Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data.

OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5-65) and 28 months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; P < 0·001) and 0·65 (95% CI 0·50-0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.

A comparison of p53 and WT1 immunohistochemical expression patterns in tubo-ovarian high-grade serous carcinoma before and after neoadjuvant chemotherapy.

AIMS: The treatment of patients with tubo-ovarian high-grade serous carcinoma (HGSC) is increasingly based on diagnosis on small biopsy samples, and the first surgical sample is often taken post-chemotherapy. p53 and WT1 are important diagnostic markers for HGSC. The effect of neoadjuvant chemotherapy on p53 and WT1 expression has not been widely studied. We aimed to compare p53 and WT1 expression in paired pre-chemotherapy and post-chemotherapy samples of HGSC. METHODS AND RESULTS: Immunohistochemistry (IHC) was carried out for p53 and WT1 on paired omental HGSC samples pre-chemotherapy and post-chemotherapy. p53 IHC was recorded as normal (wild-type) or abnormal (mutation-type), and was further classified as overexpression, complete absence, or cytoplasmic. WT1 IHC was classified as positive or negative. A subset of cases were further assessed for the extent of nuclear immunoreactivity of WT1 by use of the H-score. Fifty-seven paired samples were stained with p53. Fifty-six of 57 (98%) cases showed mutation-type p53 staining. Pre-chemotherapy and post-chemotherapy IHC results were concordant in 55 of 57 (96%) cases. For WT1, pre-chemotherapy and post-chemotherapy IHC results were concordant in 56 of 58 (97%) cases. In 23 paired WT1 cases, the mean post-treatment H-score decreased from 227 [range 20-298, standard deviation (SD) 64] to 151 (range 0-288, SD 78) (P = 0.0008). CONCLUSIONS: Immunohistochemical expression of p53 (abnormal/mutation-type pattern) and WT1 in HGSC is almost universal and is largely concordant before and after chemotherapy. This finding underscores the reliability of these diagnostic markers in small samples and in surgical samples following neoadjuvant chemotherapy, with very few exceptions. A novel finding was the significant diminution in intensity of WT1 staining following chemotherapy.