Approximately 30% to 60% of men who receive local therapy for prostate cancer have evidence of subsequent disease progression, and this rate is increased in patients who have high-risk features.4
In an attempt to improve outcomes, ongoing randomized clinical trials are investigating the role of docetaxel chemotherapy in the adjuvant and neoadjuvant settings in men with high-risk prostate cancer. However, predictive markers of response to therapy (that would be of clinical utility for patient selection and clinical trial design) remain poorly defined. The current results suggest that loss of the PTEN tumor suppressor protein in primary tumor tissue may be an independent, negative prognostic factor for PFS in men with high-risk prostate cancer who receive adjuvant docetaxel after undergoing radical prostatectomy, although these data must be viewed as exploratory and hypothesis-generating. In addition, increased expression of Ki67 and decreased expression of MYC were associated independently with higher rates of progression in this patient population. Furthermore, the prognostic accuracy of the progression model was optimized after incorporating combined information about PTEN status, Ki67 expression, and MYC expression.
Sixty-one percent of patients in the current study demonstrated PTEN loss. Although this is similar to the incidence of PTEN loss reported in prior studies of patients undergoing radical prostatectomy for localized prostate cancer,13,14
it is at the higher end of the range. This high rate of loss likely relates to the very-high-risk nature of our study cohort, because other populations had PTEN loss in as few as 20% of men.29
In the current analysis, PTEN loss did not correlate with Gleason sum. Although this may seem surprising, our study was highly enriched for prostate cancers with a Gleason sum >6; therefore, the correlation between elevated Gleason sum and PTEN loss may not be as apparent in this group of patients. In addition, PTEN status in this patient population outperformed all other clinical variables (including Gleason sum, seminal vesicle invasion, lymph node involvement, and surgical margin status) in its ability to predict progression after adjuvant docetaxel chemotherapy. This is consistent with other studies, indicating that functional loss of PTEN is associated with cancer recurrence in patients postprostatectomy16
and resistance to chemotherapy in preclinical experiments.17
It is noteworthy that, although inactivation of PTEN leads to activation of the mTOR signaling pathway, increased phosphorylation of downstream targets in this pathway (Akt, mTOR, S6) was not associated with PTEN loss in this group of patients nor with an augmented risk of disease progression. However, it is possible that the lack of association of PTEN loss and downstream target activation was the result of delays in tissue fixation and/or processing, consistent with recent studies indicating that several phosphorylated proteins examined in breast cancer specimens demonstrated marked discordance between levels observed in core-needle biopsies and levels observed in resection specimens.30
This was attributed to delays in tissue fixation (increased total cold ischemic time) in resection specimens compared with needle biopsies. Alternatively, it is possible that the effects on the PI3K/mTOR pathway mediated by PTEN loss are not reflected in steady-state levels of these various phosphorylated proteins or that PTEN loss results in effects on prostate cancer in addition to the PI3K/mTOR pathway (eg, c-Jun N-terminal kinase [JNK] signaling and/or enhancer of zeste homolog 2 [EZH2] overexpression).31,32
The observation of improved PFS with increasing MYC protein expression levels is intriguing. MYC
is a proto-oncogene implicated in the control of cellular growth, proliferation, cell survival, differentiation and apoptosis. MYC
is 1 of the most frequently activated onco-genes in human cancer, and its amplification and/or overexpression is commonly observed in many cancer types including aggressive prostate cancer.33
Interestingly, in a neoadjuvant study of docetaxel chemotherapy in patients with high-risk localized breast cancer, women with MYC
amplification (detected from presurgical tumor biopsy specimens using FISH) demonstrated higher rates of pathological complete responses (30%) than women without MYC
In a separate neoadjuvant breast cancer study examining mRNA expression signatures, tumors with coactivation of both the MYC and E2F pathways demonstrated the highest sensitivity to docetaxel chemotherapy.35
Finally, it has recently been shown in prostate cancer cell lines that over-expression of DNA-binding protein inhibitor ID-1 (ID1) (a protein known to induce docetaxel sensitivity) is mediated by binding of MYC to the ID1 promoter, thereby enhancing ID1 expression.36
These studies, together with our own observations, begin to suggest a potential role for MYC expression in predicting docetaxel response in patients with prostate (and other) cancers. Alternatively, we have previously demonstrated that steady-state levels of the MYC protein, although they are elevated in most prostate cancers, do not correlate with MYC
locus amplification as evaluated by FISH.19
Thus, it is plausible that elevated MYC protein levels are related to improved outcomes in patients with prostate cancer, regardless of adjuvant treatment with docetaxel.
Our study has several limitations. First, this retrospective analysis was not part of the original study design of the TAX2501 trial and represents a post hoc analysis. Therefore, our data are preliminary and were limited by the historic nature of this comparison and by the finding that primary tumor specimens for IHC analysis were not available from all patients. Furthermore, the sample size was relatively small, which limited our ability to exclude the possibility that unequal distribution of clinical-pathologic parameters in this patient cohort may have biased the observed results. Because the TAX2501 study enriched for patients with multiple high-risk features, baseline clinical characteristics may not be reflective of the general prostatectomy population, possibly explaining why clinical covariates did not predict PFS in multivariable analysis (as indicated in other studies). In addition, in the current study, we used a weekly docetaxel schedule that differed from the conventional 3-weekly schedule that is standard for metastatic disease, possibly limiting the utility of our findings. Finally, the median follow-up in this study was relatively short; therefore, we did not have the ability to examine clinical and IHC variables that influenced overall survival.
One additional significant limitation of our current analysis was the lack of requirement of the TAX2501 study to collect postprostatectomy prechemotherapy PSA information. For this reason, we were unable to include postoperative prechemotherapy PSA data in the univariate and multivariable regression models. Therefore, it remains possible that some of the molecular markers that were significant in our analyses may be acting as surrogates of other progression parameters, such as postoperative prechemotherapy PSA.
Despite these limitations, the association of PTEN loss, high Ki67 expression, and low MYC expression with diminished PFS after adjuvant docetaxel in men with high-risk prostate cancer merits further evaluation and should now be confirmed in a larger, independent cohort. If validated as a predictive marker of response to treatment, then this IHC signature potentially may contribute to treatment decisions, patient selection, and clinical trial design by distinguishing high-risk patients who are more likely to benefit from adjuvant chemotherapy from those who may be candidates for other approaches.