Antiestrogen Therapy Is Active in Selected Ovarian Cancer Cases: The Use of Letrozole in Estrogen Receptor–Positive Patients

Abstract

Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)^positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, m 2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.

Trastuzumab and Pertuzumab Produce Changes in Morphology and Estrogen Receptor Signaling in Ovarian Cancer Xenografts Revealing New Treatment Strategies

“…C, control; T, trastuzumab; P, pertuzumab. little information on the action or interaction of these agents in ovarian cancer, even though they have shown promise for some patients in the clinic (19,20,24). When combined, trastuzumab and pertuzumab show an enhanced antitumor activity in ovarian cancer xenografts, as they do in breast (38,39) and non-small-cell lung cancer xenografts (39 molecular phenotype and therefore responsiveness to other therapies.…”

“…Another target that may have clinical utility in ovarian cancer is the estrogen receptor a (ERa). Phase II trials of aromatase inhibitors (AI) in ovarian cancer have shown modest response but rather better disease stabilization rates, especially when patients are selected on the basis of ERa expression (24). These results suggest that targeted therapies are feasible in ovarian cancer, but rational selection of both targets and patients is required to maximize patient benefit and reduce overtreatment.…”

A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission

“…Recent clinical data support the modest efficacy of aromatase inhibition in preselected ER-positive patients with ovarian cancer, supporting a possible role for hormonal manipulation. 31 Likewise, the hypothesis that the inhibition of the andro- PFS indicates progression-free survival; PFS1, time interval from the initiation of primary therapy to the date of first disease recurrence; 95% CI, 95% confidence interval; PFS2, PFS for patients receiving protocol therapy in second disease remission; PFS3 or 4, PFS for patients receiving protocol therapy in third or fourth disease remission. PFS indicates progression-free survival; PFS2, PFS for patients receiving protocol therapy in second disease remission; PFS1, time interval from the initiation of primary therapy to the date of first disease recurrence.…”

Revisiting the Role of Antiandrogen Strategies in Ovarian Cancer

“…IHC quantification of Rab35 expression could be an initial starting point in this context. As suggested in the study by Smyth and colleagues, selection of patients according to percentage of tumor cells expressing hormone receptors might be more informative on the efficacy of a trial drug than patient selection based only on the presence or absence of the receptor [78]. We, therefore, suggest that correlation of the response to treatment with percentage of AR-expressing tumor cells also be assessed in future trials.…”

“…For example, letrozole was evaluated as therapy for biochemically only (cancer antigen [CA]125) relapsing patients following primary chemotherapy. It was demonstrated that patients with tumors expressing high levels of ER had a better response to letrozole, suggesting that the efficacy of hormonal treatment is dependent not only on the presence of relevant receptors but also on their quantity [78]. Another target for endocrine therapy is the AR.…”