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ObjectiveTo evaluate the added value of a centralized pathology review of the diagnoses of gestational trophoblastic diseases by expert pathologists and its potential impact on clinical management in a prospective multicenter study based on the Belgian Gestational Trophoblastic Diseases Registry.MethodsFrom July 2012 to December 2020, the two referral centers of the registry were solicited to advise on 1119 cases. Referral pathologists systematically reviewed all of the initial histological diagnoses. Cases initially assessed by expert pathologists were excluded. A total of 867 files were eligible for the study. Concordance between diagnoses of gestational trophoblastic diseases made by general ‘non-expert’ and expert pathologists was analyzed together with the potential impact of the alterations on clinical management. Expert pathologists were working in an academic setting with high exposure to placental pathology and national recognition.ResultsThe rate of discordance between expert and non-expert pathologists for the initial diagnoses was 35%. Almost 95% of complete moles were confirmed by the expert pathologists, but only 61% for partial moles. Compared with previous studies, ancillary techniques (p57 immunohistochemistry, karyotype) were used twice as often by both groups of pathologists in this survey. The diagnosis of gestational trophoblastic neoplasia was altered in 42% of cases. When the initial diagnosis was altered, the clinical relevance of this correction was estimated as down staging, up staging, or not relevant in 65%, 33% and 2% of cases respectively.ConclusionSystematic centralized pathological review of gestational trophoblastic diseases modified the diagnosis in a third of cases. The results also show that a change in diagnosis would impact clinical management in 98% of patients.

Supplementary methods

Combination of the mTORC1/2 inhibitor TAK-228 and the PI3K-α inhibitor alpelisib inhibits EMC041 tumor growth to the same extent as BEZ235

Immunohistochemistry stainings of potential targets.

High-grade endometrial stromal sarcoma with YMHAE/NUTM2A/B fusion and cyclin D1 expression.

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment.Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models.Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition.Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274–85. ©2017 AACR.

Supplementary tables and figure legends

Survival of uterine sarcoma patients according to tumor grade and histologic subtype.

Background Multigene signatures (MGS) select women with estrogen receptor positive human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancers where adjuvant chemotherapy (aCT) can be avoided. However, MGS are expensive and not always reimbursed. We investigated the predictive value of six inexpensive statistical models in tumors with low or high risk of relapse based on MGS and investigated the change in decision to add chemotherapy following MGS results. Patients and Methods In this retrospective study, we evaluated patients diagnosed with primary operable ER+/HER2- lymph node negative or positive breast cancer diagnosed at University Hospitals Leuven between 2013 and 2018. Tumor tissue of the patients was analyzed by MammaPrint® (MP) (n=25), OncotypeDX® (ODX) (n=44) or Prosigna® (n=57) as there was uncertainty about benefit of aCT during multidisciplinary meeting (MDM). Magee equations (ME), Memorial Sloan Kettering simplified score (MSK), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL) and PREDICT v2.0 were computed. TAILORx cut-offs were used for ODX. A 85% cut-off was used for the probability of a low (0-25) or high risk (26-100) ODX recurrence score for ODXC and a 5% cut-off was used for 10-year survival benefit with aCT for nAOL and PREDICT. Results All ME- and BCRSE-high cases were classified by MGS as high or intermediate and not as MGS-low risk (Table 1). None of the low risk classifications by ME and nAOL resulted in MGS-high risk with ODX. High risk classification with nAOL showed strong concordance with all MGS-high risk results. A switch in chemotherapy recommendation based on MDM decisions, was observed in 46% (58/126) of patients after MGS results. Following MGS testing, aCT was given to 57 patients which resulted in 17% relative and 10% absolute reduction. Conclusion Inexpensive statistical models based on clinico-pathological parameters can be useful in selecting patients that may need MGS testing. The use of MGS resulted in a substantial decisional switch and reduction in aCT-use. Table 1 Predictive value of inexpensive statistical models in MGS tested tumors.MGS high risk (n=53)MGS low risk (n=52)ODX (n=17)MP (n=11)Prosigna (n=25)ODX (n=27)MP (n=14)Prosigna (n=11)MSK high (n=32)1038150ME high (n=7)411000BCRSE high (n=6)311000ODXC high (n=4)110010nAOL high (n=105)1772423123PREDICT high (n=47)7512850MSK low (n=37)3361145ME low (n=9)012202BCRSE low (n=50)3310967ODXC low (n=67)35131469nAOL low (n=21)041428PREDICT low (n=79)1061319911 Citation Format: Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Ann Smeets, Erik Van Limbergen, Philippe Moerman, Caroline Weltens, Kevin Punie, Griet Hoste, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Lynn Jongen, Patrick Neven, Giuseppe Floris. Multigene signatures based risk estimates in early ER+/HER2- breast cancer: The predictive value of inexpensive statistical models and changes in adjuvant chemotherapy use [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-14.

Placental mesenchymal dysplasia (PMD) occurs in about 1 in 5000 pregnancies. The differential diagnosis between PMD and partial mole is difficult on ultrasound scan, and karyotyping plays a key role in distinguishing PMD from partial mole. Our report is the first to report on the discordancy for PMD in a monochorionic setting. ispartof: CLINICAL CASE REPORTS vol:6 issue:8 pages:1557-1560 ispartof: location:England status: published

Mucinous (goblet cell) carcinoids are a rare type of ovarian carcinoid tumors. Only a limited number of primary mucinous carcinoids of the ovary have been reported in the literature. We describe the case of a 55-year-old woman with a diffusely metastasized adenocarcinoma arising in a primary ovarian mucinous carcinoid. The differential diagnosis with a metastatic goblet cell carcinoid from the appendix or elsewhere can be very challenging. In our case, especially the immunohistochemical profile of the tumor with diffuse positivity for cytokeratin 7 and PAX8, and no expression of cytokeratin 20 and CDX2, directed us toward a primary ovarian origin. Expression of PAX8 in ovarian mucinous carcinoid has never been reported before.

Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

Despite excellent per-lesion performance for peritoneal staging, the additional clinical value of diffusion-weighted magnetic resonance imaging (DWI/MRI) compared to computed tomography (CT) remains to be established in ovarian cancer. Our purpose was to evaluate whole body (WB)-DWI/MRI for diagnosis, staging and operability assessment of patients suspected for ovarian cancer compared to CT. One hundred and sixty-one patients suspected for ovarian carcinoma underwent 3 T WB-DWI/MRI and contrast-enhanced CT. WB-DWI/MRI and CT were compared for confirmation of the malignant nature and primary origin of the ovarian mass, Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) staging and prediction of incomplete resection using institutional operability criteria. Interobserver agreement between two readers was determined for WB-DWI/MRI and CT. WB-DWI/MRI showed a significantly higher accuracy than CT (93 versus 82%, p = 0.001) to confirm the malignant nature of the ovarian mass and correctly identified 26 of 32 (81%) cancers of non-ovarian origin compared to 10/32 (31%) for CT (p < 0.001). WB-DWI/MRI assigned more ovarian carcinoma patients to the correct FIGO stage (82/94, 87%) compared with CT (33/94, 35%). For prediction of incomplete resection, WB-DWI/MRI showed significantly higher sensitivity (94 versus 66%), specificity (97.7 versus 77.3%) and accuracy (95.7 versus 71.3%) compared to CT (p < 0.001). Interobserver agreement was almost perfect (κ = 0.90) for WB-DWI/MRI and moderate (κ = 0.52) for CT for prediction of incomplete resection. WB-DWI/MRI was superior to CT for primary tumour characterisation, staging and prediction of incomplete resection in patients suspected for ovarian cancer

BACKGROUND: Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian carcinoma. Limited data regarding the molecular-genetic background exist beyond mutations in the RAS signaling pathway. There is a growing need to better characterize these tumors due to chemoresistance and limited therapeutic options in advanced or recurrent disease. METHODS: We performed genome-wide copy number aberration (CNA) profiles and mutation hotspot screening (KRAS, BRAF, NRAS, ERBB2, PIK3CA, TP53) in 38 LGSOC tumor samples. RESULTS: We detected mutations in the RAS-signaling pathway in 36.8% of cases, including seven KRAS, four BRAF, and three NRAS mutations. We identified two mutations in PIK3CA and one mutation in MAP3K1, EGFR, and TP53. CNAs were detected in 86.5% of cases. None of the focal aberrations was correlated with specific clinical characteristics. The most frequently detected CNA was loss of 1p36.33 in 54.1% of cases, with a trend towards lower progression-free survival and overall survival in patients with 1p36.33 loss. CONCLUSIONS: Activating RAS mutations were dominant in our series, with supplementary detection of two PIK3CA mutations which may lead to therapeutic options. Furthermore, we detected 1p36.33 deletions in half of the cases, indicating a role in tumorigenesis, and these deletions may serve as a prognostic marker. ispartof: NEOPLASIA vol:21 issue:6 pages:582-590 ispartof: location:United States status: published

ObjectivesThis study aimed to determine the overall survival (OS) and progression-free interval and the influence of fertility-preserving surgery (FPS) versus radical surgery (RS) in patients with serous borderline ovarian tumor (BOT).MethodsClinical parameters of patients with serous BOT treated between 1993 and 2013 in one institution were retrospectively investigated. All tumors were examined by one pathologist with experience in gynecological pathology.ResultsOne hundred thirty-two patients with serous BOT (inclusive 16 microinvasive) were analyzed (45% were ≤40 years), with a median follow-up of 6 years. Thirty-two percent (42/132) of the patients received FPS; 14% (18/132) relapsed (invasive or borderline). The 5-year progression-free survival was 89%. The risk of recurrence was higher in patients 40 years or younger (P = 0.019), after FPS (P = 0.002), in patients with a higher International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.016), for bilateral BOT (P = 0.0132), and for the micropapillary variant (P = 0.067). The OS at 5 years was 97%. There was no statistically significant difference in OS between FPS and RS [all (6 of 90) patients, except for 1, with RS died]. One patient died of relapsed BOT. Among the recurrences, low-grade invasive carcinoma was diagnosed in 4 patients. Three of these 4 patients were originally operated radically, 2 had a micropapillary variant FIGO stage III, and 1 had a papillary pattern FIGO stage II with microinvasion; all 3 had noninvasive implants and are alive. One patient with a micropapillary variant, FIGO stage IIIC with microinvasion and invasive implants, received FPS and died of disease.ConclusionsThe risk of recurrence is higher after FPS compared with RS; however, no influence on OS was observed. This was because most of the patients relapsed as BOT. Fertility preservation is justified in young patients with serous borderline tumors.

Background Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. The aim of this study is to describe the mutational frequency and phenotypic spectrum of the CEP120 gene. Methods Exome sequencing was performed in 145 patients with Joubert syndrome ( JS), including 15 children with oral-facial-digital syndrome type VI (OFDVI) and 21 Meckel syndrome (MKS) fetuses. Moreover, exome sequencing was performed in one fetus with tectocerebellar dysraphia with occipital encephalocele (TCDOE), molar tooth sign and additional skeletal abnormalities. As a parallel study, 346 probands with a phenotype consistent with JS or related ciliopathies underwent next-generation sequencing-based targeted sequencing of 120 previously described and candidate ciliopathy genes. Results We present six probands carrying nine distinct mutations (of which eight are novel) in the CEP120 gene, previously found mutated only in Jeune asphyxiating thoracic dystrophy ( JATD). The CEP120- associated phenotype ranges from mild classical JS in four patients to more severe conditions in two fetuses, with overlapping features of distinct ciliopathies that include TCDOE, MKS, JATD and OFD syndromes. No obvious correlation is evident between the type or location of identified mutations and the ciliopathy phenotype. Conclusion Our findings broaden the spectrum of phenotypes caused by CEP120 mutations that account for nearly 1% of patients with JS as well as for more complex ciliopathy phenotypes. The lack of clear genotype-phenotype correlation highlights the relevance of comprehensive genetic analyses in the diagnostics of ciliopathies.

Contains fulltext : 168023.pdf (Publisher’s version ) (Closed access) Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Choriocarcinoma most frequently arises in a complete hydatidiform mole. Less common are cases following a normal pregnancy or a nonmolar abortion. Its occurrence after a partial hydatidiform mole is extremely rare.Here we report a choriocarcinoma in situ diagnosed after dilation and curettage for a first tri- mester partial hydatidiform mole. The diagnosis was con- firmed by immunohistochemistry, fluorescent in situ hybridization, and microsatellite instability genotyping of the products of conception and blood of the mother and father. We demonstrated a diandric triploidy. At the time of diagnosis CT scan showed lung metastasis. The pa- tient was classified as high-risk gestational trophoblas- tic neoplasia and treated with high-dose methotrexate- etoposide.This is the first reported case of a cho- riocarcinoma arising in a first trimester partial mol.

Background Ovarian germ cell tumors (OGCT) are rare gynecological neoplasms, mostly affecting children and young women. The underlying molecular genetic background of these tumors is poorly characterized. Methods We analyzed somatic copy number aberration (CNA) profiles in 87 OGCT tumors and performed whole exome sequencing (WES) on 24 OGCT tumor and matched germline samples to further elucidate their molecular genetic landscape. Results The overall mutation rate was very low in OGCT compared to other human cancers, with an average of 0.05 mutations per Mb, consistent with their embryological origin. We identified recurrent mutations in KIT and KRAS, while CNA profiling revealed frequent focal amplifications affecting PIK3CA and AKT1 in yolk sac tumors, recurrent focal deletions affecting chromosomal regions 1p36.32, 2q11.1, 4q28.1, 5p15.33, 5q11.1 and 6q27, as well as gains in chromosome 12p that were present in all tumors, except for pure immature teratomas. Conclusion We here present the first whole exome sequencing data and to our knowledge the largest CNA study in OGCT. We confirmed that earlier reported KIT mutations were frequent in dysgerminomas and mixed forms with a dysgerminoma component, whereas chromosome 12p gains were present in all histological subtypes except pure immature teratomas. We detected recurrent KRAS mutations, recurrent focal deletions and an enrichment in the PI3K/AKT/PTEN pathway in yolk sac tumors. Several of these aberrations involve targetable pathways, offering novel treatment modalities for OGCT.

Objective. Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients. Methods. Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations. Results. We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-EZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy. Conclusion. The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups. (C) 2015 Elsevier Inc. All rights reserved

Objective. Compare surgical staging with imaging (PET-CT, PET or CT) of the para-aortic lymph nodes (PAOLN) in locally advanced cervical cancer (LACC). Methods. Monocentric retrospective study of 336 patients with cervical cancer FIGO stage IB2-IVA. All patients underwent staging of the PAOLN using imaging by PET-CT, PET or CT. Two hundred and four patients with normal or not overtly malignant PAOLN on imaging underwent surgical PAOLN staging up to the inferior mesenteric artery (189 endoscopy and 15 laparotomy). Results. The patients were divided into 4 groups: 16 with positive surgical staging and negative PAOLN imaging (sPAOLN +), 172 negative surgical staging (sPAOLN -), 20 positive imaging without surgical staging (iPAOLN +) and 128 negative imaging without surgical staging (iPAOLN -). Median operative time of staging was 70 (40-160) min and median number of removed PAOLN was 5 (0-24). Operative complications were 10 peroperative bleedings, 2 ureteral traumas, 1 carbon dioxide retention and 1 retroperitoneal abscess. The median follow-up was 31 (1-218) months. Overall survival at 2 years was for sPAOLN +, sPAOLN -, iPAOLN +, and iPAOLN-40%, 83%, 58%, and 69%, respectively (p

Evidence suggests that premenopausal obesity decreases and postmenopausal obesity increases breast cancer risk. Because it is not well known whether this is subtype dependent, we studied the association between body mass index (BMI) and age at breast cancer diagnosis, or the probability of being diagnosed with a specific breast cancer phenotype, by menopausal status. All patients with non-metastatic operable breast cancer from the University Hospital Leuven diagnosed between January 1, 2000 and December 31, 2013 were included (n = 7020) in this cross-sectional study. Linear models and logistic regression were used for statistical analysis. Allowing correction for age-related BMI-increase, we used the age-adjusted BMI score which equals the difference between a patient’s BMI score and the population-average BMI score corresponding to the patient’s age category. The quadratic relationship between the age-adjusted BMI and age at breast cancer diagnosis (p = 0.0207) interacted with menopausal status (p

Uterine leiomyosarcomas (uLMS) are rare, aggressive malignancies for which limited treatment options are available. To gain novel molecular insights into uLMS and identify potential novel therapeutic targets, we characterized 84 uLMS samples for genome-wide somatic copy number alterations, mutations, gene fusions and gene expression and performed a data integration analysis. We found that alterations affecting TP53, RB1, PTEN, MED12, YWHAE and VIPR2 were present in the majority of uLMS. Pathway analyses additionally revealed that the PI3K/AKT/mTOR, estrogen-mediated S-phase entry and DNA damage response signaling pathways, for which inhibitors have already been developed and approved, frequently harbored genetic changes. Furthermore, a significant proportion of uLMS was characterized by amplifications and overexpression of known oncogenes (CCNE1, TDO2), as well as deletions and reduced expression of tumor suppressor genes (PTEN, PRDM16). Overall, it emerged that the most frequently affected gene in our uLMS samples was VIPR2 (96%). Interestingly, VIPR2 deletion also correlated with unfavorable survival in uLMS patients (multivariate analysis; HR = 4.5, CI = 1.4-14.3, p = 1.2E-02), while VIPR2 protein expression was reduced in uLMS vs. normal myometrium. Moreover, stimulation of VIPR2 with its natural agonist VIP decreased SK-UT-1 uLMS cell proliferation in a dose-dependent manner. These data suggest that VIPR2, which is a negative regulator of smooth muscle cell proliferation, might be a novel tumor suppressor gene in uLMS. Our work further highlights the importance of integrative molecular analyses, through which we were able to uncover the genes and pathways most frequently affected by somatic alterations in uLMS.

Purpose: Uterine sarcomas are rare and heterogeneous tumors characterized by an aggressive clinical behavior. Their high rates of recurrence and mortality point to the urgent need for novel targeted therapies and alternative treatment strategies. However, no molecular prognostic or predictive biomarkers are available so far to guide choice and modality of treatment. Experimental Design: We investigated the expression of several druggable targets (phospho-S6S240 ribosomal protein, PTEN, PDGFR-α, ERBB2, and EGFR) in a large cohort of human uterine sarcoma samples (288), including leiomyosarcomas, low-grade and high-grade endometrial stromal sarcomas, undifferentiated uterine sarcomas, and adenosarcomas, together with 15 smooth muscle tumors of uncertain malignant potential (STUMP), 52 benign uterine stromal tumors, and 41 normal uterine tissues. The potential therapeutic value of the most promising target, p-S6S240, was tested in patient-derived xenograft (PDX) leiomyosarcoma models. Results: In uterine sarcomas and STUMPs, S6S240 phosphorylation (reflecting mTOR pathway activation) was associated with higher grade (P = 0.001) and recurrence (P = 0.019), as shown by logistic regression. In addition, p-S6S240 correlated with shorter progression-free survival (P = 0.034). Treatment with a dual PI3K/mTOR inhibitor significantly reduced tumor growth in 4 of 5 leiomyosarcoma PDX models (with tumor shrinkage in 2 models). Remarkably, the 4 responding models showed basal p-S6S240 expression, whereas the nonresponding model was scored as negative, suggesting a role for p-S6S240 in response prediction to PI3K/mTOR inhibition. Conclusions: Dual PI3K/mTOR inhibition represents an effective therapeutic strategy in uterine leiomyosarcoma, and p-S6S240 expression is a potential predictive biomarker for response to treatment. Clin Cancer Res; 23(5); 1274–85. ©2017 AACR.

Objective: Recent studies suggest that mucinous borderline ovarian tumors (MBOTs) belong to a high-risk group that is more likely to develop an invasive recurrence. The objective is to determine these risk factors. Methods: A monocentric retrospective review of all consecutive patients with intestinal-type MBOT diagnosed between 1993 and 2013. All tumors were evaluated by one pathologist without knowledge of clinical outcome. Extensive surgical staging and pathological tumor sampling (1 block/cm diameter in tumors 10 cm) were performed in all cases. Results: A total of 81 patients were included. Patients with micro-invasion were also included. None of the patients recurred. No bilateral tumors, nor tumors with International Federation of Gynecology and Obstetrics stage II or higher, were diagnosed. Median follow-up was 87 months. Conclusions: In our series of pure intestinal-type MBOT, including micro-invasion, no recurrences were observed. Given the heterogeneity of these tumors staging with at least unilateral salpingo-oophorectomy, extensive pathological sampling, and expert pathological review are of paramount importance to be able to diagnose a pure intestinal-type MBOT and excluding gastrointestinal mucinous tumors and more important, excluding an invasive focus, defining a mucinous ovarian carcinoma. When these conditions are fulfilled, the prognosis of pure intestinal-type MBOT is excellent.

ObjectiveNeoadjuvant chemotherapy (NACT) followed by surgery in cervical cancer is widely studied with paclitaxel-ifosfamide-cisplatinum 3 weekly (TIP). Although the response rates with TIP are high, the toxicity is substantial. Therefore, this study evaluates dose-dense paclitaxel-carboplatin (TC) as an alternative.MethodsIn this prospective phase 2 study trial, we included 36 patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB1 to IIB cervical cancer, who received 9 weeks’ NACT dose-dense TC (median weekly dose paclitaxel 60 mg/m2, carboplatinum area under the curve 2.7). Radiological response was evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Optimal pathologic response (OPT) was defined as complete disappearance of tumor (complete response [CR]) or residual disease with less than 3-mm stromal invasion (PR1). Suboptimal pathologic response consisted of persistent residual disease with more than 3-mm stromal invasion (PR2).ResultsNine patients had a FIGO stage IB1 (25%), 7 had stage IB2(19%), 3 had stage IIA (8%), and 17 had stage IIB disease (47%). Evaluation by magnetic resonance imaging after NACT showed 32 RECIST responses (89%) (CR in 11, PR in 21). Patients who were inoperable had insufficient reduction of the tumor to be operable (4 patients), progressive disease (1 patient), or stable disease (1 patient). Thirty patients were suitable for surgery after NACT. Pathology showed OPT in 50% (CR in 10, PR1 in 5). Thirteen patients had pathologic lymph nodes on radiological evaluation before start of chemotherapy. After chemotherapy, the lymph nodes were negative in 6 (47%) of these patients (pathologic complete remission). Postoperative chemoradiotherapy was administered in 11 patients (2 because of close resection margins, 5 because of metastatic lymph node after surgery, 2 because of close resection margins and metastatic lymph nodes after surgery, and 1 tumor >4 cm after NACT). Hematologic toxicity was acceptable with no febrile neutropenia and a low nonhematologic toxicity. The estimated 5-year overall survival was 70.8%.ConclusionsNeoadjuvant TC dose-dense in cervical carcinoma has a high response rate, comparable with TIP, and an acceptable toxicity.

Objective. Uterine sarcomas (US) and carcinosarcomas (CS) are rare, aggressive cancers. The lack of reliable preclinical models hampers the search for new treatment strategies and predictive biomarkers. To this end, we established and characterized US and CS patient-derived xenograft (PDX) models. Methods. Tumor fragments of US and CS were subcutaneously implanted into immunocompromised mice. Engrafted xenograft and original tumors were compared by means of histology, immunohistochemistry, whole-genome low-coverage sequencing for copy number variations, and RNA sequencing. Results. Of 13 implanted leiomyosarcomas (LMS), 10 engrafted (engraftment rate of 77%). Also 2 out of 7 CS (29%) and one high-grade US (not otherwise specified) models were successfully established. LMS xenografts showed high histological similarity to their corresponding human tumors. Expression of desmin and/or H-caldesmon was detected in 8/10 LMS PDX models. We noticed that in CS models, characterized by the concomitant presence of a mesenchymal and an epithelial component, the relative distribution of the components is varying over the generations, as confirmed by changes in vimentin and cytokeratin expression. The similarity in copy number profiles between original and xenograft tumors ranged from 57.7% to 98.2% for LMS models and from 47.4 to 65.8% for CS models. Expression pattern stability was assessed by clustering RNA expression levels of original and xenograft tumors. Six xenografts clustered together with their original tumor, while 3 (all LMS) clustered apart. Conclusions. We present here a panel of clinically annotated uterine sarcoma and carcinosarcoma PDX models, which will be a useful tool for preclinical testing of new therapies. (C) 2017 Elsevier Inc. All rights reserved.

Using exome sequencing we identify a homozygous splice site mutation in the PIGN gene in a foetus with multiple congenital anomalies including bilateral diaphragmatic hernia, cardiovascular anomalies, segmental renal dysplasia, facial dysmorphism, cleft palate, and oligodactyly. This finding expands the phenotypic spectrum associated with homozygous loss of function mutations in PIGN, and adds further support for defective GPI anchor biosynthesis as a cause of developmental abnormalities. We demonstrate that exome sequencing is a valuable approach for the identification of a genetic cause in sporadic cases of multiple congenital anomalies (MCA) due to inherited mutations.

Background Multigene signatures (MGS) select women with estrogen receptor positive human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancers where adjuvant chemotherapy (aCT) can be avoided. However, MGS are expensive and not always reimbursed. We investigated the predictive value of five inexpensive statistical models in tumors with low or high risk of relapse based on MGS and investigated the change in decision to add chemotherapy following MGS results. Patients and Methods In this retrospective study, we evaluated patients diagnosed with primary operable ER+/HER2- lymph node negative or positive breast cancer diagnosed at University Hospitals Leuven between 2013 and 2018. Patients were analyzed by MammaPrint® (MP) (n=24), OncotypeDX® (ODX) (n=44) or Prosigna®(n=57) as there was uncertainty about benefit of aCT during multidisciplinary meeting (MDM). Magee equations (ME), Memorial Sloan Kettering simplified score (MSK), Breast Cancer Recurrence Score Estimator (BCRSE), new Adjuvant! Online (nAOL) and PREDICT v2.0 were computed. TAILORx cut-offs were used for ODX. A 5% cut-off was used for 10-year survival benefit with aCT for nAOL and PREDICT. Results All ME- and BCRSE-high cases were classified by MGS as high or intermediate and not as MGS-low risk, as shown in Table 1. None of the low risk classifications by ME and nAOL resulted in MGS-high risk with ODX. High risk classification with nAOL showed strong concordance with all MGS-high risk results. Chemotherapy switch according to MGS results was observed in 46% (57/125) of patients. Following MGS testing, aCT was given to 56 patients which resulted in 19% relative and 10% absolute reduction. Conclusion Inexpensive statistical models based on pathologic parameters can be useful to select patients who may need MGS testing. Integration of MGS into MDM decisions, resulted in a substantial decisional switch and reduction in aCT administration. Table 1Predictive value of inexpensive statistical models in MGS tested tumors.MGS high risk (n=52)MGS low risk (n=52)ODX (n=17)MP (n=10)Prosigna (n=25)ODX (n=27)MP (n=14)Prosigna (n=11)MSK high59% (10/17)30% (3/10)32% (8/25)4% (1/27)36% (5/14)0% (0/11)ME high24% (4/17)10% (1/10)4% (1/25)0% (0/27)0% (0/14)0% (0/11)BCRSE high0% (0/17)10% (1/10)4% (1/25)0% (0/27)0% (0/14)0% (0/11)nAOL high100% (17/17)60% (6/10)96% (24/25)85% (23/27)86% (12/14)27% (3/11)PREDICT high47% (8/17)40% (4/10)48% (12/25)26% (7/27)36% (5/14)0% (0/11)MSK low18% (3/17)30% (3/10)24% (6/25)41% (11/27)29% (4/14)46% (5/11)ME low0% (0/17)10% (1/10)8% (2/25)7% (2/27)0% (0/14)18% (2/11)BCRSE low18% (3/17)30% (3/10)40% (10/25)26% (7/27)43% (6/14)64% (7/11)nAOL low0% (0/17)40% (4/10)4% (1/25)15% (4/27)14% (2/14)73% (8/11)PREDICT low53% (9/17)60% (6/10)52% (13/25)74% (20/27)64% (9/14)100% (11/11) Citation Format: Laurence Slembrouck, Giuseppe Floris, Hans Wildiers, Ann Smeets, Erik Van Limbergen, Philippe Moerman, Caroline Weltens, Kevin Punie, Griet Hoste, Els Van Nieuwenhuysen, Sileny Han, Ines Nevelsteen, Lynn Jongen, Patrick Neven, Isabelle Vanden Bempt. Multigene signatures based risk estimates in ER+/HER2- breast cancers: The predictive value of inexpensive statistical models and changes in adjuvant chemotherapy use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1406.

To evaluate whole-body MRI with diffusion-weighted sequence (WB-DWI/MRI) for staging and assessing operability compared with CT and FDG-PET/CT in patients with suspected ovarian cancer. Thirty-two patients underwent 3-T WB-DWI/MRI, (18) F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and CT before diagnostic open laparoscopy (DOL). Imaging findings for tumour characterisation, peritoneal and retroperitoneal staging were correlated with histopathology after DOL and/or open surgery. For distant metastases, FDG-PET/CT or image-guided biopsies were the reference standards. For tumour characterisation and peritoneal staging, WB-DWI/MRI was compared with CT and FDG-PET/CT. Interobserver agreement for WB-DWI/MRI was determined. WB-DWI/MRI showed 94 % accuracy for primary tumour characterisation compared with 88 % for CT and 94 % for FDG-PET/CT. WB-DWI/MRI showed higher accuracy of 91 % for peritoneal staging compared with CT (75 %) and FDG-PET/CT (71 %). WB-DWI/MRI and FDG-PET/CT showed higher accuracy of 87 % for detecting retroperitoneal lymphadenopathies compared with CT (71 %). WB-DWI/MRI showed excellent correlation with FDG-PET/CT (kappa = 1.00) for detecting distant metastases compared with CT (kappa = 0.34). Interobserver agreement was moderate to almost perfect (kappa = 0.58-0.91). WB-DWI/MRI shows high accuracy for characterising primary tumours, peritoneal and distant staging compared with CT and FDG-PET/CT and may be valuable for assessing operability in ovarian cancer patients. aEuro cent Whole-body MRI with diffusion weighting (WB-DWI/MRI) helps to assess the operability of suspected ovarian cancer. aEuro cent Interobserver agreement is good for primary tumour characterisation, peritoneal and distant staging. aEuro cent WB-DWI/MRI improves mesenteric/serosal metastatic spread assessment compared with CT and FDG-PET/CT. aEuro cent Retroperitoneal/cervical-thoracic nodal staging using qualitative DWI criteria was reasonably accurate. aEuro cent WB-DWI/MRI and FDG-PET/CT showed the highest diagnostic impact for detecting thoracic metastases

Purpose To investigate the clinical behavior of triple negative breast cancer (TNC), including age distribution, occurrence of LN (lymph node) invasion and prognosis in different histological subtypes. Methods For this cohort study we used data on 476 patients with newly diagnosed TNC at the University Hospitals Leuven (Belgium) between 1999 and 2009. Of these, 395 received upfront surgery, 68 neoadjuvant chemotherapy and 21 had metastases at diagnosis. Results Apocrine and invasive lobular TNC occur more often in older patients compared to IDC-NOS. Of the primarily operated patients with TNC, 35.1% has pathological LN involvement. There were no significant differences in nodal invasion between different histological subtypes, but most subtypes contained few patients. In contrast to previous reports, 6/14 of apocrine TNC had LN involvement. Disease free survival (DFS) was different in different histological subtypes, but group sizes were insufficient to be able to draw firm conclusions. Within the histologically ‘homogeneous’ IDC-NOS group with primary surgery and outcome data (n = 300), DFS with 3.5 year median follow-up decreased with increasing age, but chemotherapy and radiotherapy were much less frequently given with increasing age. In multivariable analysis, lower age, presence of LN involvement, lack of administration of chemotherapy and radiotherapy were significant predictors of relapse. Conclusion TNC is not a uniform disease. Different histological subtypes have different age distribution and behavior. The prognosis of the most common histological subgroup, IDC-NOS, is better in older patients, but this is counterbalanced by significantly decreased use of chemotherapy and radiotherapy.

Background Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. Patients and methods A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening-detected breast cancers for distant metastatic and breast cancer-specific survival. Results We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. Conclusion Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype.

Lymph node involvement is the most important prognostic factor in breast cancer. It is a multifactorial event determined by patient and tumour characteristics. The purpose of this study was to determine clinical and pathological factors predictive for axillary lymph node metastasis (ALNM) in patients with early breast cancer and to build a model to portend lymph node involvement.We evaluated 1300 consecutive patients surgically treated in our institution (2007-2009) for cT1-T2 invasive breast cancer. The patient and tumour characteristics evaluated included: age at diagnosis, number of foci, histologic grade, location, tumour size, histologic subtype, lymphovascular invasion (LVI), estrogen-receptor (ER), progesterone-receptor (PR) and Her-2 status. Univariate and multivariate analyses were performed. Factors significantly associated with ALNM by univariate analysis plus histologic subtype were included in the multivariate analysis.By univariate analysis, the incidence of ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), higher histologic grade (P 0.0001), retroareolar or lateral location in the breast (P 0.0001), multiple foci (P = 0.0002) and in patients who underwent an axillary lymph node dissection. We found no effect of age, ER⁄PR nor HER-2 status. By multivariate analysis, ALNM was significantly associated with the presence of LVI (P 0.0001), larger tumour size (P 0.0001), axillary lymph node dissection (P = 0.0003), retroareolar and lateral tumour location in the breast (P = 0.0019) and the presence of multiple foci (P = 0.0155).LVI and tumour size emerged as the most powerful independent predictors of ALNM, followed by the location of the tumour in the breast and the presence of multiple foci.

Measuring CA15.3 serum levels in the early breast cancer setting is not recommended by current ASCO guidelines. In this large single center study, we assess the prognostic value of preoperative (n = 3746), postoperative (n = 4049) and change in (n = 3252) CA15.3, also across different breast cancer phenotypes. Preoperative, postoperative and change in CA15.3 were all significant (p = 0.0348, p < 0.0001, p < 0.0001 respectively in multivariate analysis) predictors of distant metastasis free survival. For breast cancer specific survival, only postoperative and change in CA15.3 were significant predictors (p < 0.0001 both). Multivariate prognostic models did not improve by incorporating information on preoperative CA15.3, but did improve when introducing information on postoperative CA15.3 for distant metastasis (p = 0.0365) and on change in CA15.3 for breast cancer specific survival (p = 0.0291). Change in CA15.3 impacts on prognosis (distant metastasis) differently in different breast cancer phenotypes. A decrease in CA15.3 may be informative of improved prognosis in basal like and HER2 like breast cancer.

Aims: Investigate the role of expansile versus infiltrative type of primary invasive intestinal type mucinous epithelial ovarian carcinoma (mEOC) in predicting recurrence and lymph node metastases. Methods: Retrospective study. Differentiation was defined according to the Shimizu-Silverberg and expansile/infiltrative type according to the Lee-Scully criteria. Results: Out of 104 patients with mucinous ovarian carcinomas, 44 primary invasive mucinous epithelial carcinomas of the intestinal type (mEOC) were identified. Patients with a mEOC of the expansile type are mainly diagnosed in stage I (21 out 23) and have an excellent prognosis (no relapses in 21 Stage I patients). Patients with mEOC tumours of the infiltrative type are less frequently diagnosed in stage I (12 out of 21) and 2 recurrences were noted out of 12 Stage I patients. Lymph node metastases were not observed in patients with apparent Stage I disease of the expansile type, but were present in 3 out 10 patients with infiltrative disease. Degree of differentiation did not predict recurrence or the presence of lymph node metastases. Prognosis was poor in patients with Stage II or higher disease, irrespective of type of infiltration. Conclusions: Expansile mEOC is mainly diagnosed in stage I and is not associated with lymph node metastases. Infiltrative mEOC has a worse prognosis and is associated with lymph node metastases. Degree of differentiation was unreliable in predicting recurrence or lymph node metastases. (C) 2012 Elsevier Ltd. All rights reserved

Objective To report on the feasibility of assessing cardiac structures on post-mortem 3-tesla MRI (pmMRI) and to provide morphometric data in fetuses without cardiac abnormalities. Methods Retrospective single center study on 3T pmMRI of 39 consecutive fetuses without cardiac abnormalities (13–38weeks of gestation). Fetal cardiac anatomy was assessed and measurements of cardiac structures were performed on T2-weighted 3D multiplanar reconstructed images. Linear regression analysis was performed to examine changes of cardiac dimensions during gestation. Results The four-chamber view of the fetal heart could be obtained and the measurements of cardiac chambers and ventricular walls could be performed in all 39 cases. The aorta and the pulmonary artery were visualized and their diameters were measured in 38 (97.4%) fetuses, ductus arteriosus in 32 (82%). All measurements showed strong linear correlation with gestational age. The relationship of the diameters of the pulmonary artery, aorta, and ductus arteriosus remained constant over pregnancy. All these observations are consistent with what is known from prenatal ultrasound. Conclusions The present study proves the feasibility of visualizing normal cardiac structures on 3-tesla pmMRI in fetuses beyond 14weeks. We provide morphometric data that may enable diagnostic evaluation of cardiac abnormalities on pmMRI. © 2013 John Wiley & Sons, Ltd.

We report the prenatal sonographic detection of a fetus with megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephaly. Only 14 patients have been reported in the literature so far, all but one were diagnosed postnatally. The polymicrogyria in the frontoparietal lobe was confirmed by prenatal magnetic resonance imaging. Additionally, a hypoplastic thymus as seen in a 22q11 deletion was present. Although polymicrogyria along with pre-axial polydactyly has been described in 22q11 deletion, the diagnosis of Di George syndrome was ruled out. The etiology of megalencephaly, polymicrogyria, postaxial polydactyly and hydrocephaly has not been revealed yet. A dominant as well as recessive inheritance has been suggested. © 2013 John Wiley & Sons, Ltd.

In this manuscript we report 3 cases of severe lower urinary tract obstruction diagnosed before 20 weeks of pregnancy. All cases had a very similar prenatal presentation with a megacystis, bilateral hydro-ureteronephrosis and increased echogenicity of the kidneys. High-resolution postmortem magnetic resonance imaging (MRI), following termination of pregnancy, enabled accurate investigation of the underlying cause of the urinary tract obstruction, by depicting the presence of an urethral valve, urethral atresia and cloacal dysgenesis. Postmortem fetal MRI provides high anatomical detail and is very suitable to investigate congenital anomalies of the lower urinary tract. In case (timely or consented) conventional autopsy is not possible, MRI is an excellent alternative.

Objective. Endometrial cancer patients may benefit from systemic adjuvant chemotherapy, alone or in combination with targeted therapies. Prognostic and predictive markers are needed, however, to identify patients amenable for these therapies. Methods. Primary endometrial tumors were genotyped for > 100 hot spot mutations in genes potentially acting as prognostic or predictive markers. Mutations were correlated with tumor characteristics in a discovery cohort, replicated in independent cohorts and finally, confirmed in the overall population (n = 1063). Results. PIK3CA, PTEN and KRAS mutations were most frequently detected, respectively in 172 (16.2%), 164 (15.4%) and 161 (15.1%) tumors. Binary logistic regression revealed that PIK3CA mutations were more common in high-grade tumors (OR = 2.03; P = 0.001 for grade 2 and OR = 1.89; P = 0.012 for grade 3 compared to grade 1), whereas a positive TP53 status correlated with type II tumors (OR = 11.92; P

Background/Aims: We updated human chorionic gonadotropin (hCG) regression curves created in the eighties after evacuation of complete and partial molar (CM and PM, respectively) pregnancies using modern hCG assays. We created similar curves for patients in need of chemotherapy (gestational trophoblastic neoplasia [GTN]). Methods: A total of 126 patients who were diagnosed with gestational trophoblastic disease from 1990 to 2014 were included. We compared curves from 2 groups, CM and PM, with historical ones. The third group was a comparison of GTN patients receiving first-line chemotherapy and patients in need of a switch of chemotherapy. Results: The regression curves were comparable to historical ones. According to the latter, mean time to normalization was 14-15 weeks after evacuation. We observed a normalization within 12 (CM) and 12.7 (PM) weeks. In addition, a remarkable but not statistically significant vertical shift (20 IU/L higher) was observed prior to day 60 compared with historical curves. The comparison in GTN patients showed a statistical significant difference, even at day 7. Conclusion: The presented hCG regression curves in the Flemish region were comparable with the ones of the eighties but with a vertical shift, hypothetically due to more sensitive assays. In addition, regression curves in GTN patients receiving chemotherapy can be used to evaluate response.

International audience; Background/Aim: Human epidermal growth factor receptor 2 (HER2) positivity is associated with a worse prognosis in endometrial cancer (EC). Trastuzumab as a single agent did not demonstrate activity in such cases but there are no reports on its combined use with taxanes. We report the outcome in patients treated simultaneously with trastuzumab and paclitaxel for advanced or recurrent HER2-positive endometrial carcinoma and compared it to their microsatellite instability (MSI) status and PIK3CA mutational profiles. Patients and Methods: Patients with advancedor recurrent endometrial carcinoma showing HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (fluorescence in situ hybridization (FISH) HER2/chromosome 17 centromere (CEP 17) ratio >2.0) were treated with trastuzumab (8 mg/kg) and paclitaxel (90 mg/m2) every three weeks. Evaluation of the response was assessed according to the response evaluation criteria in solid tumors (RECIST) guidelines. Endometrial tumors, sampled before the beginning of trastuzumab, were genotyped for PIK3CA hot spot mutations using Sequenom iPLEX Assay technology. Results: Two uterine serous adenocarcinomas and one grade 3 endometrioid adenocarcinoma showing HER2 positivity were treated with trastuzumab and paclitaxel. Between three and seven months of treatment, the three cases showed progressive disease. The genomic analysis of the three cases showed different mutational profiles. One case was found to have MSI and had one PIK3CA mutation. The two others showed no hot spot mutation for PIK3CA. Conclusion: Even associated with paclitaxel, HER2-positive endometrial carcinomas poorly responded to trastuzumab. This report underlines the low accuracy of HER2 positivity to predict response of endometrial cancer to combined targeted therapy using trastuzumab and paclitaxe

BACKGROUND: The five prognostic surrogate phenotypes, defined by the 2011 St Gallen consensus, predict metastatic relapse following early breast cancer treatment (Brouckaert et al Ann Oncol 2012). It is unknown to what extent these surrogate phenotypes defined on the primary tumor predict metastatic survival (MS) in a cohort of consecutive women with metachronous metastases. PATIENTS & METHODS: All 4318 patients with primary operable breast cancer, diagnosed between 01–01-2000 and 31–12-2009 and treated in our center were prospectively entered in our institutional database. We included 345 patients with a (distant) metastatic relapse during their follow-up. We observed metastatic survival as the time between the diagnosis of the relapse and death. Tumor subtype was defined according to the 2011 St Gallen recommendations in 5 groups: luminal A (ER+/HER2−, grade 1–2), luminal B1 (ER+/HER2−, grade 3), luminal B2 or luminal-HER2 (ER+/HER2+), HER2-like (ER−/HER2−) and triple-negative. We focused on the value of the primary tumor subtype as a major prognostic determinant, but also assessed age at diagnosis, tumor size, lymph node involvement, tumor subtype, PR-status, primary detection (screening vs. palpation), histology, adjuvant therapy, distant-metastasis free interval (DMFI), first-line metastatic hormonal therapy, recurrence sites (isolate or multiple) and metastasis detection (clinical vs. biochemical). RESULTS: In our cohort, we recorded a median metastatic survival (MS) of 22.3 months (95% CI: 19.7–25.6) and a 5-year survival probability of 15%. Significant differences in median MS were noted when considering the primary tumor subtype (cf. table). We observed an independent prognostic effect for multiple recurrence sites (HR = 1.78, 95% CI 1.37–2.32), first-line metastatic hormonal therapy (HR = 0.30, 95% CI 0.18–0.49), DMFI (HR = 0.92 CI 0.85–0.98) and, finally, primary tumor subtype. CONCLUSION: Our results showed that primary tumor subtype, DMFI, solitary recurrence and first-line metastatic hormonal therapy act as independent prognostic factors in metastatic breast cancer. In order to overcome the biological complexity of metastatic breast cancer, we must appreciate the primary tumor subtype in our therapeutic approach. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-12.

Background Many easily measurable and readily available factors are now established as being prognostic in primary operable breast cancer. We here applied the 2011 St Gallen surrogate definition for breast cancer subclassification using tumor grade instead of Ki67. Patients and methods Four thousand three hundred and eighteen consecutive patients who had surgery for primary operable breast cancer (1 January 2000 and 31 December 2009) in UZ Leuven excluding primary metastastic male breast cancers and those receiving neoadjuvant therapy. Five different surrogate phenotypes were created using the combined expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor-2 together with tumor grade. Disease-free interval (DFI), distant metastastis-free interval (DMFI), locoregional relapse-free interval (LRRFI), breast cancer-specific survival (BCSS) and overall survival (OS) were calculated. Results Surrogate phenotypes present with significant differences in DFI, DMFI, LRRFI, BCSS and OS. ‘Luminal A’ tumors presented with the best outcome parameters but the effect weakened at longer follow-up. Conclusions The four surrogate markers, agreed upon by the 2011 St Gallen consensus, defined five prognostic surrogate phenotypes in a large series of consecutively treated breast cancer patients. Their prognostic value changed with longer follow-up. The added value of gene expression profile over classical pathological assessment remains to be defined.

Introduction Worldwide, breast cancer is the most frequently diagnosed cancer in women and the leading cause of cancer death, accounting for 23% of total cancer cases and 14% of cancer deaths. Lymph node involvement is the most important prognostic factor and varies with several tumor and patient characteristics (ie, age at diagnosis, tumor size, tumor type, tumor grade, lymphovascular invasion, multifocality, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [HER-2] status). Factors o be considered in clinical decision making include not only