PURPOSETo investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic... Show morePURPOSETo investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers.PATIENTS AND METHODSWe included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO.RESULTSOf the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective.CONCLUSIONWe detected HGSC in 1.5% (BRCA1-PV) and 0.6% (BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP. Show less
Purpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether... Show morePurpose: Whether endometrial carcinoma (EC) should be considered part of the gBRCA1/2-associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in gBRCA carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship.Experimental Design: Thirty-eight gBRCA carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gyneco-logic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the gBRCA-wild-type allele (gBRCA/LOHpos) were defined "gBRCA-associated," those without LOH (gBRCA/LOHneg) were defined "sporadic."Results: LOH could be assessed for 40 ECs (30 gBRCA1, 10 gBRCA2), of which 60% were gBRCA/LOHpos. gBRCA/LOHpos ECs were more frequently of nonendometrioid (58%, P = 0.001) and grade 3 histology (79%, P < 0.001). All but two were in the TP53-mutated TCGA-subgroup (91.7%, P < 0.001). In contrast, gBRCA/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: POLE-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and TP53-mutated (6.3%).Conclusions: We provide novel evidence in favor of EC being part of the gBRCA-associated HBOC-syndrome. gBRCA-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of gBRCA carriers. Show less
Versluis, M.A.C.; Plat, A.; Bruyn, M. de; Matias-Guiu, X.; Trovic, J.; Krakstad, C.; ... ; Hollema, H. 2018
AbstractBackground: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy ... Show moreAbstractBackground: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation.Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ).Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70).Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138). Show less
Helder-Woolderink, J.; Bock, G. de; Hullu, J. de; Hollema, H.; Zweemer, R.; Slangen, B.; ... ; Mourits, M. 2017
Conclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16... Show moreConclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. (C) 2016 AACR. Show less
Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we... Show moreImmune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs). Clinicopathological characteristics, follow-up, and data on infiltration of CD8(+) cytotoxic T lymphocytes (CTLs), FoxP3(+) regulatory T lymphocytes (Tregs), major histocompatibility complex (MHC) class I, and II molecule expression, were derived from a previously published dataset. WT1 overexpression was defined as positive immunostaining for WT1. WT1 overexpression, present in 56.3% of EOC, was associated with infiltration of Tregs [ odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.6-4.7; P < 0.001] and up-regulation of MHC class II (OR, 2.2; 95% CI, 1.2-4.1; P = 0.014). Advanced stage (OR, 4.0; 95% CI, 1.9-8.6; P < 0.001) and serous histology (OR, 6.7; 95% CI, 3.2-13.6; P < 0.001) were independent predictors of WT1 overexpressing EOC. High number of CTL was an independent prognostic factor for progression-free survival (hazard ratio, 0.5; 95% CI, 0.3-0.8; P = 0.006) in WT1 overexpressing EOC. As WT1 overexpressing EOC is associated with CTL and Treg infiltration next to MHC class II up-regulation, future clinical trials should evaluate the combination of therapeutic WT1 vaccines with strategies depleting Tregs and/or up-regulating MHC class I, in an attempt to enhance clinical efficacy in EOC patients. Show less
Oonk, M.H.; Hemel, B.M. van; Hollema, H.; Hullu, J.A. de; Ansink, A.C.; Vergote, I.; ... ; Zee, A.G. van der 2010
Background Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to... Show moreBackground Currently, all patients with vulvar cancer with a positive sentinel node undergo inguinofemoral lymphadenectomy, irrespective of the size of sentinel-node metastases. Our study aimed to assess the association between size of sentinel-node metastasis and risk of metastases in non-sentinel nodes, and risk of disease-specific survival in early stage vulvar cancer. Methods In the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINS S-V), sentinel-node detection was done in patients with T1-T2 (<4 cm) squamous-cell vulvar cancer, followed by inguinofemoral lymphadenectomy if metastatic disease was identified in the sentinel node, either by routine examination or pathological ultrastaging. For the present study, sentinel nodes were independently reviewed by two pathologists. Findings Metastatic disease was identified in one or more sentinel nodes in 135 (33%) of 403 patients, and 115 (85%) of these patients had inguinofemoral lymphadenectomy. The risk of non-sentinel-node metastases was higher when the sentinel node was found to be positive with routine pathology than with ultrastaging (23 of 85 groins vs three of 56 groins, p=0.001). For this study, 723 sentinel nodes in 260 patients (2.8 sentinel nodes per patient) were reviewed. The proportion of patients with non-sentinel-node metastases increased with size of sentinel-node metastasis: one of 24 patients with individual tumour cells had a non-sentinel-node metastasis; two of 19 with metastases 2 mm or smaller; two of 15 with metastases larger than 2 mm to 5 mm; and ten of 21 with metastases larger than 5 mm. Disease-specific survival for patients with sentinel-node metastases larger than 2 mm was lower than for those with sentinel-node metastases 2 mm or smaller (69-5% vs 94.4%, p=0.001). Interpretation Our data show that the risk of non-sentinel-node metastases increases with size of sentinel-node metastasis. No size cutoff seems to exist below which chances of non-sentinel-node metastases are dose to zero. Therefore, all patients with sentinel-node metastases should have additional groin treatment. The prognosis for patients with sentinel-node metastasis larger than 2 mm is poor, and novel treatment regimens should be explored for these patients. Show less
