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18F-FDG PET is recommended for the initial staging of locally advanced breast cancer. Studies have shown the prognostic value of 18F-FDG PET for staging, but its ability to predict pathological complete response remains uncertain. Our objective was to determine the predictive value of early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer patients. We studied a subpopulation of the prospective and multicentric French NeoTOP trial, at interim analysis. All patients were eligible for neoadjuvant chemotherapy. A 18F-FDG PET was performed at baseline and then after one cycle of neoadjuvant treatment. 18F-FDG PET were studied by three conventional methods (two visuals and one quantitative) and by textural analysis. Complete pathological response on surgical samples corresponded to grades 1/2 of Chevallier's classification and no responders corresponded to grades 3/4 of Chevallier. Pathological results were available for 21 patients. SUVmax decreased by 55% after one cycle of chemotherapy. No difference between groups was found with visuals, conventional quantitative and textural analysis of tumour uptake evaluations. Early therapeutic evaluation by 18F-FDG PET for HER2-positive breast cancer was not predictive of pathological therapeutic response after neoadjuvant treatment, with conventional study or textural analyses in this interim analysis.

Introduction/Background* As stated by ESGO-ESMO, there is a need for indicators of chemotherapy efficacy in ovarian carcinoma patients treated in first-line setting (Colombo et al, IGCS, 2020). The pathological chemotherapy response score (CRS) and the modeled CA-125 KELIM during neo-adjuvant chemotherapy were reported as potential markers. Moreover, changes in tumor infiltrating lymphocytes (TILs) after neo-adjuvant chemotherapy were reported as a prognostic factor (Leary et al, Cancer Immunol Immunother, 2021). We studied the relationships between changes in TILs, the pathological response (pR) and KELIM in patients treated with neo-adjuvant chemotherapy +/- interval debulking surgery (IDS) from CHIVA phase II trial. Methodology The patients were enrolled in the randomized phase II trial CHIVA (NCT01583322, neo-adjuvant carboplatin-paclitaxel +/- nintedanib, +/- IDS, n=188 patients). KELIM were previously calculated (You et al CCR 2020). The 30 patients with the highest KELIM (very chemosensitive) or the lowest KELIM (poorly chemosensitive) were selected. HE-stained sections from available tissue blocks at baseline and after chemotherapy were analyzed for stromal TILs (sTILs, surface of the tumor stroma occupied by lymphocytes) and intra-epithelial TILs (ieTILs, brisk or non-brisk). The pathological response (pR) was assessed on the most tumoral available tissue block obtained after chemotherapy (good response if extensive fibrous changes with no or isolated tumor cells, or Result(s)* No relationships between KELIM and TILs infiltrates on baseline tumor samples were found. However, strong associations were found between KELIM and TIL infiltrates after neo-adjuvant chemotherapy for sTILs (median KELIM for sTILs 0-5% vs >5%: 0.28 versus 1.32, P Conclusion* High consistency was found between the modeled CA125 KELIM calculated during the first 100 days of neo-adjuvant chemotherapy and the pathological response, consistent with their values as indicators of the tumor chemosensitivity in first-line setting. Moreover, TILs changes were strongly associated with chemosensitivity, opening hypotheses about the mechanisms of chemosensitivity, and immunotherapy opportunity.

Introduction/Background* In the randomized phase II NeoPembrOV study (NCT03275506), Pembrolizumab in combination with neoadjuvant chemotherapy (NACT) met its primary endpoint of complete debulking rate (CRR) for the treatment of patients with advanced up-front non-resectable high-grade serous ovarian cancer (HGSOC). However, the CRR in the control group was similar. Identification of potential predictive biomarkers is fundamental to better understand the place of Pembrolizumab in this setting. Methodology 91 Patients (pts) with HGSOC unable to received complete upfront debulking surgery were included and received Carboplatin (AUC5) Q3W + Paclitaxel (175mg/m2) Q3W +/- Pembrolizumab 200 mg Q3W IV before and after surgery. Pembrolizumab was given until 24 months maximum. After interval debulking surgery, optional bevacizumab was proposed. BRCA1/2 mutation status (BRCA) was assessed using standard algorithms. Immunohistochemical PD-L1 expression was evaluated on both tumour and immune cells (IC) using the Ventana SP263 assay. Associations of progression-free survival (PFS) with BRCA, and PD-L1 expression were evaluated. Result(s)* BRCA status was available for 81 pts (89%). 3 out of 30 pts (10%) in the control arm harboured a BRCA mutation (mBRCA) versus 13/61 in the experimental arm (21.3%). Median PFS (mPFS) in both arms in the BRCA wild-type (wtBRCA) subgroup were not different (mPFS 20.8 months [95% IC,15.0-25.7] vs 18.2 months [95%IC, 16.8.0-21.4] in control and experimental arms respectively). mPFS in the mBRCA subgroup were not reached in both arms. PD-L1 expression was available for 85/91 patients (93.4%). PD-L1 IC ≥5% was positive in 29/85 patients (34.1%) and correlated to mPFS in the whole population (18.2m in PDL1 IC Conclusion* If no benefit in adding Pembrolizumab to CT +/- bevacizumab was found in wtBRCA subgroup, exploratory PFS analyses in the PD-L1 IC ≥5% subgroup showed a trend favouring Pembrolizumab in patients with advanced HGSOC.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

Since 2005, 12 months of trastuzumab added to chemotherapy alone is the standard of care in patients with HER2-positive breast cancer. PHARE ('Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure') is the first trial comparing a reduction of adjuvant trastuzumab versus the standard 12 months. In 2012, the first analysis failed to prove that 6-months was non-inferior to 12-months of adjuvant trastuzumab (NCT00381901). The current presentation reports the final analysis. Methods: The trial was sponsored by the French National Cancer Institute (INCa) (www.e-cancer.fr), and approved by central Ethical Committee on May 15th 2006. Patients with HER2-positive early breast cancer were randomly assigned between 12 and 6 months of adjuvant trastuzumab duration. The randomization was stratified by concomitant or sequential trastuzumab administration with chemotherapy, estrogen receptor (ER) status and center. The primary objective was non-inferiority of 6- versus 12-months arms in the intent to treat population, in terms of disease-free survival (DFS) with a pre-specified hazard margin of 1.15. Overall Survival (OS) and metastasis free survival (MFS) were secondary endpoints. Results: A total of 3380 patients were randomized, their median age was 54 years (21-86). Patients and disease characteristics were well balanced between the two arms. No involved axillary node was observed in 54.5% of cases, 41.7% of tumors were ER negative. At a median follow-up of 7.5 years, 704 events counting for DFS were observed. Between the 12- and 6-months arms, the adjusted Hazard Ratio (HR) for DFS rates was 1.08 (95%CI: 0.93-1.25; p=0.39) favoring the longer exposure. The 1.15 margin of non-inferiority was included in the 95%CI. No heterogeneity in terms of treatment effect was observed, no significant difference for trastuzumab duration effects was found in any subgroups.For OS and MFS, the adjusted HR were 1.13 (95%CI 0.92-1.39) and 1.15 (95%CI 0.96-1.37), respectively. Conclusion: The choice of the non-inferiority margin will remain inherently a subject of controversy especially in the context of oncology trials where the primary outcome is survival and the least additional death could be considered unacceptable questioning the very feasibility of such trials. Nevertheless, PHARE failed to show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. The standard of care should remain 12 months of adjuvant trastuzumab. Citation Format: Pivot X, Romieu G, Debled M, Pierga J-Y, Kerbrat P, Bachelot T, Espie M, Lortholary A, Fumoleau P, Serin D, Jacquin J-P, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure Mercier C, Paget-Bailly S, Henriques J, Grouin J-M. PHARE randomized trial final results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-07.

Background Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22–93)]. RCB 0–I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4–14.9)] and chemotherapy [15.7% (95% CI 5.7–25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number NCT02400567.

This abstract was withdrawn by the authors.

Background: BC is a hormone-dependent disease for 75% of pts. HT is used in both adjuvant and metastatic settings for hormone–receptor (HR) positive tumors. In adjuvant situation, a 5-year HT period at least is recommended. Side-effects (SE) frequently alter quality of life and compliance, reducing the well-known benefits in risks of relapses and specific deaths. Underlying mechanisms are well understood for estrogen deprivation-induced events such as hot flashes, but little is known on arthralgia under aromatase inhibitors (AI). So, pharmacogenomics (PG), pharmacokinetics (PK), potential medications interactions are of value to explain individual drugs exposures, possible related side-effects and compliance to treatment. Methods: We performed a prospective, multicenter, longitudinal study registering early clinical outcomes and SE during the first 3 years of adjuvant HT with tamoxifen (T) or AI. All tumors expressed at least one HR (>10%). The choice of HT molecule and one-drug or sequential treatment were left to the investigator. Pts were followed every 6 months with clinical examination by the referent oncologist and PK sampling each time. Biologic research consisted in PG investigations of different genes involved in the PK and pharmacodynamics of T and AI (95 SNPs) at baseline. SE, concurrent medications and compliance were registered by both the pts on a diary card and the physician. Evaluation was done only on new occurrence or increased grade of symptoms. Results: This first report focuses on characteristics of the population and the results after the 6 first months of treatment. Between June 2010 and October 2014, 23 centers recruited 2000 pts. 23 were excluded leaving 1977 fully evaluable women; 879 (44%) started with T, 1098 (55%) with AI (554 letrozole (L), 390 anastrozole (A), 154 exemestane (E)). 56% of them had previously received chemotherapy, 96% radiotherapy and 8% trastuzumab. Main characteristics were well balanced between the 2 classes of drugs; T was given mainly for pre- or perimenopausal pts. Most frequent co-morbidities were hypertension (8% T, 31% AI) and dyslipidemia or diabetes (T 11%, AI 26%). To note, almost 30% of pts described arthralgias at entrance and 37% had hot flashes. At 6 months, 122 pts (6%; 43 T, 79 AI) had stopped treatment mainly for toxicity (11 T; 12 AI), progression or death (7 T; 4 IA), personal reasons (15 T; 37AI); 4 asked for changing T and 52 AI (equally for the 3 drugs). All these events were significantly more frequent for AI pts (p=0.042) and with E within the AI class (p Main changes in onset or increased intensity of symptoms concerned hot flushes with all drugs (30%), asthenia (20%), insomnia (20%), weight gain (17%), arthralgias (15% for T, 30% for AI), thrombotic events (24 of which 11 with T). 3 grade3 SAE HT-related were reported. Biological data are reported in 2 other abst. (M. White-Koning. abst.#850248, F. Thomas, abst.#851525). Conclusions: These preliminary data on the first 6-months exposure to HT on adjuvant setting in the real-life confirm early rates of withdraws and toxicities. Longer follow-up and subsequent PK analysis should help to understand persistent side-effects and reasons for non-compliance to adjuvant HT. Citation Format: Roché H, Venat-Bouvet L, Debled M, Jacot W, Suc E, Dalenc F, Molnar-Stanciu D, Dohollou N, Franck D, Ferrer C, Laharie-Mineur H, Lavau-Denes S, Massabeau C, Mauries V, Robert J, Pinguet F, Marquet P, Evrard A, Chatelut E, Filleron T. First 6-month report of the longitudinal PHACS study (Pharmacology and Hormonotherapy (HT) for Adjuvant breast Cancer (BC) Study, NCT01127295) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-10.

5508 Background: The Geriatric Vulnerability Score (GVS) combining albumin, lymphocyte count, ADL, IADL and HADS scores has been reported (Falandry C Ann Oncol 2013) to identify vulnerable elderly OC patients (pts) as those with a GVS≥3. For such pts, Carboplatin (Cb) monotherapy or weekly Cb plus paclitaxel (Pa) are often proposed as an alternative to Cb-Pa given every 3 weeks. Methods: Pts ≥70 yrs with first line FIGO stage III/IV epithelial OC were screened for GVS. Those with GVS≥3 were randomized to receive either arm A: Cb AUC5-6 + Pa 175mg/m², d1q3week or arm B: Cb AUC5-6 d1q3week or arm C:weekly Cb AUC2 + Pa 60mg/m² d1-d8-d15 q4week. Primary endpoint is treatment feasibility defined as the ability to complete 6 chemotherapy courses without disease progression, early treatment stopping due to unacceptable toxicity or death. Inclusion of 240 pts was planned. Results: Among 444 screened pts, 120 were randomized from 12/2013 to 04/2017 (armA = B = C = 40). Pts characteristics were well balanced between arms A-B-C respectively: median age (79-82-80 yrs), FIGO stage IV (32-37-27%), primary surgery (65-72-70%), absence of macroscopic residuals (CC-0) (7-5-7%), ECOG≥2 (50-50-47%). Feasibility per protocol for arms A-B-C is 65%, 47% and 60% (p = 0.15). Main reasons for treatment arrest are treatment toxicity (A:20%; B:15%; C:22.5%; p = 0.771) and disease progression (A:7.5%; B:30%; C:2%; p = 0.004). Median PFS for arm A-B-C are 12.5 mos (95%CI 10.3-15.3), 4.8 (3.8-15.3) and 8.3 (6.6-15.3), respectively (p < 0.001) and median OS for arm A-B-C is not reached (NR) (21, NR), 7.4 (5.3-NR) and 17.3 (10.8-NR), respectively (p = 0.001). At the pre-planned intermediate analysis, the IDMC recommended to prematurely close the study as survival in armB was found significantly worse and the number of potential pts required to find a significant difference between both Cb-Pa regimens (arms A&C) was out of reach. Conclusions: Compared to 3-weekly and weekly Cb-Pa regimens, Cb single agent was reported to be less active with significant worse survival outcome in vulnerable elderly pts. In this population Cb-Pa combination remains a standard. Clinical trial information: NCT02001272.

Background: Adjuvant chemotherapy decisions are relatively simple using clinicopathological parameters (Goldhirsch et al. 2007), some cases require the addition of biomarkers as in patients with node negative or micrometastatic (N0), grade II (GII) breast cancer. The objective of this study was to evaluate the impact of uPA/PAI-1 compared to classical criteria +/- KI67 in adjuvant treatment decision-making in this population. Methods: This retrospective study included patients, treated from March 2008 to May 2016 in the Department of Medical Oncology at Limoges University Hospital (France). Ki67 and uPA/PAI-1 were analyzed on the initial specimen tumor. Optimal cut-off of Ki67 was defined at 20% (Coates et al. 2015). The positivity thresholds of uPA and PAI-1 were 3 ng/mg and 14 ng/mg respectively (Look et al. 2002). A positive uPA/PAI-1 level was defined as the elevation of at least one of these markers above the positivity threshold. All clinicopathological parameters were recorded prospectively. Results: 2364 patients with breast cancer were screened. Among these patients, 256 N0, GII breast cancer patients were included with a median age of 62 years (32-87). Discordance between the two markers uPA/PAI-1 and KI67 was observed in 58% of tumors. Adding KI67 to the other classical clinicopathological parameters, 143 cases were defined as high risk versus 111 cases without KI67; low risk were defined in 113 cases versus 145 cases without KI67. Considering Ki67 status, the indication to perform adjuvant chemotherapy was increased by 29% compared to clinicopathological parameters. uPA/PAI-1 level was positive in these 143 high risk tumors in 93 cases and negative in 50 cases; in the 113 low risk tumors uPA/PAI-1 was positive in 72 cases and negative in 41 cases. uPA/PAI-1 increased indication to perform adjuvant chemotherapy by 15% compared to St Gallen criteria (including KI67) and by 49% compared to St Gallen criteria (excluding KI67). Using these two markers the final decision of chemotherapy by the multidisciplinary board was increased by 3% compared to St Gallen criteria (including KI67). Conclusions: This study highlighted that uPA/PAI-1 and Ki67 assessment provides additional information for adjuvant chemotherapy decision-making. This study confirms the difficulty to assess the level of importance (weighting) of these biomarkers in adjuvant chemotherapy decision-making. The use of uPA/PAI-1 was feasible, cost-effective in N0, GII breast cancer's patients. Citation Format: Deluche E, Venat-Bouvet L, Leobon S, Fermeaux V, Aubard Y, Saïdi N, Jammet I, Tubiana-Mathieu N. uPA/PAI-1 and adjuvant chemotherapy decision-making in early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-26.

Background Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surgery. We report a nintedanib exposure-response relationship in the nintedanib arm. Methods Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar model-building strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings. Results The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found. Conclusions An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM. Clinical trial identification 2011-006288-23. Legal entity responsible for the study ARCAGY-GINECO. Funding Boehringer Ingelheim. Disclosure N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.

Background Few data are available on survival of breast cancer (BC) patients (pts) treated with neoadjuvant endocrine therapy (NET). Understanding how tumor response to NET is related to relapse risk would help clinicians make decisions about additional treatments for these pts. Methods The primary objective was to assess 5-years relapse-free survival (RFS) in previously published two sister phase II studies evaluating anastrozole and fulvestrant as NET in post-menopausal HR-positive/HER2-negative BC pts (CARMINA02 NCT00629616 ; HORGEN NCT00871858 ). Prognostic factors of RFS were explored by pooling the two databases : age ( 70), tumor and node staging, histological type and grade, clinical response, pathological response according to the Sataloff classification, baseline and surgical ER Allred score and Ki-67 expression, treatment arm, preoperative endocrine prognostic index (PEPI) score, adjuvant chemotherapy. The factor study (Horgen vs. Carmina02) was also introduced in the model as covariate. Univariate and multivariate Cox regression analysis (covariates from univariate model with P-value Results Intention-to-treat analysis is available for 217 of 236 pts included in the two trials. Post-menopausal pts with T2–T4, N0–N1, M0, HR-positive/HER2-negative BC were randomized to receive anastrozole (PO, 1 mg daily) or fulvestrant (IM, 500 mg on D1, D15 and D29 and then every 4 weeks) for 4 to 6 months before surgery. Mean age at diagnosis was 71.2 years. Baseline tumor characteristics were : 73.7 % T2, mean tumor size 44.3 mm, 66.4 % N0, 19.4 % SBR grade 1, 98.6 % ER Allred score 6-8, mean Ki67 score 17.5 % with Ki67 > 20 % in 29.5 % of cases. A clinical response (complete or partial) was observed in 50.2 % of pts and pathological response rate defined as TA or TB and NA or NB was 15.7 %. Mean Ki67 at surgery was 8.8 % (11.4 % of cases > 20 %). Among the pts, 12.4 % were classified in PEPI risk group I (risk score 0), 35.5 % in group II (score 1–3) and 30.4 % in group III (score > 4) (PEPI not available for 21.7 % of pts) ; 21.7 % of pts received adjuvant chemotherapy. Median follow-up is 65.2 months. RFS and overall survival at 5 years are 83.7 % [95 % CI : 77.9–88 %] and 92.7 [95 % CI : 88.2–95.6 %] respectively. On univariate analysis, tumor staging (T3–4 versus T2, P = 0.0001) and PEPI score (I + II versus III, P = 0.0004) are associated with RFS. So far, no relapses/death have been observed in pts with pathological response (n = 34, 15.7 %). Multivariate analysis (T, baseline Ki67, ER Allred score at surgery, PEPI and study) shows that PEPI group III is associated with significantly worse RFS (P = 0.0014, HR : 3.9 [95 % CI : 1.7–9.0]). Conclusion Post-menopausal HR-positive/HER2-negative BC pts receiving NET have a very favorable outcome. Within this population eligible for NET, the PEPI score identifies a subset of pts of poorer prognosis who are candidate for further additional treatment like chemo/or targeted therapies. The PEPI may be a tool routinely used for individualization of adjuvant treatment in NET setting. According to recent published studies, further analysis will be performed with Ki67 > 10 % and PEPI risk (group I versus groups II–III).

Background Tumour Microvessel density (MVD) is often used as a surrogate marker for tumoral angiogenic activity. In the randomized phase II neo-adjuvant CHIVA trial, ovarian cancer patients (pts) treated with standard chemotherapy plus Nintedanib (Ni) compared to chemotherapy alone had a reduced rate of complete surgical resection at interval debulking surgery (IDS), worse PFS and OS. To explain these results we assessed the predictive/prognostic value of MVD at baseline and the MVD decrease from baseline to IDS. Methods Paired tumours from baseline and IDS were available from 79/188 randomized pts. A total of 158 virtual slides of immunostained tumor section with anti-CD31 were analysed. MVD was quantified by an image processing on whole tumor section. MVD high level was defined as MVD > 33.5 vessel/mm² which is the highest Youden index on the ROC curve for PFS. The relationship between MVD at baseline and PFS and OS was evaluated using Kaplan-Meier survival estimates. Results Main characteristics of the 79 pts were similar to the overall CHIVA population: mean age (62 years), ECOG performance status = 0 (34%), high-grade serous histology (75%). At baseline, MVD was similar in both arms and was low for 35% and 30% of the pts in the Ni and control arm respectively. The rate of complete resection (CC0) was 56% in the Ni arm versus 70% in the control arm. In the low MVD group median PFS was 13.3 months (95%CI 11 – 22.2) versus 17 months (95%CI 13.7 – 20.5) in the high MVD group (p = 0.85). In the low MVD group, PFS in the Ni and control arm were 12.8 (95%CI 10.7-22.2) and 21.3 months (95%CI 12.5-NA) respectively (p = 0.08). The corresponding PFS in the high MVD group were 18.0 (95%CI 14.4-21.6) vs 14.5 months (95%CI 12.4-22.5) (p = 0.22). No difference was observed for OS. Baseline MVD was not associated with the rate of CC0. There was no significant difference in the decrease of MVD at IDS between the Ni arm (38% of the pts) and the control arm (48%, p = 0.4). Conclusions The negative impact of Nintedanib in patients with low baseline MVD tumours may be one explanation of the poor PFS rate observed in the Nintedanib arm of the CHIVA trial. Clinical trial identification 2011-006288-23. Legal entity responsible for the study ARCAGY-GINECO. Funding Health ministry grants( PHRC). Disclosure C. Blanc-Fournier: Honoraria (self): Roche. N. Raban: Travel / Accommodation / Expenses: Roche. G. Ferron: Honoraria (self): Olympus Europe; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. C. Louvet: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca. J. Florence: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Sanofi; Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.

Background NACT is increasingly used as a model to explore new targeted therapy in combination with CT in AOC. Whether an intermediate endpoint could be used as surrogate of PFS and/or OS in pts treated with NACT remains currently elusive and was explored retrospectively in the CHIVA trial. Methods Patients (pts) with FIGO stage IIIC-IV AOC considered as unresectable after laparoscopic (Lap) evaluation were treated with 3 to 4 cycles of platinum-taxane NACT + oral nintedanib before interval debulking surgery (IDS). CT (up to 6 cycles in total) and nintedanib were pursued post-operatively. Were measured response rates at the end of NACT according to RECIST (ORR) with CT-scan and to GCIG with CA125, initial Peritoneal Cancer Index (PCI) and its evolution at IDS, complete surgical resection rate (CC0), pathologic complete or near complete response rate (pCR). These covariates in univariate analysis were included together with other prognostic clinical covariates:age, FIGO stage, ECOG, tumor size, ascitis, neutrophil/lymphocyte ratio, platelet and hemoglobin counts and symptoms (pain). Results A total of 163/188 pts included in the CHIVA trial were evaluable for the analysis. Median follow-up is 42. 6 mos (95% CI: 39.9-44.8). In the univariate Cox model, ECOG, ascitis, neutrophil/lymphocyte ratio, PCI at baseline, RECIST ORR, CC0 at IDS, pCR and treatment arm were correlated (p Conclusions Results from the CHIVA trial suggest that the rate of patients who achieve both a RECIST response to NACT and a complete surgical resection (CC0) at IDS could be used as the main primary endpoint for future NACT trials. Clinical trial identification 2011-006288-23. Legal entity responsible for the study ARCAGY-GINECO. Funding Boehringer Ingelheim. Disclosure F. Lecuru: Advisory / Consultancy, Board: AstraZeneca; Advisory / Consultancy, Proctoring: Intuitive Surgical. E. Pujade-Lauraine: Honoraria (self), Self: AstraZeneca; Honoraria (self), Self: Tesaro; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Clovis; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Tesaro; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Tesaro. N. Raban: Travel / Accommodation / Expenses: Roche. P. Pautier: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: Genentech; Research grant / Funding (institution): PharmaMar; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Tesaro. J. Alexandre: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Ipsen; Honoraria (self): Novartis; Honoraria (self): PharmaMar; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Janssen; Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Novartis. N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Tesaro; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. A. Lortholary: Honoraria (self): AstraZeneca; Honoraria (self): Tesaro. G. Ferron: Honoraria (self): Olympus Europe; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Background Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment. Patients and methods: We performed a phase III prospective, randomized trial. After the insertion of a central venous access device, consecutive outpatients with local nodes or metastatic invasion, and planned chemotherapy were randomized to no anticoagulant prophylaxis, low molecular weight heparin (LMWH : dalteparine 2500 IU, nadroparine 2850 IU, or enoxaparine 4000 IU, once daily), or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90 or sooner in case of clinical presumption of thrombosis. Results A total of 420 patients were randomized and 407 were evaluable. Forty-two catheter-related deep-vein thromboses (DVT) occurred (10.3%), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Anticoagulation significantly reduced the incidence of catheter-related DVT (P = 0.035), with no difference between warfarin and LMWH. The most frequent DVT localization was at the distal extremity of the catheter in the superior vena cava (50%). The mean delay of occurrence was 30 days, and 30 were asymptomatic (71%). Anticoagulation use also had an impact on unrelated-cathter DVT (P = 0.007 by Fisher's test on the 9 events) with no difference between warfarin and LMWH use (0.75 versus 0.72%, P = 1). Safety was good. One hundred forty six patients experienced thrombopenia, but only 24 were grade 3 or 4, chemotherapy-induced, increased by anticoagulant use (p Conclusions Prophylaxis showed a benefit regarding catheter-related and non catheter-related DVT with no increase in serious side effects. Disclosure All authors have declared no conflicts of interest.

International audience; BACKGROUND:Treatment strategies for locally advanced breast cancer in elderly patients too frail to receive neoadjuvant chemotherapy and the introduction of new classes of drugs in the early 2000s have led to the consideration of endocrine therapy as a neoadjuvant treatment for younger hormone receptor (HR)-positive, postmenopausal patients not eligible for primary breast-conserving surgery (BCS).METHODS:This was a multicenter, phase 2, randomized trial designed to evaluate as its primary objective the clinical response rate after up to 6 months of neoadjuvant endocrine therapy (NET) alone in HR-positive/human epidermal growth factor receptor 2 (HER2)-negative patients with 1 mg of anastrozole (arm A) or 500 mg of fulvestrant (arm B). Secondary objectives included the BCS rate, tumor response assessment (breast ultrasound and magnetic resonance imaging), pathological response (Sataloff classification), safety profile, relapse-free survival (RFS), and predictive markers of responses and outcomes.RESULTS:From October 2007 to April 2011, 116 women (mean age, 71.6 years) with operable infiltrating breast adenocarcinoma (T2-T4, N0-N3, M0) were randomized to receive anastrozole or fulvestrant. The clinical response rates at 6 months were 52.6% (95% confidence interval [CI], 41%-64%) in arm A and 36.8% (95% CI, 25%-49%) in arm B. BCS was performed for 57.6% of arm A patients and 50% of arm B patients. The RFS rates at 3 years were 94.9% in arm A and 91.2% in arm B. The Preoperative Endocrine Prognostic Index status was significantly predictive of RFS. Both treatments were well tolerated.CONCLUSIONS:Both drugs are effective and well tolerated as NET in postmenopausal women with HR-positive/HER2-negative breast cancer. NET could be considered a treatment option in this subpopulation. Cancer 2016;122:3032-3040. © 2016 American Cancer Society.

Les therapies orales sont en plein developpement dans la prise en charge des tumeurs solides. Elles ne sont pas denuees de toxicites et leur suivi a domicile demande une gestion extremement rigoureuse [1, 2].

L’activateur du plasminogene de type urokinase (uPA) et son inhibiteur principal (PAI-1) sont deux proteines impliquees dans les interactions entre la tumeur et son micro-environnement. La valeur pronostique de ces biomarqueurs est acquise avec un niveau de preuve eleve de type 1 dans le rapport d’expertise de l’Institut national du cancer (INCa) permettant d’identifier des sous groupes de patientes ayant un cancer du sein sans envahissement ganglionnaire (N-) en fonction du risque de recidive et permettant ainsi d’affiner nos indications de chimiotherapie adjuvante (CTA). En appliquant les seuils de 3 ng/mg de proteine cytosolique pour uPA et 14 ng/mg pour PAI-1, le score uPA-PAI-1 permet d’identifier des populations a risque faible ou eleve independamment des autres marqueurs pronostiques conventionnels [1], [2]. Notre etude effectuee du 01/01/2010 au 30/04/2011 compare les prises de decision en reunions de concertation multidisciplinaire (RCP) des indications de CTA sur le score uPA-PA-1 par rapport a l’utilisation des facteurs pronostiques conventionnels definis par les recommandations nationales. Cent vingt tumeurs du sein infiltrantes ont pu etre congelees et donc testees pour uPA-PA-1 sur 172 cancers du sein N- pris en charge pendant la periode etudiee. Les dosages ont ete effectues a Marseille dans le laboratoire de transfert d’oncologie biologique de la faculte de medecine dirige par Pierre-Marie Martin. Les tissus etaient achemines dans les 30 minutes apres l’exerese chirurgicale dans le service d’anatomopathologie puis congeles et adresses a Marseille. Un intervalle de plus de 10 jours apres la biopsie diagnostique etait respecte.

[18F]-fluorodeoxyglucose with positron-emission tomography (PET) and computed tomography (CT) scans were used to assess morphological and metabolic tumour response after chemotherapy in metastatic colorectal cancer.Twenty-five patients were evaluated after 4 courses of chemotherapy (+/-target therapy), and among them 20 patients after 2 courses. Response Evaluation Criteria In Solid Tumors (RECIST) and European Organisazion for Research and Treatment of Cancer (EORTC) criteria were used to evaluate CT and PET respectively.Discrepancies between the two procedures were noted after 4 courses of chemotherapy in patient-based analysis. Two morphologically complete responses (CR) were correlated with metabolic response. Seven morphological partial responses (PR) were evaluated as 3 metabolic PR, 2 CR and 1 progressive disease (PD). Seventeen cases of morphologically stable disease (SD) were evaluated as 3 metabolic CR, 13 PR and 1 PD. These discrepancies were confirmed in lesion-based analysis. Perfect concordance was noted between metabolic responses obtained after 2 and 4 cycles.Morphological and metabolic imaging does not permit concordant therapeutic assessment in metastatic colorectal cancer.

Background: The two phase III first-line trials GOG 218 and ICON 7 met their primary progression free survival endpoint, leading to an European Union approval in december 2011 of bevacizumab in combination with carboplatin and paclitaxel during 6 cycles, followed by a maintenance period for a total time of 15 months for the treatment of patients with FIGO IIIb-IV stage ovarian cancer. The ENCOURAGE prospective, multicenter cohort study has been developped to describe bevacizumab administration in ovarian cancer, in the daily practice, outside of trials with their usual patient selections and specific follow-up methods Trial design: A total number of 500 patients with ovarian cancer, treated with bevacizumab in first-line, in 100 French centers, will be included. Investigators will record the reasons why they indicate or exclude bevacizumab administration in the first-line treatment strategy of each of their patients with ovarian cancer. The primary endpoint is to report the cardio-vascular, renal and digestive toxicity of bevacizumab delivered in a wide scape of French centers (academic or not hospitals, private clinics, anticancer centers). The secondary endpoints include evaluation in real life of bevacizumab use in ovarian cancer treatment in first-line (the characteristics of the treated population, the reason of non administration of bevacizumab in first line), the modalities of use and the monitoring pratices. At last, the efficacy of the bevacizumab treatment strategy will be also evaluated by analysing the progression free survival in both first line and relapse with or without bevacizumab. From April 2013, to April 2014, more than 200/500 patients have been registered. Disclosure: I.L. Ray-Coquard: Roche, Pharmamar, Amgen, AstraZeneca board and lecture; A. Floquet: Investigator fees and congress participation support in Roche Clinical Studies; J. Alexandre: I am a member of an advisory board concerning bevacizumab. All other authors have declared no conflicts of interest.

Aim: Numerous studies report that adapted exercise training is a recommended component of rehabilitation in patients receiving adjuvant treatment for breast cancer. Peak oxygen consumption (VO2peak) obtained from cardiopulmonary exercise testing (CPET) are used for determine the intensity of exercise training program. However, CPET is relatively expensive and time consuming and distance walked during a six-minute walk test (6-MWT) is commonly employed in clinical practice for determine cardiorespiratory fitness (CRF). However, the relationship between VO2peak and 6 MWD has not been clearly defined in cancer rehabilitation program. Methods: 79 subjects (median age 50 years (35-70); stage I to III breast cancer) were evaluated before adjuvant chemotherapy and radiotherapy. They were included in an adapted physical activity program based on cardiopulmonary tests. They performed, under the supervision of an exercise physiologist, a 6MWT and a incremental physician-supervised CPET performed on an electronically-braked cycle ergometer. Age- and sex- predicted 6MWT was calculated from the equation of Enright, maximal oxygen uptake was the highest oxygen uptake during exercise and ventilatory threshold (VT) was determined by a systematic increase in the pulmonary ventilation during exercise. Results: Patients covered a distance of 526 ± 54 m during 6MWT at an average of 129 ± 16 beats per minute (bpm) of peak heart rate (PHR) and achieved a VO2peak of 22.6 ± 4.5 ml · kg - 1 · min- 1 at an average of 130 ± 14 bpm of PHR at VT. The distance walked was significantly correlated (p Conclusions: CPET with VO2peak may be the ideal method of measuring aerobic physical condition in cancer patients; however, this method of measurement of VO2max with CPET is not used easily in clinical oncology. PHR collected during the 6MWT seem to be a simple alternative parameter to guide exercise prescription in this cancer population. The implementation of these tests on training programs will describe. Disclosure: All authors have declared no conflicts of interest.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.