Abstract
This study assesses tumor-stroma proportion and compares this finding with the development of resistance to platinum-based chemotherapy in women newly diagnosed with ovarian carcinoma.
Standard treatment for ovarian cancer is platinum-based chemotherapy; however, 15% to 30% of patients with ovarian cancer have primary platinum-resistant or refractory disease. Resistance to platinum-based chemotherapy is a clinical designation, assessed by time to recurrence or progression of malignant disease within 6 months after cessation of platinum-based treatment.1 Refractory disease is defined as recurrence of disease during the course of platinum-based chemotherapy. There is evidence to support the hypothesis that stromatous components of malignant tumors stimulate growth and proliferation of malignant components of invasive tumors2; higher stromal content, referred to as high tumor-stroma proportion, has been associated with worse prognosis in many epithelial cancers.3,4,5 We report the results of a prospective observational study examining tumor-stroma proportion as a predictive biomarker of chemoresistance in women diagnosed with ovarian cancer.
Methods
This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Twenty-four women with newly diagnosed ovarian carcinoma were enrolled in this prospective study from April 1, 2014, to June 30, 2016. Patient data included age at diagnosis, histologic type of tumor, tumor grade and stage, tumor size, and baseline serum levels of cancer antigen 125 at diagnosis, before surgery or neoadjuvant chemotherapy. Data were analyzed between December 28, 2018, and February 28, 2019. This study was approved by the University of Minnesota Institutional Review Board, and written informed consent was obtained from all participants.
Two pathologists (M.K. and M.A.L.) examined hematoxylin/eosin–stained slides to confirm the diagnosis of ovarian carcinoma and identify sections of the primary tumor with the greatest proportion of tumor (×10 microscopic field, with tumor extending to all edges of the field). Tumor-stroma proportion was assessed as low (<50% stromal cells) or high (≥50% stromal cells); this cutoff was consistent with other published studies.3,4,6 Pathologists were blinded to chemosensitivity status.
Demographic and clinical characteristics were summarized using descriptive statistics and compared by high or low tumor-to-stroma proportion using Fisher exact tests for categorical variables and t tests and Wilcoxon rank sum tests for continuous variables. Proportions of women with high and low tumor-stroma proportion and chemoresistance status were compared using the Fisher exact test. Sensitivity, specificity, positive and negative predictive value, and corresponding 95% CIs were calculated to compare tumor-stroma proportion with chemoresistance. All analyses were conducted using SAS statistical software (version 9.4; SAS Institute Inc), and 2-sided P <.05 was considered statistically significant.
Results
Among the 24 women, mean (SD) age was 62.0 (8.1) years. Demographic and clinical characteristics were similar between patients with low and high tumor-stroma proportions, with the exception of receipt of neoadjuvant chemotherapy, which was greater in patients with high tumor-stroma proportion than in those with low tumor-stroma proportion (5 of 9 [55.6%] vs 2 of 15 [13.3%]; P = .06) (Table 1). Baseline cancer antigen125 levels were not significantly different between patients with high vs low tumor-stroma proportion (median [range], 396 [88-2336] vs 741 [32-2782] U/mL; P = .45).
Table 1. Patient Demographic and Clinical Characteristics of 24 Women With Newly Diagnosed Ovarian Cancer.
| Characteristic | No. (%) | P Value | ||
|---|---|---|---|---|
| Overall | Low Stroma (<50%) | High Stroma (≥50%) | ||
| No. | 24 | 15 | 9 | |
| Age, mean (SD), y | 62.0 (8.1) | 60.9 (8.8) | 63.9 (6.7) | .37 |
| Neoadjuvant chemotherapy | .06 | |||
| No | 17 (70.8) | 13 (86.7) | 4 (44.4) | |
| Yes | 7 (29.2) | 2 (13.3) | 5 (55.6) | |
| Ovarian cancer type | .27 | |||
| High-grade epithelial | 21 (87.5) | 12 (80.0) | 9 (100.0) | |
| Low-grade epithelial | 3 (12.5) | 3 (20.0) | 0 (0.0) | |
| Tumor grade | .42 | |||
| G1 | 2 (9.1) | 2 (15.4) | 0 (0.0) | |
| G2 | 5 (22.7) | 2 (15.4) | 3 (33.3) | |
| G3 | 15 (68.2) | 9 (69.2) | 6 (66.7) | |
| Stage | .61 | |||
| I-II | 5 (20.8) | 4 (26.7) | 1 (11.1) | |
| III-IV | 19 (79.2) | 11 (73.3) | 8 (88.9) | |
| Baseline CA-125, median (range), U/mL | 416 (32-2782) | 741 (32-2782) | 396 (88-2336) | .45 |
Abbreviation: CA 125, cancer antigen 125.
We examined the association of tumor-stroma proportion with the development of platinum chemotherapy resistance in each of the 24 patients. Four of 5 (80.0%) platinum-resistant ovarian tumors had high tumor-stroma proportion; conversely 5 of 19 (26.3%) platinum-sensitive tumors had a tumor-to-stroma proportion of 50% or greater (P = .047) (Table 2). The corresponding diagnostic statistics are as follows: sensitivity, 80.0% (95% CI, 28.4%-99.5%); specificity, 73.7% (95% CI, 48.8%-90.9%); positive predictive value, 44.4% (95% CI, 25.1%-65.7%); and negative predictive value, 93.3% (95% CI, 70.4%-98.8%). The results were similar when restricted to patients with advanced-stage disease.
Table 2. Tumor-Stroma Proportion and Chemotherapy Resistance in 24 Women With Ovarian Cancer.
| Characteristic | No. (%) | P Value | |
|---|---|---|---|
| Resistant | Sensitive | ||
| All Patients | |||
| Tumor-stroma proportion | .047 | ||
| Low (<50% stroma) | 1 (20.0) | 14 (73.7) | |
| High (≥50% stroma) | 4 (80.0) | 5 (26.3) | |
| Patients With Stage III/IV Ovarian Cancer | |||
| Tumor-stroma proportion | .11 | ||
| Low (<50% stroma) | 1 (20.0) | 10 (71.4) | |
| High (≥50% stroma) | 4 (80.0) | 4 (28.6) | |
Discussion
Our data provide evidence that tumor-stroma proportion at initial diagnosis of ovarian carcinoma is associated with eventual emergence of platinum chemoresistance. This assessment is straightforward, not cost-prohibitive because it uses already prepared slides used for routine histopathologic evaluation, and it is a parameter that can be included in pathology reports as part of the medical record. Tumor-stroma proportion assessment can be further validated through examination of tissue and correlation with outcomes of completed large-scale cooperative group trials. As newer treatment options emerge, prediction of chemoresistant tumors may be used to more effectively tailor therapy to individual patients.
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