AUA 2019: Phase II Trial of Estrogen Receptor Targeted Treatment of Non-Muscle Invasive Bladder Cancer with Tamoxifen
In this study, the authors note that pre-clinical models of NMIBC using murine / mouse models have demonstrated that targeting the estrogen receptor (ER) with selective ER modulators (SERMs) may be an effective treatment strategy. As such, they have carried this forward to a phase II trial evaluating efficacy of tamoxifen, a prototypic SERM, in this patient population – and present the data for the first time.
Study Design:
This was a single-arm, two-stage phase II study. The study employed the marker lesion design - a solitary lesion in the bladder is left behind following initial intravesical treatment to serve as a marker of response. All additional tumors and normal bladder biopsy samples were evaluated for necrosis, scarring, fibrosis, and used for assessment of proliferation (Ki-67), apoptosis (cleaved PARP-1), and expression levels of ERα and ERβ by immunohistochemistry. Subjects received 20 mg of oral tamoxifen daily for 12 weeks. Primary endpoint was defined as the reduction in size or elimination of the marker lesion, measured by the response evaluation criteria in solid tumors (RECIST) in combination with histopathologic findings
Patient Population:
Eligible patients included adult subjects with low/intermediate-risk urothelial carcinoma of the bladder
Results:
The study enrolled 15 subjects, of which 12 were evaluable for the primary endpoint. Majority of the patients were men (as are most patients with bladder cancer). The median age was 69 years (interquartile range, 61-77 years).
Of these 12 patients, 5 (42%) met the primary endpoint, including two (16.5%) with complete response (CR) and three (25%) with partial response. One of the subjects with a CR had a residual papillary tumor, but biopsy revealed benign histology.
In terms of tolerability and safety, tamoxifen was well tolerated with minimal toxicity. No grade 4 or 5 adverse events occurred – however, four (8.5%) grade 3 events were observed.
On final pathology, histology revealed no quantifiable fibrosis, scarring, or necrosis. Similarly, Ki-67 and cleaved PARP-1 markers were mostly negative across samples. ERβ was the predominantly expressed ER, with minimal ERα present. No significant differences were observed between the expression levels of the ERs in normal vs. tumor or pre vs. post-treatment samples. No gender-related associations could be made either, albeit the number of female patients was limited.
Based on these early phase II results, the authors note that oral tamoxifen effectively reduced the size or eliminated marker lesions in patients with low/intermediate-risk bladder cancer with relatively minimal toxicity. Appropriately, they recommend that clinical phase II/III trials are required to establish the benefit of tamoxifen in the management of NMIBC – and, as mentioned before, any promising therapies in the disease space warrant further investigation!
Presented by: Guilherme Godoy, MD, Baylor College of Medicine
Co-authors: Wan-fu Wu, Eunji Jo, Susan Hilsenbeck, Dolores Lamb, Carolyn Smith, Seth Lerner Houston, TX
Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois