Driver mutations in GNAQ and GNA11 genes as potential targets for precision immunotherapy in uveal melanoma patients.

Uveal melanoma (UM) is the most common ocular malignancy in adults. Nearly 95% of UM patients carry the mutually exclusive mutations in the homologous genes GNAQ (amino acid change Q209L/Q209P) and GNA11 (aminoacid change Q209L). UM is located in an immunosuppressed organ and does not suffer immunoediting. Therefore, we hypothesize that driver mutations in GNAQ/11 genes could be recognized by the immune system. Genomic and transcriptomic data from primary uveal tumors were collected from the TCGA-UM dataset (n = 80) and used to assess the immunogenic potential for GNAQ/GNA11 Q209L/Q209P mutations using a variety of tools and HLA type information. All prediction tools showed stronger GNAQ/11 Q209L binding to HLA than GNAQ/11 Q209P. The immunogenicity analysis revealed that Q209L is likely to be presented by more than 73% of individuals in 1000 G databases whereas Q209P is only predicted to be presented in 24% of individuals. GNAQ/11 Q209L showed a higher likelihood to be presented by HLA-I molecules than almost all driver mutations analyzed. Finally, samples carrying Q209L had a higher immune-reactive phenotype. Regarding cancer risk, seven HLA genotypes with low Q209L affinity show higher frequency in uveal melanoma patients than in the general population. However, no clear association was found between any HLA genotype and survival. Results suggest a high potential immunogenicity of the GNAQ/11 Q209L variant that could allow the generation of novel therapeutic tools to treat UM like neoantigen vaccinations.

Prognostic Role of Neutrophil, Monocyte and Platelet to Lymphocyte Ratios in Advanced Ovarian Cancer According to the Time of Debulking Surgery.

Despite a multimodal radical treatment, mortality of advanced epithelial ovarian cancer (AEOC) remains high. Host-related factors, such as systemic inflammatory response and its interplay with the immune system, remain underexplored. We hypothesized that the prognostic impact of this response could vary between patients undergoing primary debulking surgery (PDS) and those undergoing interval debulking surgery (IDS). Therefore, we evaluated the outcomes of two surgical groups of newly diagnosed AEOC patients according to the neutrophil, monocyte and platelet to lymphocyte ratios (NLR, MLR, PLR), taking median ratio values as cutoffs. In the PDS group (n = 61), low NLR and PLR subgroups showed significantly better overall survival (not reached (NR) vs. 72.7 months, 95% confidence interval [CI]: 40.9-95.2, p = 0.019; and NR vs. 56.1 months, 95% CI: 40.9-95.2, p = 0.004, respectively) than those with high values. Similar results were observed in progression free survival. NLR and PLR-high values resulted in negative prognostic factors, adjusting for residual disease, BRCA1/2 status and stage (HR 2.48, 95% CI: 1.03-5.99, p = 0.043, and HR 2.91, 95% CI: 1.11-7.64, p = 0.03, respectively). In the IDS group (n = 85), ratios were not significant prognostic factors. We conclude that NLR and PLR may have prognostic value in the PDS setting, but none in IDS, suggesting that time of surgery can modulate the prognostic impact of baseline complete blood count (CBC).

Exploring the Immunogenicity of Noncanonical HLA-I Tumor Ligands Identified through Proteogenomics.

PURPOSE: Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from noncanonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. EXPERIMENTAL DESIGN: Peptides presented on HLA-I were identified in 9 patient-derived tumor cell lines from melanoma, gynecologic, and head and neck cancer through proteogenomics. A total of 507 candidate tumor antigens, including nonC-TL, neoantigens, cancer-germline, or melanocyte differentiation antigens, were tested for T-cell recognition of preexisting responses in patients with cancer. Donor peripheral blood lymphocytes (PBL) were in vitro sensitized against 170 selected nonC-TL to isolate antigen-specific T-cell receptors (TCR) and evaluate their therapeutic potential. RESULTS: We found no recognition of the 507 nonC-TL tested by autologous ex vivo expanded tumor-reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However, in vitro sensitization of donor PBL against 170 selected nonC-TL, led to the identification of TCRs specific to three nonC-TL, two of which mapped to the 5' UTR regions of HOXC13 and ZKSCAN1, and one mapping to a noncoding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. CONCLUSIONS: Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies. See related commentary by Fox et al., p. 2173.

Biomarkers of tumor-reactive CD4+ and CD8+ TILs associate with improved prognosis in endometrial cancer.

BACKGROUND: Despite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear. METHODS: To better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8+ and CD4+ EC-resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8+ and CD4+ TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8+ and CD4+ tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival. RESULTS: We found that CD8+TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1- and PD-1dim, respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8+PD-1dimCD39+ and PD-1hiCD39+ T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4+ T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1hi compared with PD-1- or PD-1dim T cells, and in fact, it was the CD4+PD-1hi subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8+PD-1hiCD39+ and CD4+PD-1hi tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1hi, CD39, CXCL13 and CD103 by CD8+ TILs and PD-1hi and CXCL13 by CD4+ Tconv TILs, correlated with prolonged survival of patients with EC. CONCLUSIONS: Our results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1hi and CD39 or PD-1hi can be used to select and expand CD8+ and CD4+ tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3+, CD8+ and CD4+ lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity.

Local Resection in Choroidal Melanoma: A Review.

Surgical resection is widely used to treat small tumours located in the iris and the ciliary body, due to the accessibility of these sites. By contrast, surgical removal of choroidal tumours is substantially more challenging, which is why this procedure is performed only at specialised centres. In the present article, we review the literature on surgical resection of choroidal tumours, which can be performed as endoresection (ab interno) or transscleral resection (ab externo). An important aim of this review is to describe and compare the two approaches in terms of visual outcomes, survival rates, and complications. Both approaches are indicated for the removal of large tumours (thickness > 8 mm) with small base diameters. Surgical resection of the tumour allows clinicians to obtain valuable histopathologic and cytogenetic data from the specimen and eliminates the risks associated with radiotherapy. However, both of these surgical approaches are technically challenging procedures involving the risk of severe early and late postoperative complications.

Combination of chemotherapy with BRAF inhibitors results in effective eradication of malignant melanoma by preventing ATM-dependent DNA repair.

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.

Characterization of the Endometrial MSC Marker Ectonucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2/CD39L1) in Low- and High-Grade Endometrial Carcinomas: Loss of Stromal Expression in the Invasive Phenotypes.

Ectonucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) has been described in human non-pathological endometrium in both epithelial and stromal components without changes along the cycle. It was identified as a stromal marker of basalis. In the present study, we aimed to evaluate NTPDase2 distribution, using immunolabeling and in situ enzyme activity approaches, in endometrial carcinoma (EC) at different tumor grades. NTPDase2 was present in tumor epithelial EC cells, as in the non-pathological endometria, but the expression underwent changes in subcellular distribution and also tended to decrease with the tumor grade. In stroma, NTPDase2 was identified exclusively at the tumor-myometrial junction but this expression was lost in tumors of invasive phenotype. We have also identified in EC samples the presence of the perivascular population of endometrial mesenchymal stem cells (eMSCs) positive for sushi domain containing 2 (SUSD2) and for NTPDase2, already described in non-tumoral endometrium. Our results point to NTPDase2 as a histopathological marker of tumor invasion in EC, with diagnostic relevance especially in cases of EC coexisting with other endometrial disorders, such as adenomyosis, which occasionally hampers the assessment of tumor invasion parameters.

PSA Kinetics as Prognostic Markers of Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate.

BACKGROUND: Abiraterone acetate (AA) is widely used in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). However, a significant percentage of patients will still progress, highlighting the need to identify patients more likely to benefit from AA. Parameters linked to prostate-specific antigen (PSA) kinetics are promising prognostic markers. We have examined clinical and PSA-related factors potentially associated with overall survival (OS) in patients treated with AA. METHODS: Between 2011 and 2014, 104 patients with mCRPC treated with AA after progression to docetaxel at centers of the Catalan Institute of Oncology were included in this retrospective study. Patients were assessed monthly. Baseline characteristics and variables related to PSA kinetics were included in univariate and multivariate analyses of OS. RESULTS: Median OS was 16.4 months (range 12.4-20.6) for all patients. The univariate analysis identified the following baseline characteristics as significantly associated with OS: ECOG PS, location of metastases, time between starting androgen deprivation therapy and starting AA, time between stopping docetaxel treatment and starting AA, neutrophil-lymphocyte ratio (NLR), alkaline phosphatase levels, and PSA levels. Factors related to PSA kinetics associated with longer OS were PSA response >50%, early PSA response (>30% decline at four weeks), PSA decline >50% at week 12, PSA nadir <2.4ng/mL, time to PSA nadir >140 days, the combination of PSA nadir and time to PSA nadir, and low end-of-treatment PSA levels. The multivariate analysis identified ECOG PS (HR 37.46; p<0.001), NLR (HR 3.7; p<0.001), early PSA response (HR 1.22; p=0.002), and time to PSA nadir (HR 0.39; p=0.002) as independent prognostic markers. CONCLUSION: Our results indicate an association between PSA kinetics, especially early PSA response, and outcome to AA after progression to docetaxel. Taken together with other factors, lack of an early PSA response could identify patients who are unlikely to benefit from AA and who could be closely monitored with a view to offering alternative therapies.

Are antiangiogenics a good 'partner' for immunotherapy in ovarian cancer?

Ovarian cancer (OC) is associated with poor survival because there are a limited number of effective therapies. Two processes key to OC progression, angiogenesis and immune evasion, act synergistically to promote tumor progression. Tumor-associated angiogenesis promotes immune evasion, and tumor-related immune responses in the peritoneal cavity and tumor microenvironment (TME) affect neovascular formation. Therefore, suppressing the angiogenic pathways could facilitate the arrival of immune effector cells and reduce the presence of myeloid cells involved in immune suppression. To date, clinical studies have shown significant benefits with antiangiogenic therapy as first-line therapy in OC, as well as in recurrent disease, and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab is now an established therapy. Clinical data with immunomodulators in OC are more limited, but suggest that they could benefit some patients with recurrent disease. The preliminary results of two phase III trials have shown that the addition of immunomodulators to chemotherapy does not improve progression-free survival. For this reason, it could be interesting to look for synergistic effects between immunomodulators and other active drugs in OC. Since bevacizumab is approved for use in OC, and is tolerable when used in combination with immunotherapy in other indications, a number of clinical studies are underway to investigate the use of bevacizumab in combination with immunotherapeutic agents in OC. This strategy seeks to normalize the TME via the anti-VEGF actions of bevacizumab, while simultaneously stimulating the immune response via the immunotherapy. Results of these studies are awaited with interest.

Lung metastases share common immune features regardless of primary tumor origin.

BACKGROUND: Only certain disseminated cells are able to grow in secondary organs to create a metastatic tumor. Under the hypothesis that the immune microenvironment of the host tissue may play an important role in this process, we have categorized metastatic samples based on their immune features. METHODS: Gene expression data of metastatic samples (n=374) from four secondary sites (brain, bone, liver and lung) were used to characterize samples based on their immune and stromal infiltration using gene signatures and cell quantification tools. A clustering analysis was done that separated metastatic samples into three different immune categories: high, medium and low. RESULTS: Significant differences were found between the immune profiles of samples metastasizing in distinct organs. Metastases in lung showed a higher immunogenic score than metastases in brain, liver or bone, regardless of their primary site of origin. Also, they preferentially clustered in the high immune group. Samples in this cluster exhibited a clear inflammatory phenotype, higher levels of immune infiltrate, overexpression of programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) pathways and upregulation of genes predicting clinical response to programmed cell death protein 1 (PD-1) blockade (T-cell inflammatory signature). A decision tree algorithm was used to select CD74 as a biomarker that identify samples belonging to this high-immune subtype of metastases, having specificity of 0.96 and sensitivity of 1. CONCLUSIONS: We have found a group of lung-enriched metastases showing an inflammatory phenotype susceptible to be treated with immunotherapy.

Sensitivity of cervico-vaginal cytology in endometrial carcinoma: A systematic review and meta-analysis.

Cervico-vaginal cytology is primarily a cervical cancer screening test. The anatomical continuity of the uterine cavity with the cervix makes the Papanicolaou (Pap) test accessible to evaluate signs of disease shed from the endometrium. Our aim was to determine the sensitivity of routine Pap test in endometrial carcinoma detection and its relationship with clinico-pathologic factors. We performed a systematic review of studies reporting Pap test results prior to diagnosis of or surgery for endometrial carcinoma between 1990 and 2018 in PubMed or Web of Science. Two independent reviewers extracted data and assessed study quality using an adapted Newcastle-Ottawa Quality Assessment Scale and Quality Assessment of Diagnostic Accuracy Studies tool. We identified 45 studies including a total of 6599 women with endometrial cancer. Abnormal Pap test results prior to diagnosis of or surgery for endometrial carcinoma were observed in 45% (95% CI, 40%-50%) of study participants. This percentage was significantly higher among those of non-endometrioid histology compared with endometrioid subtypes (77% [95% CI, 66%-87%] vs 44% [95% CI, 34%-53%], respectively; P heterogeneity <.001). Several clinico-pathologic factors were related to a higher percentage of abnormal Pap test results, including high-stage, myometrial invasion >50%, high histological grade, positive peritoneal cytology, presence of lymph node metastasis, cervical involvement, and lymphovascular invasion (P heterogeneity <.05 for all variables). Routine cervical cytology can detect endometrial cancer in almost half of patients, whereas sensitivity is higher among individuals with non-endometrioid histology or more advanced cancers. This review summarizes the current clinical and prognostic value of cervical cytology in endometrial carcinoma. Recent technological developments using molecular biomarkers may improve accuracy for early cancer detection.

Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study.

PURPOSE: Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase II TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. PATIENTS AND METHODS: TRITON2 enrolled patients who had progressed on one or two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and PSA response (≥50% decrease from baseline). RESULTS: TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration [ATM (n = 49), CDK12 (n = 15), CHEK2 (n = 12), and other DDR genes (n = 14)]. Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM [2/19 (10.5%) and 2/49 (4.1%), respectively], CDK12 [0/10 (0%) and 1/15 (6.7%), respectively], or CHEK2 [1/9 (11.1%) and 2/12 (16.7%), respectively], including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. CONCLUSIONS: In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (e.g., PALB2) may benefit from PARP inhibition.See related commentary by Sokolova et al., p. 2439.

Uveal Melanoma, Angiogenesis and Immunotherapy, Is There Any Hope?

Uveal melanoma is considered a rare disease but it is the most common intraocular malignancy in adults. Local treatments are effective, but the systemic recurrence rate is unacceptably high. Moreover, once metastasis have developed the prognosis is poor, with a 5-year survival rate of less than 5%, and systemic therapies, including immunotherapy, have rendered poor results. The tumour biology is complex, but angiogenesis is a highly important pathway in these tumours. Vasculogenic mimicry, the ability of melanomas to generate vascular channels independently of endothelial cells, could play an important role, but no effective therapy targeting this process has been developed so far. Angiogenesis modulates the tumour microenvironment of melanomas, and a close interplay is established between them. Therefore, combining immune strategies with drugs targeting angiogenesis offers a new therapeutic paradigm. In preclinical studies, these approaches effectively target these tumours, and a phase I clinical study has shown encouraging results in cutaneous melanomas. In this review, we will discuss the importance of angiogenesis in uveal melanoma, with a special focus on vasculogenic mimicry, and describe the interplay between angiogenesis and the tumour microenvironment. In addition, we will suggest future therapeutic approaches based on these observations and mention ways in which to potentially enhance current treatments.

Defining a mutational signature for endometrial cancer screening and early detection.

INTRODUCTION: The current availability of genomic information represents an opportunity to develop new strategies for early detection of cancer. New molecular tests for endometrial cancer may improve performance and failure rates of histological aspirate-based diagnosis, and provide promising perspectives for a potential screening scenario. However, the selection of relevant biomarkers to develop efficient strategies can be a challenge. MATERIALS AND METHODS: We developed an algorithm to identify the largest number of patients with endometrial cancer using the minimum number of somatic mutations based on The Cancer Genome Atlas (TCGA) dataset. RESULTS: The algorithm provided the number of subjects with mutations (sensitivity) for a given number of biomarkers included in the signature. For instance, by evaluating the 50 most representative point mutations, up to 81.9% of endometrial cancers can be identified in the TCGA dataset. At gene level, a 92.9% sensitivity can be obtained by interrogating five genes. DISCUSSION: We developed a computational method to aid in the selection of relevant genomic biomarkers in endometrial cancer that can be adapted to other cancer types or diseases.

Clinical predictors of survival in metastatic uveal melanoma.

PURPOSE: To determine the clinical factors that influence survival in patients with metastatic uveal melanoma. STUDY DESIGN: Single-center, retrospective review of patients' medical records. METHODS: The following data of ninety-nine consecutive patients (49 men, 50 women) with metastatic uveal melanoma were registered: patient demographics; primary tumor characteristics; features of first melanoma-related metastasis; symptoms and patient status at distant disease debut and metastasis treatment. Overall survival was analyzed by Kaplan-Meier estimates. A Cox proportional hazards regression model was applied to identify independent predictors associated with survival. RESULTS: Mean patient age at metastatic diagnosis was 60.7 years (standard deviation, 12.8). The liver was the first metastatic site in most (92.9%) cases. The median disease-free interval was 26 months (interquartile range, 34). Median overall survival after detection of the first metastasis was 8 months (interquartile range, 14). The baseline characteristics of the primary uveal melanoma were not associated with survival in patients with stage IV disease. In the multivariate analysis, the following factors at first metastatic diagnosis were associated with improved overall survival: disease-free interval > 36 months; better performance status; and normal serum lactate dehydrogenase and gamma glutamyl transpeptidase levels. Overall survival was not influenced by specific metastatic treatment. CONCLUSION: Although metastatic uveal melanoma has a poor prognosis, this study reveals the existence of several independent prognostic factors for prolonged overall survival. These findings may help improve survival estimates in patients with advanced disease.

Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (<1%) in the placebo group (arrhythmia). INTERPRETATION: The addition of radium-223 to abiraterone acetate plus prednisone or prednisolone did not improve symptomatic skeletal event-free survival in patients with castration-resistant prostate cancer and bone metastases, and was associated with an increased frequency of bone fractures compared with placebo. Thus, we do not recommend use of this combination. FUNDING: Bayer.

PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes. PATIENTS AND METHODS: Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored. RESULTS: We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers. CONCLUSION: g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.

A Phase 1 Trial of Oncolytic Adenovirus ICOVIR-5 Administered Intravenously to Cutaneous and Uveal Melanoma Patients.

Oncolytic viruses represent a unique type of agents that combine self-amplification, lytic, and immunostimulatory properties against tumors. A local and locoregional clinical benefit has been demonstrated upon intratumoral injections of an oncolytic herpes virus in melanoma patients, leading to its approval in the United States and Europe for patients without visceral disease (up to stage IVM1a). However, in order to debulk and change the local immunosuppressive environment of tumors that cannot be injected directly, oncolyitc viruses need to be administered systemically. Among different viruses, adenovirus has been extensively used in clinical trials but with few evidences of activity upon systemic administration. Preclinical efficacy of a single intravenous administration of our oncolytic adenovirus ICOVIR5, an adenovirus type 5 responsive to the retinoblastoma pathway commonly deregulated in tumors, led us to use this virus in a dose-escalation phase 1 trial in metastatic melanoma patients. The results in 12 patients treated with a single infusion of a dose up to 1 × 1013 viral particles show that ICOVIR5 can reach melanoma metastases upon a single intravenous administration but fails to induce tumor regressions. These results support the systemic administration of armed oncolytic viruses to treat disseminated cancer.

Tumor Heterogeneity in Endometrial Carcinoma: Practical Consequences.

Endometrial carcinoma (EC) shows intertumor heterogeneity, with several different histologic types differing in their morphologic and molecular features. There is also intratumoral morphologic heterogeneity, with different neoplastic cell components within the same tumor, with different morphologic and molecular features. In this article, we discuss the consequences of tumor heterogeneity in EC at the morphologic and molecular levels, by describing some illustrative examples produced by the research team. They are (1) morphologic heterogeneity in conventional EC and mixed tumors, (2) EC with microsatellite instability, (3) branched evolution as shown by exome sequencing analysis, (4) morphologic, molecular, and metabolomic differences between the tumor surface and myometrial invasion front, (5) tumor heterogeneity at the microenviromental level, (6) the sensitivity of endometrial aspirates to detect tumor heterogeneity in EC, and (7) sampling strategies to detect tumor heterogeneity in hysterectomy specimens. Tumor heterogeneity may have an important clinical impact, since it can be challenging to identify minor tumor cell populations that may have an impact on diagnosis, prognosis, and therapeutic decisions for patients with EC.