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International audience; A need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being.

BackgroundPatients undergoing neoadjuvant chemotherapy before surgery for advanced ovarian cancer may have impaired functional capacity, nutritional status, and emotional well-being.Primary objective(s)TRAINING-01 aims to determine if a connected pre-habilitation program during neoadjuvant chemotherapy for patients treated for an advanced ovarian cancer will improve physical capacity before major abdomino-pelvic surgery.Study hypothesisA pre-habilitation program during neoadjuvant chemotherapy will bring a fitter patient to surgery and will decrease treatment morbidity and improve oncological outcomes.Trial designThis study is a prospective, multi-center, phase III study. The pre-habilitation program consists of providing multi-dimensional support during neoadjuvant chemotherapy using connected devices. The control group will receive usual care.Major inclusion/exclusion criteriaEligible patients will be women with International Federation of Gynecology and Obstetrics stage III–IV advanced ovarian cancer undergoing neoadjuvant chemotherapy. Patients must be able to perform a cardiopulmonary exercise test.Primary endpoint(s)The primary endpoint will be the comparison of the variation in maximum oxygen uptake (VO2 max) between baseline and surgery in the pre-habilitation group and control groups.Sample size136 patients (68 per arm) will be recruited to demonstrate a medium standardized effect d=0.5 in the variations of VO2 max between baseline and surgery.Estimated dates for completing accrual and presenting resultsThe duration of the study includes 24 months of recruitment and 5 years of follow up. We anticipate reporting primary endpoint results in 2024.Trial registrationTRAINING-01-IPC 2018-039 (NCT04451369).

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.

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.

International audience; Background: Hormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population.Methods: In this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+).Results: A total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m2. Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7].Conclusion: Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup.Trial registration id: NCT01980277.

Significance This work provides a report of accumulation of unconventional CD56−CD16+ NK cells in nonvirally induced malignancies. Increased frequency of CD56−CD16+ NK cells is associated with adverse clinical outcome in AML, as well as other maturation defects, and might contribute to a defective control of AML progression. Pseudotime analysis highlights a disruption in the maturation process of conventional NK cells in AML patients, leading to a bifurcation point absent in healthy subjects. This analysis, combined with the reduced frequency of conventional NK cells observed in AML patients, suggests that unconventional CD56−CD16+ NK cells derive from an aberrant maturation of conventional NK cells. Overall, accumulation of CD56−CD16+ NK cells could be an important feature of immune escape from innate immunity., Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56−CD16+ unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML (n = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects (n = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56−CD16+ unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56−CD16+ NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; P = 0.0002) and event-free survival (HR = 0.33; P = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56−CD16+ NK cells. Overall, our data suggest that the accumulation of CD56−CD16+ NK cells may be the consequence of immune escape from innate immunity during AML progression.

Simple Summary Vδ2+ γδ T cells have potent antitumor properties both in vitro and in murine preclinical models of breast cancers. However, in the context of human breast cancer, there is a lack of information for potential phenotypic alterations of this crucial immune cell subset. This is partly due to Vδ2+ γδ T cells scarcity in surgical specimens. To break this deadlock, we assessed Vδ2+ γδ T cell phenotypes using untreated breast cancer patients’ peripheral blood, so-called minimally invasive “liquid biopsy”. We show that circulating Vδ2+ γδ T cell phenotypic alterations are already established at diagnosis and related to tumor progression. Notably, terminally differentiated Vδ2+ γδ T cells expressing canonical markers of replicative senescence and exhaustion were significantly associated with tumor-draining lymph node invasion. Our results shed light on the interest of using liquid biopsy to monitor rare events and support Vδ2+ γδ T cell involvement in breast cancer pathogenesis and progression. Abstract The rationale for therapeutic targeting of Vδ2+ γδ T cells in breast cancer is strongly supported by in vitro and murine preclinical investigations, characterizing them as potent breast tumor cell killers and source of Th1-related cytokines, backing cytotoxic αβ T cells. Nonetheless, insights regarding Vδ2+ γδ T cell phenotypic alterations in human breast cancers are still lacking. This paucity of information is partly due to the challenging scarcity of these cells in surgical specimens. αβ T cell phenotypic alterations occurring in the tumor bed are detectable in the periphery and correlate with adverse clinical outcomes. Thus, we sought to determine through an exploratory study whether Vδ2+ γδ T cells phenotypic changes can be detected within breast cancer patients’ peripheral blood, along with association with tumor progression. By using mass cytometry, we quantified 130 immune variables from untreated breast cancer patients’ peripheral blood. Supervised analyses and dimensionality reduction algorithms evidenced circulating Vδ2+ γδ T cell phenotypic alterations already established at diagnosis. Foremost, terminally differentiated Vδ2+ γδ T cells displaying phenotypes of exhausted senescent T cells associated with lymph node involvement. Thereby, our results support Vδ2+ γδ T cells implication in breast cancer pathogenesis and progression, besides shedding light on liquid biopsies to monitor surrogate markers of tumor-infiltrating Vδ2+ γδ T cell antitumor activity.

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Background Following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), the phenotype and function of circulating NK Cells are altered; notably NK cells display an immature (CD56-bright/KIR -/CD57 -/NKG2A +) phenotype and a low cytotoxic activity. Since NK cells have demonstrated anti-leukemic activity in the context of Allo-HCT while less prone to induce GVHD than T cells, we hypothesized that NKG2A inhibition using the checkpoint inhibitor monalizumab (humanized IgG4 blocking monoclonal antibody) could improve NK cell mediated graft-versus-tumor effect, without triggering graft-versus-host disease. We thus performed the first clinical trial evaluating the safety of monalizumab as a prophylactic treatment after Allo-HSCT (NCT02921685). Method The objective was to determine the maximal tolerated dose (MTD) of a single infusion of monalizumab administered on day+75 or thereafter following Allo-HSCT. Inclusion criteria were: 1) adult patients who underwent first Allo-HSCT for hematological malignancy; 2) no prior history of GVHD, 3) reduced toxicity conditioning regimen, 4) ATG or PT-Cy based GVHD prophylaxis, and 5) GVHD prophylaxis with cyclosporine A ongoing at the time of monalizumab infusion. Four dose levels were investigated in this dose escalation study (0.04, 0.1, 0.3, and 1.0 mg/kg). Dose limiting toxicities (DLT) were defined by the occurrence of any grade 3 to 4 monalizumab-related adverse event within 28 days after infusion, including grade 3 to 4 acute GVHD and moderate to severe chronic GVHD. In case of DLT, a Bayesian continuous reassessment model (CRM) was used to predict the maximal tolerated dose (MTD) after each series of 3 patients treated at a given dose level. It was planned to treat 18 patients. Beyond clinical safety, blood samples were collected for NK and T cell immunomonitoring and receptor saturation assay. Results Fifteen patients received monalizumab at a median time of 83 days (range: 75-103) after Allo-HSCT (3 at 0.04 mg/kg, 3 at 0.1 mg/kg, 3 at 0.3 mg/kg, and 6 at 1 mg/kg). Patients were transplanted for hematological diseases (9 AML, 3 MDS, 1 lymphoma, 1 CLL and 1 myelofibrosis), from a matched sibling (n=8), matched unrelated (n=6) or haploidentical donor (n=1). No DLT was observed during the dose escalation process or among the 6 patients treated at the highest dose level, justifying study early termination after 15 patients. Two patients developed transient low grade GVHD that spontaneously resolved without treatment (1 grade I acute GVHD on day+8 and 1 mild chronic GVHD on day+118). Systemic steroid requiring GVHD occurred in 3 patients (20%): 1 severe overlap GVHD (day+42, CR after treatment), 1 severe chronic GVHD (day+80, death from GVHD) and 1 late severe chronic GVHD after cyclosporine tapering for mixed chimerism (day+149, complete remission [CR] after treatment). No disease recurrence was observed, except for one patient with myelofibrosis who relapsed 3 years after monalizumab infusion. At a median follow up of 22 months (3-48) after monalizumab infusion, 13 out of 15 patients are in CR from their underlining malignancy without GVHD and immunosuppressive treatment at last contact. At the dose of 1 mg/kg, receptor saturation assays (RSA) showed persistent binding of monalizumab on peripheral blood NK cells. Indeed, more than 90% of NKG2A-positive NK cells were positive for monalizumab detection (Anti-IgG4-PE) until at least 14 weeks post treatment. Conclusions Monalizumab can be safely administered after Allo-HSCT, with prolonged persistence on circulating NK cells. In the absence of DLT, MTD was not reached. Future trials will aim at measuring the clinical efficacy of monalizumab in this context, alone or in combination therapy. Disclosures boyer Chammard: Innate Pharma: Current Employment. Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

Background Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms. Patients and methods PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments. Results A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug–drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57–92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12–51%]). Conclusion Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population. Trial registration ID NCT01589861 .

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Background Genomic-based approaches in advanced breast cancer (ABC) were recently demonstrated as feasible in the clinical practice, but only a limited number of patients were actually treated with targeted therapies matching genomic alterations, with low antitumor activity. We conducted a pilot study to evaluate whether precision medicine using NGS and aCGH could be implemented prospectively at a single center in ABC patients. In addition, we examined whether PDX could be derived from ABC and thus could help inform therapeutic decision. Methods ABC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Tumor tissue from locally recurrent or metastatic disease was immediately frozen after dedicated biopsy. Genomic profiling included high-resolution 4x180K aCGH (Agilent Technologies, Massy, France) and DNA sequencing, using a library of 365 cancer candidate genes (HaloPlex target enrichment kit, Agilent technologies, Santa Clara, CA, USA) and MiSeq analyzer (Illumina, San Diego, CA, USA) with 2x150-bp, paired-end at about 300x coverage. In a subset of patients, fresh tumor was implanted orthotopically in humanized cleared fat pads of NSG mice for establishing xenotransplants. Results A total of 34 ABC patients were included, with the following characteristics: median age 54 years (35-77); molecular subtypes: 11 triple-negative (32%), 12 luminal non-HER2 (35%), 4 luminal HER2 (12%), 3 HER2 non-luminal (9%), and 4 unknown (12%); 33 with previous chemotherapy (97%); 22 with previous endocrine treatment (35%); 7 with previous anti-HER2 (21%). Tumor biopsies were obtained from liver (15), skin (6), peritoneum (4), breast (3), node (3), lung (1), pleura (1), and ascitis (1), with a median tumor cellularity of 70% (range 10-90%). aCGH and NGS were available from 34 and 33 patients, respectively. An actionable target was found in 28 patients (82%), corresponding to 66 targets, including 37 mutations (8 in PIK3CA, 7 TP53, 4 ESR1, 2 AKT1, 2 BRCA2, 2 HER2), 22 amplifications (7 for CCND1, 2 CCNE1, 2 FGFR1, 2 IGF1R) and 7 homozygous deletions (3 for PTEN, 2 CDKN2A/B,1 BRCA2, 1 STK11). A targeted therapeutic proposal was possible, either in a clinical trial (N=18, 52%) or using already registered drugs (N=17, 50%). Ten patients actually received a targeted treatment, 1 of them experienced objective response and 1 showed stable disease for more than 6 months. Of 26 patients subjected to mouse implantation, 10 had successful xenografting (6 triple-negative, 2 HER2, 1 luminal non-HER2, 1 subtype non-attributed), with a median time to reach 10 mm of 148 days. These PDX will be used as models to understand the patient's therapeutic response. Conclusion Precision medicine using high-throughput DNA sequencing and aCGH can be implemented at a single center in the context of clinical practice and may allow direct therapeutic proposal in 1/3 of patients, but antitumor activity was minimal. PDX may be obtained in a significant fraction of patients, especially in triple-negative and HER2 subtypes, and could phenotypically complement genomic data. Citation Format: Gonçalves A, Bertucci F, Chaffanet M, Guille A, Garnier S, Adelaide J, Carbuccia N, Brunelle S, Piana G, Cabaud O, Thomassin-Piana J, Paciencia-Gros M, Chereau-Ewald E, Lambaudie E, Sabatier R, Tarpin C, Provansal M, Jalaguier-Coudray A, Extra J-M, Sarran A, Pakradouni J, Viens P, Lopez M, Ginestier C, Charafe-Jauffret E, Birnbaum D. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH) and patient-derived tumor xenograft (PDX) for precision medicine in advanced breast cancer: A single-center prospective study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-23.

9561 Background: Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors (ICI). However, immune biomarkers of efficacy are still lacking. Preliminary data in leukemia and pancreatic cancer showed that soluble immune checkpoints are associated with a reduced overall survival (OS). This led us to explore the prognostic and predictive value of soluble immune checkpoints in non-small cell lung cancer (NSCLC) patients treated with chemotherapy or ICI. Methods: We analyzed 90 advanced NSCLC patients. The pilot cohort (Rennes University Hospital, France), included 48 patients treated with platinum doublets (n = 33) or ICI (n = 15) (LOC/11-16 protocol). The confirmation cohort (Paoli-Calmettes Institute) included 42 patients treated with ICI (nivolumab or pembrolizumab) in a longitudinal prospective setting (Immunosup trial, NCT03595813). In both cohorts, enzyme-linked immunosorbent assays (ELISA) were performed in baseline plasma samples for soluble forms of PD-1, PD-L1, global BTN3, BTLA, BTN3-A1 and BTN2A1. Soluble ICI levels were linked to clinical data using Kaplan-Meier, log-rank and Cox proportional-hazards models. Cut-points were determined using maxstat package for survival, R software R 3.6.2. Results: Five soluble immune checkpoints correlated and clustered together in unsupervised analysis (PD-1, PD-L1, global BTN3, BTLA, BTN3-A1), but were not associated with ICI efficacy. In patients treated with ICI, in the pilot and confirmation cohort, a high baseline plasmatic concentration of soluble BTN2A1 was significantly associated with an improved OS (confirmation cohort with a BTN2A1 cut-point of 3.55 ng/ml: HR = 0.30, 95%CI = 0.12-0.74, p = 0.0057, median OS in BTN2A1low = 7.6 months and median OS in BTN2A1hi = 19.5 months). On the contrary, in patients treated with chemotherapy, soluble BTN2A1 concentration was not associated with overall survival. Conclusions: In advanced NSCLC patients, a high baseline plasmatic concentration of soluble BTN2A1 was correlated with improved outcomes for ICI, but not for chemotherapy, suggesting that baseline soluble BTN2A1 level is a potential predictive biomarker of ICI efficacy. Additional studies are ongoing to confirm this finding.

1091 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane-resistance. LY is a dual inhibitor of p70 S6 kinase and AKT. TAKTIC study aimed to determine the recommended phase II dose (RP2D) of the combination of LY with wP (phase Ib) and to estimate overall response rate (ORR) of this regimen (phase II) in HER2-negative LA or MBC patients, both in the overall patient population and in patients with activation of PI3K/AKT pathway (PI3KAKT+). Methods: HER2-negative inoperable LA or MBC patients (pts), with (phase Ib) or without (phase II) previous cytotoxic treatment for advanced disease were eligible. Oral LY (400 or 500mg) was administered daily in combination with intravenous wP (70 or 80mg/m2). A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PI3KAKT+ was defined as activating mutation of PIK3CA and/or AKT by targeted NGS or homozygous loss of PTEN by array comparative genomic hybridization (aCGH) or loss of PTEN by immunohistochemistry, as evaluated on available fresh tumor tissue. Results: A total of 12 and 35 patients (pts) were included in the phase Ib and II, respectively. In phase Ib, only 1 dose-limiting toxicity (confusion) was observed at the last dose level (LY, 500 + wP, 80), which was determined as RP2D. Main drug-related adverse events (AE) in phase Ib were skin toxicity (92% of pts, G3-4 in 33%), and paresthesia (50% of pts, G3-4 in 8%). In the phase II study, ORR was 62.9 % [44.9,78.5] including 1 CR and 21 PR in the overall population and 55.6 % [30.8,78.5] in PI3KAKT+ pts (10 PR in 18 pts). Median progression-free survival was 12.4 months [7.9,17.9] and 6-month clinical benefit rate was 82.9% [66.4,93.4]. AEs in phase II were similar to phase I part, except that 17% of pts experienced pneumonia (G3-4 in 9%). Conclusions: Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277.

Background: A novel combination of oral lapatinib (LPT), a selective dual ErbB1/ErbB2 targeted drug, + oral buparlisib (B) a pan-class I PI3K inhibitor, could provide a synergestic antitumor activity in trastuzumab resistant disease. LPT has been shown to be a potent CYP3A4 inhibitor which is also mainly involved in BKM120 metabolism. In this study we investigated the potential pharmacokinetic (PK) drug-drug interactions (DDI) related to the association of B and LPT. Methods: Trastuzumab-resistant HER2 + metastatic breast cancer (MBC) patients were treated with a continuous once daily dosing schedule of LPT + B. Dose levels [DL, LPT (mg)/B (mg)] ranged from 750/40 to 1,250/80. For PK analysis, 2 time point samples were collected on D1 and D8 and 10 time point samples were collected on D15 of cycle 1 for LPT and B assays. Plasma concentrations of B and LPT, were measured using UPLC coupled with tandem mass spectrometry validated methods. Population PK was modeled using a non linear mixed effect model program (Monolix version 4.3s) by computing the maximum likelihood estimator of the parameters without any approximation of the model (no linearization). Results: 343 and 322 plasma concentrations were available for PK analysis of LPT and B respectively. A two-compartment open model adequately described B concentration versus time courses. The inter-individual variabilities (ISV) could be well estimated for all stuctural parameters (clearance: CL, volume of distribution: V, inter-compartmental clearance: Q) except for absorption constant: Ka. The population PK parameters obtained for the structural model were: Ka = 0.985 h−1, CL/F = 10.5L/h, V1/F = 54.8 L, Q/F = 46.3 L/h, V2/F = 582 L. Mean AUC0-24h(CV%) values for B were 10130 (34%), 15450 (29%), and 20560 (38%) ng*hr/mL for 40 mg, 60 mg and 80 mg dose level respectively. A one-compartment model adequately fitted the LPT plasma concentration-time data. The population PK parameters were CL/F = 25.7 L/h, V/F = 291 L and the absorption constant, Ka = 0.214 h−1. B has no significant effect on the PK of LPT and vice versa. Conclusions: B AUC increased proportionally with increasing dose. LPT PK parameters are consistent with those already published. There is no significant evidence for drug-drug PK interaction between LPT and B. Intra-occasion variabilities will be discussed. Citation Format: François Lokiec, Anthony Goncalves, Fanny Bret, Jihane Pakradouni, Magali Provansal, Renaud Sabatier, Jean-Marc Extra, Carole Tarpin, Nicolas Isambert, Mario Campone, Keyvan Rezai. A phase Ib pharmacokinetic drug-drug interaction evaluation of oral buparlisib in combination with lapatinib in HER2+/PI3K-activated, trastuzumab-resistant locally advanced, recurrent and metastatic breast cancer (MBC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2036.

Introduction: LY2780301 is an orally available small molecule dual inhibitor of p70 S6 kinase and AKT. LY2780301 is an inhibitor of CYP3A4. By the one hand, Paclitaxel (PXL) undergoes extensive metabolism via CYP450 2C8 and CYP450 3A4 pathways. By the other hand, PXL induces weakly CYP3A4 activity. In this study we investigated for the first time, the potential pharmacokinetic (PK) drug-drug interaction (DDI) related to the combination of both drugs LY2780301 and PXL. Methods: Women with HER2- locally advanced or metastatic breast cancer, with and without PI3/AKT pathway activation, were treated with weekly administration of PXL on day1 (D1), D8 and D15. LY2780301 was administered by a daily flat dosing regimen starting at D3. Dose levels [DL, LY2780301 (mg/day)/PXL (mg/m2/week)] ranged from 400/70 to 500/80. For PK analysis, 7 time point samples were collected on D1 and D3 of cycle 1 for PXL and LY2780301 respectively. 7 samples were collected on D8 for both drugs. LY2780301 plasma concentrations were measured using Ultra Performance Liquid Chromatography (UPLC) coupled with tandem mass spectrometry validated method. PXL plasma concentrations were measured using UPLC coupled with UV validated method. A joint population PK (PK-POP) model has been developed for LY2780301 and its main metabolite. PK-POP modelling has been performed with a non linear mixed effect model program (Monolix version 4.3.2). Results: 12 patients, 35 to 67 years old, were treated. A total of 160 and 157 concentrations for LY2780301 and its metabolite were used respectively for PK-POP modeling. A one compartment open model adequately described LY2780301 and its metabolite concentration versus time courses respectively with the estimation of the fraction of absorbed dose (fm) of LY2780301 metabolised in that metabolite. The interindividual variabilities (ISV) could be well estimated for all structural parameters (clearance: CL, volume of distribution: V, L and the absorption constant: Ka). The population PK parameters obtained for the structural model were: Ka = 0.536 h−1, CL/F = 3.57 L/h, V/F = 85.2 L, CL/(F*fm) = 13.2 L/h, V2/(F*fm) = 13.2 L, fm = 0.747 for LY2780301 and its metabolite respectively. PXL increases LY2780301 CL from 3.57 to 4.4 L/h (p = 0.016). Conclusions: We have demonstrated a PK DDI between LY2780301 and PXL. PXL increases LY2780301 CL and decreases LY2780301 AUC. PXL PK modeling is ongoing in order to verify the effect of LY2780301 on PXL PK. Citation Format: Keyvan Rezai, Samuel Huguet, Olivier Madar, Jean-Marc Extra, Magali Provansal, Carole Tarpin, Nicolas Isambert, Jihane Pakradouni, Anthony Goncalves, François Lokiec. Pharmacokinetic drug-drug interaction: a phase Ib dose escalation study of LY2780301 in combination with weekly paclitaxel. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2049.

Progression of chronic kidney disease (CKD) represents a constant challenge for the identification of new therapeutic targets. The NOV/CCN3 matricellular protein, belonging to the CCN (CYR61/CCN1, CTGF/CCN2, NOV/CCN3) family, could represent a new endogenous inhibitor of the fibrotic process that plays a crucial role in tissue damage and regression of renal function. However, the relation between NOV and renal disease remains unclear. Our objective was to study whether alterations in renal NOV expression are involved in the progression of CKD. NOV mRNA expression was significantly induced by 2.5-3 fold at 12-16 weeks in renin-transgenic mice (RenTg), a well established model of AngII-mediated nephropathy, through the Angiotensin receptor 1 (AT 1 R) compared to normotensive control animals (n=7 mice per group, p1 R was also observed in VSMC cultures. Furthermore, infection of these cells with an adenovirus recombinant for NOV strongly repressed in a dose-dependent manner the expression of the Angiotensin Receptor 1 reaching 72 and 78% (p1 R regulatory loop. In subsequent studies the NOV-induced downregulation of AT 1 R was abrogated by integrin β1 specific siRNAs. Thus, NOV can attenuate the deleterious profibrotic effects of AngII during the progression of CKD and may provide a potential therapeutic option against this pathology.

Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Lapatinib is a dual anti-HER2/EGFR tyrosine kinase inhibitor with clinical activity after trastuzumab failure in HER2-positive advanced breast cancer (ABC). BKM120 is a pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 phase Ib study aimed primarily to determine maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for BKM120 in combination with lapatinib in HER2-positive, trastuzumab-resistant, ABC. Secondary objectives included safety, antitumor activity, pharmacokinetics and biomarker assessments. Methods: PIKHER2 was a multi-center study, enrolling HER2 positive (IHC 3+ or FISH positive) ABC, with disease progressing either while on trastuzumab for metastatic disease or within 12 months of the last infusion for patients who received trastuzumab as adjuvant/neoadjuvant treatment. Oral BKM120 (B; 40, 60 or 80 mg) and lapatinib (L; 750, 1000 or 1250 mg) were administered daily. A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PIK3CA mutational status and PTEN/hormone receptor expression IHC was evaluated on available tumor tissue. Results: A total of 24 HER2-positive ABC pts, with a median number of previous lines of cytotoxics = 2 (1-5) and previous lines of anti-HER2 = 2 (1-6) for advanced stage, were treated across 5 dose-levels (B,40 + L,750; B, 60 + L,750; B,80 + L,750; B,80 + L,1000; B,80 + L,1250). Following cycle 1, 5 pts experienced DLTs: G3 ALT elevation, G3 vomiting, G3 stomatitis, G3 hyperglycemia and G3 diarrhea. MTD was reached at B,80 + L,1250 but toxicities and early treatment discontinuation beyond cycle 1 led us to select B,80 + L,1000 as the RP2D. Main drug-related adverse events were: diarrhea (83% of pts, G3 in 21%), nausea/vomiting (83% of pts, G3 in 4%), skin toxicity (75% of pts, G3 in 21%), asthenia (70% of patients, no G3), depression (58% of pts, G3 in 4%), anxiety (42% of pts, no G3), transaminases increase (29% of pts, G3 in 17%). B and L PK parameters values were consistent with those already published for both drugs. A large inter-individual variability was observed for both drugs. There was no significant evidence for drug-drug PK interaction. Disease control rate (DCR) was 79% [57-92%], one patient obtained a complete remission and 6 additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate, CBR of 29% [12-51%]). PIK3CA mutations and PTEN loss were observed in 4 of 14 and 1 of 21 patients, respectively. DCR and CBR were higher in hormone receptor-negative tumors. Conclusion: Combining BKM120 and lapatinib in HER2-positive trastuzumab-resistant was feasible. Preliminary evidences of antitumor activity were observed in this heavily pre-treated population. Citation Format: Anthony Gonçalves, Mathilde Guerin, Nicolas Isambert, Mario Campone, Keyvan Resai, Aurélie Autret, Jihane Pakradouni, Alexie Robert, Magali Provansal, Emmanuelle Charafe-Jauffret, Renaud Sabatier, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher. PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A118.

Le traitement des leucemies aigues myeloblastiques (LAM) comprend la prise en charge transfusionnelle de thrombopenies profondes. Le choix d’une attitude transfusionnelle (AT) prophylactique (sur chiffre plaquettaire) vs therapeutique (sur signes cliniques) evoque par l’etude de Slichter (2004) reste encore discute. Nous avons compare retrospectivement l’AT de l’institut Paoli-Calmettes (IPC) ayant opte jusqu’en 2012 pour une AT therapeutique, a celle du centre d’hematologie de Lyon (CHU E. Herriot, CEH), ayant opte pour une AT prophylactique. L’analyse compare chez les patients (Pts) adultes induits pour une LAM de 2001 a 2010, le nombre de deces par hemorragie et la consommation de produits sanguins durant l’induction (45 jours) et durant les 6 premiers mois de traitement. Au total, 885 Pts ont ete induits a l’IPC (âge my 59 ans, 45 % > 60 ans) et 524 au CHE (âge my 52 ans, 31 % > 60 ans). Durant l’induction, puis les 6 premiers mois, les Pts IPC et CEH ont recu en my 5,1 vs 10,3, puis 9 vs 20 CP. Durant ces 6 mois, a l’IPC et au CEH, 21 vs 6 Pts sont decedes d’hemorragie, a j18 et j130 en mediane, dont 8 vs 4 dans un contexte d’etat refractaire aux transfusions plaquettaires. A l’IPC, 4 Pts sont decedes dans un contexte de CIVD persistante, 8 dans un contexte de sepsis de grade ≥ 3. En conclusion, dans un contexte d’AT therapeutiques vs prophylactique, les TP ont ete 2 fois moins eleves mais plus de Pts sont decedes d’hemorragies, precoces et en contexte de sepsis. Ces resultats indiqueraient que le choix d’une AT prophylactique (consensus actuel), pourrait etre adapte aux facteurs de risque : pendant l’induction plutot qu’en consolidation ou lors de sepsis.

Objective: Evidence points to a founder of the multifunctional CCN family, NOV/CCN3, as a circulating molecule involved in cardiac development, vascular homeostasis and inflammation. No data are available on the relationship between plasma NOV/CCN3 levels and cardiovascular risk factors in humans. This study investigated the possible relationship between plasma NOV levels and cardiovascular risk factors in humans. Methods: NOV levels were measured in the plasma from 594 adults with a hyperlipidemia history and/or with lipid-lowering therapy and/or a body mass index (BMI) .30 kg/m 2 . Correlations were measured between NOV plasma levels and various parameters, including BMI, fat mass, and plasma triglycerides, cholesterol, glucose, and C-reactive protein. NOV expression was also evaluated in adipose tissue from obese patients and rodents and in primary cultures of adipocytes and macrophages. Results: After full multivariate adjustment, we detected a strong positive correlation between plasma NOV and BMI (r=0.36 p,0.0001) and fat mass (r=0.33 p,0.0005). According to quintiles, this relationship appeared to be linear. NOV levels were also positively correlated with C-reactive protein but not with total cholesterol, LDL-C or blood glucose. In patients with drastic weight loss induced by Roux-en-Y bariatric surgery, circulating NOV levels decreased by 28% (p,0.02) and 48% (p,0.0001) after 3 and 6 months, respectively, following surgery. In adipose tissue from obese patients, and in human primary cultures NOV protein was detected in adipocytes and macrophages. In mice fed a high fat diet NOV plasma levels and its expression in adipose tissue were also significantly increased compared to controls fed a standard diet. Conclusion: Our results strongly suggest that in obese humans and mice plasma NOV levels positively correlated with NOV expression in adipose tissue, and support a possible contribution of NOV to obesity-related inflammation. Citation: Pakradouni J, Le Goff W, Calmel C, Antoine B, Villard E, et al. (2013) Plasma NOV/CCN3 Levels Are Closely Associated with Obesity in Patients with