Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 “candidate cancer” genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a “matched therapy” and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68–75%). Only 94/550 patients (17%, 95%CI 14–21) received an “AGA-matched therapy” on progression. The most frequent AGAs leading to “matched therapy” included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such “matched therapy” improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of “matched therapy” was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with “matched therapy,” and 6-month overall survival (OS) was 62% (95%CI 52–73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a “matched therapy” in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158.

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Adrenocortical carcinomas (ACCs) are heterogeneous cancers associated with a very poor prognosis. The improvement of prognostic tools and systemic therapy are urgently needed. Targeting the immune system using checkpoint inhibitors such as PD1/PDL1 inhibitors is an attractive novel therapeutic strategy for poor-prognosis tumors. Multiple clinical trials are ongoing, including in advanced ACC. However, PDL1 expression has been studied in ACC in only one heterogeneous series of 28 clinical samples. Here, we have retrospectively analyzed PDL1 mRNA expression in 146 clinical ACC samples and searched for correlations between expression and biological and clinicopathological data, including post-operative disease-free survival (DFS). PDL1 mRNA expression was heterogeneous across samples. "PDL1-high" tumors were not associated with the classical prognostic variables but were associated with longer DFS in both uni-and multivariate analyses. High PDL1 mRNA expression was associated with biological signs of the cytotoxic local immune response. Supervised analysis between "PDL1-high" and "PDL1-low" tumors identified a robust 370-gene signature whose ontology analysis suggested the existence in "PDL1-high" tumors of a cytotoxic T-cell response, however, associated with some degree of T-cell exhaustion. In conclusion, PDL1 mRNA expression refines the prognostication in ACC and high expression is associated with longer DFS. Clinical validation at the protein level and functional validation are required to fully understand the role of PDL1 in ACC. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent a promising strategy in "PDL1-high" ACCs, supporting the ongoing clinical trials.

Background: Renal cell carcinoma is the third most prevalent urological cancer worldwide and about 30% of patients present with metastatic disease at the time of diagnosis. Systemic treatments for metastatic renal cell carcinoma have improved recently. Vascular endothelial growth factor targeting therapies were the previous standard of care. However, immune checkpoint inhibitors used in second line therapy have now been shown to improve patient survival. We report a case of metastatic renal cell carcinoma with nivolumab as a second-line therapy after progression with tyrosine kinase inhibitor therapy. Unusual adverse events in metastatic renal cell carcinoma, such as vitiligo, were observed in this patient who developed a remarkable documented pathological complete response to his renal tumor.Case presentation: A 60-year-old caucasian male was diagnosed with a pulmonary metastatic clear cell renal cell carcinoma. Sunitinib was used as first line treatment without success. He received nivolumab in second-line treatment. He developed several immune-related adverse events, most notably vitiligo. The patient had a radiological complete response on metastatic sites, with a significant decrease of renal tumor volume and underwent cytoreductive nephrectomy after 2 years of treatment, confirming the pathological complete response. The patient remains disease-free for 10 months without further systemic therapy after nivolumab discontinuation.Conclusions: Pathological complete response with nivolumab in metastatic renal cell carcinoma is rare. This case further highlights the potentially predictive role of immune-related adverse events during nivolumab therapy for metastatic renal cell carcinoma and raises questions concerning the role of nephrectomy after immune checkpoint inhibitor therapy. Further studies are needed to better identify predictive factors for treatment response to immunotherapy in metastatic renal cell carcinoma, and to better understand the role of nephrectomy after nivolumab treatment.

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