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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

ImportancePreclinical data about the synergistic activity of radiotherapy (RT) and trabectedin have been reported. The combination of trabectedin and RT in treating myxoid liposarcomas appears worth exploring.ObjectiveTo explore the effectiveness and safety of trabectedin combined with RT.Design, Setting, and ParticipantsThis international, open-label, phase 2 nonrandomized clinical trial including 46 patients with myxoid liposarcoma was conducted in 4 centers in Spain, 1 in Italy, and 2 in France from July 1, 2016, to September 30, 2019. Eligible patients had to have a histologic, centrally reviewed diagnosis of localized resectable myxoid liposarcoma arising from an extremity or the trunk wall.InterventionsTrabectedin was administered at the recommended dose stemming from the phase 1 trial (1.5 mg/m2), with intravenous infusion during 24 hours every 21 days for a total of 3 cycles. Radiotherapy was started after completion of the first trabectedin infusion (cycle 1, day 2). Patients received 25 fractions of radiation for a total of 45 Gy. Surgery was planned 3 to 4 weeks after the administration of the last preoperative cycle and not until 4 weeks after the end of preoperative RT. Pathologic specimens were mapped in tumor sections to estimate the histologic changes and the percentage of viable tumor after neoadjuvant treatment.Main Outcomes and MeasuresThe primary objective of the phase 2 part of the study was overall response. Secondary objectives were effectiveness measured by relapse-free survival and activity measured by functional imaging and pathologic response.ResultsA total of 46 patients were enrolled. Four patients were not evaluable. The median age was 43 years (range, 18-77 years), and 31 patients were male (67%). Overall, 9 of 41 patients (22%) achieved a partial response with neoadjuvant treatment with trabectedin and RT, with 5 of 39 patients (13%) achieving a complete pathologic response and 20 of 39 patients (51%) having 10% or less of a viable remaining tumor. Partial responses according to Choi criteria were observed in 24 of 29 evaluable patients (83%), and no patient had disease progression. Treatment was well tolerated.Conclusions and RelevanceAlthough the primary end point of this phase 2 nonrandomized clinical trial was not met (Response Evaluation Criteria in Solid Tumors response in ≥70% of patients), results suggest this combination was well tolerated and effective in terms of pathologic response. Thus, trabectedin plus RT might be a treatment option regarding tolerability; further evidence should be generated in this setting.

Background: Pertuzumab (P) has been aproved in neoadjuvant setting for HER2 positive early breasta cancer patients in association with Trastuzumab (T) and chemotherapy. Diverse studies support this combination as NeoSphere, Tryphaena, GeparSepto or Berenice trial. Some of these studies combine P - T with taxanes and sequencing anthracyclines, and other use antraciclines-free regimen as Carboplatine-Docetaxel-P-T. The patologic complete response (pCR) showed achieve percentages from 45.8 % to 66.6% depending on chemotherapy combination. In Spain, the approval of new drugs is a national issue, but sometimes regional regulatory agencies could modify some indications. We have carry out this study in routine patients as our daily clinical practice. Aims: This is a retrospective and multicentric study that has investigated the clinical characteristics, treatment patterns, safety and clinical outcomes for patient with HER-2 positive early breast cancer patients. Methods: We have collected all HER2 positive early breast cancer patients treated with P in neoadjuvant setting in our hospitals. The effect of adding Pertuzumab on pCR was analyzed, as well as other predictive factors of response using logistic regression analyses. Results: A total of 298 patients met the selection criteria. The median age was 50 years (range 24-88 years), 54,2% were premenopausic. 4 patients were stage I, 194 patients stage II, 95 patients were stage III and one patient was stage IV. 76,3% of the patient had a ki67 >20%. The majority of the patient received anthracyclines and taxanes with P and T regimen (80,7%), 13,2% received carboplatin-docetaxel-P-T combination and only 6,1% received taxane-P-T. 292 patients were analysed for response. pCR was seen in 61,7 % of the patients, dividing by hormonal receptor (HR) status, pCR was 53,29% in HR-positive and 72,14% in HR-negative. 63,4% of the patients received breast conservative surgery. Grade 3-4 chemo-related toxicity was presented in 14,2% of patients, 3 patients presented cardiac toxicity. Different treatments patterns were seen between hospitals: only 15 patients (5,1%) complete adjuvant Pertuzumab, 4 patients (1,4%) received adjuvant Neratinib and 2 patients (0,7%) received adjuvant TDM1. Only 12 patients (4,1%) has presented a distant recurrence, 6 of them (50%) had achieved a previous pCR. Conclusion: In our knowledge, this is the biggest real-world-data presented until this year, for Pertuzumab in the neoadjuvant setting of HER2 positive breast cancer patients. Our results are consistent with those published in previous clinical trial. pCR by subtypepCR NOpCR YESTotalLuminal B HER2+7181152HER2+39101140Total110182292 Citation Format: Alejandro Falcón González, Rocío Álvarez Ambite, Elisenda Llabrés Valenti, Rocío Urbano Cubero, Maria del Carmen Álamo de la Gala, Antonia Martínez Guisado, Carlos José Rodríguez González, Marta Amérigo Góngora, Encarnación González Flores, Salvador Gámez Casado, María Valero Arbizu, Alicia Quilez Cutillas, Josefina Cruz Jurado, Pedro Sánchez Rovira, Fernando Henao Carrasco, Javier Salvador Bofill, Manuel Ruiz Borrego. Neopersur: Neoadjuvant pertuzumab in a real world data population in the south of Spain [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-29.

Objectives Imatinib is the first therapeutic option for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Previous studies have shown an improvement in patient survival rates following the use of imatinib. Nevertheless, adequate plasma concentrations of imatinib are necessary to achieve such improvement in survival and limit the toxicity of the drug. This study aims to analyse the influence of imatinib plasma concentrations on efficacy and safety in the treatment of gastrointestinal stromal tumour. Materials and methods This descriptive, multicentre study analysed plasma levels of imatinib in patients diagnosed with gastrointestinal stromal tumour in the period 2019–2020. An optimal therapeutic range of 750–1500 ng/mL was established for the patient stratification based on their minimum plasma concentrations measured at the steady state. Results This study included 11 patients with metastatic disease in total, among whom only 54.5% (n = 6) had a minimum plasma concentrations measured at the steady state value within the therapeutic range. A median progression-free survival of 7.0 months was recorded for those patients with minimum plasma concentrations measured at the steady state 750 ng/mL ( p = 0.005). The toxicity rate was 25% and 14.3% for patients with minimum plasma concentrations measured at the steady state > 1500 ng/mL and minimum plasma concentrations measured at the steady state ≤1500 ng/mL, respectively ( p = 0.66). Conclusions The present study aims to describe the correlation between the toxicity and effectiveness of imatinib as a function of minimum plasma concentrations measured at the steady state under routine clinical practice conditions. The results described here show the usefulness of imatinib plasma concentrations monitoring as part of the standard daily routine in our hospitals.

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon’s design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years, 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2–37.9). Four patients were on treatment &gt, 6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment &gt, 6 months.

11511 Background: CDK4/6 inhibitors showed a favorable progression-free survival (PFS) in DD LPS, a sarcoma bearing 12q 13-15 amplicon that implies CDK4 amplification. The median PFS was 4 and 7 months (m) for palbociclib and abemaciclib, respectively. Preclinical experiments in 10 sarcoma cell lines and 6 PDX models, including only one DD LPS, showed higher efficacy of anti-CDK4 in cases with high expression of CDK4 and low expression of p16. This rationale supported the design of a phase II trial exploring palbociclib in a wide range of sarcomas, excluding DD LPS. Methods: Progressing pretreated advanced soft tissue sarcoma, excluding DD LPS, or osteosarcoma adult patients (pts), whose tumors overexpressed CDK4 and underexpressed CDKN2A mRNA in a baseline mandatory biopsy, were enrolled. CDK4 and CDKN2A expression were assessed by qRT-PCR, using an external control as reference (Universal human reference RNA; Agilent Technologies). The primary endpoint was 6-m PFS rate. Minimax Simon’s two-stage with type 1 and 2 errors of 10%, and null and alternative hypothesis of H0 15%, H1 40%, 6-month PFS rates were specified. The study will warrant further investigation if 6 or more pts had a PFS > 6 m from 21 evaluable pts. Palbociclib was administered orally at 125 mg/ day 21 out of 28 days. Pre-screening intended to increase the probability of positive profile in the baseline biopsy. Results: A total of 214 pts with 236 CDK4/ CDKN2A determinations were assessed for enrolment; 141 for prescreening, in archive tumor sample, and 95 for screening, in a baseline biopsy. There were 38/141 (27%) and 28/95 (29%) pts with favorable mRNA profile from pre and screening, respectively. Twenty-two pts were enrolled with a median of previous systemic lines of 3 (1-5). There were 9 different sarcoma subtypes, including 2 osteosarcomas. With a median FU of 10 m (0.4-23.3), the median PFS was 4.2 m (95% CI 0.9-7.4), while the 6- and 12-m PFS rates were 30% (95% CI 9-51) and 18% (95% CI 12-48) respectively. From 19 evaluable pts (1 early death by COVID, 1 withdrew consent and for 1 it was too early to be assessed) 11 had stable disease (58%) and 8 progressed (42%) as the best response. Patients with CDK4 expression above the median value had significantly longer mPFS in the univariate analysis: 5.9 m (95% CI 1.4-10.4) vs 1.9 m (95% CI 0.6-3.2), p = 0.046; and longer OS: 15.5 m (95% CI 6.8-24.3) vs 10.6 m (95% CI 0-23.2), p = 0.047, respectively. The probability to find a positive profile in the screening was 29%, but this proportion increased up to 41% if in pre-screening had been positive. Conclusions: Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers. Clinical trial information: NCT03242382.

Among all Soft Tissue sarcomas there are some subtypes with low incidence and/or peculiar clinical behaviour, that need to be consider separately. Most of them are orphan diseases, whose biological characteristics imply a clearly different diagnostic and therapeutic approach from other more common sarcoma tumors. We present a brief and updated multidiciplinary review, focused on practical issues, aimed at helping clinicians in decision making. In this second part we review these subtypes: Alveolar Soft Part Sarcoma, Epithelioid Sarcoma, Clear Cell Sarcoma, Desmoplastic Small Round Cell Tumor, Rhabdoid Tumor, Phyllodes Tumor, Tenosynovial Giant Cell Tumors, Myoepithelial Tumor, Perivascular Epithelioid Cell Neoplasms (PEComas), Extraskeletal Myxoid Chondrosarcoma, NTRK-fusions Sarcomas. Most of them present their own radiological and histopathological feautures, that are essential to know in order to achieve early diagnosis. In some of them, molecular diagnosis is mandatory, not only in the diagnosis, but also to plan the treatment. On the other hand, and despite the low incidence, a great scientific research effort has been made to achieve new treatment opportunities for these patients even with approved indications. These include new treatments with targeted therapies and immunotherapy, which today represent possible therapeutic options. It is especially important to be attentive to new and potential avenues of research, and to promote the conduct of specific clinical trials for rare sarcomas.

The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI &gt, 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI &gt, 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky &lt, 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0–69), with 198 patients (55%) with a GMI &lt, 1, 41 (11.5%) with a GMI 1–1.33 and 118 (33.1%) with a GMI &gt, 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.

Background: Subcutaneous trastuzumab (T-SC) administration does not allow the historical target concentration of 20 µg/mL for efficacy to be reached, from the start of treatment in patients with a body mass index (BMI) >30 kg/m2. Objectives: To analyze the influence of the strategy of dosification (fixed vs adjusted patient’s body weight dose) on the initial minimum plasma concentration ( Cmin) of trastuzumab in obese patients. Methods: This was an observational, prospective study, which included patients with HER2-positive nonmetastatic breast cancer treated with trastuzumab. The determination of the Cmin of trastuzumab was performed on day +21 of the first cycle using the ELISA technique. Patients were stratified according to the strategy of dosification and BMI. Results: A total of 50 patients were included; 16 patients received the drug intravenously and 34 in a fixed dosage subcutaneous (T-SC) regimen. The proportion of patients who achieved an adequate plasma concentration since the beginning of treatment was significantly higher when the drug was administered intravenously (93.8% vs 67.6%, P = 0.042). These differences are especially greater in T-SC patients with BMI >30 kg/m2, with only 20% of patients exceeding the pharmacokinetic target. Conclusion and Relevance: Our study suggests that trastuzumab SC fixed dose of 600 mg is not equivalent to IV administration, especially in obese patients. An adequate trastuzumab exposure in this population needs patient weight–adjusted IV dosage in the first administration. The clinical relevance of these findings remains to be elucidated, and further research, including larger controlled trials, is warranted.

11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.

11511 Background: Pazopanib (P) was assessed prospectively in a phase 2 study in SFT resulting in a longer progression free survival (PFS) and overall survival (OS) compared to historical controls treated with chemotherapy. No statistical correlation was found between angiogenic factors and P in its pivotal phase III sarcoma trial. In the last two years, a soaring interest on the prognostic and predictive value of inflammatory indexes such as neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) is emerging in sarcomas. A retrospective analysis of inflammatory indexes of patients who entered the GEIS-32 (NCT02066285) trial was performed. In that trial advanced SFT patients were treated with P from front-line. Methods: All eligible patients who entered in the typical- and malignant-SFT cohort of the GEIS-32 trial were included in this analysis. To determine NLR and PLR, baseline values of platelets (10e9/L), neutrophils (10e9/L) and lymphocytes (10e9/L) were obtained from complete blood count tests. Additionally, RDW (standardized as 1 = upper value of normal range) values at baseline were also determined. The impact of NLR, PLR and RDW on OS, PFS and Choi response were analyzed by univariate and multivariate analysis. MAXSTAT was used to determine optimal cut-off points for overall survival. Metastasis free interval (MFI), mitotic count and ECOG were also analyzed, among others. Results: Sixty-seven out of 70 enrolled SFT patients, median age 63-y and 57% female, were considered for this analysis. The median follow-up from treatment initiation was 20.0 months. High standardized RDW value at baseline (cut-off 1.03) was significantly associated with worse OS [10.7 months (95% CI 3.8-17.5) vs 49.8 months (95% CI 9.4-90.2), p < 0.001] and worse PFS [8.8 months (95% CI 0.9-7.0) vs 9.8 months (7.4-12.3), p = 0.001]. High PLR (cut-off 242) significantly correlated with worse OS [10.7 months (95% CI 5.2-16.2) vs 49.8 months (95% CI 14.6-85.0), p < 0.001] and worse PFS [4.5 months (95% CI 2.0-7.0) vs 10.1 months (95% CI 6.3-13.9), p = 0.005], and high NLR (cut-off 3.78) was significantly associated with worse OS [11.7 months (95% CI 3.5-19.8) vs NA, p < 0.001] and worse PFS [4.5 months (95% CI 1.9-7.0) vs 10.8 months (95% CI 8.7-12.9), p = 0.010]. Independent variables in multivariate analysis were NLR, RDW, MFI and mitosis for PFS; while RDW and ECOG for OS (see table). Further, NLR and mitosis were independent factors for Choi progressive disease (as best response). Conclusions: High NLR and RDW values were independent biomarkers of worse outcome in advanced SFT patients treated with pazopanib.[Table: see text]

1054 Background: PIK3CA mutations, present in ̃40% of HR+, HER2– ABC, are associated with therapeutic resistance and shorter survival. Alpelisib (ALP) + fulvestrant (FUL) demonstrated efficacy in this population for which achieving long-term (LT) disease control is challenging. Here, we report on pts with HR+, PIK3CA-altered ABC who achieved LT disease control with ALP + FUL. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP (or placebo) + FUL in HR+, HER2– ABC that progressed on/after an aromatase inhibitor. CBYL719X2101 (X2101) was a phase 1, open-label study of escalating ALP doses ± FUL in advanced solid tumors that progressed on/after anti-estrogen therapy (ET) or relapsed after adjuvant anti-ET. A cut-off ≥ median (progression-free survival [PFS] + 2 SE) was chosen based on Kaplan-Meier curves from SOLAR-1 to define LT disease control as PFS (SOLAR-1) or time on treatment (X2101) ≥18 mo. Results: In SOLAR-1, 51 of 169 pts (30.2%) randomized to ALP + FUL achieved LT disease control with a median PFS of 33.5 mo (95% CI, 27.4 mo-not reached). Baseline characteristics of pts in SOLAR-1 are in the table below. In pts with LT disease control, adverse events (AEs) of special interest (combined preferred terms) of GI toxicity were observed in 47 pts (92.2%; grade ≥3: 11.8%, n=6), of hyperglycemia in 41 pts (80.4%; grade ≥3: 39.2%, n=20), and of rash in 28 pts (54.9%; grade ≥3: 19.6%, n=10). Median ALP relative dose intensity was 79.9% and 82.1% for pts with LT disease control (n=51) and the overall population (n=168), respectively. In X2101, 7 of 52 pts (13.5%) with ABC who received ALP+FUL achieved LT disease control up to 47.8 mo. Conclusions: In this subset of pts with hard-to-treat, endocrine-resistant disease, LT disease control ≥18 mo is meaningful considering median PFS of 4.6-9.3 mo or 9.5-16.4 mo with FUL alone or with cyclin-dependent kinase 4/6 inhibitors, respectively. Here, LT disease control was observed in 2 studies of HR+, PIK3CA-altered ABC, including in pts with poor prognosis, diabetes/pre-diabetes at baseline, and heavy pre-treatment. AE profile was consistent with prior reports and did not preclude LT disease control. Further work is needed to better understand factors influencing LT disease control. Clinical trial information: NCT01219699, NCT02437318 .[Table: see text]

11546 Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.

11514 Background: Myxoid liposarcoma (ML) exhibits especial sensitivity to trabectedin (T). In prospective series, T showed responses in 44% of patients (pts) with ML. ML is also sensitive to radiation therapy (RT) and preclinical data suggested radiosensitizing properties of T. Preoperative short-course of T with concurrent low-dose RT was conducted in a multicenter, European, phase I/II trial. We present here the data from the phase II part in pts with centralized diagnosis of locally advanced, resectable ML. Methods: Pts received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8Gy/fraction). The phase I part of the study had the classic 3+3 design. Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2) Results were already reported (EClincalMedicine 2019;9:35-43) and the dose selected for the phase 2 part was 1.5 mg/m2. RECIST responses were evaluated preoperatively at week 10. Surgical specimens were processed for histologic changes and residual tumor. Results: From July 2016 to September 2019, 47 pts (M/F 31/16) with median age 43y (18-77) and median tumor size 11 cm (3-25 cm), 20 low and 24 high grade (3 not available) were enrolled in the phase II part of the study. The major grade 3/4 toxicities were neutropenia (21.3%), ALT (14.9%), GGT (8.5%) and AST (8.5%) elevation. There were no deaths due to toxicity. 43/47 patients received the planned 3 pre-operative T cycles. All pts completed RT. 1 patient started RT before the first cycle of T and was excluded from the analysis. All pts were evaluable for response: 14 achieved PR (30%), 32 SD (70%). All pts underwent surgery (37 [86%] R0/ 5 [12%] R1/ 1 [2%] R2/ 3 not available). Median viable residual tumor was 10% (0-90) with 23/43 pts (53%) with ≤ 10% viable remaining tumor. Of them 6/43 (14%) had complete responses. At a median FU of 18 months (3-41) one pt developed local recurrence and 2 distant metastases. No deaths were observed. The corresponding 2-yr disease-free survival and overall survival were 97% (95% confidence interval 95-100) and 100%. Conclusions: T in combination with RT was feasible and well tolerated in the preoperative setting. The activity of the combination compares favorably with the administration of T/RT alone. This regimen could potentially become an alternative to anthracycline+ifosfamide concurrent to RT in high risk localized ML. Clinical trial information: NCT02275286 .

Background: Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients. Methods: Data from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated. Findings: Variation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0.42 (95%CI 0.32-0.52), 0.63 (95%CI 0.53-0.72), and 0.78 (95%CI 0.68-0.85), respectively. Patients in the intermediate (HR 0.51, P = 0.002) and high (HR 0.28, P < 0.001) pr-OS categories were at statistically significant lower risk of death compared with those in the low pr-OS category. Higher rate of Choi partial tumour responses were detected in intermediate pr-OS category. Tumour response according to Choi but not to RECIST criteria stratified patient survival of pr-OS categories, particularly for patients with intermediate to low pr-OS. Analyses conducted for 10-year inc-DM were consistent with results for pr-OS for prognostic value of Sarculator predictions and Choi tumour response. Interpretation: Sarculator identifies variations in outcomes of high-risk STS treated with perioperative chemotherapy and improve prognostic classification, which is also associated with different patterns of tumour response, an outcome that further stratifies survival particularly for patients predicted at higher risk. Future trials investigating neoadjuvant chemotherapy should consider prognostic tool for selecting patients to be enrolled. (C) 2018 Elsevier Ltd. All rights reserved.

Resumen Introduccion Los tumores estromales gastrointestinales (GIST) son los tumores mesenquimales mas frecuentes del tracto gastrointestinal. Han surgido numerosas publicaciones de GIST asociados con otras neoplasias. Objetivos El objetivo de este estudio fue investigar esta posible asociacion en una poblacion aislada geneticamente. Metodos Se realizo un estudio retrospectivo de pacientes con GIST en nuestro centro entre los anos 2002-2009. Se compararon datos epidemiologicos, patologicos y familiares de pacientes con GIST sin neoplasias asociadas (grupo A) frente a pacientes con GIST y neoplasias asociadas (grupo B). Se investigo un posible mecanismo genetico comun entre GIST y las neoplasias asociadas mediante la deteccion, en todos los tumores, por el marcador inmunohistoquimico CD117. Resultados Se hallaron 22 pacientes con GIST, 10 del grupo A (45%) y 12 del grupo B (55%). En el grupo B, el tumor asociado fue maligno en 6 pacientes (50%) y benigno en otros 6 (50%). De 22 pacientes con GIST, 8 (36%) presentaron antecedentes familiares de neoplasia maligna. De estos 8 pacientes, 7 eran (87,5%) del grupo B (p = 0,03) y en 3 (37,5%) coincidieron el tipo anatomopatologico de neoplasia padecida por el paciente y su familiar. No hubo GIST en ningun familiar. Todos los GIST mostraron positividad para el CD117, mientras que las neoplasias asociadas fueron negativas para este marcador. Conclusiones No se ha demostrado positividad inmunohistoquimica para CD117 en las neoplasias asociadas. Dadas las especiales caracteristicas de la poblacion a estudio, la relacion entre GIST y las neoplasias asociadas posiblemente sea casual.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management., Supported by Pfizer.

11067 Background: GEIS 30 was a phase II study showing moderate activity of pazopanib in well-differentiated/dedifferentiated LPS (cohort A:37 pts, Progression free Survival (PFS) at 12 weeks (w) 43.2%) and no activity in Myxoid/round cell LPS (cohort B: 15 pts, PFS at 12w 13.3%). The present study aims to identify tumor and plasma biomarkers that are differently expressed in long responders (LRs) PFS > 24 w. Methods: Serum samples and paraffin-blocks at diagnosis were collected for 28 pts in cohort A and 11 in B. A total of 13 pts were LRs. Serum samples were obtained at baseline, after 3 w of treatment and at progression. A panel of 15 cytokines and growth factors were evaluated using Luminex technology (Millipore). Paraffin-blocks were evaluated for microvessel density (MVD) by CD31 immunostaining and Image Pro-Plus 7.0 Image Analysis System (Media-Cybernetics). For RNA expression analysis, the Oncology Biomarker Panel with probes for 2559 transcripts was used (HTG Molecular Diagnostics). Results: Serum cytokines showed that expression of angiopoietin (AGO) and BMP9 decreases during treatment, whereas GCSF increases. In addition, AGO and BMP overexpression at baseline was associated with worse prognosis in arm A (p = 0.09) and B (p = 0.01) respectively. No differences between study arms and outcome were appreciated by MVD. Gene expression revealed differences in some immunomodulators: PDL-1 was correlated with serum cytokines VEGFD (p = 0.04) and LEPTIN (p = 0.02); and PD-1 with VEGFD (p = 0.04), LEPTIN (p = 0.02), VEGFA (p = 0.02) and ANGIO (p = 0.03). PD1, in addition,was overexpressed in LRs (p = 0.05). Interestingly, three groups were identified in cohort A according to gene expression: Cluster 1, characterized by short-responder patients with the shortest overall survival, whereas cluster 3 (40% LRs) and 2 (63.6% LRs) showed longer survival rates (14.3%, 45.5% and 30% respectively) (p = 0.001). Conclusions: Gene expression profiling unveils three WD/DD-LPS biotypes according to their response to pazopanib, which could be potentially used to select pts for treatment

2543 Background: High levels of myeloid-derived suppressor cells (MDSCs) seem a negative prognostic factor in advanced breast cancer (ABC) patients (pts). Preclinical studies suggest an immunomodulatory effect of some classical anti-tumor agents through alteration of MDSCs homeostasis. We analyzed the association of MDSCs and clinical evolution of ABC pts, taking into account the systemic treatment (tx) modulation of MDSCs levels in pts from two studies (“A”: GEICAM/2015-04 PANGEA-BREAST, NCT03025880 “Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC”, and “B”: PI-0502-2014 “Peripheral blood analyses of immune response induced by 1st line tx of ABC according to clinical guidelines”). Methods: MDSCs (CD33+ CD11b+) levels were determined by flow-cytometry in peripheral blood samples at three time points (basal, at cycles 3 and 6) from: 39 HER2-negative heavily pretreated pts from study “A”, 43 non-pretreated pts (all subtypes) from study “B” and 20 women from a healthy cohort (HC), with no cancer diagnosis. MDSCs levels from the different cohorts were compared and correlated with pts with Clinical Benefit (CB: partial/complete response + disease stabilization) vs pts with Progressive Disease (PD). Results: Tx response was assessed in 33 pts (85%) from study “A” and 39 pts (91%) from study “B”. CB was observed in 11 pts (28%) from study “A” and in 34 (79%) from study “B” while PD was observed in 22 pts (56%) from study “A” and in 5 (12%) from study “B”. Basal MDSCs levels were significantly higher in ABC pts (studies “A”+”B”) than in HC (15.95 vs 0.81 cells/µl, p = 0.009). At cycle 6, MDSCs were considerably lower in pts with CB vs DP (2.90 vs 13.75 cells/µl, p < 0.001). This decrease was more pronounced in study “B” than in study “A” pts (p < 0.001 vs p = 0.074, respectively), probably due to differences in number of events, tumor subtypes and tx between both studies. Conclusions: Our results suggest that ABC pts show alterations in MDSCs and that their decrease along tx may have a positive predictive value, highlighting the importance that immune-competent status may play in the evolution of ABC. MDSCs may represent a target for therapeutic purposes in ABC.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Numerous studies have reported the association between GIST and other neoplasms.The aim of this study was to investigate the possible association between GIST and other tumors in a genetically isolated population.A retrospective study was conducted of patients with GIST between 2002 and 2009 at our center. Epidemiological, pathological and family data in patients with GIST alone (group A) were compared with those in patients with GIST associated with other neoplasms (group B). A possible common genetic mechanism was investigated between GIST and associated malignancies by testing the detection of the immunohistochemical marker, CD117, in all tumors.Twenty-two patients with GIST were identified, 10 in group A (45%) and 12 in group B (55%). In group B, the associated tumor was malignant in 6 patients (50%) and benign in another 6 (50%). Of the 22 patients with GIST, 8 (36%) had a family history of malignancies. Of these 8 patients, 7 (87.5%) were in group B (p=0.03) and 3 (37.5%) showed the same pathological type of neoplasm as their relatives. All GIST were positive for CD117 whereas associated malignancies were negative for this marker.We did not find immunohistochemical positivity for CD117 in malignancies associated with GIST. Given the special characteristics of the study population, the association between GIST and associated malignancies may be incidental.

Introduccion El objetivo de neustro trabajo es analizar la seguridad, tolerabilidad, respuestas y supervivencia en pacientes con linfoma no Hodgkin agresivo administrando ciclofosfamida, doxorrubicina, vincristina y prednisona (CHOP) con intensificacion de dosis.

We detail time trends in the incidence of non-Hodgin’s lymphoma over the period 1980–1894 and analyze prognostic factors in a retrospective study. To that end, 587 patients were diagnosed of non-Hogdkin’s lymphoma from 1980 to 1994. Average annual incidence rate of non-Hodgkin’s lymphoma per 100,000 persons in our study has risen from 5.5 in 1981–1985 to 8.6 in 1991–1994. The incidence rate increased by almost 22% in males, and by 79% in females. In patients 75 years and older the incidence has increased 98%. The largest increases of incidence were observed in extranodal involvement (86%), stage IV (77%) and intermediate grade (53%). Prognostic factors for the overall survival in the multivariate analysis were: histology (p

El objetivo del estudio es el analisis de la supervivencia en el cancer colorrectal metastasico tras la cirugia de rescate. Entre 1991 y 1998 se diagnosticaron 498 pacientes con cancer colorrectal. En 10 pacientes se realizo cirugia de rescate de metastasis metacronicas hepaticas o pulmonares. Se analizaron las caracteristicas clinicas, el tratamiento realizado y la supervivencia. Siete fueron hombres y 3 mujeres con edades comprendidas entre 36–75 anos (mediana: 61 anos). La localizacion mas frecuente fue recto seguida de sigma. Solo 3 pacientes tenian afectacion ganglionar. La localizacion mas frecuente de las metastasis fue hepatica, seguida de pulmonar. El nUmero de metastasis fue 3 en un paciente, 2 en 3 pacientes y en el resto fue Unica. El tamano oscilo entre 2 y 6,5 cm. La mediana del intervalo libre de enfermedad hasta el diagnostico de la metastasis fue de 17 meses (rango: 8–48). El intervalo libre de enfermedad tras metastasectomia fue de 15,5 meses de mediana (rango: 3–72). La mediana del tiempo de seguimiento fue 47 meses (rango: 19–97). La cirugia de rescate de las metastasis hepaticas y pulmonares del cancer colorrectal puede ofrecerun aumento de la supervivencia en pacientes seleccionados. The aim of this research is the analysis of the survival after metastatic colorectal cancer resection. From 1991 to 1998 a total of 498 patients with colorectal cancer were diagnosed. This study reviewed 10 patients who underwent resection of both hepatic and pulmonary metastases from colorectal cancer. The clinical characteristics, the treatment and the survival were analysed. Seven of these patients were men and three women between 36–75 years old (median: 61 years). Rectum followed by sigma was the most frequent location. Only three patients presented nodal afection. The hepatic site was the most frequent, followed by the pulmonary. The number of metastases were three in one patient, two in three patients and one for the rest. The size varied between 2 and 6.5 cm. The median of the disease free interval after metastasectomy was 15.5 months (range: 3–72 months). The median follow-up was 47 months (range: 19–97). Resection of pulmonary and hepatic metastases in colorectal cancer can offer an increase of survival in selected patients.

Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Hormone treatment is one of the key strategies in the management of metastatic breast cancer. Aromatase inhibitors (AI) have been extensively studied in this setting. This section summarizes the key data regarding the use of AI in advanced breast cancer. In postmenopausal women, AI are the first line of treatment for untreated patients, or those who had prior AI treatment and progress after 12 months of adjuvant therapy. A longer disease-free interval and absence of visceral disease is associated with a better response. If tumors recur in less than 12 months, it is recommended that tamoxifen (TAM) or the estrogen-receptor antagonist fulvestrant (FUL) treatment be initiated. In the second-line setting, the best option after progression is the administration of either FUL or TAM. In the third-line setting, reintroduction of AI is considered an acceptable option. In premenopausal women who have not received prior treatment or who have progressed after 12 months following adjuvant treatment, it is recommended to initiate therapy with a combination of TAM and a luteinizing hormone-releasing hormone (LHRH) analog. If there is treatment failure with the use of this combination, megestrol acetate or an LHRH agonist plus an AI may be reasonable alternatives. Intensive research is ongoing to understand the mechanisms of resistance to hormone therapy. In human epidermal growth factor receptor 2 positive-patients, combinations with HER2 antagonists are associated with significant clinical activity.

2524 Background: The LEA study compares the combination of endocrine therapy plus bevacizumab (ET-B) against endocrine therapy (ET), as first line treatment in patients (pts) with advanced breast c...

10052 Background: High-dose ifosfamide (HDI) has shown promising activity as single agent in first-line chemotherapy for advanced soft tissue sarcoma (STS). The purpose of this study was to assess the activity and toxicity of a preoperative doxorubicin-free regimen of HDI given concurrently with radiotherapy (RT) and followed by surgery in patients (pts) with localized high-risk STS. Methods: Pts with localized > 5 cm grade 2-3 and deep STS of the extremities and trunk wall, ≤65 years, no prior chemotherapy and ECOG PS 0-1 were enrolled in this multicenter phase II study. Pts received 3 cycles of preoperative HDI at a dose of 12 gr/m2 by continuous infusion over 5 days every 3 weeks, with mesna and prophylactic GCSF support, and concomitant external beam RT to a total dose of 50 Gy, followed by surgical resection. Postoperatively, pts with pathological response received 2 cycles of HDI and those with positive surgical margins 16 Gy of RT. The primary study endpoint was pathologic response (≥ 95% pathologic necrosis). A Simon 2-stage design (response rate P0=15%, P1=35%, α=0.10, β=0.10) required at least 2 responses in the first 17 pts to expand to a second cohort, and 7/32 responses to be considered of positive. Results: From March 08 to December 10, 34 pts were included. Two pts were ineligible. Median age was 54 (18-65). Tumor location was extremity (28 pts) and trunk wall (4). Preoperative planned treatment was completed in 87.5% pts. HDI was completed in 87.5% pts while RT in 94% pts. Grade 3-4 toxicities included neutropenic fever (3 pts), anemia (4), asthenia (2), infection (2) and radiation dermatitis (2). 31 pts underwent surgery: 27 were R0 resections, of which 2 were amputations, and 4 were R1 resections. Pathologic response was ≥ 95% necrosis in 9 pts (28%) and 50%-94% necrosis in 12 pts. After a median follow-up of 21 months, estimated 2-year rates for disease-free survival and overall survival were 58% (95%CI, 40%-77%) and 77% (95%CI, 61%-93%), respectively. Conclusions: Preoperative treatment with HDI given concurrently with RT in pts with high-risk STS is feasible and safe, yielding promising pathologic response rates.

11038 Background: SFT is a ubiquitous uncommon soft tissue sarcoma with a pronounced hemangiopericytoma-like vascular pattern, exhibiting rich VEGF (tumor and endothelial cells) and VEGFR1/2 (endothelial cells) expression. Pathologists distinguish typical SFT (T-SFT) and malignant SFT (M-SFT) based on mitosis (≤4 vs > 4), pleomorphism or necrosis. Yet, not clear boundaries are always seen between both subtypes. We have recently published a phase II trial exploring the activity of pazopanib (P) in M-SFT (Lancet Oncol Dec 2018). Here, we present the outcome of the T-SFT cohort of the same trial. Methods: Most relevant inclusion criteria were: unresectable or metastatic, T-SFT (tumor tissue from diagnostic time) confirmed by central pathology review before accrual, with evidence of STAT6 overexpression (IHC and FISH and/or NGS), ≥18 years, ECOG 0-2, progressive, measurable disease and no previous antiangiogenic agents. Main endpoint was response rate according to Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously till progression or toxicity. Results: From June 2014 to December 2018, 34 patients were enrolled in this cohort. The median age was 64 y (31-81). At baseline, ECOG 0/1/2 was distributed as 16/15/3; whereas, locally advanced/metastatic distribution was 11 (32%) and 23 (68%) respectively. At the time of the present analysis, 24 patients were deemed eligible and evaluable for response. Response rates according to local and central assessment were PR 6 (25%), SD 15 (62%), PD 3 (12%) and PR 12 (50%), SD 11 (46%), PD 1 (4%). With a median follow-up of 21 months, the median PFS following local and central assessment were 18.4 (6.6-30.1) and 9.8 (7.5-12.2) months respectively, both were clearly superior to that previously published in M-SFT cohort (5.57 m). The median of OS was 49.8 months. High tumor burden at baseline > 116 mm, ECOG 1-2 vs 0, and PD by local or central response assessment showed significantly worse OS. Metastatic vs locally advanced patients had a similar outcome regarding OS. Conclusions: T-SFT cohort exhibited clearly longer PFS than previous reported M-SFT cohort to pazopanib treatment, and pazopanib showed to improve the historical outcome obtained with chemotherapy in advanced SFT. Clinical trial information: NCT02066285.