proliferative activity in cell lines with and without Ras mutations.
It decreases a number of downstream signaling pathways and increases the efficacy of doxorubicin and cyclophophamide in a number of laboratory experiments.
This agent may have anti-angiogenesis effects as well.
Materials and Methods
In a phase I trial using a 21 of 28 day schedule, the dose limiting toxicities including neutropenia and thrombocytopenia.
Despite the absence of Ras mutations in metastatic breast cancer, this drug appears to have activity.
In a trial of tipifarnib for patients who failed tamoxifen or had estrogen negative metastatic breast cancers, 23% of patients had either an objective tumor response or stable disease for >4 weeks.
If patients did benefit, it was usually a fairly durable response, lasting an average of 9-12 months.
Continuous schedules are generally associated with more anemia, thrombocytopenia, neutropenia, and neuropathy than intermittent schedules.
Based on these results, researchers at Albert Einstein embarked on a phase I/II trial of tipifarnib with doxorubicin and cyclophosphamide in patients with metastatic or locally advanced breast cancers.
For the phase II trial, the primary endpoint was pathologic complete response rate (PCR).
Dose escalation was based on the phase I trial data on dose-limiting toxicities.
PCR rate was used as a surrogate for disease free survival and overall survival, because it has proven useful as a good predictor for positive outcomes.
However, certain trials (like the B27) have shown that an increase in PCR rate doesn&'t always predict for improvements in overall survival or disease free survival.
Patients with ER positive tumors have a lower PCR rate with doxorubicin and cyclophosphamide (AC) than patients with ER negative tumors.
The recommended phase II dose turned out to be dose-dense AC given q 2 weeks with GM-CSF support, along with 200mg BID of tipifarnib given on days 2 through 7.
With this regimen, no dose limiting toxicities were seen.
80% of patients received all 4 cycles of treatment.
The major toxicities included neutropenia (54% with grade IV neutropenia) and gastrointestinal symptoms.
They saw 7 pathologic complete responses in the breast, for a response rate of 33%.
42% of patients who had ER positive disease had a PCR, but only 22% of patients who had ER negative disease achieved a PCR.
They also measured the farnesyltranferase (FTI) activity in vivo, both before treatment and after the last dose of tipifarnib.
Virtually all patients had some inhibition of the FTI enzyme, but this did not appear to be related to PCR rate.
The Ras signal transduction pathway is one of innumerable potential targets for cancer therapy.
Ras inhibitors have been largely ineffective for the diseases that they were rationally designed for: tumors with Ras mutations associated with constitutive activation of this pathway.
Ras inhibitors have clinical activity in breast cancer, a disease that typically lacks Ras mutations.
Tipifarnib may be safely combined with dose dense AC + G-CSF.
The combination is associated with a high incidence of severe neutropenia.
The incidence of cardiac toxicity may be increased, but this requires further evaluation.
Tipifarnib inhibits farnesylation in human breast cancer in vivo.
Tipifarnib may enhance effectiveness of neoadjuvant dose-dense AC.
Locally advanced breast cancer may serve as a model for identifying potentially promising new targeted therapies combined with cytotoxic chemotherapy.
Dr Sparano presented phase I and initial phase II data on the use of a farnesyltranferase inhibitor, tipifarnib, given preoperatively, concurrently with AC chemotherapy for locally advanced breast cancer. One of the most interesting things about this research is that the FTI inhibitor appears to have activity in a disease that doesn&'t generally have mutated Ras. This is an important lesson for oncologists, because it demonstrates the principle that we don&'t fully understand how our targeted therapies actually work. There are many more pathways involved in cancer growth than we currently understand, and we don&'t exactly know why this drug seems to work in breast cancer patients. This concept might help push researchers towards testing certain targeted therapies on large groups of diverse patients to find out if and when the agents have any efficacy. Dr. Sparano&'s group should also be commended for elegantly demonstrating the efficacy of tipifarnib in vivo, which has not been done in the past. It is nice to know that the drug is doing at least one of the things that we think it should. This is exciting research, and many are looking forward to the final data presentation once the study is complete.