Many biomarkers have been proposed as prognostic indicators of EOC patient survival [34
]. However, limited value has been observed by their addition to the current biomarker repertoire. We hypothesized that evaluation of survival-associated proteins as potential blood-based biomarkers indicative of minimal residual disease may be prognostic of both PFS and OS. We elected to examine a secreted protein pair, SLPI and PGRN, in recognition of their potent pro-survival and dissemination activity in EOC [13
]. SLPI, a relative of HE4, was of interest but did not reach the level of importance and independence of its partner protein, PGRN. The isolated value of PGRN at a time at which the patient was expected to have the lowest occult tumor burden and the least potential for chemotherapy bias, the point of initial clinical complete remission at discontinuation of adjuvant therapy, was a potent and independent predictor of poor PFS and OS in this high grade advanced stage cohort. No added value was found when the FDA-approved biomarkers CA125 [9
] and HE4 [10
] were examined with PGRN and/or SLPI. Further studies should include validation of this finding in remission prediction, and examination of PGRN in pre-diagnostic sera where its signal of occult disease may be useful in development of a screening tool for aggressive subtype EOC.
Several reports have suggested that the absolute concentration of serum CA125 may be a prognostic marker of relapse and death, even when CA125 is within the normal range. Patients with normal CA125 were divided into arbitrary groups based upon on their CA125 nadir (10 vs. 11–20 vs. 21–35U/ml) [35
]. Prat et. al showed an absolute increase of CA125 of 5U/ml over baseline significantly predicted recurrence of advanced EOC with a median lead time of 58 days in patient cohorts similar to ours [39
]. We did not observe this in Kaplan Meier analyses at the CA125 median of 12U/ml or at 10U/ml (P=0.24 and 0.51, respectively). Our study included only patients in clinical remission, and therefore had a limited CA125 dynamic range. Recently, Rustin et al. reported a physician’s knowledge of and response to a rising CA125 had no impact on ovarian cancer survival [24
]. We found that the single value of PGRN at 3 months clinical response is significantly elevated in patients who recur before 18 months from CCR after chemotherapy. This discovery is different from other markers such as HE4 and CA125, that monitor recurrence by observing change in concentration as disease progresses. These findings could be combined for patient stratification in trials of maintenance therapy versus monitoring for high recurrence risk women.
Our exploratory study found the remission value of PGRN is an independent biomarker predictive of PFS less than 18 months and poor OS in patients what would be a good prognosis CCR group of patients. This 3 month time point was selected to minimize biomarker bias due to recent chemotherapy exposure. These results complement our prior findings of high PGRN gene and protein expression in serous stage III ovarian cancers compared with serous borderline ovarian tumors [19
] and a related report that increased PGRN expression in ovarian cancer, tumor stroma, and metastases was associated with poor clinical outcome [25
]. Pizarro et al. demonstrated an association between PGRN overexpression and a tumor promoting phenotype in ovarian cancer, showing PGRN protects ovarian cancer cells from chemotherapy-associated tumor injury [26
]. Tumor PGRN expression was also recently correlated with poor outcome in a third study. Cuevas-Antonio et al. showed that patients with high mRNA progranulin expression in their corresponding ovarian tumor specimens had significantly worse OS compared to patients exhibiting low-progranulin mRNA levels [41
]. Thus, both circulating PGRN as shown in our findings, and tumor PGRN expression are important prognostic tools with which to predict poor EOC outcome.
We along with others have shown SLPI to be important biochemically and have demonstrated that SLPI is over-expressed and amplified in ovarian cancer [3
]. Patients in this study with higher SLPI concentrations had significantly shorter PFS on Kaplan-Meier analyses. However, this cut-off concentration was within the range of the normal population provided by the kit manufacturer, defined by 40 random blood samples. Therefore, we conclude that SLPI may not have strength as a biomarker discriminant. We suggest, though, that the definition of the normal range for SLPI may need to be reexamined to provide a normal range more reflective of women in this age group. Although SLPI may not function as a prognostic biomarker, its biochemical function to protect and partner with PGRN makes it of biological interest. Biomarker positivity of PGRN, with its known biochemical pro-survival interaction with SLPI, may also identify a group of patients who may benefit from SLPI-targeted therapy, which is credentialed but not yet ready for clinical application [13
]. Addition of SLPI to PGRN in our biomarker analysis did not add further value to the PGRN findings.
Although this is a small post-hoc study of 23 patients, this cohort comprises a relatively homogeneous population of advanced stage high-grade EOC patients who had optimal cytoreductive surgery and platinum/taxane-based chemotherapy. This is a cohort for whom early and frequent recurrence is expected and is confirmed with the cohort median PFS of 16 months. The median PFS and OS were comparable to those of the report of Prat et al. that examined 96 patients with similar clinical characteristics [38
]. The unexpected findings of strong statistically significant merit of the initial PGRN value, and absence of utility of CA125, HE4, or combinations, suggests that either this is an unusually biased subset of otherwise unselected patients, or that this is a new and potentially valuable finding. These exploratory analyses will require independent validation. ROC analyses should be revisited to confirm the optimal cut-off value in a larger cohort. Validation of this finding can lead to consideration of PGRN as a discriminant with which to stratify high-risk patients in a maintenance clinical trial setting. The high initial PGRN concentration at the time of presumed optimal surgical and chemical cytoreduction is predictive of poor outcome and leads to the hypothesis that it also may be a marker of occult high-grade disease. We also will be examining PGRN in a pre-diagnostic sample set to assess its potential value in screening and early diagnosis of the aggressive high-grade tumors.