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CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- metastatic breast cancer (MBC) patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. Non-invasive monitoring of the efficacy of treatment could help into tailoring therapeutic regimen. Extracellular vesicles (EVs) are a group of heterogeneous nanosized bioparticles (30-1000nm), released by almost all cell types - including tumor, platelets, and immune cells – carrying informative biological material emanating from the mother cell and circulating in the blood stream. In this project, we ambition to assess whether the vesiclemia, i.e. plasmatic extracellular vesicle concentration can be used as a clinic-biological parameter to assist in the monitoring of patients. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, i.e. multi-omics approaches in MBC patients. The present study focused on patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6. Plasma samples were drawn every 3 months during the treatment until progression. The workflow for the enrichment of circulating EVs was developed from frozen plasma. A semi-automatized isolation procedure using size exclusion chromatography combined with the newly developed interference light microscopy apparatus Videodrop allowed to routinely separate plasmatic EVs and quantify vesiclemia in a fast and reliable manner for a large number of samples (longitudinal follow-up of MBC patients). RESULTS: 26 patients were included and monitored for vesiclemia. Median age was 58.5y (±13.7). Metastatic disease sites were distributed as follows: bone metastases (21; 84%), liver (21; 84%), thoracic (10; 40%), node (2; 8%), brain (1; 4%), others (2; 8%). Endocrine therapy included aromatase inhibitors (20; 77%), fulvestrant (6; 29%), GnRH agonists (5; 19%) and CDK4/6 inhibitors palbocilib (15; 57%), abemaciclib (8; 31%) and ribociclib (3; 11%). With a median follow-up time of 22.1 months (95%CI 21.2 - not reached), median progression free survival was 21.8 months (95%CI 18.1 - not reached). Median time on treatment was 19.4 months (IQR 11.6 - 22.1). Objective response rate was confirmed in 12 patients (6 with complete response). Out of the 26 patients, 12 stopped the frontline treatment due to disease progression. 135 longitudinal follow-up samples were analyzed for EVs. All patients who progressed rapidly after treatment initiation (i.e median PFS< 6 months) had an increased vesiclemia at the months 2 and 6 after inclusion. Conversely, patients who had a median PFS >18m had a stable vesiclemia during this period. CONCLUSION This study aims to use circulating EVs as a therapeutic companion to anticipate treatment resistance and tumor progression in MBC patients. Our preliminary data suggest that the vesiclemia could be used as a predictive tool to anticipate treatment failure, and thus might be used to tailor treatments in time. Citation Format: Mathilde Richard, Jean Sebastien FRENEL, Laurent Mathiot, Mario Campone, Mathilde Colombie, Marie Robert, Anne Patsouris, Frederic Bigot, Julie Gavard, Gwennan André-Grégoire, Laetitia Guevel. Extracellular vesicle-based biomarker assay for the monitoring of the efficacy of frontline endocrine therapy + CDK4-6 inhibitors in metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-09.

Around 15% of metastatic endometrial carcinoma (EC) are MMRd/MSI-H improving response to immune checkpoint inhibitors (ICI). So far, few data existed considering the chemotherapy (CT) sensitivity in MMRd/MSI-H EC, especially response to first-line platinum-based treatment.We performed a multicentric retrospective analysis reporting the response to first line platinum CT in MMRd/MSI-H EC patients. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS) with first line platinum-based CT.A total of 112 patients MMRd/MSI-H EC from 8 centers were identified. Median overall survival was 58.0 months (95% CI: 45.3-95.1). Among them, 78 patients received first line platinum CT in recurrent/metastatic setting. With a median follow up of 32.6 months (min: 0.03; max: 135.0), ORR and DCR (disease control rate) were 50% (95% CI: 38.5-61.5) and 68% (95% CI: 56.4-78.1), respectively. Median PFS and OS from first line platinum-based CT was 7.8 months (95% CI: 6.0-9.0) and 51.9 months (95% CI: 28.0-NE), respectively. Median PFS with ICI in second line (n = 48) was 10.7 months (95% CI: 3.4-NE) from ICI initiation.ORR in first line metastatic MMRd/MSI-H EC is consistent with efficacy in an all comer metastatic EC population.

Background An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. Methods This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5 center dot 4 mg/kg or trastuzumab emtansine 3 center dot 6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. Findings Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28 center dot 4 months (IQR 22 center dot 1-32 center dot 9) with trastuzumab deruxtecan and 26 center dot 5 months (14 center dot 5-31 center dot 3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28 center dot 8 months (95% CI 22 center dot 4-37 center dot 9) with trastuzumab deruxtecan and 6 center dot 8 months (5 center dot 6-8 center dot 2) with trastuzumab emtansine (hazard ratio [HR] 0 center dot 33 [95% CI 0 center dot 26-0 center dot 43]; nominal p

Background In patients with recurrent glioblastoma, corticosteroids are frequently used to mitigate intracranial pressure and to improve patient neurological functioning. To date, in these patients, no systematic studies have been performed to assess neurocognitive functioning (NCF) in relation to corticosteroid treatment. Methods Using baseline data (ie, prior to randomization) of European Organization for Research and Treatment of Cancer (EORTC) trial 26101, we performed regression analysis to assess the predictive value of corticosteroid intake on performance of the EORTC brain tumor clinical trial NCF test battery. The battery is comprised of the Hopkins Verbal Learning Test—Revised (HVLT-R), Controlled Oral Word Association Test (COWA), and Trail Making Test (A and B). Results Out of 321 patients, 148 (46.1%) were not using corticosteroids, and 173 were using dexamethasone (34.3%), methylprednisolone (9.7%), or other corticosteroids (9.9%). Patients on corticosteroids had worse performance on all neurocognitive tests. Regression analyses demonstrated a negative association between corticosteroids use and the HVLT-R free recall score (R2 change = 0.034, F change (1, 272) = 13.392, P < .001) and HVLT-R Delayed Recall score (R2 change = 0.028, F change (1, 270) = 10.623, P = .002). No statistically significant association was found for HVLT-R Delayed recognition, COWA, TMT part A and TMT part B (P > .05). Conclusions Glioblastoma patients prescribed with corticosteroids show poorer memory functions, expressive language, visual-motor scanning speed, and executive functioning than patients not using corticosteroids. Furthermore, we found a negative association between corticosteroid intake and memory functions. The possibility of deleterious effects of corticosteroids on NCF should be considered during clinical decision making.

Background Hypofractionated stereotactic radiotherapy (hFSRT) is a salvage option for recurrent glioblastoma (GB) which may synergize anti-PDL1 treatment. This phase I study evaluated the safety and the recommended phase II dose of anti-PDL1 durvalumab combined with hFSRT in patients with recurrent GB. Methods Patients were treated with 24 Gy, 8 Gy per fraction on days 1, 3, and 5 combined with the first 1500 mg Durvalumab dose on day 5, followed by infusions q4weeks until progression or for a maximum of 12 months. A standard 3 + 3 Durvalumab dose de-escalation design was used. Longitudinal lymphocytes count, cytokines analyses on plasma samples, and magnetic resonance imaging (MRI) were collected. Results Six patients were included. One dose limiting toxicity, an immune-related grade 3 vestibular neuritis related to Durvalumab, was reported. Median progression-free interval (PFI) and overall survival (OS) were 2.3 and 16.7 months, respectively. Multi-modal deep learning-based analysis including MRI, cytokines, and lymphocytes/neutrophil ratio isolated the patients presenting pseudoprogression, the longest PFI and those with the longest OS, but statistical significance cannot be established considering phase I data only. Conclusion Combination of hFSRT and Durvalumab in recurrent GB was well tolerated in this phase I study. These encouraging results led to an ongoing randomized phase II. (ClinicalTrials.gov Identifier: NCT02866747).

Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma.Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients.Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts.The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Background: Each year 5 to 10% of new breast cancers are diagnosed with a metastatic staging. Metastatic breast cancer remains an incurable disease despite significant therapeutic advances in both supportive cares and targeted specific therapies. The disease is in most cases characterized by the disruption of systemic homeostasis (coinciding with multiple interactive and dependent parameters). Decision algorithms rely on a number of objective and subjective parameters which allow the therapeutic decision making process to become the most individualized or adapted. Extrinsic objectives parameters are currently based on EBM (evidence-based-medicine). Intrinsic subjective parameters are taken into account in decision-making: parameters that are linked to the oncologist's assumptions, such asthe sensitivity to the theoretical efficacy of treatments and the definition of sensitivity. Currently, the clinician rationalizes these therapeutic indications according to the prediction of the treatment response from the "phenotypic classification". Cancer is a complex disease relying on numerous elements in dynamic, organized and evolving interactions, and analysis of a complex system requires a global approach. The research hypothesis is to evolve from a reductionist, disjunctive, analytical view of the characterization of cell components (genes, transcripts, proteins, etc.) to a global, systemic, conjunctive and organizational vision: distinct datasets are linked and we need to unravel these underlying links. With this project, we want to demonstrate the ability to exploit complex data in healthcare and in particular in cancer management. We chose a specific metastatic breast cancer model. Methods: Our project is to integrate massive and heterogeneous data concerning the patient’s environment, personal and familial history, clinical and biological data, imaging, histological results, multi-omics data, and microbiota analysis. These characteristics are multiple and in dynamic interaction overtime. The main objective is to prove feasibility of creation of a clinico-biological database prospectively by collecting epidemiological, socio-economic, clinical, biological, pathological, multi-omics data and to identify characteristics related to the disease progression before treatment and within 15 years after treatment start from a cohort of 300 patients with a metastatic breast cancer treated in our institution. Results: The EPICURE trial opened in December 2018. Overall recruitment as of July 2021 was 116 patients; 72% had history of adjuvant therapy and 28% had immediately metastatic disease. We created three groups: HR+/Her2- (75% of enrolment); HER2+ (12%); and triple-negative breast cancer (13%). For 89% of patients, we obtained metastatic biopsy during screening and at date 20 metastatic biopsies for recurrence. For all patients, we collected blood sample following the flow chart and microbiota at the screening. Conclusion: EPICURE is an original and longitudinal prospective biocollection of metastatic breast cancer patients. We expect answering specific scientific questions regarding metastatic disease with heterogeneous data, especially by collecting data without a priori value or links each other. Clinical trial information: NCT03958136. Funding: EPICURE is funded by the FEDER European fundings, Astra Zeneca and Lilly Citation Format: Mathilde Colombié, Pascal Jézéquel, Mathieu Rubeaux, Jean-Sebastien Frenel, Frédéric Bigot, Valérie Seegers, Mario Campone. Feasibility of creation of a clinico-biological database: A prospective longitudinal cohort study of metastatic breast cancer patients (epicuresein) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-20-01.

Metastatic breast cancer (mBC) progression and associated treatments can significantly impact the patients’ quality of life (QoL). However, few studies address the patients’ experience and the solutions to improve their QoL. RÉALITÉS 2 is a physicians/patients mirror survey carried out in 2020 among 57 medical doctors and 269 patients with mBC, one of which main objectives is to assess the mBC patients’ QoL and healthcare. The participating physicians were invited to distribute a questionnaire to their voluntary patients. Compared with the results of the RÉALITÉS 1 survey conducted in 2015, patients declared that they have a better knowledge of their disease in 2020. Most of the patients (76%) understood they had metastasized cancer, vs. 65% during the first wave. Regarding the information provided during mBC announcement, patients were more positive in 2020. 78% of them reported that their medical doctor spent time listening them, vs. 68% in 2015. However, for 58% of the surveyed physicians, the information provided remains difficult to understand for a minority of patients. Throughout the RÉALITÉS 2 survey, patients also expressed their satisfaction with the information received about their treatment. 81% of them said they were informed about the adverse effects of treatments and 74% felt free to ask their questions, vs 71% and 66% respectively in 2015. In 2020, patients made more use of supportive care, such as social assistance (36% vs. 26% in 2015), as well as physical activity advice (18% vs. 13% in 2015). Regarding patients who did not receive supportive care, surveyed physicians explained that they were not offered in 2/3 of cases. The main adverse effects reported while taking treatments are fatigue, hair loss, pain and vomiting, mentioned respectively in 53%, 41%, 49% and 36% of cases by the patients; information confirmed by physicians. According to 82% of patients treated with chemotherapy, these adverse effects are attributable to their treatments, vs only 61% of patients receiving endocrine therapy and 66% of patients treated with targeted therapy. Physicians also believe that side effects are more frequently mentioned in patients undergoing chemotherapy. RÉALITÉS 2 survey highlights the significant improvement in terms of mBC patient support, care and disease/treatment understanding in France. However, cancer treatments remain quite impactful on mBC patients’ QoL, especially for patients treated by CT. There is still room for improvement on delivering and promoting supportive care access. Citation Format: Jean-Sebastien Frenel, Séverine Guiu, Dominique Debiais, Isabelle Moley-Massol, Laure Gueroult-Accolas, Claudia Lefeuvre-Plesse. Analysis of knowledge, quality of life and medical management of patients with metastatic breast cancer: Results of the RÉALITÉS 2 French Survey [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-15-06.

Introduction: Endoxifen exposure, the most active metabolite of tamoxifen, may be a better predictor of tamoxifen efficacy, than CYP2D6 genotypes. However, conflicting results have been reported so far. We evaluated prospectively the impact of 5 weeks of pre-operative tamoxifen on Ki-67 levels in early-stage breast cancer (EBC) patients. We correlated CYP2D6 genotype, exposure of tamoxifen and its metabolites with long-term outcome. Patients and methods: TAM pre-op was an open-label, multicentre, phase 2 trial in which pre and postmenopausal women with WHO performance status 0-1 and HR+ HER2-, operable breast cancer were given tamoxifen (20mg per day orally) for 5 weeks before surgery. Adjuvant treatments were given as standard practice. CYP2D6 genotype was determined at initiation. Plasma concentrations of tamoxifen and its main metabolites (N-desmethyltamoxifen, Z-endoxifen, and Z-4-hydroxytamoxifen) were assessed at baseline (b), week 2 (w2) and week 5 (w5) of treatment, using a validated performed LC-MS/MS method. AUCs, used as marker of exposure, were computed with Monolix© (Lixoft, Antony, France). Tumour Ki-67 variations between baseline (Ki-67b) and w5 (Ki-67w5) were determined to assess the sensitivity to tamoxifen. We used a pre-defined 10% cut-off to dichotomize low versus high Ki-67. All these parameters were associated with disease free survival by Cox regression analyses. Results: Out of the 136 patients enrolled, 98 pts had paired Ki-67 values evaluable. With a median follow up of 78 months (IQR 58-95), 14/136 women had cancer recurrence (12 distant and 2 contralateral) with the proportion free from cancer recurrence at 5 years of 90% (95% CI 83-94). Ki-67b, Ki-67w5 and variations between baseline and week 5 were not associated with DFS. Endoxifen AUC was correlated with CYP2D6 genotype (normal/hyper metabolizer versus low metabolizer) but CYP2D6 genotype was not predictive for DFS (adjusted hazard ratio, 2.24; 95% CI, 0.29 to 17.37; P = 0.44). Endoxifen AUCs at w2 and w5 were similar in patients with low Ki67b and low Ki67w5 (low-low) (n=36), low Ki67b and high Ki67w5 (n=12), high Ki67b and low Ki67w5 (n=14) and high Ki67b and high Ki67w5 (n=30). However, low endoxifen AUC at w5 was a pejorative factor of disease free survival: 5 years PFS 81.8% vs 90.3% (HR 2.70, CI 95% [1.04-7.06], p=0.04). Conclusion: This prospective clinical study shows that endoxifen exposure at w5 of pre-operative tamoxifen is associated with DFS in patients with HR+/HER2- EBC. Translationnal studies are ongoing. N°EUDRACT 2008-007652-10. Citation Format: Jean-Sebastien Frenel, Loic Campion, Antonin Schmitt, Patricia De Cremoux, Elsa Rossignol, Celine Renaudeau, Marie Robert, Jean-Marie Bard, Christine Bobin-Dubigeon, Mario Campone. Endoxifen exposure after 5 weeks of preoperative tamoxifen is predictive of long-term outcome of operable hormone receptor positive (HR+) HER2 - early breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-07-06.

Supplementary Data 6: Monitoring of somatic genomic alterations in plasma during targeted therapy. Allele frequencies (AF) of identified mutations are represented on the left Y-axis while the sum of the target lesions on the CT scan, are represented on the right Y-axis.

Supplementary Data 1: Primers and probes for ddPCR assay Supplementary Data 2: Consort Diagram Supplementary Data 3: List of drugs Supplementary Data 4: Cross validation of PGM sequencing assay with ddPCR Supplementary Data 5: To test intra-run assay performance, 3 different libraries were prepared using the same plasma cfDNA from a single patient Supplementary Data 6: See figure 6 below. Supplementary Data 7: Time to progression for patients having a 30% decrease in plasma mutation AF, following targeted drug administration, and association with time to progression by RECIST evaluation.

Suppl. Materials and Methods; 5 Suppl. Figures; 2 Suppl Tables and List of Participating Investigators Supplementary Figure S1. Definition of MGMT cut-off with a safety margin. Supplementary Figure S2. Comparison of Overall Survival in patients with vs without markers assessments. Supplementary Figure S3. Visualization of markers analyzed in the mTOR signaling pathway from KEGG. Supplementary Figure S4. Forest plot molecular markers Supplementary Figure S5. Complete Graphical summary of consensus cluster analysis based on the matrix obtained by the reconstitution of the data in using Non-linear Iterative Partial Least Squares (NIPALS) algorithm.

Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR.

Background: About 40% of breast cancer cases occur in women 65 years old (yo) or older and 20% in women over 75 yo. These numbers are expected to increase in the near future. Ironically, older patients remain underrepresented in clinical trials with no improvement in the past decade, although they may present different efficacy/toxicity profiles compared with younger adults. In this context, real life cohorts may bring valuable insight to identify potential barriers to recruitment of older patients with metastatic breast cancer (MBC) in clinical trials. Methods: We used the national Epidemio-Strategy and Medical Economics (ESME) MBC Data Platform, a multi-center real life database using a retrospective data collection process in 18 French Cancer Centers. Cases selected were adult patients with MBC whose first metastasis was treated between January 1st, 2008 and December 31st, 2016. We selected MBC women over 70 yo at the time of MBC diagnosis, with at least one line of systemic treatment and no other cancer in the 5 years before MBC. The primary objective was to describe factors associated with enrollment in clinical trials in older patients, using a multivariable Cox model. Factors included in this model were age (continuous, and by class), period (2008-2011 vs 2012-2016), phenotype (ER+, HER2+, or ER- HER2-), ECOG Performance Status (PS), treatment, metastatic sites (brain, visceral, nodes/bone only) and number, and volume of hospital activity. No geriatric description could be extracted from the database. Results: There were 5846 patients ≥70yo (median age 77) and 15892 patients < 70 yo. Of the older ones, 245 (4.2%) were enrolled in a clinical trial in first line compared with 1602 (10%) for younger ones. Most of the older patients in this cohort (66%) had ER+ HER2+ disease, half had visceral metastases (< 3 metastatic sites in 82%). Median follow-up of older patients was 46.3 months; 95%CI 44.8-49.0. Cause of death was related to disease in 1155 (33.9%) older patients, and related to another cause or unknown in 2156 (63.3%), data were missing for 2441 patients. Median overall survival (OS) was 34.1 months in the older population, 95%CI 32.9-35.4, and specific overall survival was 70.8 months, 95%CI 66.3-80.0. Significant factors identified in the multivariable analysis for enrollment in 1st line treatment clinical trial ≥70 are shown in table. Volume of activity was not identified as one. By multivariate analysis, participation of older patients to a clinical trial was associated with an increased OS (HR 0.7; 95% CI 0.6-0.8) but not with a better breast cancer specific survival (HR 0.94; 95%CI 0.68-1.29). Conclusions: In this large real-life database, few older MBC patients were enrolled in a trial compared with younger ones. Factors associated with such participation to clinical research were younger age (< 80 yo), good PS, HER2+ disease, and investigational treatment consisting of chemotherapy or targeted therapy. There was a small improvement in accruing older patients between 2007-2011 and 2012-2016 (2.6% versus 5.5%). Most of these factors raise questions on drug availability and perceived potential benefits by investigators and medical teams. Accrual of older patients with cancer in other disease types should be more encouraged. VariableOR95%CIAge vs 70-75 75-80 80-85 85+0.74 0.47 0.170.54-1 0.31-0.71 0.06-0.37MBC diagnosis period vs 2008-2011 2012-20161.671.23-2.27Phenotype vs Others HER2+1.761.26-2.45PS vs 0 1 2-40.71 0.150.5-1 0.08-0.26Treatment4.88 5.253.08-7.9 3.48-8.14Chemotherapy vs others4.883.08-7.9Targeted treatment vs others5.253.48-8.14 Citation Format: Michael Bringuier, Matthieu Carton, Christelle Levy, Anne Patsouris, David Pasquier, Marc Debled, Olivier Rigal, William Jacot, Anthony Gonçalves, Isabelle Desmoulins, Thibault De La Motte Rouge, Thomas Bachelot, Jean-Marc Ferrero, Jean-Christophe Eymard, Florence Dalenc, Marie-Ange Mouret-Reynier, Thierry Petit, Michael Chevrot, Coralie Courtinard, Lionel Uwer, Jean-Sebastien Frenel, Capucine Baldini. Enrollment of older metastatic breast cancer patients in clinical trials [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-46.

BACKGROUND: Approximately 5% of breast cancer (BC) patients (pts) carry a deleterious germline BRCA mutation (gBRCAm). Retrospective studies suggest that overall survival (OS) is equivalent between gBRCAm carriers and non-carriers with metastatic BC (MBC). We aimed to use the large ESME multicentre national MBC database to compare outcomes of gBRCAm carriers, gBRCA wild-type (WT) and not tested (NT) pts. METHODS: We used the large ESME MBC database (NCT03275311), a unique national cohort of all consecutive pts who initiated a first-line treatment for MBC between 2008 and 2016 in one of the 18 French Comprehensive Cancer Centers. All pts with data available regarding gBRCA testing were selected for the present analysis. 26 pts with non-BRCA germline mutations were classified in the WT group. The primary endpoint was OS from date of treatment initiation in the 3 groups of patients: gBRCAm, gBRCA WT and gBRCA NT.Secondary endpoints were progression-free survival under first line treatment (PFS1), clinical and biological characteristics of the 3 groups and prognostic factors for OS. Multivariable analyses included the main known prognostic factors (age at MBC, MBC subtype, disease-free interval, presence of visceral disease, number of metastatic sites). They were conducted using Cox proportional analyses. RESULTS: 20624 pts were included in this analysis (414 gBRCAm, 1710 WT, 18500 gBRCA NT). Pts and disease characteristics are summarized in table 1. As expected, patients with gBRCAm were younger and had a higher rate of TNBC and G3 tumors. Median follow-up was 50.5 months (95%CI 49.7-51.5). Non-adjusted median OS was 30.6 months [21.9-34.3] in the gBRCAm group, 35.8 [32.2-37.8] in the WT and 39.3 [38.3-40.3] in NT groups. Median PFS1 was 7.9 months [6.6-9.3] in the gBRCAm group, 7.8 [7.3-8.5] in the WT and 9.7 months [ 9.5-10.0] in the NT groups. In multivariable analyses, OS and PFS were not significantly different between MBC patients with gBRCA and others (respective HRs 1.01 [0.88;1.17], p=0.87 and 0.94 [0.84;1.06], p=0.31). CONCLUSION: In this large scale real-life ESME MBC database analysis, outcomes of gBRCAm carriers with MBC do not differ from non carriers or not tested subgroups, when adjusted for other prognostic factors. Table 1: characteristics of patients and diseasegBRCAm. gBRCA WT. gBRCA NT Pvalue (chi-2)N = 414 N = 1710 N = 18500 Age (years) median [range]45 [23-82]48 [20- 88]61 [22-103]p Citation Format: Audrey Mailliez, Veronique D'Hondt, Amelie Lusque, Olivier Caron, Luc Cabel, Antony Goncalves, Marc Debled, Laurence Gladieff, Jean-Marc Ferrero, Thierry Petit, Marie-Ange Mouret-Reynier, Jean-Christophe Eymard, Jean-Sébastien Frenel, Thibault De La Motte Rouge, Gaëtane Simon, Suzette Delaloge. Outcomes of germline BRCA carriers versus non-carriers in the french national metastatic breast cancer ESME cohort 2008-2016 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-08.

OBJECTIVE The aim was to evaluate the impact of local surgery performed during the year following metastatic breast cancer (MBC) diagnosis on patients' outcomes from a large real-life cohort. SUMMARY BACKGROUND DATA Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS Out of 16,703 patients in the ESME database, 1,977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, p < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, p < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, p < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61 - 0.92] and 0.72 [0.63 - 0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype and age. CONCLUSIONS In the large ESME cohort, surgery within one year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

Background Current treatments for recurrent glioblastoma offer limited benefit. The authors report the antitumor activity and safety of the anti-programmed death 1 (anti-PD-1) immunotherapy, pembrolizumab, in programmed death ligand 1 (PD-L1)-positive, recurrent glioblastoma. Methods Adult patients with PD-L1-positive tumors were enrolled in the recurrent glioblastoma cohort of the multicohort, phase 1b KEYNOTE-028 study (ClinicalTrials.gov identifier, NCT02054806) and received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years. The primary endpoint was investigator-assessed overall response rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Archival tumor samples were assessed for PD-L1 expression levels (prospectively) and T-cell-inflamed gene expression profile score (retrospectively). Results After a median follow-up of 14 months (range, 2-55 months) among the 26 enrolled patients, the overall response rate was 8% (95% CI, 1%-26%). Two partial responses, lasting 8.3 and 22.8 months, occurred. Progression-free survival (median, 2.8 months; 95% CI, 1.9-8.1 months) rate at 6 months was 37.7%, and the overall survival (median, 13.1 months; 95% CI, 8.0-26.6 months) rate at 12 months was 58%. Correlation of therapeutic benefit to level of PD-L1 expression, gene expression profile score, or baseline steroid use could not be established. Treatment-related adverse events occurred in 19 patients (73%), and 5 patients experienced grade 3 or 4 events (there were no grade 5 events). Immune-mediated adverse events and infusion reactions occurred in 7 patients (27%). Conclusions Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with manageable toxicity in this small, signal-finding, recurrent glioblastoma cohort. Future studies evaluating rationally designed pembrolizumab combination regimens may improve outcomes in patients with recurrent glioblastoma.

Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.

Background: Bone-only (BO) metastatic breast cancer (MBC), defined as bone as unique site of metastasis at MBC diagnosis, is thought to carry a better prognosis among MBC. However, only small retrospective series and data from selected randomized controlled trials have been reported so far. Based on a national database, we aimed at providing a large comprehensive analysis of BO MBC, and at evaluating its impact on clinical outcome. Methods: The ESME MBC platform (NCT03275311) is a French multicenter retrospective real-life database using a clinical trial-like methodology to collect data from 18 French Comprehensive Cancer Centers. It includes data from each newly diagnosed MBC patient having initiated at least one treatment between 2008 and 2016. BO cases occurring in women were retrieved and compared to the overall non-BO population, regarding treatment effects and survival. Results: Of the 22,463 women selected in the database, 5,041 (22.4%) patients with BO disease were identified. Most (N=4,102, 81.4%) had HR+/HER2- disease while 644 (12.8%) and 295 (5.9%) patients had HER2+ or HR-/HER2- disease, respectively. Compared to non-BO MBC, BO MBC patients were older in the global cohort and in HR-/HER2- patients (mean age 61.0y versus 59.5y, and 59.3y vs 56.4y, all p Conclusion: This large comprehensive study is the largest cohort of BO MBC to date. BO MBC has a distinct presentation from non-BO MBC and carry a better prognosis compared to non-BO MBC. A significant proportion of BO MBC patients have a very long survival and may benefit from aggressive local therapy, as stereotactic radiotherapy. Dedicated studies are warranted to tailor the management of these patients. Funding: This work was supported by UNICANCER. The ESME MBC database is supported by an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analyses and publications are totally managed by R&D UNICANCER independently of the industrial consortium. TableBOBOBOBOnon-BOnon-BOnon-BOnon-BON (%)median OS monthsmedian PFS1 months5-year OS rate %N (%)median OS monthsmedian PFS1 months5-year OS rate %(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)Overall population5,041 (100%)52.1 (50.3-54.1) 13.1 (12.6-13.8) 43.41 (41.66-45.15)15,054 (100%)34.7 (34.0-35.6) 8.5 (8.3-8.7) 30.55 (29.62-31.48)HR+/HER-4,102 (81.4%)52.6 (50.5-54.8)13.6 (13.0-14.3)43.52 (41.56-45.46)9,127 (60.6%) 39.0 (37.8-40.1)9.6 (9.3-9.9)32.69 (31.47-33.93)HER2+644 (12.8%)66.4 (59.8-71.9) 14.9 (12.9-17.3) 54.49 (49.54-59.16)3,265 (21.7%) 46.5 (44.2-48.9)10.6 (10.1-11.3)39.88 (37.77-41.98)HR-/HER2-295 (5.9%)20.8 (18.3-27.4) 5.6 (4.9-7.5)16.21 (11.21-22.02)2,662 (17.7%) 14.3 (13.6-15.1)4.8 (4.6-5.0)10.89 (9.4-12.5)De novo MBC patients1,909 (37.9%)58.6 (55.4-62.1)17.9 (17.0-18.9)48.24 (45.28-51.14)4,399 (29.2%) ---Relapsed MBC patients3,132 (62.1%)48.3 (46.5-50.5)10.7 (10.2-11.2)40.51 (38.34-42.67)10,655 (70.8%)--- Citation Format: Marion Bertho, Julien Fraisse, Anne Patsouris, Paul Cottu, Suzette Delaloge, David Pérol, Anne Jaffré, Anthony Goncalves, Marie-Paule Lebitasy, Véronique D'Hondt, Florence Dalenc, Jean-Marc Ferrero, Christelle Levy, Patrick Arveux, Roman Rouzier, Frédérique Penault-Llorca, Lionel Uwer, Jean-Christophe Eymard, Mathias Breton, Michaël Chevrot, Marianne Leheurteur, Michel Velten, Gaëtane Simon, Jean-Sébastien Frenel. Impact of bone-only metastatic breast cancer on outcome in a real-life setting: A comprehensive analysis of 5,041 women from the ESME database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-19-01.

INTRODUCTION: Post-menopausal women with hormone receptor positive (HR+) early breast cancer receive generally 5 years of adjuvant aromatase inhibitor (AI). However, more than half of recurrences occur after that period and the identification of patients who could derive benefit from the prolongation of AI above 5 years is a critical task. We aimed to develop a simple prognostic tool to estimate the risk of late recurrence of patients with HR+ EBC who had completed 5 years of AI, in order to help the decision making process of extending AI. METHODS: We conducted a monocentric, retrospective study based on a local database (BERENIS), which included all patients treated for EBC at the Institut de Cancerologie de L’Ouest (ICO). We identified all post-menopausal women diagnosed with HR+ EBC and who had completed at least 54 months of adjuvant AI. We analysed the outcome after stopping AI, including HR+ metastatic, contralateral and ipsilateral relapses. RESULTS: Between January 2003 and December 2011, 1107 post-menopausal women were retrieved. Median follow-up after completion of 5y AI was 32.6 months [1-132]. The recurrence rate of HR+ disease was 8% (n=89) including 60 metastatic relapses, and 8 and 21 ipsilateral and contralateral local relapses respectively. Multivariate analysis showed that the pathological tumour size (continuous variable) (HR = 1.02; p = 0.035), the number of macro-metastases (continuous variable) (HR = 1.17; p = 0.001) and age (HR = 1.04; p = 0.012) were independent factors of HR+ invasive disease free survival. We then designed a score estimating the risk of late relapse. This was designed as follow: 10*(tumour size (mm)) +79*(number of macro metastases) +14*(years old). Patients were classified as low risk (78.8% of patients) or high risk (21.2%) with a threshold at 1200 points. Low risk patients had a mean 5- to 10-year risk of invasive HR+ local or distant recurrence of 9.8% (95% CI, 7.1% to 13.5%) as compared with 38.3% (95% CI, 27.6% to 50.9%) for high-risk groups. CONCLUSION: Our study is one of the first estimating the risk of late relapse in a population of post-menopausal women who have completed 5y of adjuvant AI for EBC. Our simple score identify accurately patients at high risk of relapse despite 5 years of treatment. This tool may help oncologist to select patients who could derive the most benefit of extending adjuvant AI above 5 years. A validation of this score in an independent population is necessary. Citation Format: Jean-Sebastien Frenel, Loïc Campion, Marie Robert, Classe Jean-Marc, Campone Mario, Camille Moreau-Bachelard. Clinical factors of late recurrence of HR+ early breast cancer after completion of 5 years of aromatase inhibitor and development of a prognostic tool. A study of 1496 women of the ICO database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-17.

Resume Introduction Le traitement dans le cancer de l’ovaire localement avance est une chirurgie optimale suivie d’une chimiotherapie. Les patientes avec une dissemination tumorale importante, un OMS superieur a deux et un âge superieur a 75 ans sont de mauvaises candidates pour une chirurgie premiere agressive. La chirurgie d’intervalle, apres une chimiotherapie neo adjuvante, a pour but d’obtenir davantage de chirurgies completes, d’augmenter la survie et de diminuer la morbidite liee a la chirurgie. Le critere principal de jugement etait la survie sans progression. Les criteres secondaires de jugement etaient la survie globale et la morbi-mortalite post-chirurgie. Methode Il s’agit d’une etude retrospective effectuee dans deux centres de reference francais entre janvier 2000 et decembre 2015. Les patientes qui ne pouvaient pas beneficier d’une chirurgie initiale complete etaient operees apres trois cures de chimiotherapie au centre Francois Baclesse et apres au moins cinq cures au centre Rene Gauducheau. Resultats La population analysee comportait 104 patientes, 43 (41,0 %) patientes traitees au centre Rene Gauducheau (groupe 1) et 61 (59,0 %) patientes traitees au centre Francois Baclesse (groupe 2). La survie sans progression et globale etait similaire entre les deux groupes. Elles etaient respectivement de 15,9 mois et 34 mois dans le groupe 1 vs 15,4 mois et 37,6 mois dans le groupe 2 (p = 0,72 ; p = 0,65). La duree d’hospitalisation moyenne et la morbidite postoperatoire etait similaire dans les deux groupes. Conclusion Pour des patientes fragiles, afin de limiter une chirurgie invasive, faire plus de cinq cures de chimiotherapie peut etre une option raisonnable.

International audience; Cancer numbers increasing, cases heterogeneity and the drug resistance emergence have pushed scientists to search for innovative solutions for patients and epimutations can be one. Methylated DNA, modified nucleosomes and noncoding RNAs are found in all cells, including tumor cells. They are intracellular actors but also have intercellular communication roles, being released in extracellular environment and in different body fluids. Here, we reviewed current literature on the use of these blood circulating epimarks in cancer monitoring. What stands out is that epimarkers must be considered as 'real time' images of the tumor, and can be isolated without invasive methods. In the future, the real challenge lies in the development of specific, sensitive, fast and clinically applicable detection and analysis methods of epimarkers.

Objective To evaluate the efficacy and safety of regorafenib versus tamoxifen in platinum-sensitive ovarian cancer biological recurrence, defined by CA-125 increase without radiological (RECIST criteria) or symptomatic evidence of progression. Patients and methods 116 patients with platinum-sensitive ovarian cancer presenting an isolated increase of CA-125 were planned to be randomized. Regorafenib was administered orally at 160 or 120 mg daily, 3 weeks on/1 week off or tamoxifen at 40 mg daily, until disease progression or development of unacceptable toxicity. The primary endpoint was Progression-Free Survival, assessed by progression according to RECIST 1.1 or death (by any cause). Secondary endpoints included Overall Survival, Best Response and CA-125 response rate. Results 68 patients were randomized. Median age was 67 years (range: 30-87). Primary site of cancer was ovarian for most patients (92.6%). Tumors were predominantly serous / (89.7%), high grade (83.6%) and initial FIGO staging was III for 69.6% of the patients. Most (79.4%) patients were included after the first line of platinum-based treatment. After a median follow-up of 32 months, there was no difference of progression-free survival (PFS) between regorafenib and tamoxifen groups (p = 0.72), with median PFS of 5.6 months (CI 90%: 3.84-7.52) for the tamoxifen arm and 4.6 months (CI 90%: 3.65-7.33) for the regorafenib arm. There was also no difference in term of overall survival, best response or CA-125 response, delay to next therapy. Regorafenib presented a less favorable safety profile than tamoxifen, with grade 3/4 events occurring for 90.9% of the patients compared to 54.3% for tamoxifen. The most frequent were cutaneous, digestive, and biological events. Notably, hand-foot syndrome occurred in 36.4% of these patients. Conclusion Regorafenib presented an unfavorable toxicity profile compared to tamoxifen, with no superior efficacy in this population of patients.

CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- MBC patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, ie. multi-omics approach in MBC patients. The present study aims at identifying progression markers in patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6 by means of transcriptomics, genomics and proteomics data. All patients had a tumor biopsy at the entry in the study (B1) and a biopsy was repeated at progression if feasible (B2). Transcriptomic (RNAseq: NextSeq550, Illumina), genomic (whole exome sequencing: NextSeq550, Illumina) and proteomic (DIA mass spectrometry: TimsTOFPro2, Bruker) were performed on B1 and B2 according to available tumor tissue. RESULTS: Fifty-one patients matching inclusion criteria were included. B1 was done at inclusion for all patients (B1) (n = 51) and B2 was performed in 8 patients. (B2) (n = 8). Eight metastatic sites were biopsied: node (n = 17); liver (n = 16); bone (n = 8); breast local recurrence (n = 5); chest wall (n = 5); skin (n = 4); pleural (n = 3); ovary (n = 1). Transcriptomic, genomic and proteomic analysis of paired biopsies (B1 and B2) was performed in parallel and separately for 8, 7 and 2 patients, respectively. Exploratory data analysis of transcriptomic and proteomic data showed that liver biopsies clustered together. In order to eliminate this anatomic bias, specific genes and proteins of liver metastases were identified by means of DESeq2 analysis (12 liver vs 39 other sites) for transcriptomic data (n = 2654) and LIMMA (4 liver vs 14 other sites) for proteomic data (n = 227), and excluded for the rest of the analysis. Differential analyses (ie. gene expression, non-synonymous mutations and protein expression) between B1 and B2 were performed for each patient. These three kind of lists were finally submitted to ToppGene, DAVID and GOrilla for Gene Ontology terms enrichment analyses. Transcriptomic analyses of the 8 paired biopsies highlighted immune response (IR) in seven B1, IR in four B2 and neurogenesis in three B2. Genomics data evaluation between B1 and B2 pointed out “transposon integration” as an important pathway. Proteomic data of the 2 paired biopsies analysed underlined high immune response in B1, and muscle development/contraction and response to tumor necrosis factor in B2 for one patient. For the second one, liver metabolism in B1 and extracellular matrix and p38 MAPK cascade were emphasised. CONCLUSION: This preliminary study based on transcriptomic, genomic and proteomic data represents an encouraging first step of the EPICURE project. In a near future, additional paired biopsies and other kinds of omics data (epigenetics, radiomics, microbiomics, exposomics) will be available. Furthermore, omics data will be analysed in an integrated manner (ie. artificial intelligence), which will make it possible to detect synergies across the different omics data. Citation Format: Jean Sebastien FRENEL, Fadoua Ben Azzouz, Frederic Bigot, Jonathan Dauve, Marie Francoise Heymann, Wilfried Gouraud, Catherine Guette, Hamza Lasla, Bertrand Michel, Alain Morel, Anne Patsouris, Marie Robert, Grégoire Siekaniec, Mathilde Colombie, Pascal Jézéquel, Mario Campone. Multi-omics approach to identify markers of resistance to endocrine therapy + CDK4/6 inhibitors in first line HR+/HER2- metastatic breast cancer (MBC) patients. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-37.

Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.

PURPOSE: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. METHODS: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. RESULTS: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). CONCLUSIONS: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

Introduction. Evidence suggests that human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) patients have different clinical characteristics and outcomes according to the hormone receptor (HR) status. We aimed to evaluate the impact of HR status in this population extracted from a large real-world database. Methods. We performed a retrospective analysis of HER2+ MBC patients (pts) included in the real world ESME MBC database (NCT03275311) between 2008 and 2017. Descriptive statistics, the Kaplan-Meier method and Cox proportional hazards models were used to report characteristics, outcomes and prognostic factors. Results. Of 4,145 HER2+ MBC pts eligible for our analysis, 1,449 (35%) had HR-negative (HR-), while 2,696 (65%) had HR-positive (HR+) tumors. Pts with HR- tumors had metastases earlier (median 9.3 vs 28.0 mo from primary cancer), had more often de novo MBC (47.6% vs 38.1%), grade III tumors (50.9% vs 33.6%), visceral metastases (70.9% vs 60.8%) and less often bone only disease (8.4% vs 21.1%) compared to those with HR+ tumors, all p Cox multivariable model for overall survival in patients with HER2-positive MBCCategoriesNHazard ratio95% CIp valueTumor gradeGrade I/II17711 Citation Format: Luc Cabel, Matthieu Carton, Veronique Dieras, Thierry Petit, Severine Guiu, Corinne Veyret, Anthony Goncalves, Lionel Uwer, Paule Augereau, Jean-Marc Ferrero, Christelle Levy, Florence Dalenc, Isabelle Desmoulins, Marie Ange Mouret-Reynier, Marc Debled, Thomas Bachelot, Jean-Christophe Eymard, Barbara Pistilli, Jean Sebastien Frenel, Michael Chevrot, Audrey Mailliez, Marcela Carausu. Impact of hormone receptor status on clinicopathological characteristics and outcomes among HER2-positive metastatic breast cancer patients in the ESME database [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-02.

Introduction: Pertuzumab, a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), inhibits the heterodimerization of HER2 with other HER receptors. It has been approved both by the Food and Drug Administration and the European Medicine Agency in the metastatic, neoadjuvant and adjuvant setting.Areas covered: This review analyses and discusses preclinical and clinical studies of pertuzumab in breast cancer. In this article, we review the status of pertuzumab, the completed and ongoing trials, and its safety.Expert opinion: Pertuzumab is a key drug for the treatment of HER2-positive metastatic or early breast cancer. However, it is imperative to identify patients that will need dual-targeting and mechanisms of resistance. Moreover, the value of pertuzumab beyond progression needs to be evaluated.

Background Precision medicine trials targeting the epidermal growth factor receptor (EGFR) in glioblastoma patients require selection for EGFR-amplified tumors. However, there is currently no gold standard in determining the amplification status of EGFR or variant III (EGFRvIII) expression. Here, we aimed to determine which technique and which cutoffs are suitable to determine EGFR amplification status. Methods We compared fluorescence in-situ hybridization (FISH) and real-time quantitative (RT-q)PCR data from patients screened for trial inclusion into the Intellance 2 clinical trial, with data from a panel-based next generation sequencing (NGS) platform (both DNA and RNA). Results By using data from >1000 samples, we show that at least 50% of EGFR amplified nuclei should be present to define EGFR gene amplification by FISH. Gene amplification (as determined by FISH) correlates with EGFR expression levels (as determined by RT-qPCR) with receiver operating characteristics analysis showing an area under the curve of up to 0.902. EGFR expression as assessed by RT-qPCR therefore may function as a surrogate marker for EGFR amplification. Our NGS data show that EGFR copy numbers can strongly vary between tumors, with levels ranging from 2 to more than 100 copies per cell. Levels exceeding 5 gene copies can be used to define EGFR-amplification by NGS; below this level, FISH detects very few (if any) EGFR amplified nuclei and none of the samples express EGFRvIII. Conclusion Our data from central laboratories and diagnostic sequencing facilities, using material from patients eligible for clinical trial inclusion, help define the optimal cutoff for various techniques to determine EGFR amplification for diagnostic purposes.

Pembrolizumab is a full-length human immunoglobulin G4 (IgG4) monoclonal antibody directed against the immune checkpoint PD-1 to remove its binding with PD-L1 and thus to restore an anti-tumor immune response of T cells. Pembrolizumab is one of the most advanced immune checkpoint inhibitors for cancer care. Apart from rare and serious adverse effects, its favorable tolerance profile enables to treat fragile patients who have often no other choice than best supportive care. The effective retained dose of pembrolizumab is a venous administration of 200 mg every 3 weeks until disease progression, intolerance or up to 24 months. Pembrolizumab has already proven its efficacy and thus obtained marketing authorization in so-called hot or hypermutated tumors or tumors expressing PD-L1 such as melanomas, non-small cell lung cancers, urothelial carcinomas, cervical cancer, etc. Pembrolizumab is also authorized in the United States in the treatment of mismatch repair-deficient tumors or with microsatellite instability. The current challenge is to expand its use in tumor types that are supposed to be less immunogenic, for example, by attempting to warm up the tumor microenvironment, or by combining pembrolizumab with other molecules. An acceptable toxicity profile of such combinations remains to explore. We review here the current indications of this drug, the main prognostic and predictive factors of its efficacy as well as the potential forthcoming indications.

INTRODUCTION The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.

Purpose: Older cancer patients are underrepresented in clinical trials. We aimed to understand barriers to clinical trial recruitment in women aged 70 years old (yo) or over with metastatic breast cancer (MBC).Methods: We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment.Results: 5552 women were aged ≥ 70 (median 74yo; IQR72-77). 14611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI; 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI; 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI; 0.08-0.27] for the PS 2-4 class), HER2+ disease (OR 1.78 [95%CI; 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI; 3.13-8.18]), and period (OR 1.65 [95%CI; 1.22–2.26] for 2012-2016, compared to 2008-2011).Conclusions: In this large database, few older MBC patients were enrolled in a trial compared with younger ones.

IntroductionGlioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation in particular, although this is the mainstay for younger patients. MethodsAll patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for chemoradiation (RCT) were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after RCT and temozolomide hematologic toxicity assessed by CTCAE v5. Results128 patients were included. The median age was 74.1 (IQR: 72-77). 15% of patients were ≥80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I-II and III-IV, respectively. 81% of patients received the entire RCT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5-17.5), median OS was 11.7 months (CI95%: 10-13 months). Median PFS was 9.5 months (CI95%: 9-10.5 months). 8% of patients experienced grade ≥3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥80 were not associated with worsened outcomes. Conclusions6-week chemoradiation was feasible for “real-life” elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities.

Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard 6-week chemoradiation (CRT) in particular, although this is the mainstay for younger patients. All patients with newly diagnosed GBM and age ≥ 70 who were referred to our institution for 6-week CRT were reviewed from 2004 to 2018. MGMT status was not available for treatment decision at that time. The primary endpoint was overall survival (OS). Secondary outcomes were progression-free survival (PFS), early adverse neurological events without neurological progression ≤ 1 month after CRT and temozolomide hematologic toxicity assessed by CTCAE v5. 128 patients were included. The median age was 74.1 (IQR: 72–77). 15% of patients were ≥ 80 years. 62.5% and 37.5% of patients fulfilled the criteria for RPA class I–II and III–IV, respectively. 81% of patients received the entire CRT and 28% completed the maintenance temozolomide. With median follow-up of 11.7 months (IQR: 6.5–17.5), median OS was 11.7 months (CI 95%: 10–13 months). Median PFS was 9.5 months (CI 95%: 9–10.5 months). 8% of patients experienced grade ≥ 3 hematologic events. 52.5% of patients without neurological progression had early adverse neurological events. Post-operative neurological disabilities and age ≥ 80 were not associated with worsened outcomes. 6-week chemoradiation was feasible for “real-life” elderly patients diagnosed with glioblastoma, even in the case of post-operative neurological disabilities. Old does not necessarily mean worse.

BackgroundPlatinum-resistant ovarian cancer patients have a poor prognosis and few treatment options are available. Preclinical and clinical data demonstrated that the combination of poly-ADP ribose polymerase inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients.Primary ObjectiveThe primary objective is to assess the efficacy of niraparib plus dostarlimab compared with chemotherapy in recurrent ovarian cancer patients not suitable for platinum treatment.Study HypothesisThis trial will assess the hypothesis that niraparib plus dostarlimab therapy is effective to increase overall survival, progression-free survival, and time to first subsequent therapy respect to chemotherapy alone, with an acceptable toxicity profile.Trial DesignThis is a phase III, multicenter trial, where recurrent ovarian cancer patients not eligible for platinum re-treatment will be randomized 1:1 to receive niraparib plus dostarlimab vs physician’s choice chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. The study will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited from 40 sites across MITO, CEEGOG, GINECO, HeCOG, MANGO, and NOGGO groups.Major Inclusion/Exclusion criteriaEligible patients must have recurrent epithelial ovarian cancer not eligible for platinum retreatment. Patients who received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors will be eligible. No more than two prior lines of treatment are allowed.Primary EndpointThe primary endpoint is overall survival defined as the time from the randomization to the date of death by any cause.Sample Size427 patients will be randomized.Estimated Dates for Completing Accrual and Presenting ResultsJune 2024Trial Registration NumberNCT04679064.

Introduction Glioblastoma (GBM) is frequent in elderly patients, but their frailty provokes debate regarding optimal treatment in general, and the standard Stupp regimen in particular, although this is the mainstay for younger (

International audience; Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.

Additional file 2: Supp Mat 2. Kaplan-Meier survival curves corresponding to 2A: Time from first cancer diagnosis until development of MAHA. 2B: Time from first metastasis until development of MAHA.

Additional file 1: Supp Mat 1. Clinical and biological parameters included in statistical analysis. 1A: Data requested from participating centres. 1B: Predictive score construction according to statistical analysis.