Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.GETUG-13 established that switching patients with poor-prognosis nonseminomatous germ-cell tumors with an unfavorable marker decline to intensified chemotherapy resulted in improved outcomes. Here, we report the GETUG-13 long-term efficacy and toxicity. Two hundred and sixty-three patients with International Germ Cell Cancer Consensus Group poor prognosis received one cycle of bleomycin, etoposide, and cisplatin (BEP): 51 with a favorable tumor marker decline continued with three cycles of BEP (Fav-BEP) and 203 with an unfavorable decline were randomly treated with three BEP (Unfav-BEP) cycles or a dose-dense regimen (Unfav-dose-dense; two cycles of paclitaxel-BEP-oxaliplatin + two cycles of cisplatin, ifosfamide, and bleomycin). The median follow-up was 7.1 years (range, 0.3-13.3). Five-year progression-free survival (PFS) rates were 58.9% in the Unfav-dose-dense arm and 46.7% in the Unfav-BEP arm (hazard ratio [HR], 0.65 [95% CI, 0.44 to 0.97]; P = .036). Five-year overall survival rates were 70.9% and 61.3% (HR, 0.74 [95% CI, 0.46 to 1.20]; P = .22). Side effects evolved favorably, with only three patients in the Unfav-dose-dense arm reporting grade 3 motor neurotoxicity at 1 year and no reported toxicity over grade 1 after year 2. Salvage high-dose chemotherapy plus a stem-cell transplant was used in 8% in the Unfav-dose-dense arm and 17% in the Unfav-BEP arm (P = .035). Long-term outcomes suggest a sustained benefit of intensified chemotherapy in terms of PFS and numerically better survival, with a minimal toxicity and reduced use of salvage high-dose chemotherapy plus stem-cell transplant.

Introduction: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors (ICI) are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its interactions with angiogenesis pathways, to search for potential therapeutic targets. Methods: The expression of immune markers (PD -L1, PD -1, PD -L2, LAG -3) and angiogenic pathways (CAIX, cMET), was analyzed by immunohistochemistry on 68 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to estimate the prevalence of PD -L1 expression and its prognostic impact in metastatic pRCC. Secondary endpoints included the evaluation of other immune markers (PD -1, PD -L2, and LAG -3) and their association with PD -L1. We also assessed angiogenic markers and their association with PD -L1. Results: Overall, 27.9 % of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.6 %), PD-1 and LAG-3 were positive in 17.6 % and 19.1 % respectively. None of these markers was correlated with PD-L1 expression. 66 % (45/68) expressed at least one immune marker, and 43 % (29/68) were "double-positive", as they expressed both immune and angiogenic markers. OS was significantly shorter for patients with PD-L1 positive pRCC. A multivariate analysis confirmed a significant association between PD-L1 expression and shorter overall survival (HR = 4.0, p = 0.01). Conclusion: These results reinforce clinical data on the expected benefit of ICI in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in this multicenter cohort.

Background: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood.Objectives: To report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC.Methods: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021.Results: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months.Conclusion: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic.

624 Background: A non-negligible portion of bladder cancers have non-pure UC histology; these tumors are often underdiagnosed and represent an unmet treatment need. Efficacy of immune checkpoint inhibitors (ICI) in non-pure UC remains unknown. We report preliminary data form the PEMBROBLAD study assessing ICI in pretreated mixed variants (UC-V) or pure non-UC (NUC) in real life condition. Methods: PEMBROBLAD is a retrospective multicenter study conducted in 24 French GETUG centers. Eligible patients had advanced UC with UC-V or NUC. All patients received ICI as a second line treatment. We excluded patients with ICI maintenance therapy. The primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression free survival (PFS), time to treatment failure (TTF) and safety. Results: A total of 139 patients (pts) were analyzed. Median age was 70 years (range 44-88), 70.8 % were male with ECOG PS 0/1, 2 and 3 in 57.7%, 26.6% and 10.1% of cases respectively. The most common variants of UC-V (n=96, 69.0%) were squamous cell differentiation (n=25, 26.0%), sarcomatoid (n=12, 12.5%), micropapillary (n=9, 9.3%), neuroendocrine (n=8, 8.3%), nested (n=7, 7.3%) and adenocarcinoma (n=5, 5.2%); squamous cell carcinoma (n=23, 53.4%) represented the majority of NUC (n=43, 31.0%). At data cutoff (August 15, 2023), median follow-up was 35.1 months (mo) (range 3.7-86.9). The most administered ICI was pembrolizumab in 85.6% of cases followed by durvalumab in 12.2% of cases. Median OS was 6.1 mo for all pts, 6.1 and 5.9 for UC-V and NUC respectively. In pts with UC-V and NUC, ORR was 31.2 % (n=30) and 18.6% (n=8) and DCR was 41.6% (n=40) and 23.2% (n=10) respectively. In all 139 pts, median TTF was 2.2 mo (95% CI, 0.1-50.0 mo). Serious TRAE occurred in 13 pts (9.3%). Discontinuation due to TRAEs occurred in 5.0% of pts. Conclusions: Our results suggest some efficacy of ICI in pretreated advanced UC-V and NUC. No new safety concerns were identified. Updated results with subgroup analysis will be reported at the meeting. [Table: see text]

Advanced age in patients with colorectal cancer is a factor of poor prognosis, but little is known about geriatric factors associated with survival and chemotherapy prescription in frail elderly patients. Our research sought to investigate these factors in older patients with metastatic colorectal cancer (mCRC). Patients and methods: patients aged >= 75 years, who were treated for mCRC and have had a Comprehensive Geriatric Assessment (CGA) due to their frailty, were included in this multicenter practice study in the Loire Valley region (France). With initial patient care for mCRC as the starting point, demographic, oncological, geriatric and survival data were collected from the regional cancer database and the medical record of each patient. We analyzed overall survival and chemotherapy prescription, according to the geriatric factors of the CGA. Results: 108 patients were enrolled (mean age 84.0 +/- 4.5 years; 57.4 % men), among whom 53 (49 %) received at least one line of chemotherapy. The median overall survival [95 %CI] was 8.05 [5.6-12.0] months. In univariate analysis, prescription of chemotherapy was associated with the number of severe co-morbidities, number of co-medications, G8 score, BMI, MMSE score, IADL and ADL scores, Lee index and Balducci criteria. Survival was significantly associated with chemotherapy, ADL and IADL scores, G8 score, repeated falls, number of severe co-morbidities, MMSE score, Lee index and Balducci criteria. In multivariate analysis, only the ADL score (HR [95 %CI]: 0.74 [0.55-0.99], p = 0.04), number of severe co-morbidities (HR [95 %CI]: 1.62 [1.06-2.47], p = 0.03) and repeated falls (HR [95 %CI]: 3.54 [1.70-7.39], p < 0.001) were significantly associated with survival. Conclusion: in frail elderly patients with mCRC, dependency, co-morbidities and repeated falls are independent factors associated with survival. As such, there could be merit in taking these into consideration before the choice of oncological treatment is made.

BACKGROUND:In women, ovarian cancer is the eighth most frequent cancer in incidence and mortality. It is often diagnosed at advanced stages; relapses are frequent, with a poor prognosis. When platinum resistant, subsequent lines of chemotherapy are of limited effect and often poorly tolerated, leading to quality of life deterioration. Various studies suggest a hormonal role in ovarian carcinogenesis, with a rationale for endocrine therapy in these cancers. PATIENTS AND METHODS:This multicenter, retrospective study assessed the use of endocrine treatment for high-grade ovarian epithelial carcinomas treated between 2010 and 2020. RESULTS:Eighty-one patients with ovarian cancers were included. The median duration of platinum sensitivity was 29 months. We observed a 35% disease control rate with endocrine therapy, and 10% reported symptom improvement. For 19 patients (23.5%), the disease was stabilized for more than 6 months. Median overall survival from diagnosis was 62.6 months. Regarding endocrine therapy predictive factors of response, in a multivariate analysis, 3 factors were statistically significant in favoring progression-free survival: platinum sensitivity (P = .021), an R0 surgical resection (P = .020), and the indication for hormone therapy being maintenance therapy (P = .002). CONCLUSION:This study shows real-life data on endocrine therapy in ovarian cancer. As it is a low-cost treatment with many advantages such as its oral administration and its safety, it may be an option to consider. A perspective lies in the search for cofactors to aim as future therapeutic targets to improve the effectiveness of hormone treatment by means of combination therapy.

Calcium (Ca2+) is an essential and ubiquitous second messenger controlling numerous cellular functions. Ca2+ signaling relied on the finely tuned oscillations of the cytosolic Ca2+ concentrations induced by components of Ca2+ signaling toolkit (ion channels, pumps and ion exchangers). The regulation of these Ca2+ oscillations define a Ca2+ signature that is representative of the cellular identity and phenotype of a cell. In cancers, molecular actors of the Ca2+ signaling toolkit are aberrantly expressed. We hypothesized that Ca2+ signature of cancer cells are representative of their cellular identity, their tissue of origins (TOO) as well as their isolation site (IS). We defined the Ca2+ signature of prostate and colon cancer cell lines by collecting the profile of cytosolic Ca 2+ responses evoked by a panel of agonists in 22904 individual cells. We then highlighted the heterogeneity of those Ca2+ profiles and successfully developed a classifier predicting the tissue of origins (TOO), the isolation site (IS) or the cellular identity of individual cancer cells using a supervised neural network. Unsupervised clustering revealed that Ca2+ profiles of single cancer cells derived from 3 main classes of Ca2+ responses sub-divided into 50 different clusters. Thus, we highlighted that supervised machine learning applied on top of single cell Ca2+ profiling is an effective method to discriminate cancer cells at single cell level and that the cancer cell Ca 2+ signature can be summarized into 3 main profiles of Ca2+ responses.### Competing Interest StatementThe authors have declared no competing interest.

PURPOSE Multiple studies have demonstrated that electronic patient-reported outcomes (ePROs) improve overall survival and quality of life in cancer care. However, there are no specific prospective data on remote ePRO monitoring in the older population, although they represent a significant proportion of patients with cancer. PATIENTS AND METHODS From February 2021 to April 2022, patients age 75 years and older under active anticancer treatment were consecutively recruited in six institutions. Remote ePRO feasibility was determined in intention-to-test (ITT) on the basis of the number of active users in the overall population. Primary failure applied to patients who had no Internet access or declined to test ePROs, while the other patients were assigned to the ITT population. Feasibility was also determined per-protocol on the basis of the number of active patients in the ITT population. RESULTS Of the 473 patients included, primary failure applied to 288 patients (233 of whom had no Internet access). Among the 185 patients in ITT, 122 used ePROs, leading to a 26% feasibility in ITT and a 66% feasibility per protocol. In a multivariate analysis, the intent to test population was from a higher socioprofessional category ( P = .009) and felt in better general condition in the Geriatric 8-score evaluation ( P = .002). Active patients significantly differed from the inactive on their self-assessment of a better general condition ( P < .001) only. CONCLUSION Our multicenter study showed a limited feasibility rate (26%) of remote ePROs monitoring for older patients with cancer, mainly because of technology barriers. Yet, among the patients who did have Internet access, most of them indeed used ePROs (66%). Given the expected benefit of ePROs, the technology barriers therefore need to be lifted to improve cancer care in older patients.

12011 Background: Web-based PROMs in cancer care improve overall survival and quality of life. There is, nonetheless, no data available on this type of follow-up in the elderly population. Methods: From February 2021 to April 2022, 75 or more years-old patients ongoing any active anti-cancer treatment (such as chemotherapy, targeted therapy, hormonotherapy, immune therapy) were included, in six French cancer centers. Feasibility of the web-based PROMs was assessed as the part of the population included that could use the Ana-Health’s web-based application “ANA” to monitor their symptoms, the others being considered as in “primary failure” due to technological barriers or refusal to participate. Among the patients that agreed to participate, we then defined as “active” those who filled at least one form during the three months follow up. We also searched for factors restraining elderly patients to use “ANA” and evaluated their satisfaction. Results: Overall, 473 patients were included in the study. There were 288 patients in “primary failure” (233 without Internet access, 17 not comfortable enough to use web-based PROMs, 38 refusals to participate). Among the 185 patients “willing to participate”, there were 122 “active” patients and 63 “inactive” ones, leading to a 26% feasibility in intention-to-test and a 66% feasibility in per protocol analysis. Patients “willing to participate” were from higher socio-professional category (p = 0.002) and had a significantly higher G8 score (13.5 versus 12, p < 0.001), particularly when considering the autonomy (p = 0.028), cognitive assessment (p = 0.003) and general condition (p < 0.001) items. In the multivariate analysis, the socio-professional category and the general condition were still significantly different (p = 0.009 and 0.002 respectively). The only factor that remained significantly different between the “active” and “inactive” populations was the better general condition in the “active” group (p < 0.001). The “inactive” patients prematurely ended their participation because they lost interest in the web-based follow up significantly more than the “active” group (28 “inactive” patients, i.e. 44%, vs 5 “active” patients, i.e. 4%, p < 0.001). Similarly, the “active” patients were significantly more satisfied with “ANA” than the “inactive” (71% vs 29%, p < 0.001). Conclusions: Our study shows that, in the elderly population treated for a cancer, a web-based application to measure PROs is feasible, however socio-professional category, general condition and above all technological barriers are of some concern.

BackgroundCIC-rearranged sarcomas (CIC-RS) represent the most frequent subset of "Ewing-like " undifferentiated small round cell sarcomas. These tumors tend to be more aggressive than Ewing sarcomas. Moreover, treatment strategy can differ according to teams. The primary aim of this retrospective study was to describe the characteristics, treatments, and outcome for patients with CIC-RS included in the French NETSARC+ database.MethodsPediatric and adult patients from 13 French centers with a diagnosis of CIC-RS were registered from October 2008 to March 2021. Patients and tumors characteristics were collected from the national network NETSARC+ database (). CIC-RS diagnosis was pathologically and molecularly confirmed with a central review by expert pathologists. Two groups of patients were studied: those treated as classical Ewing sarcomas (cohort EwS) and those treated as high-grade soft tissue sarcomas (cohort STS) according to ESMO and/or EpSSG guidelines. Survival was calculated using the Kaplan-Meier method and the log-rank test was used to compare survival.ResultsAmong 79 patients, the male/female sex ratio was 0.7 and the median age at diagnosis was 27 years (range 2-87). With a median follow-up of 37 months, 39 patients died of the disease. Median overall survival from diagnosis was 18 months, with no significant difference between both cohorts (p = 0.9). Nevertheless, when focusing on patients with metastatic disease at diagnosis (N = 21), all patients from cohort STS died of disease while some patients from cohort EwS were still alive and in complete remission.ConclusionFSG experience confirms the aggressive clinical course of CDS patients regardless of chemotherapy regimen.

Neoadjuvant cisplatin-based chemotherapy (NAC) regimen followed by local therapy is the standard of care for MIBC. However, 60-75% of these patients (pts) have residual disease after NAC. Preclinical data suggest that the use of ddMVAC regimen may induce higher immunogenic death and pathological complete response (pCR) in the NAC setting as compared to gemcitabine cisplatin regimen (GC). Thus, we aimed to evaluate the efficacy and safety of ddMVAC + D +/- T combination in a phase I/II trial. NEMIO (NCT03549715) is a multicenter open-label randomized non-comparative phase 1/2 trial evaluating neoadjuvant ddMVAC + D +/- T in pts with cT2-4N0-1 eligible for radical cystectomy (RC). The pts received 4 cycles of ddMVAC every 2 weeks with D (1500 mg) +/- T (75 mg) every 4 weeks. The co-primary endpoints were locally assessed pCR rate (ypT0N0) and grade ≥ 3 treatment related adverse events (TRAE). We assumed a pCR rate ≥ 45% to consider trial as positive. Between November 2018 and April 2022, 121 pts were enrolled in 16 centers and 119 received at least one dose of ddMVAC + D +/- T. The median age was 64 years (IQR: 58-70) with predominant ECOG PS 0 (74%). Clinical tumor stage at diagnosis was cT2, cT3 and cT4 in 86 (89%), 9 (9%) and 1 (1%), respectively, while 5 (5%) pts were cN1. Only 6 pts (6%) did not undergo RC (4 refusal and 2 progressive disease). Among the 113 pts with RC, the pCR was 47.8% (Table). All pts had at least one TRAE and 41% a G≥3 TRAE including neutropenia (12.6%) anemia (9.2%), and acute kidney injury (6.7%). ddMVAC or D +/- T were discontinued in 21 pts (17.6%), mostly due to TRAE (90.5%).Table: 2364MOddMVAC + D (N=55)ddMVAC + D + T (N=58)Pts achieved cystectomy (N=113)ypT0N027 (49.1%)27 (46.6%)54 (47.8%)ypT1, Ta, TisN012 (21.8%)8 (15.5%)21 (18.6%)ypT2-4N010 (18.2%)16 (27.6%)26 (23.0%)ypN+6 (10.9%)6 (10.3%)12 (10.6%) Open table in a new tab NEMIO is a positive trial showing one of the highest pCR achieved in the neoadjuvant setting with the use of ddMVAC + D. Nonetheless, the benefit of adding T on pathological response appears limited, pending survival outcomes.

Background Sarcoma is a heterogeneous group of diseases with few treatment options. Immunotherapy has shown little activity in studies including unselected sarcomas, but immune checkpoint blockers have shown activity in specific histotypes. We evaluated the activity of pembrolizumab in rare and ultra-rare sarcomas.Methods AcSe Pembrolizumab is an ongoing phase 2, basket, multitumour study investigating the activity of pembrolizumab monotherapy in rare cancers. Here, we report the results obtained in patients with selected histotypes of rare sarcomas (incidence of less than one case per 1 000 000 people per year) recruited at 24 French hospitals. Key inclusion criteria were age 15 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and advanced disease that was untreated and resistant to treatment. Patients were given pembrolizumab 200 mg intravenously on day 1 of every 21-day cycle for a maximum of 24 months. The primary endpoint was objective response rate at week 12 using Response Evaluation Criteria in Solid Tumours version 1.1, assessed by local investigators. The primary endpoint and safety were analysed in the intention-to-treat population. The AcSe Pembrolizumab study is registered with ClinicalTrials.gov, NCT03012620.Findings Between Sept 4, 2017, and Dec 29, 2020, 98 patients were enrolled, of whom 97 received treatment and were included in analyses (median age 51 years [IQR 35-65]; 53 [55%] were male; 44 [45%] were female; no data were collected on race or ethnicity). 34 (35%) patients had chordomas, 14 (14%) had alveolar soft part sarcomas, 12 (12%) had SMARCA4-deficient sarcomas or malignant rhabdoid tumours, eight (8%) had desmoplastic small round cell tumours, six (6%) had epithelioid sarcomas, four (4%) had dendritic cell sarcomas, three (3%) each had clear cell sarcomas, solitary fibrous tumours, and myxoid liposarcomas, and ten (10%) had other ultra-rare histotypes. As of data cutoff (April 11, 2022), median follow-up was 13 & BULL;1 months (range 0 & BULL;1-52 & BULL;8; IQR 4 & BULL;3-19 & BULL;7). At week 12, objective response rate was 6 & BULL;2% (95% CI 2 & BULL;3-13 & BULL;0), with no complete responses and six partial responses in the 97 patients. The most common grade 3-4 adverse events were anaemia (eight [8%] of 97), alanine aminotransferase and aspartate aminotransferase increase (six [6%]), and dyspnoea (five [5%]). 86 serious adverse events were reported in 37 patients. Five deaths due to adverse events were reported, none of which were determined to be related to treatment (two due to disease progression, two due to cancer, and one due to unknown cause).Interpretation Our data show the activity and manageable toxicity of pembrolizumab in some rare and ultra-rare sarcoma histotypes, and support the PD-1/PD-L1 pathway as a potential therapeutic target in selected histotypes. The completion of the basket study will provide further evidence regarding the activity and toxicity of pembrolizumab in identified rare types of cancer.

IntroductionUrachal cancer (UrC) is a rare, non-urothelial malignancy. Its natural history and management are poorly understood. Although localized to the bladder dome, the most common histological subtype of UrC is adenocarcinoma. UrC develops from an embryonic remnant, and is frequently diagnosed in advanced stage with poor prognosis. The treatment is not standardized, and based only on case reports and small series. This large retrospective multicentric study was conducted by the French Genito-Urinary Tumor Group to gain a better understanding of UrC.Material and Methodsdata has been collected retrospectively on 97 patients treated at 22 French Cancer Centers between 1996 and 2020.ResultsThe median follow-up was 59 months (range 44-96). The median age at diagnosis was 53 years (range 20-86), 45% were females and 23% had tobacco exposure. For patients with localized disease (Mayo I-II, n=46) and with lymph-node invasion (Mayo III, n=13) median progression-free-survival (mPFS) was 31 months (95% CI: 20-67) and 7 months (95% CI: 6-not reached (NR)), and median overall survival (mOS) was 73 months (95% CI: 57-NR) and 22 months (95% CI: 21-NR) respectively. For 45 patients with Mayo I-III had secondary metastatic progression, and 20 patients were metastatic at diagnosis. Metastatic localization was peritoneal for 54% of patients. Most patients with localized tumor were treated with partial cystectomy, with mPFS of 20 months (95% CI: 14-49), and only 12 patients received adjuvant therapy. Metastatic patients (Mayo IV) had a mOS of 23 months (95% CI: 19-33) and 69% received a platin-fluorouracil combination treatment.ConclusionUrC is a rare tumor of the bladder where patients are younger with a higher number of females, and a lower tobacco exposure than in standard urothelial carcinoma. For localized tumor, partial cystectomy is recommended. The mOS and mPFS were low, notably for patients with lymph node invasion. For metastatic patients the prognosis is poor and standard therapy is not well-defined. Further clinical and biological knowledge are needed.

Background: Periprostatic adipose tissue (PPAT) is likely to modulate prostate cancer (PCa) progression. We analyzed the variations in the effect of PPAT on cancer cells, according to its fatty acid (FA) composition and tumor characteristics. Methods: The expression of markers of aggressiveness Ki67 and Zeb1, and epigenetic marks that could be modified during PCa progression, was analyzed by immunohistochemistry on a tissue-micro-array containing 59 pT3 PCa, including intra-prostatic areas and extra-prostatic foci in contact with PPAT belonging to the same tumor. In addition, we cocultivated PC3 and LNCaP cell lines with PPAT, which were then analyzed for FA composition. Results: Although the contact between PPAT and cancer cells led overall to an increase in Ki67 and Zeb1, and a decrease in the epigenetic marks 5MC, 5HMC, and H3K27ac, these effects were highly heterogeneous. Increased proliferation in extraprostatic areas was associated with the international society of uropathology score. PC3 and LNCaP cocultures with PPAT led to increased Ki67, Zeb1 and H3K27me3, but only for PPAT associated with aggressive PCa. PC3 proliferation was correlated with high 20.2 n-6 and low 20.5n-3 in PPAT. Conclusions: These results suggest that the effects of PPAT on cancer cells may depend on both PCa characteristics and PPAT composition, and could lead to propose nutritional supplementation.

Background The REGOBONE multi-cohort study explored the efficacy and safety of regorafenib for patients with advanced bone sarcomas; this report details the Ewing sarcoma (ES) cohort. Methods Patients with relapsed ES progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progression. The primary endpoint was the progression-free rate at 8 weeks. With one-sided α of 0.05, and 80% power, at least 14/24 progression-free patients at 8 weeks were needed for success. Results From September 2014 to November 2019, 41 patients were accrued. 36 patients were evaluable for efficacy: 23 on regorafenib and 13 on placebo. Thirteen patients (56%; one-sided 95% CI [37.5%–[)) were progression-free at 8 weeks on regorafenib vs. 1 (7.7%; 95% CI [0.4%–[) on placebo. Median PFS was 11.4 weeks on regorafenib, and 3.9 weeks on placebo. Ten placebo patients crossed over to receive regorafenib after progression. The most common grade ≥3 regorafenib-related adverse events were pain (22%), asthenia (17%), thrombocytopenia (13%) and diarrhoea (13%). Conclusion Although the primary endpoint was not met statistically in this randomised cohort, there is evidence to suggest that regorafenib might modestly delay tumour progression in relapsed ES after failure of prior chemotherapy.

The PEACE-1 trial demonstrated improved overall survival (OS) in de novo mCSPC patients treated with a combination of androgen deprivation therapy, docetaxel, and abiraterone (AA) plus prednisone. Prostate cancers with neuroendocrine differentiation (NEPC) are rare. Most trials exclude de novo NEPC, thus their standard of care remains uncertain. As NEPC was allowed in PEACE-1, we aimed to assess the effect of AA in NEPC and those with very high-risk factors (Gleason >8, liver metastases). We reviewed local pathological reports (biopsy site, WHO pathological classification, chromogranin A (CgA), and synaptophysin immunohistochemical [NE IHC] staining) from patients randomized in PEACE-1. Baseline characteristics were compared between patients with and without NEPC. Prognostic value of NEPC and high-risk factors on radiographic progression-free survival (rPFS) and OS was studied by Cox models. Predictive value of these factors was assessed by adding an interaction between AA and each factor. Pathological reports were available for 1087 out of 1172 patients (97%). NE IHC was only locally performed in 18% of patients and NEPC diagnosed in 2.4%. Among reports with NE IHC, 13.2% (n =26) of patients had an adenocarcinoma with NE differentiation and 0.5% had pure NEPC. PSA at baseline was significantly lower in NEPC than in adenocarcinoma without NEPC (p=0.003). Baseline disease burden, visceral metastasis, and Gleason scores were similar in both group. NE features predicted for both rPFS (median 1.6 vs 2.9 years; HR 2.2, 95%CI [1.4-3.5], p=0.0004) and OS (median 2.4 vs 5.1 years; HR 2.7, 95%CI [1.7-4.4], p<0.0001). The effect of AA could not be reliably assessed due to an insufficient number of NEPC. The Gleason score (6-7 vs 8 vs 9-10) had no impact on the effect of AA on OS (p=0.73). Among patients with liver metastases (n=36), AA improved rPFS (HR 0.3, 99.9%CI [0.08-1.00], p=0.06) and tended to improve OS (HR 0.5, 95.1%CI [0.23-1.10], p=0.22). Only a very small minority of men with mCSPC are diagnosed with NEPC by their local pathologist, questioning the need for more systemic IHC in these men. AA significantly improves rPFS in patients with liver metastases.

Background We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clearcell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups. Methods This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment. Findings Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18.0 months (IQR 17.6-18.4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0,63 [95% CI 0,25-1,56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0,78 [95% CI 0,20-3,01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumabipilimumab (OR 0,95 [95% CI 0,38-2,37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumabipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumabipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib. Interpretation We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.

L'évolution habituelle des tumeurs de vessie n'infiltrant pas le muscle (TVNIM) est la récidive ou la progression vers une tumeur infiltrante (TVIM). La progression métastatique ne survient généralement qu'après la progression vers une TVIM. Cependant, certains patients atteints de TVNIM peuvent développer des métastases sans passer par le stade TVIM (TVNIMm). Les caractéristiques et l'évolution clinique de cette présentation atypique sont inconnues. Il s'agit d'une étude française rétrospective et multicentrique, cherchant à décrire les caractéristiques cliniques des TVNIMm (synchrones ou métachrones). Les patients ayant des antécédents de TVIM (prouvé ou suspecté, histologiquement ou radiologiquement), de tumeur de la voie excrétrice urinaire supérieure ou de tumeur intra-diverticulaire de la vessie ont été exclus. La survie a été évaluée à l'aide du modèle de Kaplan Meier et du modèle de régression de Cox. De 2005 à 2021, 70 patients ont été inclus dans 17 centres français, principalement des hommes (83 %) avec un âge médian au diagnostic de TVNIM de 63,8 ans. Au total, 65 patients présentaient une TVNIM à haut risque et 44 ont reçu des instillations de BCG. Le délai médian avant la progression métastatique était de 22,2 mois [19,8 ; 54 mois]. 13 patients (19 %) avaient une TVNIMm d'emblée. 21 % des patients avaient une maladie métastatique uniquement ganglionnaire. La survie globale médiane à partir du diagnostic métastatique était de 27 mois [16,6 ; NA]. Le traitement de première ligne était une chimiothérapie à base de platine pour 84 % des patients. Le taux de réponse objective était de 67 % et le délai médian avant progression était de 12,5 mois [8,3 ; 14,7]. Cette étude souligne que certaines TVNIM peuvent évoluer vers une maladie métastatique sans progression vers une MIBC. La réponse objective à la chimiothérapie à base de platine dans cette cohorte de TVNIMm est comparable aux données de la littérature chez les patients métastatiques. Une caractérisation moléculaire est en cours pour mieux comprendre l'oncogenèse de ce sous-type agressif de TVNIM.