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Quantitative histopathology and chromosome 9 polysomy in a clinical trial of 4-HPR
Jose-Miguel Yamal1, Dennis Cox, Walter N Hittelman
1Center for Biomedical Engineering, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Objective:
This trial examined the use of 4-hydroxyphenyl-retinamide (4-HPR), demonstrated to be a potent inhibitor of carcinogenesis in vitro and in animal models, in patients with cervical intraepithelial neoplasia (CIN) grades 2 to 3. Quantitative pathology and chromosome 9 polysomy were used to understand the biology and quantify the clinical histopathologic changes observed.
Methods:
Patients were randomized to 4-HPR or placebo for 6 months and followed for six more months. Cervical biopsies were obtained at baseline, 6 months, and 12 months; the biopsies were read blinded three times by the study pathologist. Feulgen-stained sections were also obtained and analyzed using computer-assisted image cytometry. Chromosome 9 polysomy was performed on tissue slices using in situ hybridization and measured quantitatively. Statistical analyses were carried out in S-Plus (Insightful Corporation, Seattle, WA) and R.
Results:
The interim analysis, planned for 40 patients, was carried out on 39. The 6- and 12-month analyses showed a statistically significant difference between the two study arms. When code was broken, the 4-HPR-treatment arm was found to have fared less well than placebo. Analyses of Feulgen-stained sections provided a quantitative measure of the increase of DNA content and texture features. Chromosome 9 polysomy was also measured using image analysis. The changes observed were consistent with those of cells displaying cancerous changes, indicating a lack of response.
Conclusion:
4-HPR is not active at 200 mg/day. The interim analysis was helpful in directing the study; and, in this case, ending it. The intermediate endpoint biomarkers of quantitative histomorphometry and chromosome 9 polysomy yielded quantitative and repeatable results consistent with the findings of the clinical pathologist.
Insights
This study found that 4-hydroxyphenyl-retinamide (4-HPR) was ineffective in treating cervical intraepithelial neoplasia (CIN). Biomarkers indicated cancerous changes, leading to early study termination.
Area of Science:
- Oncology
- Gynecologic Oncology
- Chemoprevention
Background:
- Cervical intraepithelial neoplasia (CIN) grades 2-3 represent a precancerous condition.
- 4-hydroxyphenyl-retinamide (4-HPR) showed promise as an anti-cancer agent in preclinical studies.
- Novel biomarkers are needed to assess treatment efficacy in CIN patients.
Purpose of the Study:
- To evaluate the efficacy of 4-hydroxyphenyl-retinamide (4-HPR) in patients with CIN grades 2-3.
- To utilize quantitative pathology and chromosome 9 polysomy to understand treatment response.
- To correlate biomarker changes with clinical histopathologic outcomes.
Main Methods:
- A randomized, placebo-controlled trial involving 39 patients with CIN grades 2-3.
- Patients received either 4-HPR (200 mg/day) or placebo for 6 months, with a 6-month follow-up.
- Cervical biopsies were analyzed using quantitative histomorphometry (Feulgen staining) and chromosome 9 polysomy assessment via in situ hybridization.
Main Results:
- An interim analysis revealed that the 4-HPR arm fared worse than the placebo arm.
- Quantitative analysis showed increased DNA content and texture features, consistent with cancerous changes.
- Chromosome 9 polysomy measurements also indicated a lack of therapeutic response to 4-HPR.
Conclusions:
- 4-hydroxyphenyl-retinamide (4-HPR) at 200 mg/day is not effective for treating CIN grades 2-3.
- Interim analysis and biomarker data were crucial for early study termination.
- Quantitative histomorphometry and chromosome 9 polysomy are reliable biomarkers for assessing treatment response in CIN.
