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Purpose: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients.Experimental Design: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations.Results: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients.Conclusions: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants. Clin Cancer Res; 20(5); 1158–68. ©2014 AACR.

CCR Translation for This Article from Prevalence and Characteristics of MUTYH-Associated Polyposis in Patients with Multiple Adenomatous and Serrated Polyps

Background: P led to a meaningful improvement in clinical outcomes when used in combination with endocrine therapy for first- or later-line regimen in HR[+]/HER2[-] MBC. Grade 3-4 neutropenia was the most common adverse event (AE) in the P-containing regimens. Although venous thromboembolic events (VTE) have been rarely reported in registrational trials, a systematic review and meta-analysis of randomized controlled trials demonstrated a higher rate of these AEs. Moreover, rare but severe cases of interstitial lung disease (ILD)/pneumonitis have been observed during post-approval use of P. Here, we present a comprehensive toxicity profile of pts included in the PARSIFAL study, with particular emphasis given to AEs of special interest of the overall safety population. Methods: A total of 486 pts with HR[+]/HER2[-] MBC with no prior therapy in the advanced setting and endocrine sensitive criteria (relapse >12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with de novo metastatic disease) were randomly assigned 1:1 to receive P (oral 125 mg/day [d]; 3 weeks on/1 week off) plus either F (intramuscular injection 500 mg/d; d 0, 14, 28, and then every 28 ds) or L (oral 2.5 mg/d). Pts were stratified by visceral involvement and type of disease presentation (de novo/recurrent). Safety assessments included blood analysis and collection of vital signs at screening, d1 of each cycle, and end of treatment/withdrawal. Severity was graded as per the NCI Common Terminology Criteria for Adverse Events v.4.03. Results: The incidence rate of any grade, grade 3-4, and serious AEs was 99.6%, 80.9%, and 29.9%, respectively, in the FP arm, and 99.2%, 78.5%, and 21.1% in the LP arm. Discontinuations due to AEs were 5.4% in the FP arm and 2.1% in the LP arm. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both arms. Febrile neutropenia was reported in 1.2% (3 pts) and 0.4% (1 patient) in the FP and LP arms, respectively. The rate of VTE of any grade was 5.8% (14 pts) in the FP arm and 4.5% (11 pts) in the LP arm (p = 0.531). Among 18 pts who had grade ≥ 3 pulmonary embolism (PE), the incidence reported in the FP and LP arms was 5% (12 pts) vs 2.5% (6 pts), respectively, and many of them (n=16, 88.9%) were unrelated PE. Asymptomatic grade 3 PE was reported in 10 pts of the entire study population on every 3-mo CT scan. Further, in 5 pts PE was detected in the context of progressive disease. Median time from the first dose of study drugs to occurrence of PE was 4.1 mo (range 1.4-32.0 mo) in the FP arm and 7 mo (range 1.8-19.3 mo) in the LP arm. Analysis of baseline characteristics in the whole population revealed that older pts had a significantly increased risk for developing PE (69.5 years [range 47-84 years]; p < 0.01). ECOG performance status, menopausal status, metastatic disease, visceral involvement, number of disease sites, and prior therapies including antithrombotic agents did not significantly increase the risk for developing PE. Grade 3 ILD/pneumonitis was rarely observed in the FP and LP arms (0.8% vs 1.2%, respectively) with no grade 4 AE. Conclusions: First-line treatment with FP and LP for HR[+]/HER2[-] MBC in the PARSIFAL study confirmed the favorable safety profile, with neutropenia representing the most common AE. Although rare, ILD/pneumonitis can be a side effect of P-based regimens. VTE and PE incidence rates were low and consistent with age-specific analyses from PALOMA trials and breast cancer population. Early detection of these AEs may assist in optimizing their management. Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Meritxell Bellet, Florence Dalenc, Miguel J. Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Serena Di Cosimo, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés. Palbociclib (P) in combination with fulvestrant (F) or letrozole (L) in endocrine-sensitive patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC): detailed safety analysis from a multicenter, randomized, open-label, phase II trial (PARSIFAL) [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 PS10-17.

Background The use of PPI among cancer patients (pts) is quite frequent. PAL is an oral, cyclin-dependent kinase 4 and 6 inhibitor recommended to be taken under fed conditions. PAL showed a reduced solubility when gastric pH is >4.5, a level commonly achieved by PPI. Observational, retrospective studies on concomitant PPI with PAL or ribociclib showed a shorter progression-free survival (PFS) among PPI users than nonusers. In the randomized, phase 2 PARSIFAL trial, PAL plus fulvestrant demonstrated no improvement in PFS and overall survival (OS) versus PAL plus letrozole as frontline treatment in HR+/HER2- ABC pts (Llombart-Cussac et al, JAMA Oncol 2021). Here we assessed the impact of PPI on PAL efficacy and safety in pts included in the PARSIFAL study. Methods Pts with endocrine-sensitive HR+/HER2- ABC and no prior therapy in advanced setting were randomly assigned to receive PAL (hard capsule formulation) plus either fulvestrant or letrozole. Pts with ≥1 PPI received over the entire PAL-based regimen were defined as PPI users, or PPI naïve (N-PPI) if no PPI was administered over the whole study treatment. We carried out two analyses considering early PPI users (E-PPI) –composed by pts who were receiving PPI since the PAL-based regimen initiation– and long-term PPI users (LT-PPI) –composed by pts who received PPI over the entire or ≥⅔ of the PAL-based regimen. PPI users defined as neither E-PPI nor LT-PPI were excluded from the analysis to avoid biases due to the PPI limited exposition. PFS, OS, and safety were compared among groups. Landmark analysis at 3, 6, 12, 18, 24, and 30 months (mo) was used for survival estimates conditional on surviving to certain time points and adjust for immortality bias in comparison between N-PPI and PPI users. Analyses were adjusted by stratification factors and patient characteristics. Results Of 486 pts included in the study, 325 (66.9%) were N-PPI. Among 161 (33.1%) PPI users, 64 (13.2%) were E-PPI and 91 (18.7%) were LT-PPI. Omeprazole was the most prescribed PPI in 80.7% (130 of 161) of PPI users. Median exposition to PPI for PPI users, E-PPI, and LT-PPI was 13.6, 15.9, and 19.4 mo, respectively. Compared with N-PPI, E-PPI and LT-PPI were older (median age, 60.5 vs 66.5 vs 67.0 years, respectively; P< 0.001) and had a worse functional status (ECOG PS of 0, 60.0% vs 34.0% vs 43.0%, respectively; P=0.002). Median follow-up for the whole population was 32 mo. Median PFS was 28.7 mo in N-PPI compared with 23.0 mo in E-PPI (HR 1.5; 95%CI 1.1–2.2; P=0.024) and 23.0 mo in LT-PPI (HR 1.4; 95%CI 1.0–1.9; P=0.035). Both PPI groups had poorer median PFS than N-PPI by landmark analysis at 3 and 12 mo. Subgroup analysis showed a consistent trend regardless of endocrine partner. Three-year OS rate was 81.1% in N-PPI compared with 63.5% in E-PPI (HR 2.2; 95%CI 1.3–3.7; P=0.003) and 62.0% in LT-PPI (HR 2.1; 95%CI 1.4–3.4; P=0.001). Both PPI groups had poorer 3-year OS rate than N-PPI by landmark analysis at 3, 6, 12, and 18 mo. Grade ≥3 hematological adverse events (AEs) occurred in 71.7% (233 of 325 pts) of N-PPI compared with 57.8% (37 of 64 pts; P=0.021) of E-PPI and 54.9% (50 of 91 pts; P=0.003) of LT-PPI. Dose reductions and delays due to hematological AEs were reported in 70.8% (230 of 325 pts) of N-PPI compared with 56.3% (36 of 64 pts; P=0.018) of E-PPI and 52.7% (48 of 91 pts; P=0.002) of LT-PPI. At 3 mo, 45.8% (149 of 325 pts) of N-PPI required a dose reduction or delay due to hematological AEs compared with 39.1% (25 of 64 pts; P=0.42) of E-PPI. Conclusions Early and sustained coadministration of PPI with PAL and endocrine therapy were associated with lower efficacy, hematological toxicities, and dose modifications. Despite the post-hoc nature of the study, these findings suggest pharmacokinetic interactions between PPI and PAL capsules. Further confirmatory studies including the tablet formulation of PAL, which is expected to assure its optimal absorption, are needed. Citation Format: Serena Di Cosimo, José Manuel Pérez-García, Meritxell Bellet Ezquerra, Florence Dalenc, Miguel Gil Gil, Manuel Ruiz Borrego, Joaquín Gavilá, Miguel Sampayo-Cordero, Elena Aguirre, Peter Schmid, Frederik Marmé, Joseph Gligorov, Andreas Schneeweiss, Joan Albanell, Pilar Zamora, Duncan Wheatley, Eduardo Martínez De Dueñas, Vicente Carañana, Kepa Amillano, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. PD13-10 Impact of Proton Pump Inhibitors (PPI) on Palbociclib (PAL) Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (HR+/HER2- ABC): Exploratory Analysis of the PARSIFAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-10.

This abstract was withdrawn by the authors.

Background: International consensus stresses the preference for endocrine therapies (ET) for the ER[+]/HER2[-] ABC population. However, in real-world, chemotherapy (CT) is an extended practice long before exhausting endocrine options (Swallow E, Curr Med Res Opin. 2014). There is little knowledge on the prognostic factors that drives OS among the ER[+]/HER2[-] population at the time of first line CT for ABC. Methods: The Athena trial assessed safety of different first-line CT & bevacizumab regimens in 2.264 patients (pts) treated between 2006 and 2009 over 34 countries. A total of 1.492 ER/PgR[+]/HER2[-] pts were identified, as 585 TNBC pts (control arm). We adapted the ESMO 2012 guidelines of endocrine resistance to the data collected, considering 5 years the median duration of (neo)adjuvant ET. Endocrine resistance status (ERS) at the time of inclusion was measured by: (1) Progression on ET for Early stage (EEP) [on or within the first year of], and (2) Prior ET for ABC (AEP), whatever the duration or number of endocrine lines. Three ES were pre-defined: Low sensitive (LS): patients with both EEP and AEP criteria; moderately sensitive (MS): either EEP or AEP criteria, and Highly sensitive (HS): neither EEP nor AEP criteria. Other prognostic factors (PF) identified in a prior analysis (Llombart-Cussac A, Breast 2014) were incorporated in a multivariate Cox proportional-hazard model. Results: Median age was 53 years (range 22-93); 5.2% ECOG ≥2 and 28.9% with prior analgesic treatment. ER/PgR positivity were 94.4%/76% respectively. Patients were previously exposed to anthracycline (53.5%) and taxanes (21.4%) for early stage BC. Prior endocrine therapy in (neo)adjuvant and metastatic settings were (65.3%) and (31.8%), respectively. Pts de novo metastatic represented 19.3%, and the median DFI in pts progressing from an early stage was 43.2 mo. Liver involvement was observed in 40.3% of pts and 20.5% presented ≥3 organs involved. The ES for the population was HS: 492 pts (33%), MS: 755 pts (50.6%) and LS: 245 pts (16.4%). After median follow-up of 22.6 months (range: 0.1 to 43.6) and 752 OS events (50.4% of pts), median OS for HS, MS, LS and TNBC groups were >40 mo. (median not achieved), 26.3 (95%CI: 24.5–28.4), 20.1 (95%CI: 17.8–23.9) and 18.3 (95%CI: 16.3–19.7) respectively. 3-years OS survival rates for HS, MS, LS and TNBC were 53.5%, 34.8%, 23.9% and 26.6%, respectively. Multivariate-adjusted hazard ratios of OS for (HS vs LS) and (HS vs MS) were 2 (IC95%: 1.6–2.5) and 1.5 (IC95%: 1.2–1.8). The other PF related with OS were: ECOG≥2 or analgesics or corticosteroids 1.6 (IC95%: 1.4–1.8); liver mets or>2 involved organs 1.4 (IC95%: 1.2–1.6) and adjuvant anthracyline and/or taxane 1.2 (IC95%: 1.1–1.4). Conclusions: Nearly to 40% of ER[+]/HER2[-] ABC pts confronted to first line CT were precluded as highly sensitive to ET, achieving a median OS that doubles the less sensitive groups. Confirmatory studies with post-treatment information may be important to link this benefit to ET. However Endocrine Status may be useful to appropriately characterize or select patients in future first-line CT studies for HER2[-] pts. Citation Format: Llombart A, de la Haba-Rodríguez JR, Gligorov J, Aguirre E, Sampayo M, Cortes J. Prognostic relevance of prior endocrine treatments in overall survival (OS) at the time of first line chemotherapy in ER[+]/HER2[-] advanced breast cancer (ABC) patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-09.

Purpose: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients. Experimental Design: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations. Results: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients. Conclusions: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants. Clin Cancer Res; 20(5); 1158–68. ©2014 AACR.

BACKGROUND: Clinical efficacy and safety of T-DM1 for the treatment of HER2-positive MBC has been assessed in several phase II and III trials and is now considered the standard of care in taxane-and trastuzumab-progressing patients. However, although T-DM1 has shown encouraging antitumor activity in the advanced setting, several strategies to improve T-DM1 efficacy are currently evaluated, including the combination with non-pegylated liposomal doxorubicin (NPLD), considering that: i) doxorubicin is one of the most active chemotherapeutic agents against HER2-positive breast cancer; ii) the combination of doxorubicin and trastuzumab induces synergistic antitumor activity in HER2-overexpressing preclinical models; and iii) liposomal formulations of doxorubicin have a reduced risk of developing cardiac toxicity. OBJECTIVES: The primary objective of this trial is to determine the maximum tolerated dose (MTD) of the combination of T-DM1 and NPLD in patients with HER2-positive MBC naïve of anthracyclines and previously treated with trastuzumab and a taxane. The secondary objectives include 1) safety, with special emphasis on cardiac safety evaluated by left ventricular ejection fraction, high-sensitivity troponin I and B-type natriuretic peptide (BNP) levels, 2) pharmacokinetics, 3) antitumor activity, and the 4) role of single nucleotide polymorphisms of HER2 gene for developing cardiotoxicity. TRIAL DESIGN: This is a dose-finding, open-label, non-randomized and multicenter phase I clinical trial of T-DM1 at a fixed dose of 3.6 mg/kg IV in combination with three different dose levels (DL) of NPLD (45, 50, and 60 mg/m2) IV administered on Day 1 every three weeks. The trial follows a modified dose escalation scheme with a 3+3 design.A total of three patients will be included in the first cohort and observed for dose-limiting toxicities (DLTs) during the first two cycles of treatment. If none of these patients experiences a DLT, three other patients will be treated at the next DL. However, in case of at least one patient experiences a DLT, three more patients will be treated at the same DL. The MTD will be defined as the highest DL at which ≤1 of six patients experiences a DLT during the first two cycles of treatment. An expansion cohort of six additional patients at the MTD will be included. ELIGIBILITY: Anthracycline-naïve patients with HER2-positive MBC and up to two prior chemotherapy regimens in the advanced setting who previously were treated with trastuzumab and a taxane. ECOG performance status of 0-1. Adequate organ and cardiovascular function with LVEF ≥ 55%. RECIST v1.1 evaluable disease. ACCRUAL: A total of 12-24 patients will be enrolled at four sites in Spain and France. Recruitment was opened on September 2015. To date, four patients (three at DL1 and one at DL2) have been recruited. Citation Format: López-Miranda E, Brain E, Saura C, Gligorov J, Dubot C, Dieras V, Suter TM, Aguirre E, Perez-García JM, Llombart A, Cortés J. Phase I multicenter clinical trial evaluating the combination of trastuzumab emtansine (T-DM1) and non-pegylated liposomal doxorubicin (NPLD) in HER2-positive metastatic breast cancer (MBC) (MEDOPP038 study) [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 OT1-02-03.

BACKGROUND: Olaparib is a well-tolerated oral PARP inhibitor. Olaparib has shown promising monotherapy activity in patients with germline mutations in BRCA genes and cancers that exhibited a failure in DNA repair mechanism. The aim of this trial is to evaluate the efficacy of olaparib as single agent in non-BRCA MBC patients whose tumors exhibit an homologous recombination deficiency (HRD) signature. TRIAL DESIGN: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive oral olaparib 300 mg twice a day during 28 days cycles until progression or unacceptable toxicity. HRD signature will be evaluated with one tumor tissue-based test: FMI Lynparza HRR. The stage I principal selection criteria are: (1) Confirmed non-BRCA triple negative locally advance (LA) or MBC; (2) HRD signature; (3) one to three previous lines for the MBC and prior taxanes exposure; (4) RECIST v1.1 evaluable disease. In stage II the study will be extended to patients with luminal subtype and confirmed non-BRCA LA or MBC with HRD signature. The primary goal is to evaluate the efficacy of olaparib monotherapy. Primary endpoint are the clinical benefit rate (CBR), defined as the percentage of patients who experienced overall response (as best response) or stable disease ≥24 weeks in accordance with RECISTv1.1. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CBR ≤5% while targeting an improvement of the CBR to ≥20% would be an optimal approach to evaluation of the study strategy. At first stage, ≥1 patient with clinical benefit among 17 patients will be necessary to continue. At the study end, ≥5 subjects with clinical benefit out of 35 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 39 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. We anticipate a 40% of screened TNBC and 25% of luminal (RH-positive HER2-negative) non-BRCA patients will exhibit HRD signature. Therefore, we expect to screen 48 patients in the 1st stage and 80 patients in the 2nd stages to accomplish with the accrual goal (a total of 128 patients screened). Secondary objectives include (1) efficacy measures: objective response rate (ORR), progression-free survival (PFS) and overall survival; (2) the assessment of HRD signatures agreement and validity to predict clinical benefit and overall response; and (3) safety-related outcomes. Citation Format: Elena Aguirre, Kepa Amillano, Alfonso Cortés, María José Juan, Antonia Márquez, Manuel Ruiz, Sonia Servitja, Ander Urrutikoetxea, Antonio Llombart, José Perez, Javier Cortes. A two-stage Simon Design phase II study for NOn-BRCA metastatic BReast cancer (MBC)patients with homologous recombination deficiency treated with OLAparib single agent.(NOBROLA study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT165.

Background: HER2-negative metastatic breast cancer (MBC) patients with central nervous system (CNS) involvement previously treated with a local therapy had very few possibilities of disease response with conventional systemic treatments. Liposomal irinotecan (nal-IRI) is a novel formulation of irinotecan. It has shown promising activity in patients with CNS involvement. The aim of this trial is to evaluate the efficacy of nal-IRI as single agent in HER2-negative MBC patients with CNS progression following local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy. Trial design: This is an open label, non-randomized, multicenter two-stage phase IIA clinical trial. Patients will receive intravenous nal-IRI in a fixed dose of 60 mg/m2 expressed as irinotecan hydrochloride trihydrate salt on day 1 of a 14-day cycle until progression or unacceptable toxicity. The principal selection criteria are: (1) HER2-negative inoperable MBC with CNS involvement; (2) prior local treatment with surgery, stereotactic radiosurgery or whole-brain radiotherapy; (3) prior treatment with taxanes; (4) at least one measurable brain lesion according to RECIST v1.1 criteria. The primary objective is to evaluate the efficacy of naI-IRI monotherapy. Primary endpoint is the CNS overall response rate (ORR), defined as the percentage of patients who experienced complete (CR) and partial response (PR) (as best response). It will be assessed in accordance with the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The trial uses a Simon's minimax two-stage design. We hypothesized that excluding a CNS ORR ≤5% while targeting an improvement of the CNS ORR to ≥15% would be an optimal approach for evaluating the study strategy. At least 2 responders among 23 patients will be necessary to proceed to the second stage. At the study end, ≥6 responders out of 56 evaluable subjects are required to justify this strategy in further clinical trials. Considering a drop-out rate of 10%, a sample size of 63 patients will be needed to attain 80% power at nominal level of one-sided alpha of 0.05. The secondary objectives include safety-related outcomes and efficacy measures: CNS clinical benefit rate (CR, PR and stable disease [SD] ≥12 weeks), ORR according to a CNS volumetric parameter (CR, PR and >65% reduction of CNS lesion), clinical benefit rate (CR, PR and SD ≥24 weeks), progression-free survival and overall survival. Trial registration: NCT03328884. Date of registration: November 1st, 2017. First patient included: July, 05th 2017. Citation Format: Javier Cortés, David Paez, José Manuel Pérez García, Salvador Blanch Tormo, Kepa Amillano Parraga, Manuel Ruiz Borrego, Antonio Antón Torres, María Fernández, Emilio Alba Conejo, Miguel Ángel Seguí Palmer, Joan Dorca Ribugent, Rafael López López, Mireia Margelí Vila, Elena Aguirre, Antonio Llombart. Multicenter open-label, phase II trial, to evaluate the efficacy and safety of liposomal irinotecan (nal-IRI) for progressing brain metastases in patients with HER2-negative breast cancer (The Phenomenal Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT154.