Abstract: Histone deacetylase 6 (HDAC6) is a protein modifier that is an increasingly attractive pharmacological target. Interestingly, the observation that the HDAC6 knock-out mouse is not lethal, in contrast to those undergoing complete loss of class I, II and III HDACs, suggests that specific HDAC6 inhibitors may be better tolerated than pan-HDAC inhibitors or drugs that target the other HDAC classes. In this regard, the compound ACY-1215 (Rocilinostat), the described selective HDAC6 inhibitor, is undergoing clinical trials for the treatment of multiple myeloma. Taking into account the previous information about HDAC6 inhibitor structures, the structural differences between HDAC6 and other HDAC isoforms and also the structural information of other developed HDAC inhibitors, we have previously designed and synthesized a new potential HDAC6 selective inhibitor, QTX125 with growth inhibitory effects in mantle cell lymphoma (MCL) cell lines, mouse models and ex vivo treatment of primary samples obtained from patients with MCL. Herein, we have extended these findings to show that the newly identified HDAC6 inhibitor QTX125 is also able to inhibit the growth of preclinical models of other B-cell lymphomas such as follicular lymphoma and Burkitt’s cell lymphoma, but also of acute acute myeloid leukemia. In addition beyond a-tubulin, a well known HDAC6 target, we have developed a pharmacological and proteomic screening to identify other proteins modified by HDAC6 that can contribute to the described lymphoma and leukemia phenotypes. Citation Format: Lorea Villanueva, Montserrat Perez-Salvia, Eneko Aldaba, Yosu Vara, Myriam Fabre, Cristina Ferrer, Carme Masdeu, Aizpea Zubia, Eider San Sebastian, Dorleta Otaegui, Pere Llinàs-Arias, Margalida Rosselló-Tortella, María Berdasco, Fernando Setien, Catia Moutinho, Alberto Villanueva, Eva González-Barca, Josep Muncunill, José Tomás Navarro, Miguel Ángel Piris, Fernando Cossio, Manel Esteller. Efficacy of a new small-molecule inhibitor of histone deacetylase 6 (HDAC6) in preclinical models of B-cell lymphoma and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4725.

Abstract: Purpose: The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents, and its loss in cancer cells is associated with hypermethylation of the MGMT CpG island. Thus, methylation of MGMT has been correlated with the clinical response to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in primary gliomas. Here, we investigate whether the presence of MGMT methylation in gliomas is also a good predictor of response to another emergent alkylating agent, temozolomide. Experimental Design: Using a methylation-specific PCR approach, we assessed the methylation status of the CpG island of MGMT in 92 glioma patients who received temozolomide as first-line chemotherapy or as treatment for relapses. Results: Methylation of the MGMT promoter positively correlated with the clinical response in the glioma patients receiving temozolomide as first-line chemotherapy (n = 40). Eight of 12 patients with MGMT-methylated tumors (66.7%) had a partial or complete response, compared with 7 of 28 patients with unmethylated tumors (25.0%; P = 0.030). We also found a positive association between MGMT methylation and clinical response in those patients receiving BCNU (n = 35, P = 0.041) or procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (n = 17, P = 0.043) as first-line chemotherapy. Overall, if we analyze the clinical response of all of the first-line chemotherapy treatments with temozolomide, BCNU, and procarbazine/1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea as a group in relation to the MGMT methylation status, MGMT hypermethylation was strongly associated with the presence of partial or complete clinical response (P & lt; 0.001). Finally, the MGMT methylation status determined in the initial glioma tumor did not correlate with the clinical response to temozolomide when this drug was administered as treatment for relapses (P = 0.729). Conclusions: MGMT methylation predicts the clinical response of primary gliomas to first-line chemotherapy with the alkylating agent temozolomide. These results may open up possibilities for more customized treatments of human brain tumors.

Abstract: Background: The RegistEM study is a non-interventional study that is providing prospective data from around 1900 ABC pts (females and males) diagnosed with advanced disease between 01/Jan/2016 and 31/Dec/2019, either after recurrence or at 1st diagnosis, in 38 Spanish sites representative of the national territory and whose investigators are GEICAM members. Methods: In the current analysis (cut-off date 10/May/2021, ongoing database), we describe the features of 279 pts included in the RegistEM study, with HER2+ (immunohistochemistry [IHQ] 3+, IHQ 2+ and in situ hybridization [ISH] +) tumors at any time of their ABC (5% after the 1st-line therapy). This subgroup has been evaluated because of the interest from a clinical perspective. Multivariate Cox analysis aiming to identify factors associated with overall survival (OS) were built. Results: 279 pts were identified, representing the 15% pts available in the database at the cut-off date. At first ABC diagnosis, 48% pts had recurrent BC ( & gt;12 months [mo] from initial BC diagnosis in 93%), 51% de novo metastatic BC and 1% unresectable locally advanced BC (ULABC). The median age was 59 years, 98% were white , 71% postmenopausal and only 1 male was part of this subset. Considering the BC subtype assessed in the most recent tumor lesion before the 1st-line therapy, 264 pts wereHER2 positive (67% with hormone receptor [HR] +). Family history of BC and/or ovarian cancer was reported in 31% pts, and an hereditary-risk genetic test was performed in 25% (66/267 pts). BRCA1/2 and TP53 mutations were reported in 4/20 and 4/19 pts, respectively, and p53 overexpression in 20/46 pts. Lymph nodes (56%), bone (49%), liver (34%), lung (33%), soft tissue (10%) and brain (8%) were the main metastatic sites. Additional data according to HR status and type of ABC are detailed in the table below. In HR- pts, bone metastases were less frequent and lymph nodes metastases more frequent compared to HR+ pts. Visceral disease was present in 68% pts and ≈75% had ≤3 (47% ≤2) locations involved. The most common therapies by line were: 1) 1st-line: CT + dual anti-HER2 blockade (3%), chemotherapy (CT) (almost in all pts taxane-based)+dual anti-HER2 blockade + endocrine therapy (ET) (mainly aromatase inhibitors) (35%), and ET + anti-HER2 blockade or ET + cyclin-dependent kinases 4/6 inhibitors (11%); 2) 2nd-line: anti-HER2 blockade (56%) [mostly an antibody-drug conjugate (90%)], CT + anti-HER2 blockade (18%) and ET + anti-HER2 blockade (14%); 3) 3rd-line: CT + anti-HER2 blockade (55%) and anti-HER2 blockade (22%). The median time-to-progressions to 1st-, 2nd- and 3rd-line were 14, 5, and 4 mo, respectively. A 4th-line therapy was reported in 52% of pts who received a 3rd-line. At database cut-off date, death was reported in 34% of pts. The median OS of this subset of pts was 41 mo (36-49). In a multivariate Cox regression analysis, the following variables were significantly related with worse survival (from ABC diagnosis): Brain (HR=2.62; 95% CI, 1.02-6.73) and Visceral no Brain involvement (HR=2.15; 95% CI, 1.02-4.53) compare to only soft tissue lesions; early stage at first diagnosis (HR=1.77; 95% CI, 1.15-2.73); HR- (HR=1.70; 95% CI, 1.11-2.60) and age (HR=1.04; 95% CI, 1.02-1.07). Conclusions: In this cohort of HER2+ pts with advanced disease, half of them had de novo ABC which was associated with better OS. The median PFS in 1st- and 3rd-line were slightly better in HR+ pts, and in 2nd-line was similar between HR+ and HR- cohorts. HR+181 (67%)HR- 91 (33%)Recurrent EBC134 (48%)ULABC or de novo M1 145 (52%)Time to recurrence & gt;12 mo in EBC pts., n8435125NALocation of metastaticsites, nBoneBrainLiverLungLymph nodesSoft tissue104 10 62 57 90 1829 9 3232 64 1059 15 36 47 51 2278 6 59 46 1056Líne123123123123n180935690492613385521446333Deaths, n211112111161715141584Therapies by line, nET/BT261922101910212100ET12441011022323CT/BT/ET935031038305830CT/BT4017307581552182366924CT3572353711211BT6431373651145143385The most frequent therapies, nCT + dual anti-HER2 blockade + ET8623331551CT + single-agent HER2 blockade + ET522CT + dual anti-HER2 blockade3493644391016252CT + single-agent HER2 blockade4825641588211521CT5573354711411ET*22105212162644ET + HER2 blockade1213411662782Anti-HER2 blockade6431073651145143382Median duration of treatment, mo125585310441064TTP (mo), median (range)15(1-47)5(1-32)5(0-18)11(2-38)5(1-27)4(2-12)12 (1-47)5(1-26)4(0-17)17(2-45)7(1-32)4(1-18)Median PFS, mo14561154------HR: hormone receptor; EBC: early breast cancer; ULABC: unresectable locally advanced breast cancer; M1: metastatic; mo: month; ET: endrocrine therapy; BT: biological therapy; CT: chemotherapy; TTP: time-to-progression; PFS: progression-free survival. *ET includes aromatase inhibitors or selective estrogen receptor degraders, as single-agents or combined with cyclin-dependent kinases 4/6 inhibitors. Citation Format: Isabel Álvarez, Ángel Guerrero-Zotano, Josefina Cruz, Purificación Martínez, María Hernández, César A Rodríguez, Álvaro Rodríguez-Lescure, Silvia Antolín, Encarna Adrover, Raquel Andrés, Catalina Falo, Jose Ignacio Chacón, Ana Miguel, Sonia Servitja, Maria Galán Gramaje, Mireia Margelí Vila, César Gómez Raposo, María Jose Echarri, Rafael Villanueva, Ariadna TIbau Martorell, Silvia Varela Ferreiro, Ruth Campo, Juan Jose Miralles, Susana Bezares, Federico Rojo, Sara López-Tarruella. Features of HER2+ metastasic patients (pts) from a prospective registry of advanced breast cancer (ABC), GEICAM/2014-03 (RegistEM) [abstract] . In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-04.

Abstract: Background: The incidence of breast cancer brain metastases (BCBM) is estimated to be around 5-15%, but necropsies show a much higher incidence (30-50%). Frecuency of BCBM has gradually increase likely as a result from advances in systemic treatment that allow more patients to live long enough to develop BCBM. In general, outcome for patients with BCBM is poor, with 1-year survival of approximately 20%, but some patient and tumor characteristics are associated with improved behaviour. The RegistEM study is a non-interventional cohort study providing prospective data from around 1,867 advanced breast cancer (ABC) patients (pts.). This study offers a unique opportunity to assess the incidence, potential risk factors, and outcomes for patients with BCBM. Methods: In this analysis (cut-off date 26/April/2021 and ongoing database), we describe the features of 218 pts. with BCBM included in the RegistEM study, which represent the 11% of current total number of pts. in the study. BC clinical subtypes are based on the most recent tumor lesion (distant metastasis or primary BC). The most frequent therapies by BC subtypes are detailed in the table below. At the database cut-off date, death had been reported in 74% pts with BCBM. Results: All pts. were female, 97% caucasian, and at ABC diagnosis, 66% were postmenopausal and their median age was 55 years. The subtype distribution was: Luminal (ER+/HER2-) 41%, HER2+ 35%, Triple Negative (TN) 19%, unknown 5%. Eighty pts. (37%) had BM at diagnosis of ABC, and in 17 of them BM was the only site of relapse. The median time from diagnosis of primary BC to BM at initial diagnosis of ABC was 34 months (mo), being shorter for TN (18 mo). In patients without BM at diagnosis of ABC, the median time from ABC diagnosis to onset of BM for de novo metastatic disease was: Luminal 27 mo, HER2+ 28 mo, TN 10 mo; while for EBC disease was: Luminal 18 mo, HER2+ 14 mo, TN 10 mo. De novo metastatic BC was associated with longer time to BM appearance (HR:0.527, CI 95%: 0.358-0.776) while TN subtype with shorter time (HR:4.122, CI 95%: 2.318-7.329) compared to Luminal subtype. The median survival from the onset of BM, according to BC subtype was: Luminal 6 mo, HER2 11 mo and TN 4 mo. Risk factors for worse survival were: BM at ABC (HR:1.677, CI 95%:1.169-2.406) and TN subtype (HR:3.631, CI 95%: 2.353-5.603) compared to Luminal subtype. Conclusions: TN breast cancer is associated with a shorter time to brain metastases and poorer outcome than other breast cancer subtype. Patients with de novo metastatic BC develop metastases later than patients with metastatic recurrence after primary BC. New treatment approach to avoid the onset of brain metastases in patients with ABC warrants further research. Luminaln=90 (41%)HER2+n=77 (35%)Triple Negativen=41 (19%)HRHER2+-Any+–First BC diagnosis, nEBC (stages I-III)ULABC or de novo metastatic65. 2555. 2227. 14Only CNS metastases at ABC diagnosis584Number of line (L)1L2L3L1L2L3L1L2L3Ln877158745936352515Type of therapy, nET/BT26167443---ET239531----CT/BT/ET58-15-----CT/BT10924014211331CT/ET623------CT172635321222214BT1693811---Most frequent therapies by mechanism of action, nAI/CDK4/6i 20SERD 12CT single agent 12AI single agent 11CT + antiangiogenic 9CT single agent 24SERD +/- CDK4/6i 8AI + CDK4/6i 7CT + antiangiogenic 7CT single agent 27CT combination 8SERD +/- CDK4/6i 6CT + dual anti-HER2 blockade 46CT + anti-HER2 blockade single agent 7Anti-HER2 single agent 35CT + anti-HER2 blockade single agent 12CT + anti-HER2 blockade single agent 18Anti-HER2 blockade single agent 9CT combination 12CT + antiangiogenic 12CT single agent 10CT single agent 16CT combination 6CT + antiangiogenic 4CT single agent 9CT combination 5Median Treatment duration, months (range)7 (0-31)6 (0-41)4 (0-16)12 (0-43)5 (0-47)3 (0-17)5 (0-18)3 (0-7)2 (0-6)TTP in months, median (range)8 (2-35)--12 (3-46)--6 (2-19)--Death, n635139Abbreviations: HR=hormone receptor; HER2=human epidermal growth factor receptor 2; BC=breast cancer; EBC=early breast cancer; ULABC=unresectable locally advanced breast cancer; ET=endrocrine therapy; BT=biological therapy; CT=chemotherapy; TTP=time to progression; AI=aromatase inhibitor; SERD=selective estrogen receptor degrader; CDK4/6i=cyclin dependent kinases 4 and 6 inhibitor Citation Format: Sara López-Tarruella, Ángel Guerrero-Zotano, César A Rodríguez, Josefina Cruz, María Hernández, Encarna Adrover, Álvaro Rodríguez-Lescure, Catalina Falo, Purificación Martínez, Ana Miguel, Raquel Andrés, Silvia Antolín, J. Ignacio Chacón, Jose Luis Alonso Romero, Rafael Villanueva Vázquez, Ana Isabel Ballesteros García, María Galán Gramaje, Diego Malón Jiménez, Silvia Varela Ferreiro, Diana Moreno Muñoz, Ruth Campo, María José Escudero, Susana Bezares, Federico Rojo, Isabel Alvarez. Breast cancer clinical subtypes in brain metastases patients from a prospective registry of advanced breast cancer, GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-08.

Abstract: BACKGROUND: Current treatment strategies for locally advanced and/or metastatic breast cancer (LA/MBC) are meant to prolong survival while maintaining or improving the quality of life. Nevertheless, there is a lack of recent data regarding the actual clinical management and its impact on the prognosis of these patients. It is unknown whether prior diagnosis and treatment of early breast cancer (EBC) make any difference in the outcome of the advanced disease. CASCADE is an epidemiological, retrospective, and multicenter study aimed at retrieving this information from a representative cohort of LA/MBC patients treated within the Spanish National Healthcare System. MATERIALS AND METHODS: Thirteen Spanish public hospitals covering nearly 5'000'000 inhabitants ( & gt;10% of the national population) applied several combined systematic strategies to identify patients firstly diagnosed with LA/MBC between 01/2007 and 12/2008. Once identified, patients were followed throughout their metastatic lifetime until death, lost to follow-up, or until December 2013, whichever occurs first. Data collected included demographical, pathological, diagnostic, and therapeutic information for each line of treatment. Descriptive statistics were applied. RESULTS: We identified 443 LA/MBC patients; median age at diagnosis was 59 years (CI95%: 49.5 - 71.6). Previous history of early BC was reported in 69.3% of them with a median disease-free interval of 38 months. Median Overall Survival (OS) for the whole study population was 33.5 months, while numbers for advanced cases originally diagnosed as EBC or the novo LA/MBC were 31.7 (CI95%: 26.8 - 36.0) and 38.8 months (CI95% 32.8 - 45.3; p = 0.0138) respectively. Main tumor immunohistochemical subtypes for EBC and the novo LA/MBC were: HER2+/HR- 11.3% and 15.3%, HER2+/HR+ 16.2% and 19.1%, HER2-/HR+ 41.2% and 51.1%, and Triple-negative 17.9% and 11.5%, respectively. At the end of the study follow-up (Dec 2013) 78.2% of the patients had died. Breakdown of the decaying percentage and OS for the entire study population, early-, and the novo diagnosed LA/MBC from the beginning of each line of treatment was: OS according to the type of diagnosisTreatment line1L2L3L4L5L6L7LWhole pulation Patients (%)95.370.253.538.424.215.19.5Whole pulation OS (months)32.622.616.613.513.312.48.5Early diag. LA/MBC OS (months))30.921.015.612.912.49.17.5The novo diag. LA/MBC OS (months)37.625.921.618.714.016.913.8 CONCLUSION: Our study's OS data supports the hypothesis that highly effective current neo/adjuvant treatment may cure most treatment-sensitive early tumors, allowing only those more aggressive to develop to LA/MBC, which then will fare worse than those of the novo metastatic diagnosis. Citation Format: Servitja S, Zamora P, Santaballa A, García J, de Paz L, Plata Y, Garau I, Florian J, Chacón I, de la Haba J, García P, San José B, Rodríguez-Villanueva J, Orcajo L, Martínez E, Segui MA. CASCADE study: Longer overall survival in the novo versus recidivant patients with locally advanced/metastatic breast cancer. [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 P5-08-43.

Abstract: Background: This study aims to compare patient characteristics and outcomes of everolimus (EVE) + endocrine therapy (ET) vs ET monotherapy among postmenopausal women with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (aBC) across multiple countries. Methods: This retrospective chart review included postmenopausal patients with HR+/HER2- aBC who were previously treated with a nonsteroidal aromatase inhibitor (NSAI) and later received EVE + ET, ET monotherapy, or chemotherapy (the index treatment) from 17 sites in 6 countries (Canada, the Netherlands, France, Italy, Russia, and Argentina). This is a subset analysis comparing patients who received EVE + ET vs ET monotherapy. Stratified sampling by index treatment and line of therapy was used to ensure the sample groups included different treatments and lines of therapy. Patient characteristics were compared using Wilcoxon rank-sum tests for continuous variables and Fisher exact tests for categorical variables. Progression-free survival (PFS) was estimated using Kaplan-Meier analysis and was compared between the 2 groups using Cox proportional hazards models adjusting for age, country, line of therapy, metastatic sites, symptoms, comorbidities, prior chemotherapy, recurrent vs de novo cancer, and time from the last adjuvant ET to aBC diagnosis. Results: A total of 119 patients in the EVE + ET group (77 in 1st/2nd, and 42 in 3rd/4th lines) and 102 patients in the ET monotherapy group (76 in 1st /2nd, and 26 in 3rd/4th lines) were included in the study. All but 2 patients in the EVE + ET group received EVE + exemestane; ET monotherapy included fulvestrant (46.1%), exemestane (21.6%), NSAIs (16.7%), and tamoxifen (14.7%). Patients in the EVE + ET group were numerically younger (median 63.0 vs 66.0 years; P = .10); appeared to have fewer comorbidities, particularly hypertension (11.8% vs 35.3%; P & lt; .01); had a higher proportion of visceral metastasis (43.7% vs 32.4%; P = .10) and a higher number of metastatic sites (median 2.0 vs 1.0; P = .14); had a lower proportion of bone/joint symptoms (30.3% vs 42.2%; P = .07); and had a shorter time from initiation of the last adjuvant ET to aBC diagnosis (median 43.1 vs 55.6 months; P = .05). In the unadjusted analysis, patients in the EVE + ET group had similar PFS as those in the ET monotherapy group (median 9.1 vs 9.2 months; unadjusted HR = 0.98; P = .90), but after adjustment for baseline characteristics, the hazard of progression or death of any cause was lower (adjusted HR = 0.67; P = .05). Conclusions: Patients who received EVE + ET tended to be younger with fewer comorbidities yet have disease with faster progression and a higher burden of metastases. After adjusting for these characteristics, EVE + ET was associated with longer PFS compared with ET monotherapy. Citation Format: Fernando Petracci, Jose Zarba, Andrea Michelotti, Lorenzo Livi, Cristian Villanueva, Roberto Bordonaro, Viktor Sherstnev, Rubén Kowalyszyn, Nina Marinsek, Zhou Zhou, Alexander Macalalad, Valerie Koo, Erich Trieschman, Jipan Xie, James Signorovitch, Barbara Ratto, Keiko Higuchi, Mahasti Saghatchian. Comparative effectiveness of everolimus + endocrine therapy vs endocrine monotherapy among postmenopausal women with HR+/HER2- advanced breast cancer: a multicountry retrospective chart review. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2269.

Abstract: Purpose: We aimed to maximize the performance of detecting genetic alterations in lung cancer using high-throughput sequencing for patient-derived xenografts (PDXs). Experimental Design: We undertook an integrated RNA and whole-exome sequencing of 14 PDXs. We focused on the genetic and functional analysis of β2-microglobulin (B2M), a component of the HLA class-I complex. Results: We identified alterations in genes involved in various functions, such as B2M involved in immunosurveillance. We extended the mutational analysis of B2M to about 230 lung cancers. Five percent of the lung cancers carried somatic mutations, most of which impaired the correct formation of the HLA-I complex. We also report that genes such as CALR, PDIA3, and TAP1, which are involved in the maturation of the HLA-I complex, are altered in lung cancer. By gene expression microarrays, we observed that restitution of B2M in lung cancer cells upregulated targets of IFNα/IFNγ. Furthermore, one third of the lung cancers lacked the HLA-I complex, which was associated with lower cytotoxic CD8+ lymphocyte infiltration. The levels of B2M and HLA-I proteins correlated with those of PD-L1. Finally, a deficiency in HLA-I complex and CD8+ infiltration tended to correlate with reduced survival of patients with lung cancer treated with anti-PD-1/anti-PD-L1. Conclusions: Here, we report recurrent inactivation of B2M in lung cancer. These observations, coupled with the mutations found at CALR, PDIA3, and TAP1, and the downregulation of the HLA-I complex, indicate that an abnormal immunosurveillance axis contributes to lung cancer development. Finally, our observations suggest that an impaired HLA-I complex affects the response to anti-PD-1/anti-PD-L1 therapies. Clin Cancer Res; 23(12); 3203–13. ©2016 AACR.

Abstract: Background Metastatic triple-negative breast cancer (mTNBC) exhibits a particularly poor clinical outcome, generally with rapid progression and worse overall survival (OS) than other BC subtypes. Among the few therapeutic options, chemotherapy-based combinations are associated with increased toxicity and limited survival benefit, being treatment with sequential single agents, such as paclitaxel considered an appropriate first-line regimen for the metastatic setting for PDL-1 negative patients. Herein, there is an urgent need for clinically active agents for the mTNBC. Adoptive cell transfer (ACT)-based immunotherapy using ex vivo activated and expanded tumor-infiltrating lymphocytes (TILs) has shown promising therapeutic outcomes in some patients with metastatic tumors. The identification, selection, and enrichment of tumor-reactive lymphocytes at the early stages of the ACT generation could enhance their clinical activity. Thus, the selection of reactive T cells, such as PD1-positive (PD1+) TILs, could improve the responses achieved in those settings. TILS001 trial aims to explore the safety, tolerability and efficacy of selected PD1+ T-cell infusion with a previous pre-selection of mRNA PD1-high expression in patients with mTNBC. Study design: TILs001 trial is an open-label, single-arm, multicenter phase I/II prospective study with a two-stage design evaluating treatment with PD1+ TILs infusion in advanced or mTNBC, defined as HER2 negative and Hormonal Receptor & lt; 10%. The study involves three different parts before PD1+TILs treatment. Tumor samples evaluable for PD1 mRNA expression and life expectancy ≥6 months are mandatory for part 1. Patients with high levels of PD1 mRNA, defined by the pre-specified cutoff, candidates for receiving a first-line taxane-based containing regimen and with at least 1 accessible target lesion to generate TILs are eligible for part 2. Finally, once the complete expansion of PD1+TILs is reached, patients will receive the non-myeloablative lymphodepleting chemotherapy regimen followed by PD1+TIL infusion and IL-2 treatment. Allogeneic hematopoietic stem cell transplantation, immune system-related disease or clinically active cerebral metastasis are not allowed. The primary objectives are to evaluate the safety and tolerability of the PD1+ TIL product, as per incidence of grade 3-5 adverse events (AE) or any grade AE that leads to treatment discontinuation and to assess the efficacy of ACT therapy with selected PD1+ TILs in mTNBC in terms of progression-free survival (PFS) at 6 months. The secondary endpoints are clinical benefit rate at 6 months (CBR6), overall response rate, duration of response (DoR), PFS and OS. Further translational research including immunophenotyping, TCR sequencing and mutational analysis will also be performed. The first 3 patients will be included in a safety run-in phase where safety will be evaluated 24h after PD1+/TILs infusion (before IL-2 treatment) and a phase II stage where efficacy will be evaluated, which will include up to 20 patients. Patients will be enrolled in 4 sites in Spain. Recruitment is expected to start by July 2022 and to be completed within 24 months. This study is financially supported by the Asociación Española Contra el Cáncer (GCAEC19010PRAT). NCT05451784 Citation Format: Nuria Chic, Eva Ciruelos, Cristina Saura, Europa-Azucena Gonzalez, Luís Álvarez-Vallina, Juan José Lasarte, Alena Gros, Lorea Villanueva, Jordi Canes, Laura Angelats, Aleix Prat, Tomás Pascual, Marta Santisteban, Manel Juan. Treatment of advanced or metastatic triple-negative breast cancer with adoptive therapy of PD1+ tumor-infiltrating lymphocytes (TILS001 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 OT2-10-04.

Abstract: INTRODUCTION Radiotherapy is an area of medicine that is little known by patients and that requires a long time for the doctor to be able to explain and resolve the doubts that arise in the first consultation, which may cause anxiety and low adherence to treatment recommendations. A mobile app called Canswer was developed to address this problem in a novel way to help patients learn about radiation oncology in their free time. OBJECTIVE Developed a mobile app that provides oncology radiotherapy information to patients. MATERIAL AND METHODS The patients who attended the consultation for the first time were provided with information and obtained verbal consent, later they were provided with the Canswer application on their mobile device, and at the end, a Likert-type perception survey was applied and the Cancer Treatment Survey (CATS), which analyzed the information needs of patients. Anxiety and depression were analyzed through the Hospital Anxiety and Depression Scale (HADS). RESULTS Of the total number of patients recruited, 17 patients from northeast Mexico with breast cancer agreed that the use of the application would be useful to them and were interested in receiving additional information after their first-time radiotherapy consultation from March to June 2022. Average age of respondents was 45 years. A total of 7 patients (41%) had doubts about radiotherapy after consultation. When analyzing their knowledge, only 1 patient identified that radiotherapy works by DNA damage, the rest had wrong information, 14 patients thought that this treatment works by heating the cells; 2 thought that radiation therapy causes cells to burst. 8 patients (47%) understood how teletherapy works and 5 how brachytherapy works (19%). A question was included about the best skin care during breast radiotherapy in which 76% correctly answered that the skin should be washed daily with water and neutral soap, but 24% answered that hydrating creams should be applied just before stepping into the machine. Regarding the duration of the consultation, a total of 10 patients (60%) thought it was too short. 47% felt the limited time of the consultation did not allow an adequate evaluation. 100% of the respondents were satisfied with the information provided about the type of treatment, its benefits, and adverse effects, however, 47% persisted with doubts at the end of the consultation. 47% of patients (n=8) had some level of anxiety with 29% mild, 11% moderate and 6% severe. Incidence of depression was 24% with 18% having mild form and 6% severe. Regarding the information provided by the doctor during the consultation, 8 patients (47%) would like their doctor to have told them more about anxiety and depression, 7 about sexuality concerns (41%), and 6 (35%) about alternative medicine. 79% of patients wanted to know more about the side effects the treatment might cause after their visit, and 71% reported wanting to know more about how to prevent side effects. 66% also reported that they would like more information about how the treatment feels when it begins. DISCUSSION AND CONCLUSION This analysis revealed that most patients have doubts about radiotherapy, even after the information provided in their first consultation. This may be multifactorial but a key factor may be work overload at radiotherapy centers and a consultation of short duration. This application seems to be an effective, easily accessible, free tool that provides the necessary information, even on topics that are difficult to explain in a standard consultation. Important aspects that the app needs to focus on in future updates include side effects and their management, sexuality, nutrition, depression, and alternative medicine. This application also revealed misconceptions that should be routinely addressed, such as skin care during treatment. Link to app: https://www.canswer.info/?page_id=393 Citation Format: Jose F. Muñoz Lozano, Diana Cristina Pérez Ibave, Estefania Abundis Marquez, Fernando Alcorta Nuñez, Celia B. Gonzalez Alcorta, Carlos Salazar Mejia, Maria Fernanda Noriega, Omar Zayas Villanueva, Victor Oyervides Juarez, Larisa M. Renteria Garcia, Adelina Alcorta Garza, Juan Francisco Gonzalez Guerrero, Valeria Luna, David Hernandez, Rafael Piñeiro Retif, Oscar Vidal Gutiérrez. EXPLORATORY ANALYSIS OF A MOBILE APP THAT ADDRESSES RADIOTHERAPY INFORMATIONAL NEEDS FOR BREAST CANCER PATIENTS [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 P1-08-03.

Abstract: The phosphoinositide-3-kinase (PI3K) signaling pathway is activated in a variety of solid and non-solid tumors. In many instances this is due to either activating mutations in the catalytic subunit of PI3Kα, p110α, or inactivating mutations or deletions of the tumor suppressor PTEN. In addition, the PI3K pathway is activated by mutations in certain receptor tyrosine kinases as well as by mutation of the oncogene KRAS. All of these lesions lead to enhanced activity of both PI3K and mTOR. Hence there is great interest to discover inhibitors of PI3K and mTOR for the treatment for cancer. Following a rational design strategy, we identified the fused thiadiazole derivative ETP-47187 as a potent dual inhibitor of PI3Kα and mTOR Kis = 0.18 nM and 1.2 nM, respectively. ETP-47187 also inhibits three oncogenc mutants of p110α: p110α E542K Ki = 0.38 nM, p110α E545K Ki = 0.2 nM and p110α H1047R Ki = 0.29 nM as well as PI3Kβ, PI3KΔ and PI3Kγ Kis 2.7, 0.26 and 1.5 nM, respectively. The compound inhibits PI3K signaling in treated tumor cell lines; the EC50 for inhibition of the phosphorylation of Akt was 5 nM. ETP-47187 has a pharmacokinetic profile suitable for oral dosing in mice (%F = 73%, Cl = 0.11 L/hr/kg; Vds = 0.38 L/h/kg). Treatment of tumor bearing mice with the compound causes a dose dependent reduction in P-Akt levels in the tumor. Once a day treatment of mice bearing human tumor xenografts with ETP-47187 results in significant tumor growth delay and is well tolerated. In a mouse model of lung cancer induced by expression of an oncogenic mutant KRAS, treatment with ETP-47187 blocked tumor growth and lead to a significant PET response. These and combination data will be discussed. We believe ETP-47187 and compounds like it are suitable to propose for clinical development in cancer patients with activated PI3K signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2011-627