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Purpose: Individualized selection of patients with early stage hormone receptor positive (HR+) breast cancer for extended endocrine therapy (EET) are required to balance modest gains in outcome with toxicities of prolonged use. This study examined the Breast Cancer Index (BCI) [HOXB13/IL17BR ratio (H/I)] as a predictive biomarker of EET benefit in patients from the Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial.Experimental design: BCI was tested in primary tumor specimens from 908 patients randomized to receive 2.5 vs 5 years of extended letrozole. The primary endpoint was recurrence-free interval (RFI). Cox models and likelihood ratios tested the interaction between EET and BCI (H/I).Results: BCI (H/I)-High significantly predicted benefit from extended letrozole in the Overall cohort (HR 0.42, 95% CI 0.21-0.84; P=0.011) and Any AI subset (HR 0.34, 0.16-0.73; P=0.004), whereas BCI (H/I)-Low patients did not derive significant benefit (HR 0.95, 0.58-1.56; P=0.84, HR 0.90, 0.53-1.55; P=0.71, respectively); treatment to biomarker interaction was significant (P=0.045, P=0.025, respectively). BCI identified ~50% of patients with clinically high-risk disease that did not benefit, and with clinically low-risk disease that derived significant benefit, from an additional 2.5 years of EET.Conclusions: BCI (H/I) predicted preferential benefit from 5 vs 2.5 years of EET and identified patients with improved outcomes from completing 10 years of adjuvant endocrine therapy. Findings expand the clinical utility of BCI (H/I) to a broader range of patients and beyond prognostic risk factors as a predictive endocrine response biomarker for early stage HR+ breast cancer.

Purpose In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. Methods 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery. Results Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients’ perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet. Conclusions FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449.

Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m−2, to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90–100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449. Preclinical evidence suggests that a fasting mimicking diet (FMD) can make cancer cells more vulnerable to chemotherapy, while protecting normal cells. In this randomized phase II clinical trial of 131 patients with HER2 negative early stage breast cancer, the authors demonstrate that FMD is safe and enhances the effects of neoadjuvant chemotherapy on radiological and pathological tumor response.

PURPOSE Most distant recurrences (DRs) in women with hormone receptor-positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5- predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P,.001). The CTS5 was not predictive for extended AET duration. CONCLUSION The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients. © 2020 by American Society of Clinical Oncology.

Purpose For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. Methods In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. Results In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions. Conclusions This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

Background Extended endocrine therapy beyond 5 years for postmenopausal breast cancer has been studied within multiple phase III trials. Treatment compliance in these trials is generally poor. In this analysis, we aimed to determine factors that were associated with participation in the phase III Investigation on the Duration of Extended Adjuvant Letrozole (IDEAL) trial and with early treatment discontinuation, and how this influenced survival outcome. Methods In the IDEAL trial, postmenopausal patients were randomised between 2.5 or 5 years of extended letrozole, after completing 5 years of endocrine therapy for hormone receptor-positive early breast cancer. A subgroup of this population participated earlier in the Tamoxifen Exemestane Adjuvant Multinational trial (5 years of exemestane or 2.5 years of tamoxifen followed by exemestane as primary adjuvant therapy) in which we explored which factors were determinative for enrolment in the IDEAL study. In the IDEAL cohort, we evaluated which factors predicted for early treatment discontinuation and the effect of early treatment discontinuation on disease-free survival (DFS). Results Nodal status, younger age and adjuvant chemotherapy were significantly associated with higher enrolment in the IDEAL trial. In the IDEAL cohort, adverse events (AEs), the type of primary endocrine therapy and the interval between primary and extended therapy were associated with early treatment discontinuation. Among the reported AEs, depressive feelings (56%) were most frequently associated with early treatment discontinuation. Early treatment discontinuation was not associated with worse DFS (hazard ratio [HR] = 1.02, 95% confidence interval = 0.76–1.37). Conclusions In this analysis, we found that risk factors were most strongly associated enrolment in the IDEAL trial. In contrast, patient experiences were the most significant factors leading to early treatment discontinuation, with no effect on DFS.

Las tablas tradicionales y rígidas en socorrismo acuático han sido rechazadas en muchos servicios de socorrismo por los problemas que generaban. La experiencia con tablas hinchables (AIRSUPRA) ha demostrado muchas ventajas y las objeciones sobre este material están desapareciendo y ya comienzan a utilizarse en servicios de socorrismo, que antes eran reticentes. El objetivo de este estudio fue analizar el efecto del uso de la tabla AIRSUPRA en el tiempo de aproximación en una distancia de 100 metros, con una muestra de 16 socorristas profesionales (13 hombres y 3 mujeres), certificados y actualizados en técnicas de rescate, pero sin experiencia con tablas AIRSUPRA. Los resultados demuestran que cuando se realiza la aproximación con la tabla AIRSUPRA (TR1) se obtiene un tiempo de 54.13 + 8.58, mientras que cuando se realiza la aproximación a nado el tiempo es 93.19 + 25.52, con una diferencia de 39.06 segundos, estadísticamente significativa (p, The use of traditional and rigid boards in aquatic lifesaving cause more problems than advantages, for this reason was frequently rejected in many lifesaving services. However, based on knowledge and experimentation with inflatable boards many advantages have been proven, doubts and objections on this material are disappearing and, in fact, are beginning to be used in lifesaving services that were previously reluctant to use them. The aim of this study was to analyze the effect of using the table AIRSUPRA in the time of approaching for a distance of 100 meters. The sample was integrated by 16 professionals (13 men and 3 women), all of them with rescue techniques certification and updated training, but with no experience managing boards AIRSUPRA. The results show that when the approximation with AIRSUPRA table (TR1) is performed the time was of 54.13 + 8.58, whereas when the approaching is performed swmming the time was of 93.19 + 25.52, with a difference of 39.06 seconds, statistically significant (p

An approach to identify beta-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (twodimensional N-15 heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space.

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Because of their roles in controlling the activity of several bio-active peptides, members of the neprilysin family of zinc metallopeptidases have been identified as putative targets for the design of therapeutic agents. Presently, six members have been reported, these are: neprilysin, endothelin-converting enzyme (ECE)-1 and ECE-2, the Kell blood group protein, PHEX (product of the phosphate-regulating gene with homologies to endopeptidase on the X chromosome) and X-converting enzyme (XCE). In order to identify new members of this important family of peptidases, we designed a reverse transcriptase-PCR strategy based on conserved amino acid sequences of neprilysin, ECE-1 and PHEX. We now report the cloning from mouse testis of a novel neprilysin-like peptidase that we called NL1. NL1 is a glycoprotein that, among the members of the family, shows the strongest sequence identity with neprilysin. However, in contrast with neprilysin and other members of the family which are type II integral membrane proteins, NL1 was secreted when expressed in cultured mammalian cells, likely due to cleavage by a subtilisin-like convertase at a furin-like site located 22 amino acid residues in the C-terminus of the transmembrane domain. The recombinant enzyme exhibited neprilysin-like peptidase activity and was efficiently inhibited by phosphoramidon and thiorphan, two inhibitors of neprilysin. Northern blot analysis and in situ hybridization showed that NL1 mRNA was found predominantly in testis, specifically in round and elongated spermatids. This distribution of NL1 mRNA suggests that it could be involved in sperm formation or other processes related to fertility.

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