Prognostic significance of PD-L1 protein expression and copy number gains in locally advanced cervical cancer.

BACKGROUND: Although immune checkpoint inhibitors against programmed death-1 (PD-1) and its ligand (PD-L1) have demonstrated promising results in several solid malignancies, including cervical cancer, there are some limitations to using PD-L1 immunohistochemical expression as a predictive biomarker for selecting patients who may benefit from such therapy. OBJECTIVE: To examine the protein expression and genetic status of PD-L1 with clinical outcomes in locally advanced cer- vical cancer. METHODS: We investigated the PD-L1 gene copy number gains assessed by fluorescence in situ hybridization (FISH) and PD-L1 expression using immunohistochemistry in 123 patients with locally advanced cervical cancers between December 2008 and December 2016. RESULTS: The prevalence of PD-L1 immunohistochemical expression was detected in 103/123(83%) cases. PD-L1 gene am- plification and polysomy were detected in 7% and 40% of cases, respectively. PD-L1 gene amplification and polysomy were associated with positive PD-L1 immunostaining (score 1+ to 3+) in 88% and 68% of cases, respectively. Clinically, PD-L1 immunopositivity was associated with parametrial invasion at diagnosis. In contrast, PD-L1 polysomy was associated with parametrial invasion and FIGO stages III-IV, whereas PD-L1 amplification was associated with nodal metastasis. In multi- variate analysis, PD-L1 amplification was predictive of worse RFS (HR, 5.68; 95%CI, 1.98-16.28; p = 0.001), whereas PD-L1 polysomy was predictive of worse LRR (HR, 4.13; 95%CI, 1.63-10.49; p = 0.003). PD-L1 immunohistochemical expression was not associated with worse outcomes in Cox models. CONCLUSIONS: Our results showed that an increase in PD-L1 gene copy number could be a novel prognostic and possible predictive biomarker for anti-PD-1/PD-L1 therapy in locally advanced cervical cancer.

Prevalence and prognostic role of mismatch repair gene defect in endometrial cancer patients.

The study was to evaluate the prevalence of mismatch repair gene defect among Thai patients with endometrial cancer and its association with clinico-pathological features and survivals. The formalin fixed paraffin-embedded blocks of EMC tissue from hysterectomy specimens of patients having surgery in our institution between 1 Jan 1995 and 31 December 2016 were assessed for the immunohistochemical expression of 4 mismatch repair proteins (MLH1, PMS, MSH2, MSH 6). Mismatch repair gene defect was determined by a negative expression of at least 1 protein. Among 385 EMC patients included in the study, mean age was 57.3 ± 10.8 years with 62.3% aged ⩽ 60 years. The most frequent mismatch repair gene defect was MSH6 (38.7%), followed by PMS2 (34.3%), MLH1 (33.2%), and MSH2 (16.4%). Overall, 55.1% showed negative expression of at least one protein. We found significantly higher mismatch repair gene defect in patients aged ⩽ 60 years, with early stage disease, and negative lymph node status than the other comparative groups: 59.2% vs 48.3% for age (p = 0.037), 58.2% vs 45.2% (p = 0.027) for stage, and 58.1% vs 44.6% (p = 0.048) for nodal status. The 5-year progression-free survival, overall survival, and endometrial cancer-specific survival of patients with mismatch repair gene defect was higher than those without gene defect. The differences were statistically significant for only progression-free survival and endometrial cancer-specific survival: 87.7% (95% confidence interval = 83.0%-92.4%) vs 81.5% (95% confidence interval = 75.4%-87.6%) (p = 0.049) for progression-free survival and 91.0% (95% confidence interval = 86.9%-95.1%) vs 85.5% (95% confidence interval = 80.0%-91.0%) (p = 0.044) for endometrial cancer-specific survival, respectively. In conclusion, more than half of Thai endometrial cancer patients had mismatch repair gene defect. The patients with mismatch repair gene defect had significantly younger age (⩽ 60 years) and better prognosis in terms of early stage, negative nodal status, and longer survivals.

Expression of the p16 and Ki67 in Cervical Squamous Intraepithelial Lesions and Cancer.

PURPOSE: To evaluate the expression of p16 and Ki67 in cervical intraepithelial neoplasia (CIN) and cancer. MATERIALS AND METHODS: We performed a immunohistochemical study of p16 and Ki67 in 243 cervical tissues 53 nondysplastic lesions, 106 CIN1, 61 CIN2/3 and 23 squamous cell carcinomas. The expression of p16 and Ki67 was interpreted independently by 2 researchers and the sensitivity and specificity to detect clinically significant lesions (≥ CIN2) were determined. RESULTS: The overall agreement results of positive or negative immunostaining of intrainter observer variability were 0.659 for p16 and 0.808 for Ki67. p16 expression was demonstrated in 91.3% of invasive carcinomas, 78.7% of CIN2/3, 10.4% of CIN1 and 9.4% of nondysplasic lesions. The corresponding Ki67 expression was: 100% of all invasive carcinomas, 75.4% of CIN2/3, 22.6% of CIN1, and 11.3% with nondysplasia. The expression was significantly different between CIN2/3 vs CIN1 for both p16 and Ki67 (pvalues <0.001 both), and cancer vs CIN2/3 for Ki67 (pvalue 0.008). The differences were not significant between CIN1 vs nondysplasia (pvalues 1.000 for p16 and 0.130 of Ki67), and cancer vs CIN2/3 for p16 (p value 0.219). The sensitivity and specificity to detect > CIN2 were 84.5% and 90.5% by p16 and 82.1% and 88.6% by Ki67. CONCLUSIONS: The rates for 16 and Ki67 expression were directly associated with the severity of cervical lesions. Significant differences in these markers expression may be useful in cases with equivocal histologic features among cervical intraepithelial lesions, but not between CIN1 and nondysplastic lesions. The two markers had high sensitivity and specificity in determining >CIN2.

Expression of estrogen receptor, progesterone receptor, and Her-2/ neu in primary and extra-corporeal endometrial cancer.

OBJECTIVE: To compare immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu in the primary tumors of endometrial cancer (EMC) and their extra-corporeal lesions. METHODS: Paraffin-embedded tissues of the primary and extra-corporeal tumors of EMC were retrieved for IHC study. Expression of ER, PR, and Her-2/ neu in the primary tumors and extra-corporeal lesions were compared. RESULTS: From 72 EMC patients with 87 extra-corporeal lesions, positive PR expression was significantly lower in the extra-corporeal lesions than that in the primary sites: 42.5% vs. 63.9%, respectively (p=0.007). No statistically significant differences of ER and Her-2/ neu expressions in the extra-corporeal and the primary sites were found: 42.5% and 55.6% for ER (p=0.102) and 20.7% vs. 13.9% for Her-2/ neu (p=0.262), respectively. The expression of extra-corporeal lesions were concordant to the primary tumor in 65.5% of ER (k=0.319), 71.2% of PR (k=0.445), and 83.9% of Her-2/ neu (k=0.413). From 15 cases wherein IHC from two extra-corporeal sites were studied, 73% had concordant ER expression between the two extra-corporeal lesions (k=0.412) while 93.3% had concordant PR and concordant Her-2/ neu expression (k=0.842 for PR and 0.634 for Her-2/ neu). CONCLUSION: PR expression was significantly higher in the primary tumors than the extra-corporeal sites. Higher ER and lower Her-2/ neu expressions in the primary tumors were also observed but the differences were not significant. The tumors heterogeneity suggests it may be important to study tumor tissues from both primary and extra-corporeal sites when planning treatment, especially by hormonal or targeted therapies.

Expression of ER, PR, and Her-2/neu in endometrial cancer: a clinicopathological study.

OBJECTIVE: To determine any association between expression of estrogen receptor (ER), progesterone receptor (PR), and Her-2/neu and clinicopathological features, including survival, of endometrial carcinoma (EMC) patients. METHODS: Samples of formalin-fixed, paraffin-embedded tissue of 108 patients with EMC treated at our institution between January 1994 and December 2007 were immunohistochemically studied. RESULTS: ER, PR, and Her-2/neu expression were positive in 59.3%, 65.7% and 2.8% of cases, respectively. Positive ER expression was significantly associated with grade I-II tumor while PR expression was linked with endometrioid histology, grade I-II tumor, less myometrial invasion (MI) and negative lymph node involvement. Her-2/neu expression was significantly associated with deep MI, while positive ER and negative Her-2/neu expression in combination was significantly associated with longer disease-free and overall survival. CONCLUSION: ER expression is a good prognostic factor while Her-2/neu expression appears to be a poor indicator for both disease-free and overall survival, while PR tended to show favorable influence for only disease-free survival of Thai EMCs.

Endometrial cancer in Thai women: clinico-pathological presentation and survival.

OBJECTIVE: To assess the characteristic features, treatment, survival, and prognostic factors of Thai endometrial cancer (EMC) patients. METHODS: Clinico-pathological data of EMC patients who were treated in the institution from 1992 to 2008 were collected. Survival rates and prognostic factors were studied. RESULTS: The mean age of the 261 patients was 55.4 ± 9.92 years. The most common complaint was abnormal uterine bleeding (87.3%). More than half (75.4%) had other medical illnesses or other cancers (10.7%). The majority (78%) had early stage disease. Post-operative adjuvant therapy was given in 41.4%; the most common was radiation therapy (37.2%). From a median follow-up of 57.5 months (range 0.03-212.3 months), progressive disease was encountered in 16 patients. Eighteen experienced recurrence (three local, 13 distant metastases and two local and distant). Overall, 30 patients died of cancer, while 18 died of other medical illnesses. The 5-year progression-free, cancer specific, and overall survivals (95% confidence intervals) were 86.5% (82.1-90.8%), 88.0% (83.9-92.2%), and 83.6% (78.7-88.4%), respectively. Significant prognostic factors for survival were: histology, grade, depth of myometrial invasion, cervical involvement, lymphovascular invasion, lymph node status, and Her-2/ neu expression. CONCLUSION: Most endometrial cancer patients in Thailand present at early stages and experience good survival outcomes.

Clinicopathological features including hormonal receptor expression and survival in young endometrial cancer patients: a case control study.

OBJECTIVE: To compare clinicopathological features, including hormonal receptor expression and survival, in young Thai endometrial carcinoma (EMC) patients with older patients. METHODS: Young EMC patients aged ≤45 years, treated in the institution from 1992 to 2008, were identified as cases. Controls included EMC patients aged >45 years who had an operation on the nearest dates to the cases. Clinicopathological data and survival of the cases and controls were compared. RESULTS: Mean ages of 41 cases and 123 controls were 40.4 ± 3.7 years and 58.4 ± 8.3 years, respectively. Cases were significantly different from controls in terms of having more nulliparity (58% vs 25%), less medical illness (57% vs 79%), more low-grade tumors (49% vs 14%), more positive estrogen (78% vs 56%) and progesterone (97% vs 61%) receptors expression, and fewer nodal metastases (3% vs 21%). Adjuvant therapy was administered in 29% of the cases and 46% of the controls. From a median follow up of 51 months, cases had significantly fewer progression events and recurrence (5% vs 19%), cancer-related deaths (2% vs 16%), and all deaths (5% vs 23%), with significantly longer 5-year disease-free (97.2% vs 79.6%, p=0.023), cancer-specific (97.1% vs 83.2%, p=0.020), and overall survival (93.1% vs 78.8% p=0.005) than controls as determined by univariate analysis. Survival of cases and controls were not significantly different after adjusting for other prognostic factors. CONCLUSION: Young Thai EMC patients had more favorable clinicopathological features with significantly longer survival than older patients as determined by univariate analysis.