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Background Radiotherapy and cisplatin-based combination chemotherapy are accepted standard-of-care treatments for metastatic seminoma with excellent survival outcomes but with established short- and long-term morbidity. Carboplatin monotherapy may be a less toxic alternative; however early historic studies at AUC7 showed inferior outcomes. Objectives To evaluate multi-institutional data on and toxicity and longer-term survival for metastatic seminoma patients treated with the single-agent carboplatin AUC10. Methods We undertook a multi-institutional analysis incorporating all men with the International Germ Cell Cancer Collaborative Group good-prognosis metastatic seminoma treated until 2018. Carboplatin AUC10 was given every 21 days. Toxicity, progression-free survival (PFS), disease-specific survival (DSS) and overall survival were noted. Variables predictive of progression were identified. Results and limitations 216 patients were treated. The three-year PFS rate was 96.5%, and five-year DSS was 98.3%. There were seven relapses, of which 5 were successfully salvaged with further chemotherapy ± surgery, and three non-seminoma–related deaths. There were no treatment-related deaths. Of 148/216 evaluable patients for toxicity, 37% and 27% suffered >/ = grade III neutropenia and thrombocytopenia, respectively. Twelve percent of patients needed a platelet or blood transfusion (or both). The incidence of febrile neutropenia was 5%. Conclusion For metastatic seminoma, carboplatin AUC10 harbours a similar oncological efficacy to established therapies, with a low failure risk. The major acute toxicity was myelosuppression. Our study establishes carboplatin AUC10 as another standard-of-care treatment option for good-prognosis metastatic seminoma, with a potentially lower toxicity profile than other therapies.

Fig. S7. Dose-response curves and clinical responses. (A) Dose-response curves of primary tumor cultures performed for patient 4-7, 9 and 10. The chemotherapeutic agent that was given to the patient is depicted in color the rest of the screened chemotherapeutics is depicted with a gray line and colored dots. (B) CT-scans of patient 4-7, 9 and 10 before and after treatment with the drugs selected based on the in vitro drug screen. Response evaluation was done using modified RECIST for mesothelioma. Colored boxes around CT-scans indicate in vitro response prediction before treatment and actual response after treatment. Green: partial response, yellow: stable disease, red: progressive disease. Tumor-rinds are indicated by red line.

Table S5. List of differential expressed genes. Symbol and gene name of differential expressed genes between the responder and the non-responder groups. 57 DEGs could not be identified by Ingenuity pathway analysis.

Purpose: Finding new treatment options for patients with malignant pleural mesothelioma is challenging due to the rarity and heterogeneity of this cancer type. The absence of druggable targets further complicates the development of new therapies. Current treatment options are therefore limited, and prognosis remains poor.Experimental Design: We performed drug screening on primary mesothelioma cultures to guide treatment decisions of corresponding patients that were progressive after first- or second-line treatment.Results: We observed a high concordance between in vitro results and clinical outcomes. We defined three subgroups responding differently to the anticancer drugs tested. In addition, gene expression profiling yielded distinct signatures that segregated the differently responding subgroups. These genes signatures involved various pathways, most prominently the fibroblast growth factor pathway.Conclusions: Our primary mesothelioma culture system has proved to be suitable to test novel drugs. Chemical profiling of primary mesothelioma cultures allows personalizing treatment for a group of patients with a rare tumor type where clinical trials are notoriously difficult. This personalized treatment strategy is expected to improve the poor prospects of patients with mesothelioma. Clin Cancer Res; 24(7); 1761–70. ©2017 AACR.See related commentary by John and Chia, p. 1513

Figure S1. A subset MPM cell lines respond to FGFR inhibition. A) AZD4547 at a fixed dose of 500nM and B) BGJ-398 at a fixed dose of 300nM. Figure S2. A subset of pleural fluid derived early passage primary cultures (EPL) respond to FGFR inhibition. Figure S3. BAP1 mutation status does not correlate fully with protein expression. Figure S4. BAP1 null cell lines show increased activity of multiple receptor tyrosine kinases. Figure S5. FGF9 activates FGFR3 and modulates growth and phenotype. Figure S6. Gene expression studies comparing H226 BAP1 C91 vs BAP1 wt construct cell line. Figure S7. xenograft Immunohistochemistry for ki67, Caspase 3 under various experimental conditions. Figure S8. Anchor based combination drug screen in MPM using Pi3 kinase inhibitor as anchor drug.

Supplemental legends

Supplementary Table , tab 1 List of compounds used in the chemical inhibitor screen. Supplementary table ,tab 2 SPIA pathway analysis performed highlighting significantly upregulated/downregulated pathways between BAP1 mutant and BAP1 wild type lines. Supplementary table, tab 3. GEO data analysis of 40 BAP1wt vs 11 BAP1mt mesothelioma tumours showing fold change in mRNA expression.

Purpose: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response.Experimental design: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models.Results: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples.Conclusions: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. Clin Cancer Res; 24(1); 84–94. ©2017 AACR.

Background and Aims Testicular Germ Cell Tumours (TGCTs) are the commonest young adult male cancer, with excellent survival outcomes even with metastatic disease. Chemotherapy, radiotherapy, and surgery are international guideline-dictated standard of care (SOC) treatments for International Germ Cell Cancer Collaborative Group (IGCCCG) “good risk” TGCT, but are associated with significant toxicities. Therapy de-escalation aims to reduce treatment morbidity whilst preserving cure rates, and has been adopted by some centres for stage IIA/B seminoma. Here, we report on the contemporary UK treatment landscape for stage IIA/B seminoma. Methods A questionnaire-based survey of NHS England-designated specialist cancer centres hosting supra-regional specialist multi-disciplinary team (sMDT) services (n = 13) as well those within NHS Scotland, NHS Wales and Health and Social Care Northern Ireland. Respondents were asked to order preferences of SOC and therapy de-escalation treatments for stage IIA/B seminoma. Results We identified significant geographical heterogeneity in treatment preferences. Whilst up to a third of centres have adopted a treatment de-escalation regimen, the majority deliver combination chemotherapy or radiotherapy. Conclusion A wider recognition of UK treatment heterogeneity and consideration of therapy de-escalation strategies at supra-regional sMDTs will increase stage IIA/B seminoma treatment options as part of clinical trials with oncological and quality of life endpoints.

To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour. Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction. RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND—median blood loss (50 versus 400 ml, p

To report the management outcomes of men with ≤20-mm small testicular masses (STMs) and to identify clinical and histopathological factors associated with malignancy.A retrospective analysis of men managed at a single centre between January 2010 and December 2020 with a STM ≤20 mm in size was performed.Overall, 307 men with a median (interquartile range [IQR]) age of 36 (30-44) years were included. Of these, 161 (52.4%), 82 (26.7%), 62 (20.2%) and 2 men (0.7%) underwent surveillance with interval ultrasonography (USS), primary excisional testicular biopsy (TBx) or primary radical orchidectomy (RO), or were discharged, respectively. The median (IQR) surveillance duration was 6 (3-18) months. The majority of men who underwent surveillance had lesions5 mm (59.0%) and no lesion vascularity (67.1%) on USS. Thirty-three (20.5%) men undergoing surveillance had a TBx based on changes on interval USS or patient choice; seven (21.2%) were found to be malignant. The overall rate of malignancy in the surveillance cohort was 4.3%. The majority of men who underwent primary RO had lesions ≥10 mm (85.5%) and the presence of vascularity (61.7%) on USS. Nineteen men (23.2%) who underwent primary TBx (median lesion size 6 mm) had a malignancy confirmed on biopsy and underwent RO. A total of 88 men (28.7%) underwent RO, and malignancy was confirmed in 73 (83.0%) of them. The overall malignancy rate in the whole STM cohort was 23.8%. Malignant RO specimens had significantly larger lesion sizes (median [IQR] 11 [8-15] mm, vs benign: median [IQR] 8 [5-10] mm; P = 0.04).Small testicular masses can be stratified and managed based on lesion size and USS features. The overall malignancy rate in men with an STM was 23.8% (4.3% in the surveillance group). Surveillance should be considered in lesions10 mm in size, with a TBx or frozen-section examination offered prior to RO in order to preserve testicular function.

BACKGROUND The option of semen cryopreservation following a diagnosis of testicular cancer shows a variable uptake with the option to cryopreserve before surgery often dependent on the preference of the treating clinician and the fertility laboratory resources available. OBJECTIVES To assess whether the introduction of a patient-centric pathway for managing suspected testicular cancer increases the uptake of semen cryopreservation and the impact of this on surgical waiting times. MATERIALS AND METHODS A multicentre retrospective analysis of patients treated as part of a patient-centric pathway was conducted for suspected testicular cancer at two specialist centres within a one-stop testicular clinic. Clinical information, including semen cryopreservation acceptance rate, time intervals to surgery and CT scan, TNM stage, histology and age, was recorded from an institutional database. RESULTS Eighty nine patients (median age: 34 years (range: 14-89)) underwent orchidectomy for suspected testicular cancer over a 15-month period after the introduction of a patient-centric testicular cancer pathway at two UK centres. The overall uptake of semen cryopreservation was 68.5% (n = 61) with all men under the age of 33 years accepting this option. A microdissection oncoTESE was performed in 9/61 (14.8%) patients who attempted cryopreservation but were found to be azoospermic. Pre-operative CT imaging was completed for 85.4% of patients, and the median time from initial outpatient consultation to orchidectomy was 9 days. DISCUSSION AND CONCLUSIONS A patient-centric pathway ensures that the uptake of semen cryopreservation remains high particularly for those men within the common age for paternity. It also identifies men who may benefit from microdissection oncoTESE for complex cases such as tumours in solitary testicles, bilateral tumours or an atrophic contralateral testicle as well as those diagnosed with de novo azoospermia. The additional time taken for semen cryopreservation to be performed did not significantly delay orchidectomy or influence the decisions for adjuvant treatment.

Germ-cell tumours of the testis affect predominantly younger males aged between 15 and 40 years, with nearly 74,500 new cases estimated globally in 2020. Their rarity and the complex morphology, mean that, in nonexpert hands, there is a significant risk of misdiagnosis of both type and staging of these neoplasms.There have been significant changes in the 2016 WHO classification of Testicular tumours that need to be understood by both pathologists and clinicians for streamlining management. Standardised structured reporting guidelines and discussion at the multidisciplinary-team meetings lead to subsequently better health outcomes and patient safety.Therefore, communication with high-quality reports and understanding of clinicians of what constitutes an adequate report, is the key to ensure proper management of these patients. We attempt to discuss the key updates and pathological features that influence management and need to be communicated with clarity and precision.

9 Background: The efficacy of neoadjuvant platinum-based chemotherapy (NAPC) in penile squamous cell carcinoma (PSCC) was provided by small clinical trials, leaving clinicians with scant evidence-based guidance. Thus, we aimed to analyze real-world outcomes of patients with PSCC who received NAPC prior to surgical resection. Methods: Patients from 9 tertiary care centers who had undergone NAPC prior surgical resection for PSCC were included with locally advanced (cTany, cN+), non-metastatic (M0) disease. The primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), Response was determined via best overall response measured with RECIST 1.1 criteria. Results: 167 patients were included, 137 (84%), of which received TIP prior to surgical resection. Ninety-two (55%) patients died during follow up, and the mean follow up for survivors was 57 months. The median OS was 42 months, while the median PFS was 17 months. The table details the response rates to NAPC, the associated survival, and Cox Proportional Hazards Modelling of OS and PFS. Predictors for OS and RFS included lymphovascular invasion, positive number of lymph nodes, extranodal extension, downstaging, best overall response, and ypN status. Figure 1 demonstrates OS outcomes by RECIST best response after chemotherapy, presence of downstaging after NAPC, ypN stage, and presence of extranodal extension. Conclusions: Upfront NAPC is effective in patients with lymph node metastases from penile carcinoma. Unsurprisingly, patients who demonstrated a robust response to therapy had improved survival outcomes compared to those who had not—as measured by RECIST criteria, tumor downstaging, pN staging, and presence of extranodal extension. This study represents the largest conglomeration of multi-institutional penile carcinoma patients treated with NAPC, and provides further supportive data for multimodal therapy for advanced penile cancer patients while prospective clinical trials complete accrual. [Table: see text]

Bladder cancer is a heterogeneous group of tumours with at least 40 histological subgroups. Patients with localized disease can be cured with surgical resection or radiotherapy, but such curative options are limited in the setting of recurrent disease or distant spread, in which case systemic therapy is used to control disease and palliate symptoms. Cytotoxic chemotherapy has been the mainstay of treatment for advanced bladder cancer, but high-quality evidence is lacking to inform the management of rare subgroups that are often excluded from studies. Advances in molecular pathology, the development of targeted therapies and the resurgence of immunotherapy have led to the reclassification of bladder cancer subgroups and rigorous efforts to define predictive biomarkers for cancer therapies. In this Review, we present the current evidence for the management of conventional, variant and divergent urothelial cancer subtypes, as well as non-urothelial bladder cancers, and discuss how the integration of genomic, transcriptomic and proteomic characterization of bladder cancer could guide future therapies.

To describe and compare differences in peri-operative outcomes of robot-assisted (RA-RPLND) and open (O-RPLND) retroperitoneal lymph node dissection performed by a single surgeon where chemotherapy is the standard initial treatment for Stage 2 or greater non-seminomatous germ cell tumour.Review of a prospective database of all RA-RPLNDs (28 patients) and O-RPLNDs (72 patients) performed by a single surgeon from 2014 to 2020. Peri-operative outcomes were compared for patients having RA-RPLND to all O-RPLNDs and a matched cohort of patients having O-RPLND (20 patients). Further comparison was performed between all patients in the RA-RPLND group (21 patients) and matched O-RPLND group (18 patients) who had previous chemotherapy. RA-RPLND was performed for patients suitable for a unilateral template dissection. O-RPLND was performed prior to the introduction of RA-RPLND and for patients not suitable for RA-RPLND after its introduction.RA-RPLND showed improved peri-operative outcomes compared to the matched cohort of O-RPLND-median blood loss (50 versus 400 ml, p 0.00001), operative duration (150 versus 195 min, p = 0.023) length-of-stay (1 versus 5 days, p 0.00001) and anejaculation (0 versus 4, p = 0.0249). There was no statistical difference in complication rates. RA-RPLND had lower median lymph node yields although not significant (9 versus 13, p = 0.070). These improved peri-operative outcomes were also seen in the post-chemotherapy RA-RPLND versus O-RPLND analysis. There were no tumour recurrences seen in either group with median follow-up of 36 months and 60 months, respectively.Post-chemotherapy RA-RPLND may have decreased blood loss, operative duration, hospital length-of-stay and anejaculation rates in selected cases and should, therefore, be considered in selected patients. Differences in oncological outcomes require longer term follow-up.

Highlights • In response to the dramatic impact of the COVID-19 pandemic on health care pathways and delivery, including delays in management of aggressive cancers, an international expert panel was convened to address the management pathways for patients with penile cancer. • This study reports the statements developed by the panel to reconfigure the management pathways for penile cancer patients during the COVID-19 acute waves. • The adaptation of the EAU and NCCN penile cancer guidelines for use in the setting of COVID-19 acute waves was guided mainly by 2 necessities: To minimize the numbers of hospital visits and hospitalization and to prevent COVID-19-related complications attributed to cancer treatment • A consensus was reached regarding multiple items related to the diagnosis and management of penile cancer throughout the COVID-19 acute waves. • Non-urgent procedures should be postponed and non-invasive procedures should be encouraged to delay or avoid the need for procedures that require general anesthesia because of the morbidity associated with perioperative severe acute respiratory syndrome coronavirus 2 infection., Objectives To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. Materials and methods A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. Results Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. Conclusions The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

Pathological risk factors for metastatic disease in patients with testicular non-seminomatous germ cell tumors are debated. The tumor-node-metastasis (TNM) classification eighth edition for testicular cancers includes divergent versions, by the International Union Against Cancer (UICC) and by the American Joint Committee for cancer (AJCC). We investigated pathological predictors of metastatic disease at presentation in 219 non-seminomatous germ cell tumors with reference to both classifications. Age, tumor size, percentage of embryonal carcinoma, lymphovascular invasion, invasion of stromal rete testis, hilar soft tissue, epididymis, spermatic cord, and tunica vaginalis, as well as tumor at spermatic cord margin, were assessed and correlated with clinical stage at presentation. Of the 219 NSGCT cases, 151 (69%) were clinical stage I, 68 (31%) were clinical stage II/III. On univariate analysis, tumor size (P = 0.028), percentage of embryonal carcinoma (P = 0.004), lymphovascular invasion (P = 0.001), stromal rete testis invasion (P = 0.001), hilar soft tissue invasion (P = 0.010), epididymis invasion (P = 0.010), direct spermatic cord invasion (P = 0.001), and tumor at spermatic cord margin ((P = 0.009) were associated with higher clinical stage. On multivariate analysis, lymphovascular invasion (P = 0.003), tumor size (P = 0.005), percentage of embryonal carcinoma (P = 0.005), stromal rete testis invasion (P = 0.008) remained significant. A tumor size of 6 cm and an embryonal carcinoma percentage of 70% were the significant cut-off values. We conclude that in addition to lymphovascular invasion, stromal rete testis invasion, tumor size, and embryonal carcinoma percentage are strong predictors of metastatic disease at presentation and their inclusion should be considered in any future TNM revision. Further, our results support the changes in the AJCC TNM eighth edition as invasion of the epididymis and hilar soft tissue were both univariately significant.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >105 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.

BACKGROUND: Bleomycin, Etoposide and Cisplatin (BEP) chemotherapy is the conventional treatment regimen for patients with germ cell tumours. The regimen is highly emetogenic and immunosuppressive. High dose steroids are often prescribed with this regimen as antiemetic prophylaxis but may have adverse effects in the context of immunosuppression. OBJECTIVE: To investigate whether the use of a steroid-sparing antiemetic protocol (substituting dexamethasone with olanzapine) affects the incidence of neutropenia and associated hospital admissions in patients receiving BEP chemotherapy. DESIGN, SETTING, PARTICIPANTS AND STATISTICAL ANALYSIS: Records from 108 patients who received BEP in St Bartholomew's Hospital, London were divided into two groups by antiemetic regimen. Group 1 (treated 2008-2013) were treated with a steroid-containing antiemetic protocol and Group 2 (treated 2014-2017) were given a steroid-sparing protocol, i.e. using olanzapine. Outcomes include incidence of neutropenia at nadir blood count, severity of neutropenia, hospital admissions due to febrile neutropenia (FN) and baseline risk factors associated with FN. Statistical analyses were performed using two-sided Chi-squared tests. RESULTS AND LIMITATIONS: Baseline characteristics were balanced in age, gender, histology, and proportion of IGCCCG poor-risk patients. The incidence of neutropenia of any grade (Group 1, 96.2%, Group 2, 98.1%) was comparable although Group 2 had more patients with severe neutropenia (77.7%, G1 vs 88.8%, G2). There was a significant difference in FN Incidence (22%, G1 vs 7.5%, in G2, p=0.030). Most cases of FN occurred in Cycle 1. Two baseline characteristics were over-represented in patients who developed FN - females and patients ≥ 50 years old. CONCLUSION: By comparing two cohorts who received prophylactic antibiotics, our audit suggests that rates of febrile neutropenia related admissions have decreased in the cohort of patients that we employed a steroid-sparing antiemetic protocol.

417 Background: Following relapse from first line chemotherapy, 30-60% of patients with germ cell tumors (GCTs) can be salvaged with further chemotherapy. Oxaliplatin-based therapies may offer reduced toxicity. Methods: Eligible patients with GCTs who progressed following cisplatin-based chemotherapy were recruited into this single-arm, phase II clinical trial (NCT01782339). Participants were recruited from six centers and received four 21-day cycles of: Actinomycin D 1mg/m2, high dose Methotrexate 5-8g/m2 day 1, Paclitaxel 80mg/m2 days 1, 8 and 15, Oxaliplatin 85mg/m2 days 4 and 8 with Pegfilgrastim support. Participants underwent an FDG-PET scan at baseline, prior to cycle 2 and on completion of treatment. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Results: 44 patients received at least one dose of the study medication between November 2012 and February 2020. In this full analysis set (FAS) population, the median age was 38 (range 20-57), with 9 (20%) with seminoma, 23 (52%) non-seminoma and 12 (27%) of other histology. 31 (70%) patients had at least intermediate risk disease by IPFSG risk group criteria (n = 16, 36% intermediate risk, n = 6, 14% high risk, n = 9, 20% very high risk). 39 patients received 2 or more cycles of the treatment regimen and were deemed part of the subgroup of patients in the evaluable population. The ORR of the FAS population was 52.3% and 59.0% in the evaluable population. The metabolic response rate (MRR) was 52.3% in the FAS population and 59.0% in the evaluable population. The median radiological PFS in the FAS population was 17.0 months (95% CI, 5.7 months- not reached, NR) with a radiological PFS rate at two years of 38.7% (95% CI, 22.3%-54.9%). The median combined radiological or tumour marker PFS in the FAS population was 8.3 months (95% CI, 2.6 months-17.4 months) with a combined radiological or tumour marker PFS rate at two years of 28.9% (95% CI, 16.0%-43.1%). At a median follow-up of 26.8 months, the median OS in the FAS population was not reached (95% confidence interval [CI], 17.0 months-NR) with an OS rate at two years of 62.5% (95% CI, 46.1%-75.2%). Toxicity data and correlation between early metabolic response and outcomes will be presented at the meeting. Conclusions: The GAMMA chemotherapy regimen has demonstrated encouraging anti-tumor activity in relapsed GCT, despite recruiting a cohort of patients with relatively unfavorable outcomes. Clinical trial information: NCT01782339.

Background Late relapse (LR) in testicular cancer is defined as disease recurrence more than 2 yr after primary treatment. Optimal management for this rare group is unknown. Objective To identify prognostic factors relevant to outcomes in a large LR series following primary treatment with platinum-based chemotherapy. Design, setting, and participants We performed a retrospective analysis of all patients treated for advanced testicular cancer within the Anglian Germ Cell Cancer Network between 1995 and 2016. We identified 53 cases of LR following initial treatment for metastatic disease with platinum-based chemotherapy, and collected data on patient and tumour characteristics, treatments, and outcomes. Outcome measurements and statistical analysis Progression-free survival (PFS) and overall survival (OS) were calculated for all patients. Survival curves were plotted according to the Kaplan-Meier method and univariate analysis of descriptive variables was performed using the log-rank method. Results and limitations Across the cohort, PFS at 36 mo was 41% and OS was 61%. Multiple factors were correlated with PFS. Use of dose-intense or high-dose chemotherapy was associated with better PFS compared to conventional-dose chemotherapy (PFS 48 vs 9.8 mo; p = 0.0036). Resection of residual disease post-relapse chemotherapy was associated with better PFS (hazard ratio 3.46; p = 0.0076). There was a nonsignificant trend towards worse PFS in very late (>7 yr) relapses. The study is limited by its retrospective nature and selection bias cannot be excluded. Conclusions This study provides new insight into prognostic factors in LR. It confirms that surgery is critical to optimal outcomes, and suggests that dose-intense or high-dose chemotherapy in multisite nonresectable disease should be considered wherever feasible. Patient summary We studied patients with testicular cancer that recurred at least 2 yr after initial treatment with chemotherapy. We found that patients who are able to have surgery to remove cancer and who have more intensive chemotherapy may be more likely to live longer.

Cancer-specific survival rates in patients with learning difficulties (LD) are poorer than the general population. Issues such as delayed diagnosis, compliance, consent and needs for individualised care and support requirements can make it more demanding to manage these patients in a busy clinical environment. Our case highlights a patient with learning disabilities who presented with advanced testicular cancer due to delayed detection, and the challenges needing consideration to ensure such patients receive good care. This report also highlights an example of adapting curative intent treatment to an individual with complex needs, and the importance of patient and family involvement in decision-making to ensure these vulnerable patients receive safe and effective healthcare. The practicalities of multidisciplinary team working in the context of key legislation and existing frameworks to guide practice in the management of LD patients are also discussed.

To report a single-centre experience of the regimen GAMEC (granulocyte colony-stimulating factor, actinomycin-D, methotrexate with folinic acid rescue, etoposide and cisplatin) over 18 years in both untreated disease and relapse settings.This retrospective cohort study was based on 162 patients who received GAMEC dose-dense chemotherapy incorporating actinomycin and high dose methotrexate. Survival outcomes were compared. Risk categorization based on (1) the International Prognostic Factor Study Group (IPFSG) criteria and (2) two factors, lactate dehydrogenase (LDH) levels greater than the upper limit of normal and age ≥35 years, were also compared in terms of survival outcomes using Cox proportional hazard regression modelling.Seventy-five patients with poor-prognosis disease, according to International Germ Cell Cancer Collaborative Group classification, received GAMEC as initial therapy. With a median follow-up of 63 months, the median progression-free survival (PFS) was14 months. The 2-year PFS rate was 61.5% (95% confidence interval [CI] 49.1-71.6), and the 3-year overall survival (OS) rate was 71.9%. Seventy-six patients received GAMEC as second-line therapy (following failure of bleomycin, etoposide and cisplatin or etoposide cisplatin). The median PFS was 7.5 months (95% CI 5.2-not evaluable), the 2-year PFS rate was 43.5% (95% CI 32.1-54.4) and the 3-year OS rate was 53.7% (95% CI 41.6-64.3). In the third-line setting (n = 11), the 2-year PFS was 18.2% (95% CI 2.8-44.2). Overall, the treatment-related death rate declined from 10.5% in the first 15 years to 2.6% in the last 5 years.GAMEC was an effective regimen in untreated poor-prognosis disease and on relapse following conventional cisplatin and etoposide-based chemotherapy. Risk categorization based on LDH/age is more sensitive than that based on the updated IPFSG criteria. It is possible to identify patients who are particularly likely to benefit from this treatment, which has the important advantages of short duration and absence of bleomycin, particularly in patients with central nervous system and mediastinal disease. Low-dose induction treatment is associated with safer delivery of treatment without compromising survival.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Patients with small tumors have few copies of ctDNA in plasma, resulting in limited sensitivity to detect low-volume or residual disease. We show that sampling limitations can be overcome and sensitivity for ctDNA detection can be improved by massively parallel sequencing when hundreds to thousands of mutations are identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) analysis pipeline, which combines patient-specific mutation lists with both custom error-suppression methods and signal enrichment based on biological features of ctDNA. In this framework, the sensitivity can be estimated independently for each sample based on the number of informative reads, which is the product of the number of mutations analyzed and the average depth of unique sequencing reads. We applied INVAR to deep sequencing data generated by custom hybrid-capture panels, and showed that when ~106 informative reads were obtained INVAR allowed detection of tumor-derived DNA fractions to parts per million (ppm). In serial samples from patients with advanced melanoma on treatment, we detected ctDNA when imaging confirmed tumor volume of ~1cm3. In patients with resected early-stage melanoma, ctDNA was detected in 40% of patients who later relapsed, with higher rates of detection when more informative reads were obtained. We further demonstrated that INVAR can be generalized and allows improved detection of ctDNA from whole-exome and low-depth whole-genome sequencing data.

As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company’s submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company’s health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG’s probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.

Background/aim The occurrence of somatic transformation in germ cell tumour (GCT) is rare, with increased incidence in teratomatous tumours. The aim of this study was to understand the clinical outcomes of patients with metastatic GCT with somatic transformation. Materials and methods A retrospective study was conducted in two tertiary cancer centres in London. Between 1998 and 2016, 30 cases of somatic transformation in GCT treated at the Mount Vernon Cancer Centre and St. Bartholomew's Hospital were identified. The median age at diagnosis was 34 years (range=18-56 years). The histological diagnosis at transformation was rhabdomyosarcoma, sarcomatoid yolk sac, sarcoma (non-specified), clear cell carcinoma, adenocarcinoma and primitive neuro ectodermal tumour (PNET). Results The 5-year survival rate of all patients was 47%, and that of patients with testicular primary (n=26 patients) was 37%. Conclusion Somatic transformation component in testicular GCTs is generally considered to be an adverse prognostic factor, however, a reasonable 5-year overall survival rate (87.5%) was observed in patients who present with this at first diagnosis.

Background Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. Patients and Methods Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. Results Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. Conclusion Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol.

Introduction Malignant mesothelioma (MM) has no biomarker driven therapies in routine clinical use. We used a drug screen of molecularly characterised MM lines to identify novel genomic biomarker driven therapy. This led to the discovery of a subset of MMs, defined by loss of function (LOF) of the nuclear deubiquitinase BRCA associated protein 1 (BAP1), that demonstrate heightened sensitivity to tumour necrosis factor related apoptosis inducing ligand (TRAIL). We then validated this association across in vitro, in vivo and ex vivo models and delineated the underlying mechanism. Methods 15 MM lines were characterised for mutations in five MM tumour driver genes and screened for response to 95 compounds. The identified BAP1-TRAIL association was validated in an extended panel of MM lines with apoptosis and cell viability assays. 25 early passage MM cultures, mouse xenograft and human tumour explant models were used to further validate the association. Knock-in and knock-out models in BAP1 mutant and wild type lines confirmed the effect of loss of BAP1 expression on TRAIL sensitivity. 6 mutant BAP1 constructs were generated and identified which functional BAP1 sites modulate TRAIL sensitivity. The effect of BAP1 function on the downstream death receptor/apoptosis pathway components was determined using microarray and immunoblot analysis. Results BAP1 LOF significantly correlated with TRAIL sensitivity in established MM lines (p=0.015) and primary MM cultures (p Conclusions We identify loss of BAP1 as a novel biomarker for TRAIL sensitivity in MM. BAP1 LOF is observed in up to 67% of MM tumours and BAP1 immunohistochemistry is in use as a diagnostic tool; hence this approach is validated and ready for immediate and actionable clinical use for this disease.

The treatment of poor prognosis chemotherapy naïve or relapsed testicular cancer is challenging. In poor prognosis treatment naïve disease, the outlook for patients with standard approaches utilising three weekly cisplatin based regimens, most commonly bleomycin, etoposide and cisplatin (BEP) is suboptimal, and one can expect more than half of patients to relapse or progress and need salvage treatment. Recent randomised studies have lent weight to the use of dose intensified treatments in these selected patient groups. In relapsed testicular cancer, post platinum based chemotherapy controversy exists as to the optimum relapse regimen as significant cure rates can be expected by re-treating with both conventional dose and high dose or dose intense regimens. Areas covered: This review seeks to outline the evidence for alternative approaches beyond standard three weekly cisplatin based regimens in poor risk metastatic disease. It also explores the evidence available for selection between conventional dose and high dose strategies on relapse. Expert commentary: An overview of the data is presented to support personalising therapy selection in both poor risk and relapsed metastatic germ cell tumors.

Highlights • Case describes a response to sunitinib in clear cell ovarian cancer. • Discussion of unique molecular characteristics of clear cell ovarian cancers • Practical points regarding dosing and toxicity when using sunitinib discussed