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Endometrial cancer (EC) is the second most common gynecological malignancy worldwide, the first in developed countries [Sung et al. in CA Cancer J Clin 71:209–249, 2021]. Although a majority is diagnosed at an early stage with a low risk of relapse, an important proportion of patients will relapse. Better knowledge of molecular abnormalities is crucial to identify high-risk groups in early stages as well as for recurrent or metastatic disease for whom adjuvant treatment must be personalized. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of EC, and to provide evidence-based recommendations for clinical practice.

Background: The presence of stromal tumor-infiltrating lymphocytes (TILs) represents an independent prognostic factor in HER2-positive early-stage breast cancer (EBC) treated with trastuzumab/pertuzumab-containing regimens. Among distinct subsets of TILs, conventional CD8+ αβ T cells require TCR signaling as a part of adaptive immunity, while γδ T cells display also innate-like activity via the NKG2D receptor contributing to a very rapid tumor immunosurveillance. Specific γδ T cell subsets were associated with remission and improved overall survival of patients with triple-negative breast cancer. However, very little is known about circulating αβ and γδ T cells and their immunological status in HER2-positive breast cancer. In this substudy, we aimed to characterize the αβ and γδ T cell subsets and the association with clinical outcome in peripheral blood of patients with HER2-positive EBC enrolled in the PHERGain trial, which assessed the possibility of chemotherapy de-escalation with neoadjuvant dual HER2 blockade with trastuzumab and pertuzumab using an 18F-fluorodeoxyglucose-PET and pathological response-adapted strategy. Methods: Peripheral blood was obtained from 24 consecutive patients who were assigned to the trastuzumab and pertuzumab group (+/- endocrine therapy as per hormone receptor status) before randomization (baseline) and after 2 treatment cycles (6 weeks). Blood samples were also collected from 48 age-matched healthy donors who represented the control group. Absolute numbers of CD3+, CD3+/CD4+, CD3+/CD8+, and CD3+/CD56+ according to the TCR expression, and annexin V apoptotic rate on αβ and γδ T cells were evaluated by flow cytometry. Subset distribution of T cell differentiation within naïve, central memory, effector memory, and terminally differentiated effector memory cells was also determined. The changes in the frequency of peripheral T cells and rate of apoptotic subsets between timepoints, patients, and healthy donors were compared with Wilcoxon test. The analyses were set at two-sided 0.05 level of significance. Results: Among 24 patients with evaluable blood samples at both timepoints, median age was 50.5 years (IQR 45.8-61), 45.8% had node-positive disease, 79.2% had hormone receptor-positive status, 79.2% had tumors with HER2 IHC 3+ status, and 54.2% achieved a pathological complete response (ypT0/is ypN0) after treatment. At baseline, levels of αβ and γδ T cells in EBC patients were significantly lower than levels in healthy subjects (P ≤0.05). After 6 weeks of study treatment, these levels in EBC patients did not significantly differ from those at baseline. Baseline rates of apoptotic subsets were higher in EBC patients than rates in healthy subjects (P Citation Format: Juan Carlos Andreu-Ballester, José Manuel Pérez-García, Begoña Bermejo, Vicente Carañana, Vega Iranzo, Joaquín Gavilà, Ana Santaballa, María Carmen Gómez-Soler, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes, Antonio Llombart-Cussac. Analysis of αβ and γδ circulating T cells in the PHERGain randomized phase 2 trial for patients with HER2-positive early breast cancer receiving neoadjuvant trastuzumab and pertuzumab without chemotherapy: LINGain [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 P5-13-30.

Background: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. Methods: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. Results: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1–6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2–11.6 months). Among 33 patients (median 5 [range, 1–9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1–3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. Conclusion Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.

Infertility is one of the main sequelae of cancer and its treatment in both children and adults of reproductive age. It is, therefore, essential that oncologists and haematologists provide adequate information about the risk of infertility and the possibilities for its preservation before starting treatment. Although many international clinical guidelines address this issue, this document is the first Spanish multidisciplinary guideline in paediatric and adult oncological patients. Experts from the Spanish Society of Medical Oncology, the Spanish Fertility Society, the Spanish Society of Haematology and Haemotherapy, the Spanish Society of Paediatric Haematology and Oncology and the Spanish Society of Radiation Oncology have collaborated to develop a multidisciplinary consensus.

Lurbinectedin; Neuroendocrine tumours; Small cell Lurbinectedina; Tumores neuroendocrinos; Célula pequeña Lurbinectedina; Tumors neuroendocrins; Cèl·lula petita Background Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. Patients and methods This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8–21.4%). Median DoR was 4.7 months (95% CI, 4.0–5.4 months), median PFS was 1.4 months (95% CI, 1.2–3.0 months) and median OS was 7.4 months (95% CI, 3.4–16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). Conclusions Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population.

Background: The addition of a cyclin-dependent kinase 4-6 inhibitor (CDK4/6i) to letrozole or fulvestrant significantly improves progression-free survival (PFS) and overall survival (OS) in HR[+]/HER2[-] MBC pts. At present, the optimal endocrine treatment (ET) after progression on a CDK4/6i remains unknown. However, preliminary findings revealed drivers of adaptive resistance more frequently related to ET than to CDK4/6i. BIOPER explored the efficacy and safety of continuing the same CDK4/6i in combination with a different ET agent beyond progression on prior P-based regimen in HR[+]/HER2[-] MBC and assessed predictive biomarkers to identify those pts who are more likely to benefit from this strategy. Methods: BIOPER (NCT03184090) is a multicenter, non-controlled, phase II trial. Eligible pts included pre- and post-menopausal women aged ≥18 years with HR[+]/HER2[-] MBC that showed a confirmed progressive disease (PD) after having achieved clinical benefit (response or stable disease ≥24 weeks) on immediately prior P plus ET-based regimen. Up to two prior ET lines and not more than one line of prior chemotherapy for MBC were allowed. Pts received P (oral, 75/100/125 mg/day 3 weeks on/1 week off) combined with ET of physician’s choice (including tamoxifen, exemestane, fulvestrant, anastrozole, or letrozole) until PD or unacceptable toxicity. Co-primary endpoints were clinical benefit rate (CBR) -in terms of complete or partial response [PR] and stable disease lasting ≥24 weeks as per RECIST 1.1 (H0: CBR≤5% versus H1: CBR≥20%)- and tumor molecular alterations in the cyclin D-CDK 4/6-retinoblastoma pathway detected at baseline as markers of resistance and sensitivity to P rechallenge. Secondary endpoints included investigator-assessed PFS, objective response rate (ORR), OS, and safety using the Common Terminology Criteria for Adverse Events (AEs) 4.03. Results: Between June 15, 2017 and April 25, 2019, a total of 33 pts from 21 centers in 2 countries were enrolled. Among the 33 pts who were included in the safety set, 1 patient who did not achieve clinical benefit on prior P-based regimen was excluded from the efficacy analysis (n=32). The median age was 59.5 years (range 42-80 years) and all pts were post-menopausal. A total of 25 (78.1%) pts had visceral disease (56.3% of whom with liver metastases), 16 (50%) had ECOG 0, and 19 (59.4%) presented ≥3 metastatic sites. Of 32 pts, 15 (46.9%) received letrozole, 14 (43.8%) received fulvestrant, and 3 (9.4%) exemestane. The median PFS for the prior P-based regimen was 13.8 months (mo) (95% confidence interval [CI] 5.6-47.1 mo). The median number of prior ET and chemotherapy lines for MBC was 2 (range 1-4). By the data cutoff date, 26 PFS events occurred, 5 pts were still on treatment, and 1 patient discontinued treatment because of investigator’s decision. The CBR was 34.4% (95% CI 18.6-53.2%) reaching the prespecified primary endpoint. The ORR was 3.1% (95% CI 0.1-16.2%) with 1 patient with PR. The median PFS was 2.6 mo (95% CI 1.8-5.5 mo). With a median follow-up of 11.8 mo, the OS data were immature with a total of 8 deaths (25%). The incidence of all grade (G) and G 3 or 4 (G3-4) AEs were 90.9% and 48.5%, respectively. The most common G3-4 AEs were neutropenia (42.4%) and leukopenia (6.1%). No discontinuations due to AEs and treatment-related deaths occurred. A comprehensive molecular tumor profiling will be presented during the symposium. Conclusions: Prolonging CDK4/6 blockade beyond progression on prior P-based treatment achieved the prespecified clinical benefit among pts with HR[+]/HER2[-] MBC. This strategy is currently being evaluated in the randomized phase II PALMIRA trial. Further research is ongoing to identify patient subgroups who could benefit from this treatment strategy. Citation Format: Antonio Llombart-Cussac, Javier Cortés, Beatriz Bellosillo Paricio, Miguel Gil Gil, Giuseppe Curigliano, José Manuel Pérez-García, Laura Comerma Blesa, Manuel Ruíz Borrego, Enrique Espinosa, Lourdes Calvo, Begoña Bermejo, Meritxell Bellet, Federico Rojo Todo, Juan de la Haba, Vanesa Quiroga, Alessandro Minisini, Ana Santaballa, Miguel Sampayo, Andrea Malfettone, Joan Albanell. A phase II proof-of-concept study of palbociclib (P) rechallenge in patients (pts) with hormone receptor (HR)[+]/HER2[-] metastatic breast cancer (MBC) and clinical benefit to prior P-based treatment (BIOPER) [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 PS10-27.

BACKGROUND The appearance of secondary hypertension (HTN) is one of the most common side effects of anti-angiogenic agents since it emerges in over 50% of the patients with these therapies. Independently of tumor type, in most clinical trials it was possible to observe a positive association between secondary HTN and better clinical outcome, including Progression Free Survival (PFS) and Overall Survival (OS). Preeclampsia is one of the biological models that better resembles the anti-VEGF/VEGFR action of these therapies. DNA methylation is one of the epigenetic mechanisms potentially related to variation in susceptibility to gestational HTN. The objective of our study is to define a specific epigenetic signature that could predict secondary HTN to anti-angiogenic treatment in patients that received bevacizumab in combination with chemotherapy (CT) from the BRECOL study. METHODS Patients (n=113) from BRECOL study (NCT01733628) received bevacizumab in combination with oxaliplatin or irinotecan + fluoropyrimidines for metastatic colorectal cancer (n=49), and with paclitaxel or capecitabine for metastatic breast cancer (n=64). Blood pressure (BP) was recorded with a Holter measurement (24 hours registration starting 2 hours after treatment administration). A methylation analysis was carried out on DNA obtained from pretreatment peripheral blood samples in 32 patients (28%) distributed in 4 experimental groups (8 patients / each) and classified according to their HTN history and to their BP variation upon bevacizumab plus CT: • Group A: patients with HTN history and with BP increase • Group B: patients with HTN history and with no BP increase • Group C: patients without HTN history and with BP increase • Group D: patients without HTN history and with no BP increase Analysis was realized with the “Infinium Human Methylation EPIC BeadChip” array (Illumina®) on bisulfite-converted DNA and differentially methylated sites were identified with the LIMMA (“Linear Models for Microarray Analysis”) bioinformatics tool (Bioconductor®). RESULTS Upon analysis of 850000 different methylation sites distributed all over the genome, we identified 27 (18 localized in the coding regions of the genes: FMNL2, METTL3, ACOT6, SCARNA20, PREX1, DNAI2, RAET1G, KCNJ8, GDF7, SYNPO2, CUGBP1, FRMD8, MKL2, HIF1A, TMEM177, UTP23, PXK and TNPO1; 9 localized in intergenic regions) that are differentially methylated in patients that showed secondary HTN to bevacizumab plus CT, independently of HTN history (Groups A + C vs. B + D). Based on Principal Components (PC) analysis, we defined a methylation score predictive of elevated BP. First PC (PC1) explains the 83.2% of the variability of the 27 identified methylation sites and allows to distinguish between patients that do and do not show secondary HTN. CONCLUSIONS High BP upon anti-angiogenic treatment is associated to specific DNA methylation profiles. We identified an epigenetic methylation signature putative predictive of secondary HTN to bevacizumab treatment in metastatic breast and colorectal cancer. Citation Format: Juan de la Haba, Teresa Morales-Ruiz, Pilar García-Alfonso, Jose Ponce Lorenzo, Lourdes Calvo, Antonio Antón, Raul Marquez, Pedro Sánchez-Rovira, Ana Santaballa, Eva Ciruelos, María Victoria García-Ortiz, Teresa Roldán-Arjona, Jesús Herranz, Massimo Chiesa, Rosalía Caballero, Javier Gallego, Álvaro Rodríguez-Lescure. Identification of a specific epigenetic signature in patients showing secondary hypertension upon anti-VEGF treatment from the GEICAM/2011-04 (BRECOL) study [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 P4-10-28.

Hormone receptor; Advanced breast cancer Càncer de mama avançat; Receptor hormonal Cáncer de mama avanzado; Receptor hormonal Purpose: To assess the efficacy and exploratory biomarkers of continuing palbociclib plus endocrine therapy (ET) beyond progression on prior palbociclib-based regimen in patients with hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer (ABC). Patients and Methods: The multicenter, open-label, phase II BioPER trial included women who had experienced a progressive disease (PD) after having achieved clinical benefit on the immediately prior palbociclib plus ET regimen. Palbociclib (125 mg, 100 mg, or 75 mg daily orally for 3 weeks and 1 week off as per prior palbociclib-based regimen) plus ET of physician's choice were administered in 4-week cycles until PD or unacceptable toxicity. Coprimary endpoints were clinical benefit rate (CBR) and percentage of tumors with baseline loss of retinoblastoma (Rb) protein expression. Additional endpoints included safety and biomarker analysis. Results: Among 33 patients enrolled, CBR was 34.4% [95% confidence interval (CI), 18.6–53.2; P < 0.001] and 13.0% of tumors (95% CI, 5.2–27.5) showed loss of Rb protein expression, meeting both coprimary endpoints. Median progression-free survival was 2.6 months (95% CI, 1.8–6.7). No new safety signals were reported. A signature that included baseline mediators of therapeutic resistance to palbociclib and ET (low Rb score, high cyclin E1 score, ESR1 mutation) was independently associated with shorter median progression-free survival (HR, 22.0; 95% CI, 1.71–282.9; P = 0.018). Conclusions: Maintaining palbociclib after progression on prior palbociclib-based regimen seems to be a reasonable, investigational approach for selected patients. A composite biomarker signature predicts a subset of patients who may not derive a greater benefit from palbociclib rechallenge, warranting further validation in larger randomized controlled trials. This work was supported by Pfizer. The authors would like to thank the patients, their caregivers, and their families for participating in this study and all investigators and site personnel. The BioPER study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with Pfizer Inc., which funded the study and provided palbociclib. J. Albanell acknowledges CIBERONC CB16/12/00241, PI21/00002, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, Generalitat de Catalunya (2017 SGR 507).

BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT).

BACKGROUND: The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. PATIENTS AND METHODS: In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. RESULTS: In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36-0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37-0.64, P = 0.001). The most frequent grade 3-4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3-4 adverse event was fatigue (4.3% vs. 0%). CONCLUSIONS: Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients.

Simple Summary Left ventricular dysfunction (LVD) induced by anthracycline-based cancer chemotherapy (ACC) is becoming an urgent healthcare concern. Myocardial fibrosis (MF) may contribute to LVD after ACC. We show that elevated circulating levels of procollagen type I C-terminal propeptide (PICP, biomarker of MF) are associated with early subclinical LVD and predict later development of cardiotoxicity in patients treated with ACC. In addition, an association between PICP and LVD in patients with ACC-induced heart failure is observed. These results provide novel insights into MF as a mechanism underlying LVD after ACC, with PICP emerging as a promising tool to monitor cardiotoxicity in patients treated with ACC. Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio >= 2.95 per doubling PICP, p

Introduction An increase in the number of cancer cases is expected in the near future. Breast cancer (BC) mortality rates increase with age even when adjusted for other variables. Here we analyzed BC disease-free survival (BCDFS) and BC specific survival (BCSS) in the El Alamo III BC registry of GEICAM Spanish Breast Cancer Group. Materials and methods El Alamo III is a retrospective registry of BC patients diagnosed between 1998 and 2001. Patients with stage I-III invasive BC of age groups 55-64 years (y), 70-74 years and >= 75 years were included. Patients and tumors characteristics, treatments and recurrences and deaths were analyzed. Results 4343 patients were included within the following age intervals: 2288 (55-64 years), 960 (70-74 years), and 1095 (>= 75 years). Older patients (>= 70 years) were diagnosed with more advanced tumors (stage III) than younger patients (21.5% versus 13.4%, p < 0.0001). Mastectomies were performed more on older patients and they received less chemotherapy than younger patients (66.6% versus 43.1%, p < 0.00001 and 30.8% versus 71.6%, p < 0.0001, respectively). With a median follow-up of 5.9 years, 17.7% patients had BCDFS events in the younger group and 19.8% in the older group (p < 0.0001). A decrease in BCSS was also observed in older patients, either when analyzing patients >= 70y (p < 0.0001) and when differentiating by the two older groups (p < 0.0001). Conclusions Our study suggests that older BC patients have worse outcomes what can be a consequence of receiving inadequate adjuvant treatments. Specific trials for these patients are warranted to allow us to treat them with the same scientific rigor than younger patients.

BACKGROUND Despite the recent advances in triple negative breast cancer (TNBC) stratification, TNBC is still a highly heterogeneous subtype that clusters distinct molecular and genetic alterations with diverse responses to neoadjuvant chemotherapy (NAC). Molecular profiling after NAC has unraveled a group of actionable targets in residual TNBC that supports the implementation of targeted therapies in a personalized manner. However, unresponsive or poor NAC responders after first line treatment are committed to poorer outcome. Therefore, early identification of poor NAC responders is essential to select patients that may benefit from alternative therapies, including initial tumor resection before chemotherapy. MATERIAL AND METHODS We have conducted a study on 37 non-metastatic TNBC patients at La Fe Hospital that were homogeneously treated with anthracycline and cyclophosphamide followed by paclitaxel. Tissue and blood-derived biopsies were obtained at diagnosis. Metabolites and miRNA exosomes in plasma were analyzed by ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometric and by miRNA 3.0 arrays (Affymetrix) respectively. Immunosuppressive subpopulations of cells were quantified by flow cytometry with specific markers. IDO1 in situ expression was assessed by immunohistochemistry on the tissue biopsies. RESULTS In order to identify blood-derived liquid biopsy NAC predictor biomarkers in TNBC we have studied blood circulating cells and molecules known for their immunomodulation capacity and found that eMDSC and a profile of tryptophan-derived metabolites predict NAC response. In addition, we identified a circulating exosome miRNA profile that identifies poor NAC responders. Interestingly, this profile of miRNAs target pathways involved in the immune response. IDO1 expression in the tumor inversely correlated with circulating tryptophan levels and directly associated with eMDSC. We also observed a trend correlating IDO1 expression levels with poorer response. CONCLUSIONS Our results strongly support the role of immunosuppression in TNBC poor responders and establish an easy and non-invasive tool for the early identification of poor NAC responders, opening the possibility to use alternative strategies. Acknowledgements: The authors would like to thank the Cytomics Unit, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain for its technical support. This work was partially financed with FEDER funds (CIBERONC (CB16/ 12/00284)) and AMACMA breast cancer association. Citation Format: Salvador-Coloma C, Font De Mora J, Cordón L, Palomar L, Santaballa A. Immunosuppressive profiles in liquid biopsy predict response to neoadjuvant chemotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-16.

Background There is limited evidence for the benefit of olaparib in platinum-resistant ovarian cancer (PROC) patients with BRCA wild-type tumors. This study investigated whether this combination of a DNA-damaging chemotherapy plus olaparib is effective in PROC regardless BRCA status. Patients and methods Patients with high-grade serous or endometrioid ovarian carcinoma and one previous PROC recurrence were enrolled regardless of BRCA status. Patients with ≤4 previous lines (up to 5 in BRCA-mut) with at least one previous platinum-sensitive relapse were included; primary PROC was allowed only in case of BRCA-mut. Patients initially received six cycles of olaparib 300 mg b.i.d. (biduum) + intravenous pegylated liposomal doxorubicin (PLD) 40 mg/m2 (PLD40) every 28 days, followed by maintenance with olaparib 300 mg b.i.d. until progression or toxicity. The PLD dose was reduced to 30 mg/m2 (PLD30) due to toxicity. The primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS) by RECIST version 1.1. A proportion of 40% 6m-PFS or more was considered of clinical interest. Results From 2017 to 2020, 31 PROC patients were included. BRCA mutations were present in 16%. The median of previous lines was 2 (range 1-5). The overall disease control rate was 77% (partial response rate of 29% and stable disease rate of 48%). After a median follow-up of 10 months, the 6m-PFS and median PFS were 47% and 5.8 months, respectively. Grade ≥3 treatment-related adverse events occurred in 74% of patients, with neutropenia/anemia being the most frequent. With PLD30 serious AEs were less frequent than with PLD40 (21% versus 47%, respectively); moreover, PLD30 was associated with less PLD delays (32% versus 38%) and reductions (16% versus 22%). Conclusions The PLD–olaparib combination has shown significant activity in PROC regardless of BRCA status. PLD at 30 mg/m2 is better tolerated in the combination., Highlights • Olaparib with PLD is effective in PROC. • The combination achieved a 6m-PFS of 46.6%, above the pre-established futility threshold of 40%. • The olaparib–PLD combination reached efficacy independent of BRCA mutation status. • Olaparib 300 mg b.i.d. and PLD 30 mg/m2 were safely administered with a good toxicity profile.

e17598 Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients’ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/ 2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ≥3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure. [Table: see text]

e17562 Background: Rucaparib is a PARP inhibitor approved for the treatment of high-grade ovarian cancer (HGOC). Clinical trials have demonstrated its benefit both as maintenance therapy (MTN) for platinum (Pt)-sensitive recurrent HGOC, and as treatment (Tx) in BRCA-mutated relapsed or recurrent HGOC patients. Here we analyze real-world data from the rucaparib early access program (RAP) in Spain with focus in the long-term responder patients (LTR). Methods: A retrospective observational study was performed by GEICO at 22 hospitals in Spain that had treated patients within the RAP. Adult women with HGOC, fallopian tube, or primary peritoneal cancer were included and received rucaparib (600 mg BID) in the MTN, Tx Pt-sensitive or Tx Pt-resistant setting. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. In this analysis, long-term response was defined as progression-free survival (PFS) ≥12 months for the MTN group and ≥6 months for the Tx group. LTR were stratified based on the rucaparib indication (MTN/Tx). Results: Between July 2020 and February 2021, 51 patients were recruited: 18 received rucaparib as MTN and 33 as Tx. In the MTN group, 6 patients (33.3%) were LTR, with a median age of 65 years (54-79). Of them, 2 patients (33.2%) harbored BRCA or RAD51C mutations. The median number of prior lines was 3 (2-6), being ≥5 in 33.2%, and 50.0% received prior bevacizumab. ECOG PS was ≤1 in all these patients, 66.6% had measurable disease and 50.0% achieved a partial response to prior Pt-based chemotherapy. In the Tx group, 10 patients (30.3%) were LTR, with a median age of 71 years (47-86). All of them harbored BRCA and/or RAD51C mutations. The median number of prior lines was 6 (2-9), with 60.0% receiving ≥5 prior lines, and 50.0% received prior bevacizumab. Regarding Pt-status, 40.0% of patients were Pt-sensitive and 60.0% were Pt-resistant. The ECOG PS was ≥1 in 30.0% of patients and 60.0% had measurable disease. The median PFS of LTR was not achieved in the MTN group and was 10.9 months (95% CI: 7.0-16.7) in the Tx group. Adverse events (AE) of any grade were reported in 66.6% of LTR within the MTN group and in 100.0% within the Tx group, while AE of grade ≥3 occurred in 16.6% and 50.0%, respectively. Rucaparib dose was reduced in 50.0% of LTR in the MTN group and 80.0% in the Tx group. Discontinuation rate due to rucaparib toxicity was 20.0% in the Tx group and there were no discontinuations due to toxicity in the MTN group. No new safety signals were detected. At present, 3 and 1 patients are still receiving rucaparib as MTN and Tx, respectively. Conclusions: A durable response was achieved in a notable proportion of patients, even despite their unfavorable conditions at treatment initiation (heavily pre-treated patients, partial response or resistance to Pt, or high volume of disease). The safety profile of rucaparib in this real-world setting is consistent with that reported in clinical trials.

5558 Background: In the Phase IIIb OReO/ENGOT Ov-38 trial (NCT03106987), maintenance olaparib (O) rechallenge significantly improved progression-free survival (PFS) vs placebo in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) regardless of their BRCA status (Pujade-Lauraine, ESMO 2021). The impact of prognostic factors on this PFS benefit were unknown. Methods: Pts had PSROC, one prior line of PARP inhibitor (PARPi) maintenance and were in response to platinum-based chemotherapy (Cx). Pts were enrolled into two cohorts – BRCA mutated (BRCAm) and non-BRCAm – and randomized to receive maintenance O (300 mg bid) or placebo. Primary endpoint was PFS. Post-hoc individual patient data meta-analysis was used to combine both cohorts using fixed and random effect models, interaction, and stratified tests in the Cox model. Stepwise Cox multivariate model for PFS and logistic regression models were used for late relapse, defined as disease progression occurring >24 weeks after randomization. Randomization stratification criteria and cohort effect were included in all models. Results: This study included 220 pts from the BRCAm (n=112) and non-BRCAm (n=108) cohorts recruited between October 3, 2017 and February 10, 2021. No heterogeneity was detected between cohorts: Cochran’s Q test P=0.53 (fixed and random); interaction test P=0.63. The O effect was consistent, and no significant interactions were observed between subgroups. In the multivariate PFS analyses, the main independent factors for prognosis were CA-125 level, visceral disease (liver, lung, pleura, brain), and treatment arm. These factors were independent predictive factors for late relapse among the 181 evaluable pts with the opportunity of at least 6 months of follow-up (Table). Conclusions: In the OReO/ENGOT Ov-38 trial, CA-125 level and presence of visceral disease at baseline were the best predictors of patient outcome. Maintenance olaparib rechallenge was effective overall regardless of prognostic subgroup. Clinical trial information: NCT03106987. [Table: see text]

Background Women represent an increasing proportion of the oncology workforce; however, globally this does not translate into leadership roles, reflecting disparities in career opportunities between men and women. The Spanish Society of Medical Oncology (SEOM) undertook a survey to investigate gender disparity in the Spanish oncology context. Design An online survey was made available to SEOM medical oncologists between February and May 2019. It included demographics, professional context and achievements, parenthood and family conciliation issues, workplace gender bias, and approaches to address disparities. Results Of the 316 eligible respondents, 71.5% were women, 59.5% were aged 45 or younger, and 66.1% had children. Among women, 12.4% were division or unit heads, compared with 45.5% of men, with most women (74.3%) being attending medical oncologists, compared with 45.5% of men. More males were professors (34.4% versus 14.2% of females), had a PhD (46.7% versus 28.8%), and/or had led clinical research groups (41.1% versus 9.7%). Spending time overseas after completing a residency was also more common for men than women (34.4% versus 20.4%). Professional satisfaction was similar between genders, driven primarily by patient care and intellectual stimulation. More women (40.7%) considered parenthood to have a strong negative impact on their career, compared with men (9.0%). Main perceived barriers to gender equality included a lack of work–life balance (72.6% women, 44.4% men), bias of peers and superiors (50.0% women, 18.9% men), and different career goals (41.2% women, 24.4% men). Preferred solutions included educational programs and scholarships (52.9%), communication and leadership training (35.8%), childcare at conferences (33.2%), and postmaternity return-to-work incentives (32.0%). Conclusion There is a clear paucity of equal opportunities for female oncologists in Spain. This can be addressed by encouraging professional development and merit recognition particularly for younger female oncologists, and empowering women to be involved in management and leadership of institutions and professional societies., Highlights • Under-representation of women in leadership roles in oncology is a widely acknowledged issue receiving global attention. • This study is a national description of leadership and educational opportunities in terms of gender and family circumstances. • Perceptions of gender bias in the workplace gender inequality or family conciliation issues and are described. • Initiatives for equal opportunities in oncology are needed supporting female academic career development and recognition.

Background: Triple-negative breast cancer (TNBC) is characterised by high pathological complete response to neoadjuvant chemotherapy (NAC). However, refractory and poor NAC responders still face very poor outcome, emphasising the urgent need for tools that facilitate identification of these patients, so that surgery or alternatives to NAC are considered early in the treatment protocol. Materials and methods: We combined metabolomics, exosome circulating miRNAs and flow cytometry experimental approaches in TNBC patients at diagnosis with immunohistochemistry in needle biopsy tumours to generate NAC-response predictive models. We also co-cultured and studied crosstalk between isolated patient-derived early myeloid-derived suppressor cells (eMDSCs) and TNBC cancer cell lines. Results: Blood-derived liquid biopsy biomarkers display a novel immunosuppressive profile of tryptophan-derived metabolites and eMDSC levels that significantly predict NAC response. Notably, indoleamine 2,3-dioxygenase 1 (IDO1) expression in tumour cells inversely correlated with circulating tryptophan levels but directly correlated with the level of eMDSCs. In addition, a set of circulating exosome miRNAs that target pathways of immune maturation also predicted poor NAC response prior to chemotherapy. Interestingly, expression of IDO1 increased when TNBC cell lines were co-cultured with patient-derived eMDSCs and this, in turn, promoted proliferation of eMDSCs. Conclusion: Our findings demonstrate that the suppressive pathways of the immune system play a key role in modulating the NAC response in TNBC. We identify a crosstalk mechanism between tumour cells and eMDSCs that exacerbates immunosuppression. These results provide a potential new tool to identify poor NAC responders for alternative strategies of treatment, including early surgical resection of the tumour, and to explore in them alternative immune therapies. (C) 2020 The Authors. Published by Elsevier Ltd.

Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. This was a retrospective analysis of 1246 patients with lymph node-positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08–1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico-pathological factors. However, dNLR ≥ 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2-enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer. EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7–11, 2016, Copenhagen, Denmark (oral presentation).

Background Retrospective data suggest better outcomes for patients with double hormonal receptor (oestrogen [ER] and progesterone receptor [PgR])–positive (dHR+) early breast cancer, compared with single hormonal receptor–positive, sHR+, (ER+/PgR– or ER–/PgR+) disease. Here, we evaluate the classification according to intrinsic subtypes and clinical outcomes of sHR+ versus dHR+ in HER2-negative breast cancer patients enrolled in GEICAM/9906 study ( NCT00129922 ). Methods Archival tumours were retrieved retrospectively for the analysis of ER, PgR and HER2 status and classified into intrinsic subtypes using the PAM50 gene expression assay. Disease-free survival (DFS) and overall survival (OS) were explored using a Cox proportional hazard analysis. Results Data on intrinsic subtypes were available in 571 (50%) patients with ER+ and/or PR+, and HER2-negative primary tumours. The incidence of luminal A and luminal B subtypes were 52%/36% in dHR+ tumours (ER+/PgR+), and 15%/58% in ER+/PgR–tumours. ER–/PgR+ tumours were mainly luminal A (52%). Compared with ER+/PgR+ patients, DFS was similar in ER–/PgR+ (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.57–2.34, p = 0.70) but worse in ER+/PgR– patients (HR 1.60, 95% CI 1.12–2.28, p Conclusions The ER+/PgR– group is characterised by higher proliferation and worse outcomes. In spite of the ER–/PgR+ subgroup resembles ER+/PgR+ disease in terms of molecular subtypes and outcomes, the small number of patients in this subgroup prevents from drawing any conclusions. Trial registration EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). Clinicaltrials.gov Identifier NCT00129922 (retrospectively registered 10/08/2005).

Cyclin-dependent kinases (CDKs) play a key role in cell cycle regulation, which makes them a clear therapeutic target to interfere with cell division and proliferation in cancer patients. Palbociclib, a specific inhibitor of CDK4/6 with outstanding clinical efficacy data and limited toxicity, has been recently approved for the treatment of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy. This review describes the mechanism of action, preclinical experiences and clinical data of palbociclib, with a special focus on integrating this data with the positioning of palbociclib in the current clinical guidelines for advanced HR-positive/HER2-negative breast cancer. Aspects of the ongoing major studies are also presented, as well as future prospects in the development of palbociclib.

BACKGROUND The incidence of cardiotoxicity in patients receiving treatment for breast cancer is unknown. There is not enough evidence about early detection and appropriate management of cardiotoxicity. The aim of this study is to identify early markers of risk of cardiac toxicity. MATERIAL AND METHOD Prospective study was conducted between 2014 and 2017 based on a cohort of 97 patients diagnosed with breast cancer treated with chemotherapy. Analytical biomarkers (natriuretic peptide, ultra-sensitive T troponin), echocardiogram parameters (left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS)) and electrocardiogram were performed. Analytical biomarkers were measured each chemotherapy cycle and cardiology test were performed before starting chemotherapy, 3 months afterwards, and then every six months during 5 years. Cardiotoxicity was defined as a reduction in basal LVEF >10% with LVEF5% with LVEF RESULTS Patients characteristics are shown in table 1 Patients characteristicsVariablesNo cardiotoxicity (n=88)Cardiotoxicity (n=12)Gender (women/men)88/012/0Median age (range)53 years (29-79)47 years (37-70)Smoker (former smoker)13 (3)2 (2)Arterial hypertension202Dyslipemia160Diabetes62Previous chemotherapy11Prior mediastinal radiation therapy01 . All patients had the basal LVEF in normal range. Median follow-up was 26.5 months (13,5-39,6 months). A total of 10.3% had cardiotoxicity with reduction in basal LVEF >10% with LVEF In 50 patients SLG was calculated, in 30% it was lower than -12% in some measurement phase. In 5 cases the LVEF fell below 55% and the LRP decreased by 12% coincided. The others patients, although they did not develop cardiotoxicity according to the established criteria, a decrease of the LVEF is observed during the treatment and in the first control, between 3-7%, which subsequently tends to recover spontaneously. miRNA 21-5p, miRNA-133b, miRNA 210-3p, miRNA 423-5p, and miRNA-663b were analyzed. A model has been evaluated where a correlation between the levels of miRNA-133b, miRNA-21-5p and miRNA-210-3p and the decrease of LVEF in relation to treatment was observed. CONCLUSIONS Control by echocardiography and serum markers allowed us to detect early cardiotoxicity events and provide us an opportunity to start heart failure therapy on time with the aim of improving the control and evolution of it.Levels of miR-133b, miR-21-5p and miR-210 may alert for a risk of cardiotoxicity and can help to make decisions about treatments. Acknowledgements: Project funded by European Comission (Hecatos FP7-HEALTH-2013-INNOVATION-1. Reference: CP-IP 602156-1) and RETICS program (RD12/0019/0025) cofunded by FEDER "una manera de hacer Europa”. Citation Format: Salvador-Coloma C, Hernándiz A, Tejedor S, Miró V, Palomar L, Salvador A, Sepúlveda P, Santaballa A. Early detection of chemotherapy-induced cardiotoxicity in breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-07.

The coming into force of Directive 2001/20/EC represented a step forward in harmonising clinical trial regulation in European countries, guaranteeing a uniform protection of subjects participating in clinical research across Europe. However, it led to a disproportionate increase in the bureaucratization, and thus, it became evident that procedures needed to be simplified without detriment to patient’s safety. Thus, Regulation 536/2014, that repealed Directive 2001/20/EC, with the aim of decreasing the growing bureaucratization and stimulating clinical research in Europe, established simplified procedures, such as regulating a common procedure for authorising trials in Europe, the institution of strict assessment timelines, or the definition of new concepts, such as “low-intervention clinical trial”. The legal form of a Regulation allowed the norm to be directly applied to Member States without the need for transposition. By means of the new Royal Decree, the national legislation is adapted to make the application of the regulation feasible and it allows the development of the aspects that the Regulation leaves to national legislation. Both documents seek to stimulate clinical research with medicinal products to foster knowledge, facilitate transparency, and reinforce subjects’ safety. This will surely be the case, but with this revision, we will look at the novelties and key aspects that are most relevant to investigators and we will analyse the consequences for all parties involved in clinical research.

BACKGROUND: Appraisal of the impact that current therapeutic strategies of advanced breast cancer (ABC) have on the survival expectancy, is vital to understand the prognosis of this disease. This entails assessing simultaneously the tumour phenotype and the therapeutic approach used per line of treatment. CASCADE is an epidemiological, retrospective, multicenter study aimed to retrieve demographic and clinical information from a representative cohort of ABC patients treated within the Spanish National Healthcare System. MATERIAL AND METHODS: 13 Spanish public hospitals serving nearly 5M inhabitants (~10% of the national population) identified 422 ABC patients between 01/2007 and 12/2008 who received active treatment for their disease and were followed until death, lost to follow-up, or until December 2013. Overall Survival (OS) was analysed per tumour immunotype and treatment line from the diagnosis until a minimum of 10 patients were still evaluable. OS resulting from the different therapeutic approaches per line was also revised. Data collected included demographical, pathological, diagnostic, and therapeutic information for the entire follow-up. Descriptive statistics were applied (Methods previously described in SABCS 2015 Poster P3-07-39). RESULTS: Remarkably, by the 2nd line of treatment, on average, one third of the OS is already gone. Tumour type imposes clear differences in this decline rate. As expected, triple-negative patients have the shortest survival expectancy at diagnosis, but their OS attrition rate is the slowest compared to the other subgroups (Table 1). Table 1. OS per tumour type and line of treatment in ABC.PopulationOS from ABC Diagnosis (months)OS from 1L (months)OS from 2L (months)OS from 3L (months)OS from 4L (months)OS from 5L (months)Whole (N=422)33.532.622.616.613.513.3HER2-/HR+ (N=187)38.637.122.415.612.610.2Triple-negative (N=67)19.016.515.814.110.29.5HER2+/HR+ (N=72)34.433.729.421.620.318.9HER2+/HR- (N=53)36.335.423.113.19.314.1 OS time derived from the five mayor therapeutic approaches used at any given line, could only be registered for chemotherapy, hormone therapy and chemo + anti-HER2 therapy. Regardless of their treatment history, patients treated exclusively with hormone therapy portray a less aggressive behaviour than those treated with chemotherapy only, resembling the natural history of HER2-/HR+ and triple-negative phenotypes (Table 2). Table 2. OS per pharmacological approach and line of treatment in ABC.Pharmacological treatmentOS from 1L (months)OS from 2L (months)OS from 3L (months)OS from 4L (months)OS from 5L (months)OS from 6L (months)OS from 7L (months)Chemotherapy (N=155)25.012.513.310.88.310.87.2Hormone therapy (N=92)44.030.922.311.214.0--Chemo + Anti-HER2 thp. (N=57)36.927.218.814.125.8--Chemo + Other Targeted thp. (N=44)19.721.014.121.1---Chemo + Hormone thp. (N=38)44.325.0-----Other Targeted thp.: anti-angiogenic antibody, mTOR inhibitor, anti-EGFR antibody, etc. CONCLUSION: Chances to benefit from effective treatments may be jeopardized if their start is postponed to late lines. Only the most widely used therapies and, ultimately chemotherapy, hold until very late in the treatment of the advanced disease. Citation Format: García J, De La Haba J, Servitja S, Santaballa A, De Paz L, Plata Y, Garau I, Florián J, Chacón JI, García P, Zamora P, Orcajo L, Rodríguez-Villanueva J, San José B, Martínez E, Seguí MA. CASCADE study: Rapid survival decline per treatment line in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-33.

Cancer is one of the major public health problems in our society. It is estimated that more than 18 million new cases are diagnosed worldwide every year; 280,000 in Spain. Incidence in following a growing trend. This epidemic could be controlled with research into new treatments and, above all, with adequate prevention. Primary prevention could prevent avoid up to half of all cases. For many others, secondary prevention is essential, as it make diagnosis possible in the stages of the disease when it is easily curable. These guidelines present the scientific evidence regarding secondary prevention in tumors in which its use is well-accepted: breast, cervical, colorectal, prostate, lung, ovarian, melanoma, and gastric cancer.

PurposeHormone receptor (HR)-positive, Human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) requires a therapeutic approach that takes into account multiple factors, with treatment being based on anti-estrogen hormone therapy (HT). As consensus documents are valuable tools that assist in the decision-making process for establishing clinical strategies and optimize the delivery of health services, this consensus document has been created with the aim of developing recommendations on cretiera for hormone sensitivity and resistance in HER2-negative luminal MBC and facilitating clinical decision-making.MethodsThis consensus document was generated using a modification of the RAND/UCLA methodology, which included the definition of the project and identification of issues of interest, a non-exhaustive systematic review of the literature, an analysis and synthesis of the scientific evidence, preparation of recommendations, and external evaluation with a panel of 64 medical oncologists specializing in breast cancer.ResultsA Spanish panel of experts reached consensus on 32 of the 32 recommendations/conclusions presented in the first round and were accepted with an approval rate of 100% about definition of metastatic disease not susceptible to local curative treatment, definition of hormone sensitivity and hormone resistance in metastatic luminal disease and therapeutic decision-making.ConclusionWe have developed a consensus document with recommendations on the treatment of patients with HER2-negative luminal MBC that will help to improve therapeutic benefits.

Debulking surgery, followed by taxane/platinum-based chemotherapy has traditionally been the first-line treatment for advanced ovarian cancer. However, most patients will experience recurrence afterwards, and receive subsequent lines of therapy. It has been proposed that extending the treatment-free interval of platinum can improve the response to a subsequent platinum-based chemotherapy, and reduce associated toxicities in women with recurrent, platinum-sensitive ovarian cancer. The aim was to determine the impact, in clinical practice, of trabectedin with pegylated liposomal doxorubicin (trabectedin/PLD) on the subsequent platinum-based therapy in these patients, and to explore the prognosis for breast cancer gene status and the expression of diverse genes. This was a multicenter, retrospective, postauthorization study that involved 79 patients. Germline or somatic mutations of breast cancer gene 1/2 were present in 21.5%. The median time between trabectedin/PLD and the onset of the subsequent treatment was 6.7 months. The overall response rate during the trabectedin/PLD period was 36.7%. In the subsequent first-line platinum-based therapy, the overall response rate was 51.4%. Progression-free survival and overall survival were 11.8 and 25.4 months, respectively, from the onset of trabectedin/PLD treatment. Partially platinum-sensitive (between 6 and 12 months) and platinum-sensitive patients (treatment-free interval of platinum >= 12 months) showed no differences in progression-free survival and overall survival. Grade 3 neutropenia and asthenia were reported in 15.2 and 10.1% of patients, respectively. Most frequent adverse events in more than 10% of patients were neutropenia (45.6%), asthenia (43.0%), nausea (25.3%), and anemia (13.9%). The intercalation with a nonplatinum regimen may improve the response to a subsequent platinum-based therapy in women with recurrent, platinum-sensitive ovarian cancer.

5549 Background: The prognosis for patients with platinum-resistant/refractory ovarian cancer (PROC) is poor, and the aim of treatment is focused primarily on symptom control and maintenance of QoL. The objective of this study was to assess the impact on QoL of the combination of pegylated liposomal doxorubicin (PLD) with olaparib (OLA) in PROC patients (pts). Methods: ROLANDO is a single arm phase II trial that enrolled pts with high-grade serous or endometrioid and at least one previous PROC recurrence (between 28 days - 6 months after last platinum). Up to 4 previous lines (up to 5 in BRCA-mut) were allowed. Pts received 6 cycles of PLD 40 mg/m2 intravenously every 28 days + OLA 300 mg b.i.d. followed by OLA 300 mg b.i.d. monotherapy until progression or unacceptable toxicity. QoL was measured by European Organization for Research and Treatment of Cancer QLQ C30 questionnaire evaluating functional status, and symptom intensity and QLQ OV-28 ovarian cancer specific module, both filled out by pts every 4 months (mo) regardless of disease progression. Questionnaire compliance was reported as percentage of the initial number of pts. Changes between baseline and subsequent visits (Wilcoxon rank test) were evaluated. P values < 0.05 were considered significant. Results: From 2017 to 2020, 31 pts were recruited. Median age was 57 y.o., ECOG 0/1: 32.3%/67.7%. Median of prior lines was 2 (range 1-5) and pts were on study treatment for a median of 5 mo (range 1.4-19.5) for OLA and 5 cycles (range 2 - 6) for PLD. QoL information was available at baseline for 30 (97%) pts and decayed to 22 (71%), 13 (42%), 6 (19%) and 4 (13%) pts at 4, 8, 12, and 16 mo respectively. Global health status measured by QLQ C30 and QLQ OV-28 scores was maintained throughout all time points with no significant differences. Significant transient improvement was seen in social functioning after 12 mo (p = 0.013). Nausea-vomiting (p = 0.02), hair loss (p = 0.012) and constipation (p = 0.037) showed a significant increase at 4 mo overlapping with PLD administration, and returned to baseline levels afterwards. This was in line with the reported adverse reactions frequency of nausea (58.1%) and vomiting (45.2%). Dyspnea showed a transient significant increase at 12 mo (p = 0.012), whereas insomnia (p = 0.038) and attitude towards disease (p = 0.007) improved at 16 mo. Symptoms such as appetite and constipation did not change after 12 mo. Most functional scales (physical, role, emotional, cognitive, body, sexuality) and symptom scales (fatigue, pain, appetite loss, diarrhoea, neurologic, hormonal and economic burden) had no statistically significant changes. Conclusions: Pts treated with OLA+PLD combination reported no signs of clinically relevant deterioration of QoL while on treatment. All QoL items changes were transient in no more than 1 time-point. Clinical trial information: NCT03161132.

Background: CDK 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) combination therapy have improved outcomes in patients (pts) with hormonal receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-) advanced breast cancer (ABC). However, most pts eventually develop resistance to these drugs, and one third never respond. Aside from HR positivity, predictive markers of clinical benefit from CDK 4/6i remains elusive. We aimed to identify biomarkers of response to palbociclib (PAL) and analyze potential therapeutic targets to reverse resistance. Methods: PEARL trial is a multicenter phase 3 study that assigned 601 postmenopausal HR+/HER2- ABC pts, whose disease progressed on aromatase inhibitors (AIs), to receive PAL + ET vs capecitabine (CAPE). We performed a differential gene expression analysis in pre-treatment tumors in extreme responders to PAL using the HTG EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics, Inc.), containing 2534 cancer related genes. Samples were subset in 2 categories: refractory (progressive disease as best response) vs sensitive (progression-free survival (PFS) within the upper quartile). Cox regression and Significance Analysis of Microarrays (SAM) analysis adjusting for multiple comparisons were performed. Results: We analyzed 455 (75.7%) pts with pre-treatment tumors available [from them, PAL + ET arm: 229 (50.3%) pts; CAPE arm: 226 (49.7%) pts]. Fifty genes (false discovery rate (FDR) median) of PLK1 (PLK1-high) treated with PAL, had a worse PFS in a multivariate model (5.7 months (m) vs 9.3 m of median PFS in PLK1-High vs -Low; HR=1.64, 95% CI (1.25-2.34), p=0.0008; adjusted model for confounders: age, site of disease, sites of metastasis, prior chemotherapy and Ki67). There were no differences in population treated with CAPE (9.9 m vs 9.4 m, PLK1-High vs -Low; HR=0.82, 95% CI (0.56-1.21), p=0.3189). In the METABRIC cohort, PLK1-High was associated with worse overall survival in HR+/HER2- BC but not in triple negative nor in HER2+ tumors. Among HR+/HER2- tumors, PLK1 expression was higher in luminal B and HER2-enriched intrinsic subtypes. We interrogated DepMap database and found that in BC cells lines there was an inverse correlation between PLK1 expression and effect on cell viability of CDK4 CRISPR knock-out (Pearson correlation r:0.54, p=0.009), but not of CDK6 knock-out. Also, HR+/HER2-/High Ki67 BC cell lines (HCC1428, EFM19 and MCF7) showed resistance to PAL on cell proliferation assays but sensitivity to the PLK1 inhibitor BI-2536. Conclusion: High expression of PLK1 is associated with intrinsic resistance to PAL and ET, this might be overcome with PLK1 inhibition. Table 1PATIENT CHARACTERISTICSCluster 1Cluster 2ALLn=57n=47n=104RespondersSensitive42 (73.68%)14 (29.79%)56 (53.85%)Refractory15 (26.32%)33 (70.21%)48 (46.15%)ESR1Mutated9 (15.79%)13 (27.66%)22 (21.15%)Wild type45 (78.95%)34 (72.34%)79 (75.96%)Unknown3 (5.26%)0 (0%)3 (2.88%)PriorQTN42 (73.68%)31 (65.96%)73 (70.19%)Y15 (26.32%)16 (34.04%)31 (29.81%)SubtypeLumA43 (75.44%)10 (21.28%)53 (50.96%)LumB14 (24.56%)28 (59.57%)42 (40.38%)Non Luminal0 (0%)9 (19.15%)9 (8.65%)MetastasisOne21 (36.84%)15 (31.91%)36 (34.62%)Multiple36 (63.16%)32 (68.09%)68 (65.38%)KI67 20%KI67 Citation Format: Angel Guerrero- Zotano, Christoph Zielinski, Miguel Gil-Gil, Manuel Ruiz-Borrego, Eva M. Ciruelos, Montserrat Munoz, Begoña Bermejo, Mireia Margeli, Antonio Antón, Tibor Csöszi, Andrés García-Palomo, Ana Santaballa, Jose Luis Alonso, Antonio Fernández, Massimo Corsaro, Jesús Herranz, Paula López, Rosalia Caballero, Christiane Thallinger, Miguel Martin. Plk1 expression & efficacy of palbociclib in advanced hormonal receptor-positive breast cancer patients from PEARL study (GEICAM 2012-03) [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 PS2-01.

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 (>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.

BACKGROUND: Currently available therapeutic armamentarium for locally advanced and/or metastatic breast cancer (LA/MBC) allows an increasing tailored approach for each of the major tumor immunophenotypes. Nevertheless, there is scarce information about how these subgroups fare and how the alternative therapeutic approaches are actually being used during the disease course. CASCADE is an epidemiological, retrospective, and multicenter study aimed to retrieve demographic and clinical information from a representative cohort of LA/MBC patients treated within the Spanish National Healthcare System. MATERIALS AND METHODS: Several strategies were used to identify patients diagnosed with LA/MBC for the first time between 01/2007 and 12/2008 in 13 Spanish public hospitals covering nearly 5'000'000 inhabitants (>10% of the national population) and followed throughout their metastatic lifetime until death, lost to follow-up, or until December 2013. Data collected included demographical and clinical information for each line of treatment. Descriptive statistics were applied to analyze the information. RESULTS: We identified 443 LA/MBC patients. Median age at diagnosis was 59 years (CI95%: 49.5 - 71.6). Significant differences in dropout rates per line of treatment were found according to the tumor intrinsic immunophenotype. Patients reaching a 4th line were: whole study population 38.4%, HER2-/HR+ 42.8%, HER2+/HR- 41.5%, HER2+/HR+ 39.5%, and Triple-negative 31.9%. Median Overall survival (OS) and per line Progression Free Survival (PFS) for each line of treatment by tumor subtype were: Median OS and per line PFS by tumor subtype Subtype (%)OS (months)PFS (months)PFS (months)PFS (months)PFS (months)PFS (months)Treatment line--1L2L3L4L5LWhole PopulationAll33.57.25.94.33.73.0HER2-/HR+43.838.68.85.84.43.33.0HER2+/HR-12.036.37.46.74.34.03.0HER2+/HR+17.234.411.27.94.95.83.5Triple-negative16.319.04.03.52.43.32.9 Percent use of the four major pharmacological families per line of LA/MBC treatment was: Pharmacological families used per line of LA/MBC treatmentTreatment line1L2L3L4L5L6L7LChemotherapy75.463.075.979.487.976.178.6Anti-HER219.721.919.420.618.720.921.4Hormone therapy37.939.225.318.811.217.916.7Other targeted therapy13.09.612.212.47.511.914.3 CONCLUSION: Our study identifies differences in OS and PFS among BC immunophenotypes, with Triple-negatives faring the poorest. Among therapeutic families, chemotherapy clearly prevails along the disease lifetime, with hormone therapy being primarily used during the initial lines of treatment. Citation Format: Zamora P, Servitja S, Santaballa A, García J, de Paz L, Plata Y, Garau I, Florian J, Chacón I, de la Haba J, García P, Artime E, Rodríguez-Villanueva J, Velasco A, Martínez E, Segui MA. CASCADE study: Treatment and clinical outcomes of metastatic breast cancer by tumor immunophenotypes. [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 P3-07-39.

Cancer is the leading social and healthcare problem of the twenty-first century. The aim of primary prevention is to decrease the incidence of cancer by avoiding the known causes and risk factors. Nevertheless, it has been estimated that cancer diagnoses could be halved through primary prevention measures. A comprehensive review of the scientific evidence regarding the main carcinogens and risk factors and primary prevention recommendations have been put forth based on this evidence. The GRADE scale has been used to classify the grade of evidence. We present the scientific evidence and recommendations for primary prevention of the major modifiable risk factors: smoking, alcohol, diet, obesity, physical activity, occupational and environmental factors, ultraviolet radiation, infections, and socioeconomic factors. Primary prevention is a simple, effective means to lower the incidence of cancer. Preventive measures must be circulated in the fight against cancer.

PurposeTo determine the current management of oral and intravenous chemotherapy (OC and IVC) in outpatient clinics of Oncology Departments in Spain to detect opportunities for improvement.Materials and methodsThe Spanish Society of Medical Oncology designed a questionnaire specifically for Heads of Oncology Department: 142 were invited and 52 responded.ResultsIn most centers, the waiting time (69.7%) and time at the outpatient clinic (84.8%) was shorter for patients receiving OC compared to those receiving IVC. The time spent at the outpatient clinic by the patients having OC was approximately 30min (88.5%). In addition, the time expended by the oncologist with each patient was shorter when they were treated with OC in 21.2% of cases.ConclusionsPatients' waiting times and individual dedication of oncologists might be reduced by administering OC, and general management might be improved. This should be considered when planning therapies if OC is an option.

One of the most common side effects of cancer treatment is cardiovascular disease, which substantially impacts long-term survivor's prognosis. Cardiotoxicity can be related with either a direct side effect of antitumor therapies or an accelerated development of cardiovascular diseases in the presence of preexisting risk factors. Even though it is widely recognized as an alarming clinical problem, scientific evidence is scarce in the management of these complications in cancer patients. Consequently, current recommendations are based on expert consensus. This Guideline represents SEOM's ongoing commitment to progressing and improving supportive care for cancer patients.

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies.

The study aims to identify the relevance of immunohistochemistry (IHC), copy number aberrations (CNA) and epigenetic disorders in BRCAness breast cancers (BCs). We studied 95 paraffin included BCs, of which 41 carried BRCA1/BRCA2 germline mutations and 54 were non hereditary (BRCAX/Sporadic). Samples were assessed for BRCA1ness and CNAs by Multiplex Ligation-dependent Probe Amplification (MLPA); promoter methylation (PM) was assessed by methylation-specific-MLPA and the expression of miR-4417, miR-423-3p, miR-590-5p and miR-187-3p by quantitative RT-PCR. IHC markers Ki67, ER, PR, HER2, CK5/6, EGFR and CK18 were detected with specific primary antibodies (DAKO, Denmark). BRCAness association with covariates was performed using multivariate binary logistic regression (stepwise backwards Wald option). BRCA1/2 mutational status (p = 0.027), large tumor size (p = 0.041) and advanced histological grade (p = 0.017) among clinic-pathological variables; ER (p < 0.001) among IHC markers; MYC (p < 0.001) among CNA; APC (p = 0.065), ATM (p = 0.014) and RASSF1 (p = 0.044) among PM; and miR-590-5p (p = 0.001), miR-4417 (p = 0.019) and miR-423 (p = 0.013) among microRNA expression, were the selected parameters significantly related with the BRCAness status. The logistic regression performed with all these parameters selected ER+ as linked with the lack of BRCAness (p = 0.001) and MYC CNA, APC PM and miR-590-5p expression with BRCAness (p = 0.014, 0.045 and 0.007, respectively). In conclusion, the parameters ER expression, APC PM, MYC CNA and miR-590-5p expression, allowed detection of most BRCAness BCs. The identification of BRCAness can help establish a personalized medicine addressed to predict the response to specific treatments.

Purpose Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. Patients and Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m2, respectively, × four cycles), followed by docetaxel (100 mg/m2 × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m2, respectively, × four cycles), followed by capecitabine (1,250 mg/m2 twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). Results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). Conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

Background: Vertical dual blockade with L and T in heavily pretreated HER2+ MBC patients has shown consistent survival gain in a phase III trial (Blackwell KL et al. 2012), justifying an EMA approval for the hormone-negative subgroup. However, there is very limited information about the futility of the combination in clinical practice, mostly in patients progressing also on prior L regimens. Methods: We conducted a retrospective analysis among patients treated in Spain by compassionate uses for the combination of T-L. The study was approved by the regulatory authorities and ethics committees from the 14 participating centers. Major inclusion criteria were (1) HER2+ MBC; (2) progression on at least one prior line of T for advanced disease; and (3) T-L treatment started between JAN/2005 and DEC/2012. Concomitant endocrine therapy for HR+ patients as well as prior exposure to L was allowed. Chemotherapy combinations were excluded. A total of 111 patients were predefined for the primary outcome: clinical benefit rate (CBR). Secondary endpoints included time to progression (TTP), overall survival (OS) and toxicity. 114 women were included and externally monitored. Results: The median age was 60 years (34 - 89); 64% HR+; 77% visceral disease; 32% CNS disease (37 patients); 47% with ≥3 organs involved. Mean number of prior T lines 4 (range 0-13); 64% previously treated with L. A total of 40 patients (35%) achieved a CBR (95%CI 26–44%); 6 CR, 19 PR and 15 SD lasting >24 weeks. The median time to progression was 3.8 months (95%CI 3.3–5.1) and the median overall survival 21.6 months (95%CI 17.1–27.3). CBR, median TTP and median OS achieved in patients with CNS disease were 32.4% (95%CI 17.3–47.5%), 3.6 (95%CI 2.8–5.9) and 15.4 (95%CI 10.9–27.3) months, respectively. The CBR was independent of L treatment (41.5% L naïve vs. 31.5% L pretreated, p=0.285) and HR status (39% HR- vs. 32.9% HR+, p=0.509). Patients with Conclusions: The combination of T-L seems safe and active in heavily pretreated patients. The combination remains active among patients progressing on prior L. Future research may focus on the ability of endocrine therapy to increase activity among HER2+/HR+ patients. REFERENCES: 1 Blackwell KL, Burstein HJ, Storniolo AM, et al: Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol 2012;30(21):2585-2592. Citation Format: Joaquin Gavilá, Begoña Bermejo, Álvaro Rodríguez-Lescure, Juan Lao Romera, Luis Manso, Joan Brunet, Eva Muñoz, Marta Santisteban, César A Rodríguez, Ana Santaballa, Juan de la Haba, Pedro Sánchez-Rovira, Manuel Ruiz-Borrego, Jose Ángel García-Saenz, Javier Cortés, Antonio Llombart. TRASTYVERE study: A retrospective analysis of HER2-positive metastatic breast cancer (MBC) patients treated in Spain with lapatinib (L) plus trastuzumab (T) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-21.

Introduction: Retrospective data from institutional series and population-based databases have suggested a potential benefit of the primary tumor (PT) surgery in de novo metastatic breast cancer (MBC) patients (pts). Recently reported prospective data from 2 randomized trials and a multicenter registry questioned the real role of the local approach in the modern individualized systemic treatment era. Methods: The ALAMO (A) is a retrospective analysis of pts diagnosed with BC between 1990 and 2001 across 56 GEICAM hospitals in Spain. Patterns of BC presentation (tumor and host characteristics), treatment and survival were recorded in 3 cohorts, AI (1990-93, 4529 pts, closed by 2000), AII (1994-97, 10453 pts, closed by 2003) and AIII (1998-2001, 10675 pts, closed by 2007). MBC pts at first diagnosis excluding those without complete information about their PT surgery were included. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Results: 5.5% (N=1415) of the ALAMO database pts were initially diagnosed with MBC, 1331 fulfilled the present analysis criteria (327 from AI, 619 from AII and 385 from AIII). Median age was 63.1 years (range: 21.6-96.0), 51.8% had single-organ metastasis, and their distribution according to the predominant site of disease was skin/soft tissue (16.2%), bone (33.7%), and visceral (48.4%). Surgery of the PT was done in 44.5% (N=592) of pts (512 with radical procedures, 46 with palliative procedures and 34 unknown); besides, 427 pts underwent axillary dissection. Initial local treatment was the choice for 380 pts (358 surgery and 22 radiotherapy), 722 received initial systemic therapy (480 chemotherapy, 214 endocrine treatment and 28 both), 29 received best supportive care and for 200 pts the treatment sequence could not be established. Pts in the surgery (S) group were younger (19.5% vs 11.8% were Citation Format: Sara López-Tarruella, María José Escudero, Miguel Martín, Carlos Jara, Ángel Guerrero, Ana Lluch, Ana Santaballa, Purificación Martínez del Prado, Juan Lao, Emilio Alba, Antonio Fernández, Raquel Andrés, Antonio Llombart, Norberto Batista, Ignacio Porras, José Manuel López-Vega, Encarna Adrover, Lourdes Calvo, Marina Pollán, Eva Carrasco. Impact on survival of primary tumor resection in women with de novo metastatic breast cancer. The GEICAM Alamo I-III breast cancer registry (1990-2001) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-17.

Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies.

Gestational trophoblastic disease (GTD) is a rare but curable disease. Recent improvements in diagnosis and molecular biology have resulted in changes in staging and treatment. These guidelines provide evidence-based recommendation on how to manage GTD.

Background: Several prognostic multigene tests are available for the management of breast cancer patients, but so far there is little data available directly comparing the classification performance of different breast cancer tests in the same patient cohort. Here, we compared the prognostic performance of two second generation multigene tests in ER+/HER2- early node-positive breast cancer patients treated with adjuvant chemotherapy followed by endocrine therapy. Patients and methods: The EndoPredict (EP) score and two research laboratory-based versions of the PAM50 risk of recurrence (ROR based on subtype [ROR-S] and based on subtype and proliferation [ROR-P]) score were compared in 536 ER+/HER2- breast cancer patients who participated in the GEICAM/ 9906 trial. Patients had either been treated with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P), and endocrine therapy. ROR and EP scores were combined with clinical information to obtain the following hybrid scores as published before: a) ROR-T score (subtype and tumor size), b) ROR-PT score (subtype, proliferation and tumor size) scores, and c) EPclin score (EP Score plus tumor size and nodal status). Each patient was assigned to risk categories according to pre-specified cut-off levels for the scores. The primary endpoint was distant metastasis. Metastasis rates were estimated using the Kaplan-Meier method. C-index analysis was used to estimate the performance of the different scores. Results: The PAM50 ROR-S and ROR-P scores, and the EP score were prognostic in patients with ER+/HER2- tumors and consistently identified a low-risk group with a particular good outcome (10 year MFS rate - ROR-S: 81.7%, ROR-P: 82.9% and EP: 89.4%). Combining the molecular signatures with clinical information, improved the prognostic performance of all signatures (10 year MFS rate - ROR-T: 83.4%, ROR-PT: 87.3% and EPclin: 100%). All signatures added prognostic information to common clinical parameters. Among the signatures evaluated only EPclin added a significantly improved prediction of distant metastasis to ROR-T (p < 0.001) and ROR-PT (p < 0.001), which may be due to the feature that EPClin includes a term for node status, but which is not included in any ROR-based model. Conclusions: Our study suggests that PAM50 ROR and EP can be used to reliably predict risk of distant metastasis in node-positive ER+/HER2- breast cancer patients treated with chemotherapy. There was no significant difference between the molecular signatures in terms of low risk classification. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-11-06.

Background Trastuzumab has shown an improvement in survival outcomes among patients with HER2+ metastatic breast cancer (MBC). Identification of pathological, clinical factors and tumor genetic profile that may predict long-term remission has become a key-issue. We aimed to describe the clinicopathological and biological characteristics of MBC patients who experienced complete response (CR), partial response (PR), or stable disease (SD) during at least 3 years and their management in routine clinical practice. Methods: Multicenter, observational, cross-sectional study. Data were collected from women with HER2+ MBC treated with a trastuzumab-based regimen who maintained a partial or complete remission or disease stabilization beyond 3 years. The interim results from the first 65 patients evaluated are presented. Results: Median age: 59 (52-70) years. Metastatic disease was diagnosed after a median of 23.5 (1.6−48.8) months since primary tumor diagnosis. The predominant tumor type was ductal carcinoma (89.2%) and 47% showed histological grade III. Mean tumor size: 3.6±2.2cm (anatomical pathology), 5.1±2.8cm (imaging studies). Hormonal status: Progesterone receptor positive 46% and estrogen receptor positive 43%. Most common metastatic sites: lung (23%), liver (17%) and bone (14%). Overexpression of HER2 was assessed by IHC in 97% of patients, of whom 94% were HER2+ (3+) and 17% had FISH+ HER2 status. Tumor was positive for p53 and Ki67 in 23% and 41.5%, respectively. Surgery was performed on 83% of patients, of which 73% underwent radical mastectomy; 96% had their axillary nodes removed. Surgery of metastases was performed on 7.8%. First line chemotherapy was received by 91% with the most frequent schemes being paclitaxel (24%), vinorelbine (15%) and paclitaxel/carboplatine (14%). First line hormonal therapy and radiotherapy was used in 45% and 12%, respectively. All patients received first line trastuzumab, administered on a weekly schedule in 51%. Trastuzumab was used in combination in most of patients (89.2%) with a median number of cycles of 18 (7.0−41.5) and during a median of 53.3±25 months. 66% of patients achieved a CR, 21% PR and 13% had SD. Median time since trastuzumab was initiated to CR, PR or SD was 5 (4-7) months. Median duration of CR, PR or SD was 56 (44.5−78.0) months. Trastuzumab was maintained beyond CR, PR or SD in 99% during a median of 46.5 (35-67) months. 75% of patients continue on treatment with trastuzumab. Only 2 patients discontinued trastuzumab due to toxicity. At the time of the analysis, 19% had progressed, 57% were alive and free of disease and among patients on treatment (93%), 54% were on trastuzumab. Cardiac toxicity was the most common toxicity (36%) among those suffering at least one (22%). Conclusions: The preliminary findings support that trastuzumab provides a substantial long-term survival benefit with a manageable safety profile in HER2+ MBC patients. This study adds to the evidence that there may be benefit in continuing trastuzumab after achieving remission or disease stabilization. Final results will be presented in the forthcoming congress. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-22.