Previous studies have shown that pathological complete response in the breast after preoperative chemotherapy correlates strongly with improved disease-free and overall survival, indicating that breast pCR may be a useful short-term surrogate for predicting improved long-term outcomes.28
Since most patients with locally advanced breast cancer require preoperative chemotherapy, and some patients with operable breast cancer may require preoperative therapy in order to facilitate breast conservation, these settings represent an appropriate model to determine whether the addition of targeted therapies enhance the effectiveness of standard cytotoxic therapy. We hypothesized that the addition of tipifarnib might enhance the effectiveness of standard AC chemotherapy, and designed this trial to determine whether the addition of tipifarnib improved the breast pCR rate from the approximately 10−15% historical rate to 25%.or higher28
The study design required observing at least 8 breast pCRs among 50 evaluable patients; we observed 11 breast pCRs among 44 (25%) evaluable patients, and therefore met our primary prespecified endpoint. Although it is possible that these improved results may be attributed in part to the dose-dense administration of AC, this seems unlikely given the particularly efficacy of the combination in ER-positive disease, a subset that has not been clearly shown to benefit from adjuvant dose-dense therapy.32
We also demonstrated that most tumors exhibited near complete inhibition of the arget enzyme, farnesyl transferase, when biopsied on the sixth and final day of tipifarnib therapy approximately two hours after the last 200 mg tipifarnib dose. Notably, there were variable changes in GGTase I enzyme activity, indicating a specific effect of tipifarnib on FTase. The inhibition of FTase was also associated with reduction in p-STAT3 expression in the majority of samples evaluated, although there were variable effects on other signaling molecules. STAT3 may be an important therapeutic target in breast cancer and other tumors, and STAT3 inhibition potentiates the cytotoxicity of doxorubicin. 33, 34
We also evaluated a panel of biomarkers in order to determine whether markers predictive of breast pCR could be identified in pretreatment tumor specimens. The markers evaluated included Ki-67, p27, p21, p-ERK, p-STAT3 (and total STAT3), p-AKT (and total AKT), RhoA, RhoB, and RhoC, all of which were chosen because of evidence that they might identify tumors sensitive to cytotoxic therapy and/or FTI inhibition. The only marker found to be predictive was Ki-67, which is known to reflect cellular proliferation, and which also is more likely to be elevated in ER-negative tumors. This is consistent with previous reports that an elevated Oncotype DX Recurrence Score predicted response to preoperative doxorubicin-containing chemotherapy, since proliferation genes comprise a significant component of the algorithm used to compute Recurrence Score. 35
It is also consistent with previous studies demonstrating higher breast pCR rates in ER-negative disease, as this phenotype is usually associated with higher expression of proliferation associated genes than ER-positive disease.30
It is notable that tipifarnib appeared to augment the breast CR rate in patients with ER-positive and ER-negative disease, although the trial was not adequately powered to establish this with certainty.
The incremental improvement in breast pCR associated with AC-tipifarnib combination is comparable to the effect of administering a longer duration of chemotherapy. For example, in the NSABP B27 trial, the breast pCR was significantly higher in patients treated with four cycles of AC followed by four cycles of docetaxel compared with four cycles of AC alone (27% vs. 13%). Although our results are encouraging, it is noteworthy that the NSABP B27 trial failed to demonstrate an improvement in disease-free survival or overall survival for the docetaxel arm despite an significant improvement in the breast pCR rate30
, indicating that a greater improvement in breast pCR rates may be required. In addition, although a higher breast pCR rate was observed when docetaxel was used in ER-positive (14% vs. 6%) and ER-negative (23% vs. 14%), the breast pCR rate was substantially lower in the ER-positive subgroup in docetaxel treated patients (14% vs. 23%), which is consistent with adjuvant trials demonstrating relatively greater benefit from adjuvant taxane therapy in ER-negative disease.36
In contrast to the modest improvement in breast pCR rate observed in B27, a randomized phase II trial comparing preoperative chemotherapy used alone or in combination with trastuzumab in Her2/neu
positive breast cancer demonstrated significantly higher pCR rate in the trastuzumab containing arm (65% vs. 25%)37
, which was consistent with several trials demonstrating a 50% reduction in the risk of recurrence associated with adjuvant postoperative trastuzumab. 38-40
Taken together, these finding suggest that if breast pCR rate is to be utilized as a short term surrogate to screen for promising strategies to subsequently test in phase III adjuvant or neoadjuvant trials, that the target breast pCR rates should be substantially higher than the 25% rate observed in the B27 trial, and that different thresholds may required for different phenotypic subsets (ie, HR-positive vs. HR-negative disease).
In conclusion, we found that the combination of dose-dense doxorubicin-cyclophosphamide (AC) was feasible and tolerable when combined with tipifarnib given orally at a dose of 200 mg twice daily for six days following each chemotherapy dose. We also found that tipifarnib inhibited tumor FTase in vivo, inhibited p-STAT3 activation in most patients, and produced a significantly higher breast pCR rate than expected for chemotherapy alone. Based upon these encouraging results, we have initiated a second trial combining tipifarnib plus paclitaxel followed sequentially by tipifarnib plus dose-dense AC chemotherapy (ClinicalTrials.Gov identifier NCT00470301). Addition of tipifarnib to the paclitaxel component of sequential dose dense therapy represents a logical continuation of our previous effort for two reasons. Firstly, compared with every 3 week paclitaxel, weekly paclitaxel has been shown to produce higher breast pCR rates when given preoperatively, and improved overall survival when given postoperatively, irrespective hormone receptor expression.41 42
Second, preclinical evidence suggests that FTIs synergistically augment the effect of anti-tubulin agents such as paclitaxel.43-46
This trial may establish whether FTIs such as tipifarnib merit further evaluation in definitive, large-scale phase III adjuvant trials