Background Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) primarily relies on FOLFIRINOX (LV5FU- irinotecan – Oxaliplatine) and Gemcitabine – Nab-Paclitaxel in the first-line setting. However, second-lines remain less well-defined and there is limited data regarding third-line treatments. The objective of our study was to determine the proportion of patients advancing to third line chemotherapy, to outline the various third-line chemotherapy regimens used in routine practice and to evaluate their respective efficacy. Methods A retrospective single-center cohort from 2010-2022 compiled baseline characteristics, treatment outcomes and survival of PDAC patients who received at least one chemotherapy line in a French tertiary-center. Overall survivals (OS) were analyzed using a Cox multivariable model. Results In total, 676 patients were included, with a median follow-up time of 69.4 months, (Interquartile Range (IQR) = 72.1). Of these, 251 patients (37%) that proceeded to 3 rd -line chemotherapy. The median PFS in 3 rd line was 2.03 months, [CI95%: 1.83, 2.36]. The median 3 rd line overall survival was 5.5 months, [CI95%: 4.8, 6.3]. In multivariable analysis erlotinib-based chemotherapy was found to be deleterious (HR=2.38, [CI95%: 1.30, 4.34], p =0.005) compared to fluoropyrimidine-based chemotherapy in terms of 3 rd line overall survival while gemcitabine monotherapy showed a tendency towards negative outcomes. First and 2 nd line chemotherapies sequence didn’t influence 3 rd line outcome. Conclusion In our cohort, one-third of treated patients proceeded to 3 rd line chemotherapy resulting in a 5.5 months median 3 rd line OS, consistent with treatments at advanced stage. Our results argue against the use of erlotinib and gemcitabine monotherapy.

First-line treatment for mCRC pts consists of a fluoropyrimidine-based chemotherapy (5-FU or capecitabine combined with oxaliplatin and/or irinotecan) with VEGF or EGFR inhibitors. Once these treatment options have been used, or are no longer appropriate, pts are eligible for either reg or t/t treatment. Although both treatments are approved in mCRC, no randomised trial has investigated the sequence of reg and t/t. The optimal strategy to extend survival while maintaining quality of life still needs to be determined. We have designed this trial to evaluate both treatment sequences and determine the best one in this setting. This international, randomized phase II, open-label trial is designed to compare the feasibility of the treatment sequences: reg followed by t/t vs t/t followed by reg. Pts ≥18 years, with mCRC, ECOG PS 0-1, after failure of fluoropyrimidine-based chemotherapy combined with oxaliplatin and/or irinotecan as well as EGFR (if RAS wild-type) and/or VEGF inhibitors are enrolled. Reg will be given according to ReDOS dose-escalation scheme at 1st cycle (increasing from 80 mg to 160 mg daily over 3 weeks) to determine the highest dose tolerated that will be then used for the next cycles (3 weeks followed by 1 week off). T/t 35 mg/m2 will be taken orally twice daily on D1-D5 and D8-D12 of each 4-week cycle. The primary endpoint is the treatment feasibility of the 2 sequences, assessed as the percentage of pts able to receive at least 2 cycles of both treatments, which corresponds to the first tumor evaluation at each line. If a pt does not receive the second treatment, he will be considered a failure. Secondary endpoints are overall survival, progression-free survival, disease control rate, objective response rate, time to treatment failure, time to ECOG PS ≥2 deterioration, quality of life and safety. We assume that 50% of the pts receiving t/t will be able to receive further treatment as compared to 65% with reg. With a Chi-square test between the 2 arms, a bilateral α-risk of 5% and a power of 80%, 170 pts are required in each arm. Since November 2020, 42 pts are enrolled in 14 sites. NCT04450836 - initial release 24 June 2020 EudraCT 2019-004196-39. UNICANCER, a private, non-profit French healthcare cooperative group, with its registered offices at 101, rue de Tolbiac, 75654 Paris, France. Bayer HealthCare Pharmaceuticals Inc.

Abstract Background: Increased levels of CTC and a persistent elevated level after just one cycle of chemotherapy are very strong and independent markers of worse progression-free survival (PFS) and overall survival (OS) in patients (pts) with metastatic breast cancer (MBC) (Bidard et al, Lancet Oncol 2014). ctDNA can be used to detect mutation associated with resistance to treatment. It has also been shown that dynamic changes in ctDNA levels closely reflect changes in tumor burden. We prospectively monitored CTC and ctDNA early variations during first line chemotherapy for MBC. Patients & methods: The French cohort COMET is a prospective study including first line HER2 negative patients (pts) receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort is to evaluate clinical, biological and radiological parameters associated with pts outcome (CTC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat, serum estradiol level and quality of life). We present here the first planned analysis on pts evaluated for CTC (CellSearch) and ctDNA using targeted sequencing (Roche SeqCap technology) of a panel of 46 genes and 8 promoters, using unique molecular identifiers to increase ctDNA detection sensitivity. Blood samples were obtained at baseline (BL) and before the second cycle of chemotherapy (C2). Results: From 09/2012 to 5/2014, 218 pts were included in this substudy. Median age was 55 years and 22% of pts had triple negative BC. At BL, 70% of pts had ≥1 detectable CTC per 7.5 ml of blood (median 4 CTC, range 1- 30,000) and 37% at C2. With a threshold of ≥5 CTC, 47% of pts were positive at BL and 22% at C2. For ctDNA, out of the first 141 pts analyzed, 105 had at least one somatic mutation detected in plasma (74%). The average number of mutations per pt was 2.7 and most commonly mutated genes were TP53 and PIK3CA. ESR1 was found mutated in 9% of all cases and restricted to the ER+ subgroup. Median Allelic Frequency was 10% (range 0.6-83%). Only 33% of pts had detectable ctDNA at C2. At BL, CTC and ctDNA levels were correlated (r=0.46, p<0.0001). Despite no complete overlap, 11% of pts had no CTC nor ctDNA detected. Median follow-up was 53 months and median OS was 32 months. Increased level of CTC and ctDNA were significantly associated with decreased PFS and OS. At C2, ≥5 CTC or still detectable ctDNA were strong markers of reduced OS: HR 4.6 (CI95 3.1-7) and HR 3.2 (CI95 1.8 – 5.5), respectively (both p< 0.0001). At multivariate analysis for PFS, detectable ctDNA at C2 and triple negative status were the only significant prognostic factors. None of serum marker level at BL or their early variations had prognostic value. Conclusion: This is the largest prospective cohort assessing the respective prognostic values of early CTC and ctDNA changes in homogenously treated first line MBC patients. Analysis of mutations profile variations and comparison with primary tumor and metastasis biopsies are ongoing and may reveal early mechanisms of resistance. Citation Format: Pierga J-Y, Silveira A, Lorgis V, Tanguy M-L, Tredan O, Dubot C, Jacot W, Goncalves A, Debled M, Levy C, Ferrero J-M, Jouannaud C, Luporsi E, Mouret-Reynier M-A, Dalenc F, Lemonnier J, Berger F, Proudon C, Bidard F-C. Circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) predictive value in HER2 negative metastatic breast cancer patients treated with first line weekly paclitaxel and bevacizumab: Results of a prospective cohort from the French Breast Cancer InterGroup Unicancer (UCBG): COMET study [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 PD2-03.

Abstract Background The NEOSPHERE trial suggested that pertuzumab (P) added to a combination of docetaxel and trastuzumab (T) as a neoadjuvant therapy in HER2 positive breast cancer (HER2+ BC) patients (pts) significantly enhances pathological complete response (pCR) rates. Here, we report our institution experience, focusing on stage III tumors. Methods We reviewed clinical and pathological response (residual cancer burden, RCB) in 355 HER2+ BC treated between 2010 and 2017 with neoadjuvant chemotherapy combined with T (n = 291) or TP (n = 64). Results were adjusted according to clinical stage, hormone receptors (HR) status, and chemotherapy regimen. In a subset of 157 pts matched on clinical TNM stage and HR expression (T, n = 98; TP, n = 59), a baseline pathological biomarker analysis was performed to assess TILs, PTEN, FOXP3 and PD-L1 expression. Results Among 355 patients, tumor clinical stages were T3 -T4 for 40% vs. 72% of T and TP pts (p  Conclusions This retrospective study did not suggest any benefit of neoadjuvant TP dual HER2 blockade regarding pathological response for stage III HER2+ BC. Baseline pathological expressions of PTEN, FOXP3, TILs, PD-L1 did not correlate with pathological response. Legal entity responsible for the study Institut Curie. Funding Institut Curie. Disclosure All authors have declared no conflicts of interest.

Abstract Background and Purpose: Recent phase 3 clinical trials have evaluated the addition of bevacizumab (B) to standard chemotherapy in the treatment of patients with non-metastatic breast cancer. But few data are available about the tolerance of B with locoregional radiation therapy (RT). The objective was to evaluate the 5 years late toxicities of the concurrent B and RT in non-metastatic breast cancer. Material and methods: This is a multicenter prospective study including non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT (BEATRICE, BETH, BEVERLY 1, BERVERLY 2) versus RT alone. All patients received neo-adjuvant or adjuvant chemotherapy and normo-fractionated breast or chest wall RT, with or without regional lymph nodes RT. B was administrated as an equivalent of 5 mg/kg every week for 1 year. The safety profile (using the Common Terminology Criteria for Adverse Events version 3.0) was evaluated at 1, 3 and 5 years after the completion of radiotherapy. Results: From October 2007 to January 2012, 151 patients totally included. Median follow-up was 60 months (36-84) and 5 years late toxicities were available for 104 patients (46 with B and RT, 58 with RT alone). Median age was 51 (22-81). 61% of patients received regional lymph nodes RT. The majority of tumor was triple negative (65.6%), tumor size <2cm (50%) and nodal status negative (63.8%). Median total dose of B was 15000 mg (13200 – 18550) and median duration was 11.2 months (11-12.6). No grade ≥3 toxicity was observed. Only 16 patients had grade 1-2 toxicities (8 treated with B and RT, 8 with RT alone): n=4 (3.8%) had grade 1 pain, n=5 (4.8%) had grade 1-2 fibrosis, n=1 (1%) had grade 2 telangiectasia and n=5 (4.8%) had grade 1-2 lymphoedema. No significant difference between the 2 arms was observed. One patient of 46 evaluated had Left Ventricular Ejection Fraction inferior to 50%. At 5 years, overall survival was 93.8%, disease free-survival 89% and locoregional free-survival 93.1 %. Conclusion: Concurrent B and locoregional RT provides acceptable 5-years toxicities in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed. Citation Format: Clément-Zhao A, Tanguy M-L, Cottu P, De La Lande B, Bontemps P, Lemanski C, Baumann P, Levy C, Peignaux K, Reynaud-Bougnoux A, Gobillion A, Kirova Y. TOxicities of Locoregional Radiotherapy Associated with Bevacizumab in patients with non-metastatic breast cancer (TOLERAB): Final long-term evaluation [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 P3-12-06.