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Metastatic breast cancer (MBC) is the leading non hematologic cause of leptomeningeal metastases (LM), associated with a poor prognosis. Amongst breast cancer (BC) subtypes, HER2+ tumors present a high LM incidence. Intravenous (IV) trastuzumab (T) has improved survival of MBC patients but better control of central nervous system (CNS) disease is needed. The main physiopathological hypothesis for intracranial recurrences is the low level of T in cerebrospinal fluid (CSF) due to his high molecular weight (148kD). Intraventricular (via Ommaya port) or intrathecal (IT) T administration would permit LM progression control through high therapeutic T concentrations in the CSF. This prospective trial, sponsored by Institut Curie, was the first Phase I-II study to investigate the safety and efficacy of IT T administration for HER2+ LM in BC. The final results of the Phase I cohort are reported herein. Methods: LM diagnosis was based on either CSF with HER2+ cytology or clinical/MRI imagings of meningitis. Adequate organs functions for all patients were required. The T IT (or via Ommaya port) injections were given on weekly basis during 8 weeks. We used a Fibonacci dose escalation design, 4 dose levels (DL) (30-150mg). The objectives of this phase I were to investigate the maximum tolerated dose (MTD) and the recommend dose (DR) of T. A pharmacokinetic (PK) data analysis was performed. We targeted a concentration in the CSF close to the residual serum concentration (30µg/mL) achieved with standard IV schedule. Results: Starting May 2011, 19 patients were included, with 16 evaluable for toxicity (three had not received the treatment) treated in 4 DL (30-150mg). Twelve patients were evaluable for PK and 210 samples T concentrations available (103 in the LCR and 107 in the serum). The MTD was not reached and the treatment appears to have been well tolerated by the patients. Neither Grade ≥3 toxicity nor neurological toxicity related to IT T was observed. The T target-concentration in the CSF was reached at DL4 and the recommended T dose for the Phase II trial is 150 mg. Five patients have experimented a evident clinical benefit and received more than 8 weekly injections with an average of 23 [12-40]. Extended data on clinical outcome and PK will be presented. Conclusion: Intraventricular or IT injections appears to be safe at the dose of 150 mg and possibly effective. The Phase II study will investigate the efficacy of the recommended dose on neurological progression-free survival at 2 months in 19 patients. This trial was performed with Roche funding. Citation Format: Maya Gutierrez, Emmanuelle Mouret Fourme, Emilie Le Rhun, Olivier Tredan, Veronique Dieras, Patricia Tresca, Fawzia Mefti, Isabelle Turbiez, Sophie Taillibert, Céline Desvignes, Gilles Paintaud. Final results of the phase I "HIT" study: A multicenter phase I-II study evaluating trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer (MBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-17.

Background: Neaodjuvant endocrine therapy (NET) has demonstrated efficacy in terms of clinical response and outcome in hormone-receptor positive (HR+) post-menopausal patients (pts) with breast cancer (BC) not eligible for primary breast conservative surgery (BCS). However, the monitoring of tumor response to NET is challenging and clinical response is the current gold standard. The aim of the present study was to investigate the contribution of the early metabolic response (eMR) at one month in FDG-PET/CT in a NET setting for post-menopausal pts with HR+, HER2- BC compared to morphological and pathological responses. We also aimed to evaluate the prognostic value of eMR. Methods: This was a prospective and ancillary study of CARMINA 02, UCBG0609 (Cancer in press), a phase II clinical trial evaluating the efficacy of 4 to 6 months neoadjuvant anastrozole or fulvestrant. FDG-PET/CT exams were performed at baseline (M0), after 1 month of treatment (M1: eMR) and pre-Op (late metabolic response: lMR) in 11 pts (74.2 years ± 3.6) from 2007 to 2010. Pts were classified “metabolic responders” (mR) if SUVmax values decrease was ≥ 40% at M1 and “non-metabolic responders” (mNR) if otherwise; lMR was also assessed in mR and mNR groups defined at M1. We compared eMR to morphological response (clinical, breast US and MRI) at M1 and pre-op, to the pathological response according to Sataloff classification and to Ki67 score variation during treatment. Early metabolic response was also correlated with the PEPI (Preoperative Endocrine Prognostic Index) score and survival (overall survival, OS and relapse free survival, RFS). Results: Main results are summarized in Table I. There was a significant difference between mR and mNR pts at M1 (eMR) and pre-op (lMR). One patient with a complete metabolic response at pre-op had the best pathological response (Sataloff TB). Also, mR pts had a better clinical response: 2 partial response (PR) in mR vs 1 in mNR group and 2 mNR patients were classified PD (progressive disease). There was a trend toward better survival for mR pts in OS and RFS (Kaplan-Meier p=0.18 and 0.06, respectively) and all the pejorative events occurred in the mNR group: 3 deaths and 3 metastatic progressions. Besides, no difference in eMR was observed regarding the histological subtype (ductal or lobular; p>0.05) nor the treatment group (p>0.05). Table I: Metabolic, morphological and pathological response at M1, Pre-Op and on the surgical specimen. MR : 5ptsmNR : 6ptsP valueM1SUVmax2.6±1.13.9±1.40.00017 Clinical size42.5mm±11.951.7mm±7.50.19 US size22.6mm±6.334.2mm±2.40.02 MRI size21.2mm±4.239.7mm±4.79.16 E-5 Ki 673.6%±1.98.2%±80.19Pre-OpSUVmax2±1.33.3±1.40.018 Clinical size31mm±12.448.3mm±10.80.035 US size18.5mm±7.331.3mm±9.50.07 MRI size17.9mm±7.134.8mm±7.70.003Surgical SpecimenSataloff (TA+TB vs TC+TD)20% vs 80%0 vs 100%1 PEPI score (I+II vs III)80% vs 20%33 vs 67%0.048 Ki 678.6%±9.812.3%±7.90.41 Conclusions: These preliminary results showed the value of the early metabolic response in FDG- PET/CT in a NET setting compared to the morphological or the pathological responses alone. Early metabolic responders patients had better OS, RFS and PEPI scores. Citation Format: Boughdad S, Champion L, Becette V, Cherel P, Fourme E, Edeline V, Lemonnier J, Lerebours F, Alberini JL. Predictive value of FDG-PET/CT after neoadjuvant endocrine treatment in 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 P4-01-03.

Abstract #4101 Background Taxanes have been approved in the adjuvant setting for the treatment of node positive (pN+) breast cancer (BC) patients (pts), given either sequentially or in combination with anthracyclines. Controversies remain regarding their role in high-risk node negative (pN0) disease. Methods In 1999, we initiated a randomised phase III trial comparing 4 cycles of adjuvant doxorubicin + docetaxel (AT, 50/75/mg/m²) with 4 cycles of standard doxorubicin + cyclophosphamide (AC, 60/600/mg/m²) in a mixed population of high-risk pN0 and limited pN+ (≤3) early BC pts. Chemotherapy was delivered postoperatively q3w without prophylactic G-CSF, followed by radiation therapy according to standard guidelines and endocrine treatment for 5 years in pts with ER±PgR-positive tumours. This trial was closed prematurely for toxicity in 2003 and we have reported the safety data (JAMA 293:2367, 2005). We now report on time to recurrence (TTR, primary endpoint defined as locoregional relapse, controlateral BC or distant metastasis, which ever occurs first) as well as the effect of treatment by stratification factors [pN and Ki67 (90%). Multivariate analysis including all prognostic covariates will be performed and presented at the meeting. Given the high risk of life-threatening complications already reported, AT is not manageable without preventive strategies (e.g. G-CSF) and cannot be considered as a standard combination for intermediate risk early BC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4101.