Cyclo-oxygenase-2 (Cox-2) expression and resistance to platinum versus platinum/paclitaxel containing chemotherapy in advanced ovarian cancer

Ovarian cancer represents the fifth leading cause of death for cancer in women [1]. More than 70% of cases present with advanced stage of disease at diagnosis and despite advances in cytoreductive surgery and establishment of carboplatin/paclitaxel combination as the standard chemotherapy regimen, intrinsic or acquired tumor chemoresistance remains the major determinant of chemotherapy failure and unfavourable clinical outcome [1, 2].

Several molecular alterations have been proposed to support tumor resistance to cytotoxic drugs, such as the expression of MDR phenotype, mutation of p53, bcl2 overexpression [3‐5], but only very recently it has been recognized that specific molecular or biological profiles might characterize tumor sensitivity to classes of agents with different mechanisms of action. For instance, mutation of p53 has been demonstrated to be strictly associated with platinum resistance in in vitro, and preclinical models as well as in humans [4, 6], while it is likely to sustain a higher chance of susceptibility to paclitaxel containing regimens [7, 8]. Recently, expression of survivin, a member of the inhibitors of apoptosis protein [9], has been shown to be unrelated to response to cisplatin-based treatment, while its overexpression correlates with resistance to paclitaxel/platinum containing regimen in advanced ovarian carcinoma [10].

We showed that cyclooxygenase-2 (COX-2), the key enzyme in the conversion of arachidonic acid to prostaglandins, involved in critical steps of tumor onset and progression [10], is a strong predictor of chemotherapy resistance and poor outcome in advanced ovarian cancer, as well as cervical cancer patients [12‐14]. These findings, also confirmed in other solid tumors, have also provided the rationale for the combination of selective COX-2 inhibitors with cytotoxic agents [15, 16].

To our knowledge, no data has been reported until now about the association between COX-2 status and response to different chemotherapy regimens.

The aim of the study was to investigate the association of COX-2 with outcome and response to platinum versus platinum/paclitaxel containing regimens as first line treatment in a single institutional series of primary untreated advanced ovarian cancer patients.

Table 1 summarizes the clinico-pathological characteristics of cases in the whole series and according to the type of first line chemotherapy agents.

In the overall series median age was 57 years (range: 28–81). Fifty cases (73.5%) were stage IIIC and 18 (26.5%) were stage IV disease.

Cytoreduction to residual tumor 0.5–1 cm was achieved in 18 (26.5%) of cases, while cytoreduction to residual tumor >1 cm was accomplished in 23 (33.8%) of cases. In 27 (39.7%) cases only multiple biopsies (exploratory laparotomy) were performed.

Overall, COX-2 positivity was documented in 32/68 cases (47.0%). In COX-2 positive cases the percentage of positive staining per total tumor area ranged from 15% to 45% (median value 20%). Although the use of raw data provides more information, we decided to use the cut-off value in order to define different risk patient categories. There was no difference in the distribution of age, stage, residual tumor, and histopathological findings, in cases administered platinum versus platinum/paclitaxel containing chemotherapy. As far as response to chemotherapy is concerned, in the overall series 47 patients (69.1%) were considered to be responsive to treatment, while 21 (30.9%) patients were classified as no responders (Table 2).

In Table 2 the association between COX-2 status and response to chemotherapy in the overall series is also summarized: COX-2 positivity was found in a statistically significant higher percentage of not responding cases than in patients responding to chemotherapy (n = 15/21; 71.4% versus n = 17/47; 36.1%; p value = 0.0072).

Logistic regression analysis including variables likely to affect response to treatment showed that the extent of residual tumor at surgery maintained an independent role as predictor of resistance to treatment (Table 3). The p value of 0.17 of the interaction COX-2/type of treatment suggests that the role of COX-2 on differential response depending on different treatments needs to be clarified in a larger series of cases.

As shown in Table 4, in the group of patients administered platinum-based chemotherapy, COX-2 positivity was found in 11 out of 13 (84.6%) of not responding patients versus 9 out of 26 (34.6%) of responding patients. On the other hand, in cases administered platinum/paclitaxel containing chemotherapy, COX-2 positivity was found in 4 out o 8 (50.0%) of unresponsive versus 8 out of 21 (38.1%) of responsive cases.

This is the first study investigating the association between COX2 status and susceptibility to chemotherapy according to type of cytotoxic agents used in first line treatment of advanced ovarian cancer with measurable disease after first surgery.

Our findings suggest that there could be a difference in the influence of COX-2 expression depending on type of chemotherapeutic regimen (a difference greater in platinum-based treated cases), although a larger sample series is needed before a definitive conclusion can be drawn.

Our data seems to confirm the association between high COX-expression and poor chance of response to chemotherapy reported in ovarian and cervical tumors [13, 14, 20]. This finding remains to be clarified at biochemical level, although it is conceivable that the involvement of COX-2 in the crucial biochemical pathways of tumor cell biology might play a major role: indeed, COX-2 has been reported to induce the antiapoptotic bcl-2 protein [21], and to be associated with neoangiogenesis in tumor bearing mice [22]. Since both inhibition of apoptosis and promotion of neoangiogenesis are strictly associated with chemotherapy resistance, it is conceivable that COX-2 expression could play a role as indicator of platinum resistance in ovarian cancer. Moreover, biochemical links between COX-2 and peptidic growth factor system alterations, which are renowned to be associated with resistance to several cytotoxic agents, have been documented [23, 24]. Finally, very recent evidences demonstrated the relevant role of COX-2 in the inhibition of DNA damage induction of apoptosis mediated by p53 [25, 26]; therefore, tumors overexpressing COX2 are likely to exhibit a reduction of wild-type p53 mediated apoptosis induced by DNA damaging chemotherapeutics, such as platinum compounds, alkylants and anthracyclines, often used in combination. Indeed, a direct association between high COX-2 content and overexpression/mutation of p53 has been reported in ovarian tumors, although conflicting data has been also provided [27‐29].

Although the relatively small sample series has to be taken into account as a limit to the power of the analysis, it is conceivable that the addition of taxanes could hinder the COX-2 involvement in drug resistance, by acting on different molecular targets such as microtubule function or bcl-2 [30, 31].

It remains to be clarified why there was no significant difference in terms of response rate and clinical outcome in patients administered platinum versus platinum/paclitaxel containing regimens: even if the impact of the relatively small size of our sample series cannot be ruled out, an alternative intriguing working hypothesis is represented by the interference of taxanes with COX-2 promoted pathways. Indeed, it has been reported that the two clinically available taxanes, namely paclitaxel and docetaxel increase COX-2 expression by inducing mRNA transcription and stabilization [32‐35]. Moreover, the addition of the specific COX-2 inhibitor celecoxib has been shown to abrogate the marked increase of PGE₂ levels observed in non small cell lung cancer patients after carboplatin/paclitaxel administration [36]. Whether the potentiation of COX-2 promoted activities by taxanes could influence the overall sensitivity of ovarian cancer cells to the combination platinum/paclitaxel, by conceivably reducing the favourable impact of paclitaxel addition, remains to be verified. In this context, it is noteworthy that the vast majority of the studies exploring the association of taxanes with COX-2 inhibitors were able to document a synergistic antitumor activity in vitro and in vivo [33‐35].

Finally, although the significance of our findings is not certain given that the standard first-line treatment for ovarian cancer is a combination of platinum with a taxane, we think that our data could provide, if confirmed in a wider series, the rationale to ask for the immunohistochemical assessment of COX-2 status as predictor of response to treatment, only in cases triaged to platinum-based therapy (including platinum/anthracycline or platinum/alkylants combinations, which are still a valid option in selected patients).

Although these findings need to be confirmed in a larger series, our study suggests a possible indication that there is a difference in the influence of COX-2 on response depending on treatment regimen. The analysis of COX-2 expression in ovarian cancer tissues before and after carboplatin/paclitaxel treatment in patients submitted to exploratory laparotomy and interval debulking surgery after successful neoadjuvant treatment, would be helpful in order to assess whether this regimen can modulate COX-2 expression in vivo, as very recently reported by Altorki et al. [37].