Search

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 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 gynecologic 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., (©2019 American Association for Cancer Research.)

Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics., Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA -associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort., Results: Most endometrial cancers included in the final analysis ( n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% ( n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA -associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC ( P < 0.001)., Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53 -mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors., (©2018 American Association for Cancer Research.)

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE -mutant cancers. Experimental Design: We examined the recurrence-free survival of women with POLE -mutant and POLE- wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial ( N = 245 patients with stage I endometrial cancer for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole -mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 ( Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial ( N = 245), women with POLE -mutant endometrial cancers ( N = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for POLE- wild-type; HR, 0.143; 95% confidence interval, 0.001-0.996; P = 0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole -mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC 50 Pole P286R-mutant vs. wild-type: 0.05 vs. 0.17 μmol/L for cytarabine, 4.62 vs. 11.1 μmol/L for fludarabine; P < 0.001 for both comparisons). Conclusions: The favorable prognosis of POLE -mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE -mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogues, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE -mutant cancers. Clin Cancer Res; 24(13); 3197-203. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers. Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort). Results: Frequent recurrent mutations were identified in HPV-negative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower ( P = 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV + , HPV - /p53wt, HPV - /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV + , 16.3% for HPV - /p53wt and 22.6% for HPV - /p53abn tumors ( P = 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis ( P = 0.020). Conclusions: HPV - and HPV + vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV - /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV + VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC. Clin Cancer Res; 23(22); 6781-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)