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Simple Summary The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the ``matched therapy group'' than in the ``non-matched therapy group''. Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio >= 1.3 versus 5% in the ``non-matched therapy group'' (n = 25). The objective response and disease control rates were higher in the ``matched therapy group'' (33% and 58%, respectively) than in the ``non-matched therapy group'' (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to ``matched therapy'' in 19%, and provided clinical benefit in 8%.

BackgroundCirculating tumor cells (CTCs) have a strong potential as a quasi-non-invasive tool to set up precision medicine strategy for cancer patients. Tremendous efforts have been made to develop the second-generation of “filtration-based” technologies to detect CTCs, revealing a surprising heterogeneity among those cells. Here, we performed the largest and simultaneous analysis of all atypical circulating tumor cells (aCTCs) detected with a filtration-based technology, in a cohort of metastatic breast cancer (mBC) patients, and correlated their presence with clinicopathological and survival data.MethodsThe PERMED-01 study enrolled patients with mBC refractory to systemic therapy. We prospectively analyzed aCTCs present at the time of inclusion in the study, using the Screencell®Cyto device (n=91). Subsets cut-offs were established and evaluated for correlation with clinicopathological data, including progression-free survival (PFS) and overall survival (OS).ResultsThe median number of aCTCs found in mBC was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in mBC patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter PFS and OS in multivariate analyses. For 23 cases, the analysis was completed with advanced immunofluorescence staining and showed that CTM and g-aCTCs displayed a hybrid phenotype for epithelial and mesenchymal markers.ConclusionsThis study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels when using a Screencell®Cyto device. It reveals the g-aCTC subset as a prognostic factor and a potential stratification tool that might help to orientate late-stage mBC patients’ therapeutic care.

Background: PD-1 blockade (αPD-1) has shown limited efficacy in breast & gynecologic cancers. In other types of solid tumor, regulatory T cells (Tregs) harbouring markers of highly suppressive effector Tregs (eTregs) correlates with poor responses to PD-1 blockade, prompting combination therapy based on eTregs depletion. Yet, subsets of Tregs remain to be determined in breast & gynecologic cancers, in order to: (i) evaluate the role of eTregs in resistances to PD-1 blockade, (ii) identify the most selective target for eTregs depletion tailored to tumors context and combination strategy. Methods: We collected public single-cell RNA/TCR-sequencing data from primary tumors and metastases of Triple-Negative Breast Cancer patients (TNBC, N = 28) biopsied before and after αPD-1 (pembrolizumab). Microarray data from primary TNBC (N = 124) biopsied before and after αPD-1 were quired for association with clinical responses. Deep phenotyping of Tregs from normal breast tissues (N = 4) and primary breast tumors (N = 8) or gynecologic tumors (N = 17) was performed by mass cytometry. ALD2510 (αCD25NIB, Alderaan Biotechnology) is a novel non-IL-2 blocking Fc-optimized anti-CD25 mAb (1). αPD-1 and αCD25NIB combination was evaluated using: (i) a humanized αCD25NIB in CD34+ humanized NSG mice grafted with human TNBC cell lines, (ii) a murine surrogate of αCD25NIB in a syngeneic TNBC mouse model. Results: CD25high Tregs were accumulating in breast & gynecologic tumor tissues. In TNBC patients treated with αPD-1, fractions of CD25high Tregs were further increased. CD25high Tregs highly expressed eTregs-related molecules in primary tumors, invaded tumor-draining lymph nodes and distant metastases. Amongst the potential therapeutic targets for Treg depletion, only CD25, 4-1BB and CCR8 were largely restricted to intratumoral CD25high eTregs. Yet, CD25 was the best candidate for CD25high eTregs depletion with limited on-target off-Treg effects, as: (i) CCR8 marked a small fractions of CD25high eTregs in primary tumors and was not detected in metastasis, (ii) 4-1BB marked antigen-experienced αβCD8 T cell revigorated by PD-1 blockade, (iii) only CD25high eTregs expressed 4-1BB and CCR8, yet TCR clonotype analysis revealed that CD25high eTregs originate in part from activated CD25+ Tregs, suggesting that anti-CCR8/-4-1BB mAbs may be ineffective due to CD25high eTregs replenishment in tumors. In murine models resistant to αPD-1 alone, αCD25NIB effectively depleted intratumoral CD25high eTregs, with limited effects on peripheral Tregs, and synergized with αPD-1 by restoring a positive effector αβCD8 T cells/Tregs ratio, leading to tumor clearance without adverse effects. Conclusions: This study supports clinical evaluation of CD25high effector Tregs depletion by ALD2510 in patients with breast or gynecologic cancers resistant to PD-1 blockade. Citation Format: Stéphane FATTORI, Aude Le Roy, Jemila Houacine, Lucie Robert, Riad Abes, Laurent Gorvel, Samuel Granjeaud, Marie-Sarah Rouvière, Amira Ben Amara, Nicolas Boucherit, Carole Tarpin, Jihane Pakradouni, Emmanuelle Charafe-Jauffret, Julien Barrou, Gilles Houvenaeghel, Eric Lambaudie, François Bertucci, Philippe Rochigneux, Anthony Gonçalves, Arnaud Foussat, Anne-Sophie Chrétien, Daniel Olive. Selective depletion of regulatory T cells by ALD2510, a novel IL-2-sparing anti-CD25 antibody, synergizes with PD-1 blockade in breast and gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3239.