PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.

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, c-MET), 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.

Combination of Targeted Therapies for Colorectal Cancer Treatment.

The design of innovative therapeutic strategies enabling the selective destruction of tumor cells while sparing healthy tissues remains highly challenging in cancer therapy. Here, we show that the combination of two targeted therapies, including bevacizumab (Bev), and a ß-glucuronidase-responsive albumin-binding prodrug of monomethyl auristatin E (MMAE), is efficient for the treatment of colorectal cancer implanted in mice. This combined therapy produces a therapeutic activity superior to that of the association of FOLFOX and Bev currently used to treat patients with this pathology. The increased anticancer efficacy is due to either a synergistic or an additive effect between Bev and MMAE selectively released from the glucuronide prodrug in the tumor microenvironment. Since numerous drug delivery systems such as antibody-drug conjugates employ MMAE as a cytotoxic payload, this finding may be of great interest for improving their therapeutic index by combining them with Bev, particularly for the therapy of colorectal cancer.

Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular Features.

BACKGROUND & AIMS: Brain metastases (BMs) from colorectal cancer (CRC) are associated with significant morbidity and mortality, with chemoresistance and short overall survival. Migrating cancer stem cells with the ability to initiate BM have been described in breast and lung cancers. In this study, we describe the identification and characterization of cancer stem cells in BM from CRC. METHODS: Four brain metastasis stem cell lines from patients with colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) were obtained by mechanical dissociation of patient's tumors and selection of cancer stem cells by appropriate culture conditions. BM-SC-CRCs were characterized in vitro by clonogenic and limiting-dilution assays, as well as immunofluorescence and Western blot analyses. In ovo, a chicken chorioallantoic membrane (CAM) model and in vivo, xenograft experiments using BALB/c-nude mice were realized. Finally, a whole exome and RNA sequencing analyses were performed. RESULTS: BM-SC-CRC formed metaspheres and contained tumor-initiating cells with self-renewal properties. They expressed stem cell surface markers (CD44v6, CD44, and EpCAM) in serum-free medium and CRC markers (CK19, CK20 and CDX-2) in fetal bovine serum-enriched medium. The CAM model demonstrated their invasive and migratory capabilities. Moreover, mice intracranial xenotransplantation of BM-SC-CRCs adequately recapitulated the original patient BM phenotype. Finally, transcriptomic and genomic approaches showed a significant enrichment of invasiveness and specific stemness signatures and highlighted KMT2C as a potential candidate gene to potentially identify high-risk CRC patients. CONCLUSIONS: This original study represents the first step in CRC BM initiation and progression comprehension, and further investigation could open the way to new therapeutics avenues to improve patient prognosis.

Cabozantinib-nivolumab sequence in metastatic renal cell carcinoma: The CABIR study.

Nivolumab and cabozantinib are approved agents in mRCC patients after sunitinib/pazopanib (TKI) failure. However, the optimal sequence, cabozantinib then nivolumab (CN) or nivolumab then cabozantinib (NC), is still unknown. The CABIR study aimed to identify the optimal sequence between CN and NC after frontline VEGFR-TKI. In this multicenter retrospective study, we collected data from mRCC pts receiving CN or NC, after frontline VEGFR-TKI. A propensity score (PrS) was calculated to manage bias selection, and sequence comparisons were carried out with a cox model on a matched sample 1:1. The primary endpoint was progression-free survival (PFS) from the start of second line to progression in third line (PFS2-3 ). Key secondary endpoints included overall survival from second line (OS2 ). Out of 139 included mRCC patients, 38 (27%) and 101 (73%) received CN and NC, respectively. Overlap in PrS allowed 1:1 matching for each CN pts, with characteristics well balanced. For both PFS2-3 and OS2 , NC sequence was superior to CN (PFS2-3 : HR = 0.58 [0.34-0.98], P = .043; OS2 : 0.66 [0.42-1.05], P = .080). Superior PFS2-3 was in patients treated between 6 and 18 months with prior VEGFR-TKI (P = .019) and was driven by a higher PFSL3 with cabozantinib when given after nivolumab (P < .001). The CABIR study shows a prolonged PFS of the NC sequence compared to CN in mRCC after first line VEGFR-TKI failure. The data suggest that cabozantinib may be more effective than nivolumab in the third-line setting, possibly related to an ability of cabozantinib to overcome resistance to PD-1 blockade.

CHRONO: randomized trial of the CHROnology of surgery after Neoadjuvant chemotherapy for Ovarian cancer.

BACKGROUND: In patients treated for advanced ovarian cancer not suitable for complete primary surgery, interval surgery after three courses of neoadjuvant chemotherapy has been considered standard management since the EORTC randomized trial published in 2010. An alternative approach with delayed surgery after six courses of neoadjuvant chemotherapy was reported in retrospective series. PRIMARY OBJECTIVES: To assess the efficacy on progression free survival of interval cytoreduction surgery after three cycles of neoadjuvant chemotherapy compared with delayed surgery after six cycles of neoadjuvant chemotherapy. STUDY HYPOTHESIS: In women with ovarian cancer not suitable for primary surgical cytoreduction, surgery after six cycles of neoadjuvant chemotherapy will prove better disease-free survival than cytoreductive surgery after only three cycles. TRIAL DESIGN: CHRONO is a multicenter, randomized phase III trial. After three courses of neoadjuvant chemotherapy, eligible patients will be randomized (1:1) to either completion surgery followed by an additional five cycles of chemotherapy (control arm) or an additional three cycles of neoadjuvant chemotherapy followed by completion surgery and then two additional cycles of chemotherapy (experimental arm). Patients in both groups will receive eight total cycles of chemotherapy. MAJOR INCLUSION/EXCLUSION CRITERIA: The main inclusion criteria are histologically confirmed epithelial high-grade serous or endometrioid ovarian cancer, documented FIGO stage IIIB-IVA unsuitable for complete primary surgery but considered resectable after three courses of neoadjuvant chemotherapy. The main exclusion criteria are mucinous, clear cell, carcinosarcoma, or low-grade serous histologies. PRIMARY ENDPOINT: The primary endpoint is progression-free survival. SAMPLE SIZE: 210 eligible patients ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The estimated date for completing accrual will be Q2 2023. The estimated date for presentation of the first results is Q3 2028. TRIAL REGISTRATION NUMBER: NCT03579394.

New Artificial Intelligence Score and Immune Infiltrates as Prognostic Factors in Colorectal Cancer With Brain Metastases.

Incidence of brain metastases has increased in patients with colorectal cancer (CRC) as their survival has improved. CD3 T-cells and, lately, DGMate (DiGital tuMor pArameTErs) score, have been identified as prognostic factors in locally advanced CRC. Until now, there is no data concerning the prognostic value of these markers in patients with CRC-derived brain metastases. All consecutive patients with CRC-derived brain metastases diagnosed between 2000 and 2017 were retrospectively included. Staining for CD3, CD8, PD-1, PD-L1 and DGMate analyses were performed using tissue micro-array from primary tumors and, if available, brain metastases. All in all, 83 patients were included with 80 primary tumor samples and 37 brain metastases samples available. CD3 and CD8 T-cell infiltration was higher in primary tumors compared to brain metastases. We observed a significant higher DGMate score in rectal tumors compared to colon tumors (p=0.03). We also noted a trend of higher CD3 T-cell infiltration in primary tumors when brain metastases were both supra and subtentorial compared to brain metastases that were only subtentorial or supratentorial (p=0.36 and p=0.03, respectively). No correlation was found between CD3 or CD8 infiltration or DGMate score in primary tumors or brain metastases and overall survival (OS) in the overall population. In patients with rectal tumors, a high DGMate score in brain metastases was associated with longer OS (13.4 ± 6.1 months versus 6.1 ± 1.4 months, p=0.02). High CD3 T-cell infiltration in brain metastases was associated with lower OS in patients with supratentorial brain metastases (9.8 ± 3.3 months versus 16.7 ± 5.9 months, p=0.03). PD-L1 overexpression was rare, both in primary tumors and brain metastases, but PD-L1 positive primary tumors were associated with worse OS (p=0.01). In contrast to breast and lung cancer derived brain metastases, CD3 and CD8 infiltration and DGMate score are not major prognostic factors in patients with CRC-derived brain metastases.

Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

BACKGROUND: Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. PATIENTS AND METHODS: In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging (

Everolimus or sunitinib as first-line treatment of metastatic papillary renal cell carcinoma: A retrospective study of the GETUG group (Groupe d'Etude des Tumeurs Uro-Génitales).

BACKGROUND: Two phase II trials (NCT00688753 and NCT00541008) reported efficacy data of sunitinib and everolimus in first-line treatment of metastatic papillary renal cell carcinoma (mpRCC). Although most patients receive sunitinib or a mammalian target of rapamycin (mTOR) inhibitor in first- and second-line treatment, the optimal strategy remained unknown. MATERIAL AND METHODS: In 23 centres of the Groupe d'Etude des Tumeurs Urogénitales group, after centralised pathological review, we analysed retrospectively progression-free survival (PFS) of patients with mpRCC treated in first-line treatment (PFS-1) with sunitinib or everolimus (primary end-point), PFS in second-line treatment (PFS-2), overall survival (OS), objective response rate, disease control rate (DCR), overall sequence and prognostic factors for OS (secondary end-points). RESULTS: One hundred thirty-eight patients (119 men and 19 women), median age 62.5 years, with mpRCC type 1 (n = 24) or non-type 1 (n = 114), received first-line sunitinib (n = 107) or everolimus (n = 31). With a median follow-up of 92 months, we found no significant difference between the treatment groups in terms of PFS-1 (5.5 versus 6.2 months) and DCR (69% versus 83%). Ninety-eight patients received a second-line treatment, 69% with mTOR inhibitors after sunitinib and 100% with tyrosine kinase inhibitors after everolimus, with similar DCR (64% versus 58%), median PFS-2 (3.4 versus 4.8 months) and OS (16.0 versus 20.3 months). No factor was prognostic for PFS-1, whereas leukocytosis, anaemia and the time from diagnosis to first systemic therapy < 1 year were prognostic for OS. We found no prognostic difference between both pRCC subtypes. The International Metastatic Renal Cell Database Consortium risk factors were prognostic for OS. CONCLUSION: Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC.

Prognostic factors of colorectal cancer patients with brain metastases.

INTRODUCTION: Brain metastases (BMs) from colorectal cancer (CRC) are rare (≈2%) but are increasing with the improvement of CRC prognosis. The main objective of this study was to evaluate the prognostic factors of BM from CRC. MATERIALS AND METHODS: This multicenter retrospective study included all consecutive patients with BM from CRC diagnosed between 2000 and 2017. THEORY/CALCULATION: Prognostic factors of OS were evaluated in univariate (log-rank test) and multivariate analyses (Cox regression model). These prognostic factors could help the management of patients with BM from CRC. RESULTS: A total of 358 patients were included with a median age of 65.5 years. Primary tumors were mostly located in the rectum (42.4%) or left colon (37.2%) and frequently KRAS-mutated (56.9%). The median time from metastatic CRC diagnosis to BM diagnosis was 18.5 ± 2.5 months. BMs were predominantly single (56.9%) and only supratentorial (54.4%). BM resection was performed in 33.0% of the cases and 73.2% of patients had brain radiotherapy alone or after surgery. Median OS was 5.1 ± 0.3 months. In multivariate analysis, age under 65 years, ECOG performance status 0-1, single BM and less than 3 chemotherapy lines before BM diagnosis were associated with better OS. Prognostic scores, i.e. recursive partitioning analysis (RPA), Graded Prognostic Assessment (GPA), Disease Specific-Graded Prognostic Assessment (DS-GPA), Gastro-Intestinal-Graded Prognostic Assessment (GI-GPA) and the nomogram were statistically significantly associated with OS but the most relevant prognosis criteria seemed the ECOG performance status 0-1. CONCLUSIONS: ECOG performance status, number of BM and number of chemotherapy lines are the most relevant factors in the management of patients with BM from CRC.

Skin inflammatory response and efficacy of anti-epidermal growth factor receptor therapy in metastatic colorectal cancer (CUTACETUX).

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy. This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1ß, IL-6, TNF-α and OSM), T-reg-related cytokines (IL-10 and TGF-ß), Th1-related cytokine (IFN-γ), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR. Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 (p = .04) and IL-23 (p = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 (p = .02), BD-2 (p = .02), IL-1ß (p = .004) and OSM (p = .02) in the rash zone were associated with longer progression-free survival. Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.

Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases.

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.

Results and challenges of immune checkpoint inhibitors in colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and clinical outcome has improved substantially during the last two decades with targeted therapies. The immune system has a major role in cancers, especially the CD8 + T cells specific to tumor antigens. However, tumors can escape immune response by different mechanisms including upregulation of inhibitory immune checkpoint receptors, such as well-known Programmed cell Death protein-1 (PD-1)/Programmed cell Death Ligand 1 (PD-L1) interaction, leading CD8 + T cells to a state of anergy. Immunotherapy, with the so-called immune checkpoint inhibitors (CPIs), has recently been approved in treatment of multiple cancers due to its prolonged disease control and acceptable toxicities. The recent groundbreaking success involving anti-PD-1 CPIs in metastatic CRC with deficient mismatch repair system (dMMR) is promising, with several trials ongoing. Major challenges are ahead in order to determine how, when and for which patients we should use these CPIs in CRC. AREAS COVERED: This review highlights some promises and challenges concerning personalized immunotherapy in CRC. First results and ongoing breakthrough trials are presented. The crucial role of biomarkers in selecting patient is also discussed. EXPERT OPINION: As of now, dMMR and POLE mutations (DNA polymerase ε) with ultramutator phenotype are the most powerful predictive biomarkers of CPI efficacy. The most challenging issue is pMMR mCRC and determination of how to convert a 'nonimmunogenic' neoplasm into an 'immunogenic' neoplasm, a combination of CPIs with radiation or MEK inhibitor probably being the most relevant strategy. Next-generation sequencing (NGS) assays to quantify mutational load could be more reliable predictive biomarkers of CPIs efficacy than PD-L1 expression or immune scores.

Clinical outcome of portal vein thrombosis in patients with digestive cancers: A large AGEO multicenter study.

INTRODUCTION: Management of portal vein thrombosis (PVT) in cancer patients remains discussed. AIMS: The objective of this multicenter retrospective study was to investigate the management and outcome of PVT in patients with digestive cancers other than hepatocellular carcinoma (HCC). METHOD: Main inclusion criteria were trunk or branch PVT in patients with locally advanced or metastatic digestive cancers. Predictive factors of bleeding and overall survival (OS) were evaluated in univariate and multivariate analysis. RESULTS: Between 2012 and 2016, 118 patients with PVT and digestive cancers were identified. The majority had a pancreatic cancer (50%). Sixty-six percent of patients had trunk PVT location. Endoscopic screening of portal hypertension was performed in only 7 patients (1%) and 5 had esophageal varices. Gastrointestinal bleeding occurred in 22 patients (19%) and 12 patient deaths (17%) were related to a gastrointestinal hemorrhage. Metastatic disease (HR=2.83 [95%CI 1.47-5.43], p<0.01) and gastrointestinal hemorrhage (HR=1.68 [95%CI 1.01-2.78], p=0.04) were associated with OS in multivariate analysis. Only trunk PVT location was significantly associated with gastrointestinal hemorrhage in multivariate analysis (HR=5.56 [95%CI 1.18-26.32], p=0.03). CONCLUSION: A high rate of variceal bleeding leading to death was found in this cohort. Endoscopic screening and the efficacy of prophylactic treatment of variceal bleeding remain to be evaluated in a prospective study.

Clinical activity of eribulin in advanced desmoplastic small round-cell tumor.

Desmoplastic small round-cell tumor is a rare but highly aggressive tumor occurring mainly in adolescents and young adults. Prolonged progression-free survival has been documented in patients who have undergone aggressive multimodality therapy - that is, multiagent intensive chemotherapy, debulking surgery, and radiation therapy. Eribulin is a microtubule-dynamics inhibitor, and it has recently been shown to be active in liposarcomas. In preclinical models, eribulin activities have also been shown to occur in Ewing's sarcoma cell lines, rhabdomyosarcomas and osteosarcomas. In this study, we report three cases of male patients suffering from desmoplastic small round-cell tumor and the clinical response to eribulin in two of them.

Clinical efficacy of eribulin mesylate for the treatment of metastatic soft tissue sarcoma.

INTRODUCTION: Metastatic soft tissue sarcoma, a devastating disease, has a median overall survival of only 12-18 months. Treatment options remain scarce. However, eribulin mesylate, a first-in-class halichondrin B-based microtubule dynamics inhibitor, has recently been approved for the management of patients with advanced liposarcoma. Areas covered: Based on a review of the literature between 2005 and 2017, we present a summary of eribulin mesylate's mechanism of action and the studies showing its clinical efficacy in locally advanced or metastatic sarcomas. Expert commentary: Future development includes the definition of a biomarker signature related to patient outcome with eribulin. Further investigation via controlled clinical trials is needed to identify combination regimens that can optimize the efficacy of eribulin while providing an acceptable safety profile in sarcoma patients.