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With the approval of new therapies targeting the PI3K pathway, the detection of PIK3CA mutations has become a key factor in treatment management for HR+/HER2− metastatic breast cancer (MBC). We developed multiplex digital PCR (dPCR) assays to detect and quantify PIK3CA mutations. A first screening assay allows the detection of 21 mutations, with a drop-off system targeting the 542–546 hotspot mutations combined with the simultaneous detection of N345K, C420R, H1047L and H1047R mutations. In the case of a positive result, a sequential strategy based on other assays that we have developped allows for precise mutation identification. Clinical validity was determined by analyzing plasma circulating free DNA (cfDNA) from 213 HR+/HER2− MBC samples, as well as DNA extracted from 97 available matched tumors from 89 patients. Our assays have shown reliable specificity, accuracy and reproducibility, with limits of blank of three and four droplets for the screening assay. Sixty-eight patients (32%) had at least one PIK3CA mutation detectable in their plasma, and we obtained 83.1% agreement between the cfDNA analysis and the corresponding tumors. The high sensitivity and robustness of these new dPCR assays make them well-suited for rapid and cost-effective detection of PIK3CA mutations in the plasma of MBC patients.

Aims: In HER2CLIMB, tucatinib significantly improved progression-free and overall survival in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer. We evaluated the impact of tucatinib on health-related quality of life (HR-QoL) in HER2CLIMB. Methods: Patients were randomised 2:1 to tucatinib or placebo combined with trastuzumab and capecitabine. Starting with protocol version 7, the EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaire and EQ visual analogue scale (VAS) were administered at day 1 of cycle 1, every two cycles during cycles 3–9, every three cycles during cycle 12 and thereafter and at each patient's 30-day follow-up visit. Results: Among 364 patients eligible for HR-QoL assessment, 331 (91%) completed ≥1 assessment. EQ-VAS scores were similar for both arms at baseline and maintained throughout treatment. EQ-5D-5L scores were similar between the treatment arms, stable throughout therapy and worsened after discontinuing treatment. Risk of meaningful deterioration (≥7 points) on EQ-VAS was reduced 19% in the tucatinib vs. placebo arm (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.55, 1.18); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.8 months (4.3, -) in the placebo arm. Among patients with brain metastases (n = 164), risk of meaningful deterioration on EQ-VAS was reduced 49% in the tucatinib arm (HR: 0.51; 95% CI: 0.28, 0.93); the median (95% CI) time to deterioration was not reached in the tucatinib arm and was 5.5 months (4.2, -) in the placebo arm. Conclusions: HR-QoL was preserved for patients with HER2+ metastatic breast cancer who were treated with tucatinib added to trastuzumab and capecitabine and maintained longer with tucatinib therapy than without it among those with brain metastases. Clinical Trial Registration: NCT02614794

Purpose: Genomic signatures, such as EndoPredict®, may help clinicians to decide which adjuvant treatment is the most appropriate. Methods: We propose the EndoPredict® assay for unclear cases of adjuvant treatment in patients treated in our comprehensive cancer center. We prospectively and retrospectively report the decision of adjuvant treatment before and after the EndoPredict® assay, respectively, compared to the PREDICT’s tool scores. Results: From November 2016 to March 2019, 159 breast cancer tumors were analyzed and presented before and after the EndoPredict® assay. Before the EndoPredict® results, clinicians recommended chemotherapy for 57 patients (57/159, 36%). A total of 108 patients (108/159, 68%) were classified as EPclin high-risk score. There was only a slight agreement between clinicians’ decisions and EPclin risk score. The EPclin score led to 37% changes in treatment (59/159); chemotherapy was favored in 80% of cases (47/59). The PREDICT tool recommended chemotherapy for 16 high-risk patients (16/159, 10%). Conclusion: Although genomic tests were developed in order to de-escalate adjuvant treatment, in our comprehensive cancer center the use of the EndoPredict® assay led to an increase in prescribed chemotherapy.

Purpose Fumarate hydratase–deficient (FHdef) renal cell carcinoma (RCC) is a rare entity associated with the hereditary leiomyomatosis and RCC syndrome with no standard therapy approved. The aim of this retrospective study was to evaluate the efficacy of different systemic treatments in this population. Methods We performed a multicentre retrospective analysis of Fhdef RCC patients to determine the response to systemic treatments. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and overall survival (OS). The two latter were estimated using the Kaplan–Meier method. Results Twenty-four Fhdef RCC patients were identified, and 21 under systemic therapy were included in the analysis: ten received cabozantinib, 14 received sunitinib, nine received “other antiangiogenics” (sorafenib, pazopanib, and axitinib), three received erlotinib-bevacizumab (E-B), three received mTOR inhibitors, and 11 received immune checkpoint blockers (ICBs). ORR for treatments were 50% for cabozantinib, 43% for sunitinib, 63% for “other antiangiogenics,” and 30% for E-B, whereas ORR was 0% for mTOR inhibitors and 18% for ICBs. The median TTF (mTTF) was significantly higher with antiangiogenics (11.6 months) than with mTOR inhibitors (4.4 months) or ICBs (2.7 months). In the first-line setting, antiangiogenics presented a higher ORR compared with nivolumab-ipilimumab (64% versus 25%) and a significantly superior mTTF (11.0 months vs 2.5 months; p = 0.0027). The median OS from the start of the first systemic treatment was 44.0 months (95% confidence interval: 13.0–95.0). Conclusions We report the first European retrospective study of Fhdef RCC patients treated with systemic therapy with a remarkably long median OS of 44.0 months. Our results suggest that antiangiogenics may be superior to ICB/mTOR inhibitors in this population.

Background Hepatocellular carcinoma (HCC) is a major cause of cancer-related death. It is a highly vascular tumour with multiple angiogenic factors, most importantly vascular endothelial growth factor (VEGF), involved in HCC progression. Tivozanib is an oral inhibitor of VEGFR-1/2/3 with promising activity against HCC in vivo. Methods We conducted a phase 1b/2 study of tivozanib in patients with advanced HCC. The safety, dosing, pharmacokinetics, pharmacodynamics, and preliminary antineoplastic efficacy of tivozanib were evaluated. Results Twenty-seven patients received at least one dose of tivozanib. Using a 3+3 design, the recommended phase 2 dose (RP2D) of tivozanib was determined to be 1 mg per os once daily, 21 days on–7 days off. The median progression-free and overall survival were 24 weeks and 9 months, respectively, for patients treated at RP2D. The overall response rate was 21%. Treatment was well tolerated. A significant decrease in soluble plasma VEGFR-2 was noted, assuring adequate target engagement. Conclusions Although this study did not proceed to stage 2, there was an early efficacy signal with a very favourable toxicity profile. A phase 1/2 trial of tivozanib in combination with durvalumab is currently underway. Trial registration ClinicalTrials.gov NCT01835223, registered on 15 April 2013.

International audience; Renal cell carcinoma is the third type of urologic cancer and has a poor prognosis with 30% of metastatic patients at diagnosis. The antiangiogenics and targeted immunotherapies led to treatment remodeling emphasizing the role of the tumour microenvironment. However, long-term responses are rare with a high rate of resistance. New strategies are emerging to improve the efficacy and the emerging drugs are under evaluation in ongoing trials. With the different treatment options, there is an urgent need to identify biomarkers in order to predict the efficacy of drugs and to better stratify patients. Owing to the limitations of programmed death-ligand 1 (PD-L1), the most studied immunohistochemistry biomarkers, and of the tumor mutational burden, the identification of more reliable markers is an unmet need. New technologies could help in this purpose.

INTRODUCTION AND OBJECTIVE:To evaluate the value of radiomic data for predicting progression free survival (PFS) in patients with metastatic metastatic clear cell renal carcinoma (cCCR) treated wit...

Background Sorafenib is the standard treatment of advanced hepatocellular carcinoma. Because of its unique toxicities, improving patients' tolerance merits close follow-up. Nurses can play a crucial role by leading a patient educational program (EP). Objectives The aim of this study was to assess whether adding EP to usual care (UC) improves patient's care. Methods Since 2011, oncologists referred patients treated by sorafenib to the EP led by clinical nurses. The EP included a visit before the first administration, weekly telephone calls, and a visit with the nurse before each oncologist consultation. We retrospectively compared patients in the EP with those in UC followed by an oncologist and patients included in a clinical trial. Results Since 2005, 129 patients were treated with sorafenib for hepatocellular carcinoma: 31 in the EP (24%), 22 in a clinical trial (17%), and 76 with UC (59%). Seventy-one percent of the patients in the EP had toxicities identified during a telephone call, which prompted symptomatic measures in 65% of the patients, leading to treatment modification before the planned on-site visit in 29% of the patients. Educational program patients required fewer dose reductions (39% vs 61% for UC, P = .04), and median time to first dose reduction was shorter with EP than with UC (25 vs 45 days, P = .036). Conclusions This study suggests a clinical benefit of EP related to improved toxicity management of sorafenib that resulted in fewer dose reductions. Implications for practice Patients treated with sorafenib may benefit from an EP. Different types of EP should be compared prospectively, focusing on patients' quality of life.

Background Patients (pts) with human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (MBC) who have brain metastases (BM) have limited treatment options and lower health-related quality of life (HRQoL) compared with pts without BM (Hurvitz 2019). HER2CLIMB is a randomized trial (2:1) of tucatinib vs. placebo in combination with trastuzumab and capecitabine in pts with HER2+ MBC that included pts with stable and active brain metastases (NCT02614794). In HER2CLIMB, the addition of tucatinib to trastuzumab + capecitabine demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) in pts with HER2+ MBC and in those with stable and active BM, with importantly, a tolerable and manageable safety profile (Murthy 2020). An evaluation of the impact of tucatinib on HRQoL in pts with stable and active BM is presented here. Methods HRQoL data were available from 330 of 612 pts, including 163 pts with BMs. HRQoL was assessed using the EQ-5D-5L tool which includes a visual analog scale (EQ-VAS) and a descriptive system (EQ-5D) comprising 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Data were collected at Cycle 1 Day 1, Cycles 3-9 (every 2 cycles; 21-day cycles), Cycle 12 and beyond (every 3 cycles), and at the 30-day follow-up. The EQ-5D-5L scores were summarized by cycle for each treatment arm. Time to deterioration, defined as a >7-point change from baseline on the EQ-VAS, was estimated by the Kaplan-Meier approach. The median time to deterioration (and 95% CIs) were computed for each arm. Results In total, 163 pts with stable and active BM were included in this HRQoL analysis, 107 pts on the tucatinib arm and 56 pts on the placebo arm. Compared to the placebo arm, pts on the tucatinib arm had an approximately 49% reduction in the risk of deterioration (hazard ratio: 0.51; 95% CI: 0.28, 0.93); the median time to deterioration has not been reached in the tucatinib arm with available follow-up and was 5.5 months (95% CI; 4.2, -) in the placebo arm. Decline in all domains of the EQ-5D-5L and the EQ-VAS scores were seen once pts discontinued therapy, particularly on the ‘usual activities’ domain. Additional available QoL data will be presented. Conclusions Pts with MBC and BM treated with tucatinib in combination with trastuzumab + capecitabine demonstrated significantly longer and clinically meaningful time to deterioration of HRQoL. HRQoL was maintained throughout the treatment course, allowing them to receive full benefit of the therapeutic approach and resulting in statistically significant and clinically meaningful improvement in OS. References Hurvitz SA, O’Shaugnessy J, Mason G, et al. Central Nervous System Metastasis in Patients with HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from SystHERs. Clin Cancer Res. 2019;25(8):2433-2441.Murthy RK, Loi S, Okines A, et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2020;382(7):597-609. Citation Format: Andrew Wardley, Volkmar Mueller, Elisavet Paplomata, Laurence Crouzet, Nayyer Iqbal, Sramila Aithal, Margaret Block, Søren Cold, Marie-Agnes By, Olwen Hahn, Teja Poosarla, Erica Stringer-Reasor, Marco Colleoni, David Cameron, Giuseppe Curigliano, Kendra DeBusk, Muriel Siadak, Jorge Ramos, Xuebei An, Karen Gelmon. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with stable and active brain metastases [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 PD13-04.

Managing endocrine resistance and resistance to endocrine therapy for ER+ HER2- breast cancer with the CDK 4/6 inhibitors in the metastatic setting. New antibodies drug conjugates for HER2+ and TNBC. Targeting DNA damage and synthetic lethality strategies with PARP inhibitors for breast cancer patients harboring BRCA mutation. Immunotherapies in 1st line metastatic setting of TNBC.

Resume Introduction Le sorafenib est le standard de traitement du carcinome hepatocellulaire (CHC) avance. Ce medicament est administre par voie orale et associee a une toxicite significative. Nous avons cherche a ameliorer le suivi par l’oncologue medical (OM) en impliquant des infirmieres cliniciennes dediees (ID). Patients et methodes Depuis janvier 2011, les patients sont vus par les ID pendant une heure avant le debut du traitement, puis suivis toutes les semaines par des appels telephoniques. Dans cette etude, nous avons compare de maniere retrospective les patients suivis par les ID avec ceux suivis en OM ou en essai therapeutique. Resultats Depuis 2008, 129 patients ont ete traites dans notre institution par sorafenib pour CHC, 31 (24 %) avec suivi par ID, 22 (17 %) dans un essai et 76 (59 %) en OM. Les patients suivis par les ID ont necessite moins de reduction de dose (39 % vs 61 % en OM, p = 0,04). Le temps median jusqu’a la premiere diminution de dose etait plus court (25 jours vs 45 jours, p = 0,04). Il y avait une tendance a moins de pause de traitement (19 % vs 34 %, p = 0,13) et vers moins d’arret du traitement pour toxicite (26 % vs 36 %, p = 0,33). Cependant, il n’y avait pas de difference dans la survenue de toxicite severe (48 % pour ID vs 42 % pour OM, p = 0,73). Conclusion Bien que retrospective, cette analyse suggere un interet du suivi par ID, avec une meilleure gestion des effets indesirables qui conduit a une reaction plus rapide et moins de reductions posologiques.

420 Background: Only scarce data exist on the management of residual masses in men who have received two lines of chemotherapy for advanced seminoma. Due to the lack of data, the role of PET scanning, surgery and other additional treatments is controversial in these men. Methods: Data from men with pure seminoma and residual masses after salvage chemotherapy were retrospectively collected from 10 high-volume centers in 3 European countries. We analyzed the clinical management of residual masses (imaging, surgery, pathological data, and additional treatment modalities) and long-term outcomes. Residual mass was defined as a lesion of ≥1 cm after two lines of platin-based chemotherapy. Results: To date, data from 48 patients (pts) with non-progressing residual masses after second line (salvage) chemotherapy have been collected and are included in this analysis. Median age at diagnosis was 36 years (range 31; 42). A post-chemotherapy PET-FDG was performed in 32 (67%) pts. Surgery was performed in 20/48 (41%) pts irrespectively of FDG uptake (no, n=8; yes, n=5). Complete necrosis was found in 16 (80%), viable seminoma in 3 (15%), and teratoma in 1 pt, respectively. All pts with a negative PET (PET-) who underwent surgery (8/8) had complete necrosis. 5/11 pts with a positive PET (PET+) underwent surgery: 3 had a complete necrosis while 2 had viable seminoma. Among those with a PET+, 3 pts (28%) experienced either viable seminoma in residual masses or a subsequent relapse. The absence of FDG uptake correlated with absence of viable cancer (p=0.04). A second relapse occurred in 5/48 pts (10%). Only 2/20 pts who had residual masses resected post 1st salvage chemotherapy subsequently relapsed (one had viable seminoma in the residuals). At a median follow up of 4 years (IC95% [3.5-5.5]), 41/48 pts (87%) were alive. 7/48 patients died of cancer progression. Conclusions: Most men with residual masses after 1st salvage chemotherapy for advanced seminoma may achieve a cure. Pending validation with more pts in this rare situation, PET-FDG may help guide who should be selected for post-chemotherapy resection. Updated results will be presented at the congress.

International audience; PURPOSE: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). The peak incidence of HCC is around 70 years. We aimed to evaluate safety and efficacy of sorafenib in the elderly population. METHODS: We retrospectively reviewed data from patients treated with sorafenib for HCC at our institution. We compared safety and efficacy data across different age groups. RESULTS: Since 2005, 129 patients were treated, 78 (60.5 %) were \textless70 years old and 51 (39.5 %) were ≥70. The frequency of dose reduction was similar between the two groups (48.7 vs. 58.8 %), as was the occurrence of severe toxicities (41.0 vs. 51.0 %) and hospitalization due to toxicity (9.0 vs. 13.7 %). However, asthenia and bleeding were more frequent in the elderly. The higher frequency of bleeding was explained by concomitant antiplatelet treatments, and major asthenia was frequent in PS1 elderly patients. There was a trend toward less frequent interruption of treatment in the younger group (25.6 vs. 39.2 %) and significantly less frequent definitive discontinuation of treatment due to toxicity (24.4 vs. 45.1 %). Median progression-free survival was 5.6 months in both age groups, while median overall survival was 9.6 months in the younger age group and 12.6 months in the older age group. CONCLUSION: Sorafenib showed similar results in terms of safety and efficacy in the elderly and younger HCC populations. Careful baseline evaluation is needed for patient's selection in the elderly population, including discussion about antiplatelet therapy discontinuation and caution in PS1 patients, as well as active management of toxicity.

International audience; PURPOSE: Tumoural portal vein thrombosis (PVT) is a major prognostic factor in hepatocellular carcinoma (HCC). The efficacy of sorafenib, the only treatment approved at an advanced stage, is limited. Based on previous data, selective internal radiation therapy (SIRT), or (90)Y radioembolization, seems an interesting option. We aimed to compare both treatments in this population. METHODS: We retrospectively compared patients treated in two centres for HCC with tumoural PVT. We compared overall survival (OS) between patients treated with SIRT and patients treated with sorafenib. Analyses were performed before and after 1:1 matching with a propensity score for controlling indication bias, using a Cox proportional hazards model. RESULTS: A total of 151 patients were analysed, 34 patients treated with SIRT and 117 patients treated with sorafenib only. In the whole population, SIRT was associated with a higher median OS as compared with sorafenib: 18.8 vs 6.5 months (log-rank p \textless 0.001). There was an imbalance of baseline characteristics between patients treated by SIRT and sorafenib, which justified patient matching with use of a propensity score: 24 patients treated with SIRT could be matched with 24 patients treated with sorafenib. OS was estimated with a median of 26.2 vs 8.7 months in patients treated with SIRT vs sorafenib, respectively (log-rank p = 0.054). Before and after patient matching, the adjusted hazard ratio related to treatment by SIRT was estimated at 0.62 [95 % confidence interval (CI) 0.39-0.97] (p = 0.037) and 0.40 (95 % CI 0.19-0.82) (p = 0.013), respectively. CONCLUSION: SIRT seems more effective than sorafenib in patients presenting with HCC and tumoural PVT. This hypothesis is being tested in prospective randomized trials

International audience; Synergy between yttrium-90 ((90)Y) and antineoplastic drugs was investigated. Viability of HepaRG (hepatocellular carcinoma) and HuCCT1 (cholangiocarcinoma) cells was studied through a tetrazolium dye reduction assay. A combination index (CI) was calculated, with CI \textless 1 denoting synergy and CI \textgreater 1 denoting antagonism. In HepaRG cells, gemcitabine showed synergy with (90)Y (CI = 0.70 [95% confidence interval = 0.65-0.75]), whereas oxaliplatin (CI = 1.15 [1.08-1.21]), paclitaxel (CI = 1.26 [1.15-1.37]), and sorafenib (CI = 1.77 [1.65-1.89]) showed antagonism. In HuCCT1 cells, gemcitabine (CI = 0.54 [0.50-0.58]) and oxaliplatin (CI = 0.86 [0.82-0.90]) showed synergy with (90)Y, whereas paclitaxel (CI = 1.18 [1.09-1.27]) and sorafenib (CI = 1.21 [1.12-1.30]) showed antagonism. These results suggest that gemcitabine and oxaliplatin should be tested in combination with (90)Y radioembolization for treatment of liver cancer.

11053 Background: Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor and in most of cases, is characterized by an inactivation of the tumor suppressor gene VHL (Von Hippel-Lindau). This...