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Since Coronavirus Disease 2019 (COVID-19) was declared pandemic in March 2020, there have been 545.226.550 cases up to 4 July 2022 (1). Several studies concluded that patients (pts) with cancer are at increased risk of COVID-19 infection, morbidity and mortality. Those undergoing neoadyuvant treatment are at particularly risk of disease progression if chemotherapy or surgery are delayed. Also, is known that a higher NLR (neutrophil to limphocyte ratio) is related to worse outcomes (3). Our hospital is located at the Northwest of Spain and in the last months we noticed a never seen number of infections in cancer population. The aim of this study is to evaluate the severity of COVID-19 and its impact on chemotherapy and surgery delay in pts undergoing neoadjuvant chemotherapy breast cancer. METHODS: We conducted a ambispective, unicenter, observational study of breast cancer pts, treated with neoadjuvant chemotherapy, between March 2020 and May 2022 at University Hospital A Coruña (Spain). We analyzed type of infection, need of hospitalization, chemotherapy and surgical delay, and its association with tumor type; BRCA germline mutation; clinical stage; treatment; vaccination status; and neutrophils, lymphocytes, and NLR before COVID-19 disease. RESULTS: During the study period, from 1 March 2020 to 31 May 2022, 183 pts underwent neoadjuvant chemotherapy. A total of 23 (12.5%) pts experienced COVID-19 infection, of which 21 were diagnosed between January and May 2022. The median age was 47,91 years [range 33 – 69 years]. Luminal B HER 2 negative comprised the most common molecular subtype (40.9%), followed by Triple Negative (36.4%), Luminal B HER 2 positive (13.6%), and HER 2 enriched (9.1%). Germline mutations in BRCA account for 13.6% pts. At diagnosis, 4.5%, 72.7%, and 22.7% had stages I, II, and III respectively. Chemotherapy treatments included: paclitaxel followed by Adryamicine-Cyclophosphamide (AC) (45.4%); carboplatin – paclitaxel – trastuzumab - pertuzumab (18,2%); carboplatin – paclitaxel followed by AC (18,2%); KEYNOTE-756: pembrolizumab/placebo - paclitaxel followed by AC (13.7%); and paclitaxel – trastuzumab – pertuzumab followed by myocet – cyclophosphamide – trastuzumab - pertuzumab (4.5%). The association of G-CSF ocurred in 9 pts (40.9%). 22 pts were fully vaccinated, 8 pts (36.4%) with two doses and 13 pts (59.1%) with three doses. 77.3% pts experienced mild respiratory symptoms with 9.1% hospitalizations. The median duration of delays was 15 days for chemotherapy and 29,58 days for surgery. NLR percentil 25 was associated with COVID-19 type of infection. For those pts with a lower rate, infection was asymptomatic and for those with a higher rate symptoms were moderate (Χ2= 5,119, p = 0,024). CONCLUSIONS: COVID-19 disease become a high prevalent infection in pts undergoing neoadjuvant breast cancer chemotherapy. Most pts are fully vaccinated and experienced an indolent infection. NLR is an easily measurable and cost-effective parameter that could be useful as a prognostic marker of severity in COVID-19. We will continue to follow-up these pts to see the impact of chemotherapy or surgery delay in pathological complete response and disease-free survival until the congress in December 2022. BIBLIOGRAPHY: 1. WHO Coronavirus (COVID-19) Dashboard [Internet]. world health organization. 2022 [3rd July 2022]. Disponible en: https://covid19.who.int. 2. YekedÜz E, Utkan G, ÜrÜn Y. A systematic review and meta-analysis: the effect of active cancer treatment on severity of COVID-19 [Internet]. European Journal of Cancer. 2020. [24th June 2022]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538140/pdf/main.pdf 3. Jimeno S, Ventura PS, Castellano JM, García-Adasme SI, Miranda M, Touza P, et al. Prognostic implications of neutrophil-lymphocyte ratio in COVID-19 [Internet]. Eur J Clin Invest. 2021. [22th June 2022]. Disponible en: https://onlinelibrary.wiley.com/doi/10.1111/eci.13404. Table 1: Clinical characteristics of patients Table 2: Blood cell count in percentils Citation Format: Beatriz Alonso de Castro, Igor Gomez-Randulfe Rodriguez, Sofia Silva Diaz, Cristina Reboredo, Silvia Antolin Novoa, Eva Perez Lopez, Patricia Cordeiro, Rocio Lesta, Iria Parajo Vazquez, Lourdes Calvo. NEOADYUVANT TREATMENT IN THE COVID ERA [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-39.

In recent years, cultural changes in today's society and improved risk assessment have increased the indication for mastectomies in women with breast cancer. Various studies have confirmed the oncological safety of sparing mastectomies and immediate reconstruction. The objective of this study is to analyze the incidence of locoregional relapses of this procedure and its impact on reconstruction and overall survival.Prospective study of patients with breast carcinoma who underwent a sparing mastectomy and immediate reconstruction. Locoregional relapses and their treatment and their impact on survival were analyzed.The study group is made up of 271 women with breast carcinoma treated with a skin-sparing mastectomy and immediate reconstruction. The mean follow-up was 7.98 years and during the same 18 locoregional relapses (6.6%) were diagnosed: 72.2% in the mastectomy flap and 27.8% lymph node. There were no significant differences in the pathological characteristics of the primary tumor between patients with and without locoregional relapse, although the percentage of women with hormone-sensitive tumors was higher in the group without relapse. Patients with lymph node relapse had larger tumors (80% T2-T3) and 60% had axillary metastases at diagnosis, compared to 7.7% of women with skin relapse (p = 0.047). All patients operated on for locoregional relapse preserved their reconstruction. The incidence of metastases and deaths was significantly higher in patients with a relapse, causing a non-significant decrease in overall survival.Locoregional relapses are a rare event in women with a sparing mastectomy and immediate reconstruction. Most patients with locoregional relapse can preserve their initial reconstruction through local resection of the tumor and adjuvant and / or neoadjuvant therapies.

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

Supercritical CO2 (scCO2) is utilized in the supercritical fluid extraction of emulsions (SFEE) to swiftly extract the organic phase (O) from an O/W emulsion. The dissolved substances in the organic phase precipitate into small particles and remain suspended in the water (W) with the aid of a surfactant. The process can be continuously conducted using a packed column in a counter-current flow of the emulsion and scCO2, at moderate pressure (8–10 MPa) and temperature (37–40 °C). To ensure the commercial viability of this technique, the organic solvent must be separated from the CO2 to facilitate the recirculation of both streams within the process while minimizing environmental impact. Thus, the aim of this work was to design a plant to produce submicron materials using SFEE, integrating the recovery of both solvents. First, experimental equilibrium data of the ternary system involved (CO2/ethyl acetate/water) were fitted with a proper thermodynamic model. Then, simulations of the whole integrated process at different scales were carried out using Aspen Plus®, along with economical evaluations. This work proposes the organic solvent separation with a distillation column. Thus, the two solvents can be recovered and recycled to the process in almost their entirety. Furthermore, the particles in the aqueous raffinate are produced free of solvents and sterilized for further safe use. The costs showed an important economy scale-up. This work could ease the transfer of the SFEE technology to the industry.

Summary of all adverse events according to NCI-CTCAE version 4.0.3.

Supplementary Table S1. Selection Criteria; Supplementary Table S2. Recruiting Sites, Principal Investigators, and Patient Numbers; Supplementary Table S3. Study Members; Supplementary Table S4. List of antibodies used for immunohistochemistry analysis; Supplementary Table S5. Cutoff values for the quantitative assessment of biomarkers by immunohistochemistry; Supplementary Table S6. The 77-gene panel by the AVENIO ctDNA Expanded Kit used for targeted NGS on plasma samples; Supplementary Table S7. Representativeness of study participants; Supplementary Table S8. Association of baseline clinical and pathologic characteristics of trial participants included in the efficacy analysis with clinical benefit; Supplementary Table S9. Relative dose intensity and drug discontinuation; Supplementary Table S10. All causality AEs according to NCI-CTCAE version 4.0.3 occurring in at least 5% of the patients; Supplementary Table S11. Adverse events of special interest according to NCI-CTCAE version 4.0.3; Supplementary Table S12. Baseline clinical and pathologic characteristics of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S13. Tumor best response according to RECIST version 1.1 of trial participants included in the retinoblastoma and signature subsets; Supplementary Table S14. Association of biomarkers and composite signatures with clinical benefit.

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.

Supplemental Methods, Tables and Figures Tables Table S1. CES association with chemotherapy sensitivity (measured as pCR) in the MDACC-based dataset. Table S2. CES association with chemotherapy sensitivity (measured as Residual Cancer Burden [RCB]) in the MDACC-based dataset. Model A. Table S3. CES association with chemotherapy sensitivity (measured as Residual Cancer Burden [RCB]) in the MDACC-based dataset. Model B. Table S4. Univariate association of CES and various signatures with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S5. Association of CES and PAM50 Proliferation Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S6. Association of CES and CHEMOPRED Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S7. Association of CES and the proliferation component of the Genomic Health Index (GHI; OncotypeDX Recurrence Score) with chemotherapy sensitivity in HR+/HER2- negative disease from the MDACC-based dataset. Table S8. Association of CES and Genomic Grade Index (GGI) Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S9. Association of CES and SET index Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S10. Association of CES and RCBPRED Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S11. Association of CES and DLDA30 Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S12. Association of CES and ROR-P Signature with chemotherapy sensitivity in HR+/HER2-negative disease from the MDACC-based dataset. Table S13. Association of CES and Ki67 by IHC with chemotherapy sensitivity in HR+/HER2-negative disease of the Malaga cohort. 7 Table S14. Association of CES and PAM50 ROR with chemotherapy sensitivity in HR+/HER2-negative disease of the Malaga cohort. Table S15. CES association with endocrine sensitivity in the Marsden dataset (n=103). Table S16. CES association with endocrine sensitivity in the Marsden dataset within HER2-negative disease (n=89). Figures Fig. S1. Association of CES with Miller-Payne following chemotherapy in HR+/HER2- negative disease from the Malaga-based cohort. Fig. S2. CES association with endocrine sensitivity in the Edinburgh dataset (n=120). (A) Tumor volume changes of each patient and response classification. (B) Association of CES and other variables with response (defined as at least 70% reduction by 90 days) in the overall population. (C) Association of CES and other variables with response within HER2-negative disease. Fig. S3. Association of CES with pCR in the combined dataset from the MDACC- and Malaga-based cohorts.

Purpose: Hormone receptor–positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2− disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine–sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035–44. ©2016 AACR.

Background. Chemotherapy is one of the most widely used therapies for breast cancer, triggering important repercussions on people’s quality of life. However, little research has been undertaken about podiatric adverse effects. This study aimed was to determine the prevalence of podiatric pathology developed in people with breast cancer who receive chemotherapy. Methods. Observational, descriptive, and cross-sectional study was conducted in the Oncology service of the A Coruña University Hospital (northwest Spain). People with breast cancer and undergoing chemotherapy treatment of legal age (≥18), who signed the informed consent (n=117) were included. Sociodemographic, comorbidity, disease and foot health variables, as well as two self-administered questionnaires (Foot Health Status Questionnaire and Foot Function Index) were studied. The current ethical-legal aspects were followed. Results. Foot health problems were highly prevalent, highlighting nail color changes (60.3%), onychocryptosis (39.7%), xerosis (62.1%), plantar fasciitis (12.9%), and neuropathic symptoms (75.2%). Some foot pain was presented in 77.8% of the sample, predominantly at nail level (15.4%) or sole of the foot and nail (14.5%). Most participants described their foot health as fair or poor (56.4%) and felt limited in walking (65.8%). The lowest score for the Foot Health Status Questionnaire was footwear (32.5±42.1). Conclusions. Foot health adverse effects represent worrisome problems in women with breast cancer undergoing chemotherapy, due to their high prevalence and negative implications on quality of life. These problems are critical as they may have implications for stopping or reducing chemotherapy. All these results call for the development of more research to contribute to the care and wellbeing of people with cancer who receive treatments such as chemotherapy. Thus, this line of research is a new path to be developed by the podiatry community.

Even though more than two years have passed since the emergence of COVID-19, the research for novel or repositioned medicines from a natural source or chemically synthesized is still an unmet clinical need. In this review, the application of supercritical fluids to the development of novel or repurposed medicines for COVID-19 and their secondary bacterial complications will be discussed. We envision three main applications of the supercritical fluids in this field: (i) drug micronization, (ii) supercritical fluid extraction of bioactives and (iii) sterilization. The supercritical fluids micronization techniques can help to improve the aqueous solubility and oral bioavailability of drugs, and consequently, the need for lower doses to elicit the same pharmacological effects can result in the reduction in the dose administered and adverse effects. In addition, micronization between 1 and 5 µm can aid in the manufacturing of pulmonary formulations to target the drug directly to the lung. Supercritical fluids also have enormous potential in the extraction of natural bioactive compounds, which have shown remarkable efficacy against COVID-19. Finally, the successful application of supercritical fluids in the inactivation of viruses opens up an opportunity for their application in drug sterilization and in the healthcare field.

The enamel defects, hypoplasia and hypo mineralization, are classified as dental anomalies of structure, being frequently found in deciduous and permanent dentitions, since the permanent teeth and second deciduous molars finish their total mineralization after the age of three. The aim of the present study was to identify the presence of hypo mineralization and/or enamel hypoplasia and to associate it with respiratory problems in infant patients. Of the 90 patients evaluated, it was found that 23 male children (57.5%) and 22 female children (44%) had defects in the structure of tooth enamel. Most children were born by cesarean operation (64.4%), with no complications during birth (90.0%), 12.2% of children had dental anomalies (agenesis, ectopic canine, ankylosis, fusion, conoid tooth, and macrodontia, only 7 children showed an association between dental anomalies and enamel defects. Regarding respiratory problems that occurred up to 3 years of age, 38.9% had an episode of asthma, bronchitis, sinusitis, rhinitis, or pneumonia, and 55% had similar results at the current age. There was a positive association (Chi-square tests) between the presence of changes in the structure of tooth enamel and the presence of respiratory problems up to 3 years of age (p

Summary Background Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy. Methods We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I–IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration–time curve 6 mg/mL per min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2–6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov ( NCT03161353 ), and is ongoing. Findings Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3–6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6–44·5; p Interpretation 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy. Funding F Hoffmann-La Roche.

Background Pembrolizumab has modest activity if used in patients with hormone-receptor–positive (HR+), HER2-negative, previously treated metastatic breast cancer (BC). Our study investigated whether there would be any clinical benefit in combining chemotherapy with pembrolizumab in a similar patient population. Methods This single-arm, phase Ⅱ trial enrolled women aged ≥18 years with HR+, HER2-negative, inoperable, locally recurrent or metastatic BC. Patients were previously treated with hormonal therapy and 1–2 chemotherapy regimens for locally recurrent and/or metastatic BC. On each 21-day cycle, patients received intravenous pembrolizumab 200 mg on day 1 and eribulin 1∙23 mg/m2 on days 1 and 8. The primary endpoint was the clinical benefit rate. Analysis of safety and activity was carried out in all patients who met the screening criteria and received at least 1 dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT03222856. Results Of the 44 patients enrolled between January 29 and October 17, 2018, clinical benefit was achieved in 25 (56∙8%, 95% confidence interval [CI]: 41∙0–71∙7), objective response in 18 (40∙9%, 95% CI: 26∙3–56∙8), median progression-free survival was 6∙0 months (95% CI: 3∙7–8∙4), and 1-year overall survival was 59∙1% (95% CI: 45∙8–76∙2). The most common treatment-emergent adverse events (AEs) of any grade were neutropenia (20 [45∙5%]), anaemia (17 [38∙6%]), alopecia (19 [43∙2%]), asthenia (19 [43∙2%]), diarrhoea (14 [31∙8%]), fatigue (14 [31∙8%]), and peripheral neuropathy (12 [27∙3%]). Serious AEs occurred in 14 (31∙8%) patients including febrile neutropenia (3 [6∙8%]), neutropenia (2 [4∙5%]), fever (2 [4∙5%]) and peripheral neuropathy (2 [4∙5%]). Immune-related AEs occurred in 11 (25∙0%) patients. One (2∙3%) patient died of cardiac arrest unrelated to study treatment. Conclusion Pembrolizumab plus eribulin demonstrates encouraging antitumour activity in patients with heavily pre-treated, HR+, HER2-negative, locally recurrent or metastatic BC. The safety and tolerability of the combination is similar to eribulin or pembrolizumab monotherapy.

There are contradictory data regarding the correlation between HER2 amplification level determined by in situ hybridization and evolution after treatment with anti-HER2 therapies. The aim of this study was to correlate quantitative results of FISH (ratio HER2/CEP17 and number of HER2 signals/nucleus) with pathological response achieved after neoadjuvant treatment with trastuzumab and chemotherapy. For this purpose, we analysed 100 consecutive HER2-positive cases of breast carcinoma treated with neoadjuvant therapy. HER2 amplification determined by FISH was found in 92 of the 100 cases studied. pCR was obtained in 58% of the patients whose tumours presented amplification. In contrast, no pCR was obtained in the 8 patients with non-amplified tumours. A significant direct correlation between HER2 high amplification (HER2/CEP17 ratio > 5 or HER2 signals/nucleus > 10) and pCR was found. In conclusion, HER2 amplification levels are clinically relevant because they provide oncologists with valuable information on the possibilities of achieving pCR after neoadjuvant treatment.

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.

INTRODUCTION AND OBJECTIVES Palbociclib associated with hormone therapy (HT) has shown significant benefit in progression-free survival (PFS) and response rate versus HT alone in patients with HR+, HER2- MBC. The PALBOSPAIN study evaluates the efficacy and safety of palbociclib treatment under real-life conditions. The main objective of the study was to assess PFS, and secondary objectives were overall survival (OS), response rate, time to next line of treatment, percentage of dose reduction and safety. MATERIAL AND METHODS This is an observational, ambispective, multicenter, nation-wide study. Patients diagnosed with HR+/HER2- MBC who had started first-line treatment with palbociclib between November 2017 and November 2019 were included. Patients treated within a clinical trial were excluded, as were those who had received any previous systemic treatment for advanced disease. RESULTS 762 patients from 35 centers were included. 79% (n=600) were postmenopausal, 54.9% (n=418) had visceral disease, and 30.6% (n=233) had de-novo metastatic disease. Palbocliclib was combined with an aromatase inhibitor in 69.6% of patients and fulvestrant in 30.2% Four groups were established to assess efficacy (table 1): overall population; patients with de-novo metastatic disease (cohort A); patients relapsing >12 months after the end of adjuvant hormonal therapy (cohort B); and patients relapsing within 12 months after the end of adjuvant hormonal therapy (cohort C). Median PFS was 24 months (CI 95%; 25-27) overall and 28 (IC 95%; 23-39), 29 (IC 95%;25-35) and 14 months (IC 95%;11-17) for cohorts a, B and C, respectively. Median overall survival was 42 months (40-NA). The most common side effects were neutropenia (71.3%, grade 3-4 in 52.5%, no episodes of febrile neutropenia), fatigue (38.6%), leucopenia (29.8%), anemia (28.9%), articular pain (19%), and thrombocytopenia (2,2%). 49% (n=385) of patients required dose reduction of palbociclib (one level in 27.6% and two levels in 21.4%). CONCLUSION In the first two years after its approval in Spain, palbociclib in first line of HR+/HER2- MBC in real-life conditions yielded PFS and safety results comparable to those of PALOMA 2 and PALOMA 3 clinical trials. OS results were poorer, although the population included in this retrospective study is heterogeneous and median survival values have not been reached in some subgroups. Table 1. Efficay results of palbociclib in real world Citation Format: Noelia Martínez-Jáñez, Meritxell Bellet Ezquerra, Fernando Henao, Luis Manso, Antonio Antón, Pilar Zamora, Serafin Morales Murillo, Pablo Tolosa, Raquel Andrés, Lourdes Calvo, Elena Galve, Rafael Lopez, Francisco Ayala de la Peña, Sara López-Tarruella, Laia Boronat, Tamara Martos, J. Ignacio Chacón, Isabel Álvarez, Juan de la Haba-Rodríguez, Fernando Moreno Antón. PALBOSPAIN: OBSERVATIONAL ANALYSIS OF FIRST-LINE THERAPY WITH PALBOCICLIB IN PATIENTS WITH HR+/HER2- METASTATIC BREAST CANCER (MBC) IN REAL-LIFE CONDITIONS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-28.

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).

As more genes are incorporated into pharmacogenomic care processes and more importance is given to rare variants, the use of targeted capture sequencing panels has been proposed as a very efficient alternative due to their affordability, high throughput, and deep coverage, all of them characteristics of high-quality next-generation sequencing data. The purpose of this study is to describe the prevalence of clinically actionable pharmacogenetic variants previously described in the scientific literature, as well as that of new variants identified by next-generation sequencing technologies, and to evaluate the drugs potentially affected by such variants.A panel of 18 clinically actionable pharmacogenomics-related genes was evaluated in 41 subjects diagnosed with breast cancer undergoing neoadjuvant treatment. The prevalence of previously descri- bed clinically actionable variants as well as of phenotypes classified according to current interpretation standards was studied. The pharmacological treatments potentially affected by the identified variants were also evaluated. An estimation was made of the prevalence of not previously described, possibly deleterious, variants selected using bioinformatics criteria.All subjects carried clinically actionable variants, with a mean of 4.02 genes affected by each variant per individual. VKORC1, CYP4F2, CYP2C19, CYP2D6 and CYP2B6 were the most polymorphic genes and were present with actionable phenotypes in more than 50% of patients; 15-50% had actionable phonotypes in UGT1A1, SLCO1B1, CYP2C9 and TPMT and 2-15% in HLA-B, CYP3A5, HLA-A and DPYD. No actionable variants were identified in RYR1, CACNA1S, G6PD, F5 and NUDT15. These variants had the potential to affect response to 84% of the drugs described in the leading pharmacogenetic guidelines. Possibly deleterious variants not previously described accounted for 11.4% of all clinically actionable variants and were present in 12.2% of patients.The results obtained show a high prevalence of clinically actionable variants, both common, i.e., previously described in the literature, and rare, i.e., not previously studied with conventional technological approaches. The latter are candidates for a more exhaustive molecular and/or clinical characterization.A medida que se incorporan más genes a los procesos farmacogenómicos asistenciales y se otorga más importancia a las variantes raras, el uso de paneles de secuenciación dirigida por captura se ha propuesto como una alternativa muy eficiente atendiendo a sus costes, su rendimiento y la cobertura profunda, característica de los datos de secuenciación de nueva generación de alta calidad. El objeto de este trabajo es describir la prevalencia de variantes farmacogenéticas clínicamente procesables descritas previamente en la literatura científica, así como de nuevas variantes identificadas mediante tecnologías de secuenciación de nueva generación y evaluar los fármacos potencialmente afectados por estas variantes.Método: Se evaluó un panel de 18 genes relacionados con la farmacogenómica clínicamente procesables en 41 individuos con diagnóstico de cáncer de mama que van a recibir tratamiento adyuvante y neoadyuvante. Se estudió la literatura científica, así como de los fenotipos farmacogenéticos clasificados según los estándares de interpretación actuales. Asimismo, se evaluaron los tratamientos farmacológicos potencialmente afectados por las variantes identificadas. Se estimó la prevalencia de variantes posiblemente deletéreas no descritas previamente seleccionadas con criterios bioinformáticos.Todos los individuos fueron portadores de variantes clínicamente procesables, con una media de 4,02 genes afectados por alguna variante por individuo. Los genes VKORC1, CYP4F2, CYP2C19, CYP2D6 y CYP2B6 fueron los más polimórficos, con más de un 50% de pacientes con fenotipos procesables; un 15-50% en UGT1A1, SLCO1B1, CYP2C9 y TPMT y un 2-15% HLA-B, CYP3A5, HLA-A y DPYD. No se identificaron variantes procesables en RYR1, CACNA1S, G6PD, F5 y NUDT15. Estas variantes afectarían a la respuesta de un 84% de los fármacos descritos en las principales guías de farmacogenética. Las variantes posiblemente deletéreas no descritas previamente supusieron un 11,4% del total de variantes clínicamente procesables y están presentes en un 12,2% de los pacientes.Los resultados obtenidos constatan una alta prevalencia de variantes clínicamente procesables tanto comunes, previamente descritas en la literatura, como raras, no estudiadas con abordajes tecnológicos convencionales y candidatas a una caracterización molecular y/o clínica más exhaustiva.

The ideal technique for lymph node staging for patients with pathologically confirmed node-positive breast cancer at diagnosis and neoadjuvant chemotherapy (NAC) is unclear. The aim of this study was to analyze the feasibility of wire/clip localization and sentinel lymph node biopsy (SLNB) for the axillary staging of these patients. We conducted a prospective study in which lymph node staging was performed using wire localization of positive lymph nodes and an SLNB with dual tracer. All patients who presented no metastatic involvement of the sentinel lymph node (SLN) or clip/wire-marked lymph node were spared an axillary lymph node dissection (ALND). The multidisciplinary committee agreed on axillary treatment for patients with lymph node involvement. Forty-two patients met the inclusion criteria. We identified and extirpated the clip/wire-marked node in all patients (100%), with SLNB performed successfully in 95.3% of patients. The SLN and wire-marked node matched in 80% of patients; 73.8% of patients did not undergo ALND. Several studies have evaluated the efficacy of various procedures for lymph node marking for women with prechemotherapy lymph node involvement. Most of the studies reported high identification rates (> 94.8%), with false negative rates of

O objetivo é avaliar a frequência dos traumatismos em dentes decíduos, as sequelas advindas das injúrias envolvendo os tecidos de sustentação, bem como a associação destas injúrias às sequelas clínicas e radiográficas. Trata-se de um estudo clínico longitudinal, no qual foram avaliados 342 dentes traumatizados, atendidas no serviço odontológico de uma instituição pública, as avaliações foram realizadas após o traumatismo e decorrido 24 meses. Os dados foram submetidos a uma análise descritiva e ao teste Qui-quadrado (p≤0,05). A maior frequência de traumas acorreu na idade 24-35 meses, o principal fator etiológico à queda da própria altura (77,8 %), gênero masculino (59,5%), arco dentário o superior (96,5%), dente 51 (43,1%); 70,6% possuíam mais de um dente afetado e 8,2% histórico de trauma; a injúria mais prevalente foi a luxação lateral (33,6%). Na proservação, houve associação entre tipo de injúria ao tecido de suporte com a presença de sequelas radiográficas (p=0,02) e perda precoce (p=0,01). Conclui-se que as principais sequelas observadas foram a descoloração coronária e reabsorção radicular inflamatória e houve associação significante entre as variáveis tipo de injúria ao tecido de sustentação com a presença de sequelas radiográficas e a perda precoce do dente decíduo traumatizado.

Objectives: To evaluate the efficacy and cardiotoxicity profile of liposomal anthracycline or Carboplatin as part of neoadjuvant therapy added to taxanes and dual blockade in HER2-positive operable breast cancer patients. Methods: A total of 60 patients diagnosed from August 2016 to May 2019 were included in the study. The treatment consisted of a sequential regimen of taxanes and non- pegilated liposomal anthracycline (Myocet) plus trastuzumab and pertuzumab, or taxanes in combination with carboplatin plus trastuzumab and pertuzumab. The clinical and pathologic responses were evaluated and correlated with clinical and biological factors. Pathologic complete response was defined as the total absence of invasive tumor in both breast and axillary nodes (ypT0/is ypN0).The cardiotoxicity profile was also analyzed. Results: The median age was 52(26-77) years and 5%, 62% and 33% of patients had stage I, II and III breast cancer, respectively, while 7% had inflammatory breast cancer at diagnosis. Hormone receptor (HR) status was negative in 48%, and 65% and 50% had grade III and ki-67 value up to 35%, respectively breast cancer. 65% of patients received weekly paclitaxelx12-trastuzumab-pertuzumab followed by Myocet-cyclophosphamide with -trastuzumab x 4 cycles or this sequence but beginning with the anthracycline, 23% of patients the same regimen but with pertuzumab concurrently with all chemotherapy treatment. The remaining 12% received docetaxel-carboplatin x6 cycles plus trastuzumab and pertuzumab. All treatment was administered previous surgery. The clinical complete response rate, was 57% and 63%, as assessed using ultrasound and MRI, respectively, and this allowed a high rate of conservative surgery (60%). The pathologic complete response (pCR) rate was 52%, and it was higher in HR-negative (61%) than in HR-positive (39%), in grade 3 (71%) than in grade 2(29%) tumors. There were not statistical significant differences in pCR between different chemotherapy treatments. Five patients showed a 10% decrease in left ventricular ejection fraction (LVEF) to below 50% at the end of neoadjuvant treatment. Asymptomatic drops in 2 patients and with heart failure symptoms in 3 of them. Myocet was part of chemotherapy in all of them. All patients recovered after discontinuation of adjuvant trastuzumab and heart medication. Two of these patients did not complete all preplanned adjuvant trastuzumab doses. Conclusion: A sequential regimen of taxanes and non-pegilated liposomal anthracycline or carboplatin plus trastuzumab and pertuzumab was effective, with high pCR rates and a good cardiotoxicity profile. Citation Format: Silvia Antolin, Cristina Reboredo, Rocío Lesta, Aurea Molina, Joaquin Mosquera, Patricia Cordeiro, Eva Pérez, Lourdes Calvo. Myocet or carboplatin as part of chemotherapy in HER2-positive operable breast cancer treated with trastuzumab and pertuzumab in the neoadjuvant setting: Efficacy data and cardiotoxicity in 60 patients diagnosed from 2016-2019 at a single institution [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-28.

Background: Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) recur after standard treatment, while the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously developed and validated an MHCII Immune Activation assay, which measures a gene expression signature that includes the major histocompatibility complex class II (MHCII) pathway genes and markers of activated tumor infiltrating lymphocytes. The MHCII Immune Activation assay was recently shown to accurately assess the risk of recurrence in Basal-like TNBC patients using FFPE tissues from an institutional cohort. A limitation of the previous study is that the patients’ treatment regimens in the institutional cohort were heterogeneous. The goal of this study was to determine if the MHCII Immune Activation assay can accurately assess the DFS in Basal-like TNBC patients who received uniform chemotherapy regimens in the context of a randomized clinical trial. Methods: The MHCII Immune Activation assay was applied to RNA isolated from 60 Basal-like TNBC FFPE specimens from the GEICAM/9906 clinical trial, a multicenter randomized phase III study evaluating adjuvant chemotherapy in node-positive operable BC patients. Thirty nine (65%) of the patients were treated with fluorouracil, epirubicin, and cyclophosphamide (FEC), and 21 (35%) patients received FEC followed by paclitaxel (FEC-P) (median follow-up 9.7 years). The MHCII Immune Activation Score was calculated from the assay using methods described previously, and patients were categorized into a High Risk of Recurrence (High ROR) group using pre-specified thresholds. The association between the MHCII Immune Activation Score and DFS was assessed using Kaplan-Meier analysis and cox proportional hazards models. Results: Across both arms, 32/60 (53.3%) patients were classified into the High ROR group based on their Low MHCII Immune Activation Scores. Patients in the High ROR group had significantly shorter DFS (Hazard Ratio (HR)=2.9 (CI95%:1.27-6.66), p-value=0.0081). Cox proportional hazard regression of the log10 transformed MHCII Immune Activation Score confirmed that MHCII Immune Activation Score is significantly associated with DFS (Wald Test p=0.0127). In the FEC arm, there were 22/39 (56.41%) patients classified into the High ROR group (Low MHCII Immune Activation Score). Patients in the High ROR group in the FEC arm showed a trend toward shorter DFS (HR=1.99 (CI95%:0.74-5.31)), but it was not significant (p-value=0.1595). In the FEC-P arm, there were 10/21 (47.62%) patients classified into the High ROR group (Low MHCII Immune Activation Score). Patients in the High ROR group in the FEC-P arm had significantly shorter DFS (HR=6.28 (CI95%:1.28-30.73), p-value=0.0111). Larger cohorts will be needed to confirm if the association between DFS and MHCII Immune Activation Score is stronger when patients are treated with chemotherapy regimens that include paclitaxel. Conclusions: The MHCII Immune Activation assay can be applied to RNA from FFPE tumor specimens to assess risk of recurrence in TNBC patients. The MHCII Immune Activation Score is associated with risk of recurrence in TNBC patients treated with uniform adjuvant chemotherapy regimens. Citation Format: Miguel Martín, Katherine L Updike, Alvaro Rodríguez-Lescure, Lourdes Calvo, Jesús Herranz, Nuria Martín, Philip S Bernard, Katherine E Varley. The MHCII immune activation assay is prognostic for disease free survival in basal-like TNBC breast cancer patients in the GEICAM/9906 clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-09.

BACKGROUND: Studies of checkpoint inhibitor monotherapy have shown only modest activity in hormone receptor (HR)-positive (+)/human epidermal growth factor receptor 2 (HER2)-negative (-) metastatic breast cancer (MBC). However, pembrolizumab (P) added to standard neoadjuvant therapy significantly improved the estimated pathologic complete response rate in HR+/HER2- early breast cancer in the I-SPY-2 trial. The KELLY trial aimed to evaluate the efficacy and safety of P in combination with eribulin (E) in anthracycline- and taxane-pretreated patients (pts) with HR+/HER2- inoperable locally recurrent or MBC irrespective of programmed death-ligand 1 (PD-L1) status. METHODS: This is an open-label, single-arm, multicenter phase IIA clinical trial (ClinicalTrials.gov identifier: NCT03222856). Eligible pts had HR+/HER2- inoperable locally recurrent or MBC, who were previously treated with endocrine therapy and at least one, but not more than two, prior chemotherapeutic regimens for treatment of locally recurrent and/or metastatic disease, and with prior anthracycline/taxane exposure either in the early or metastatic setting. Pts received E 1.23 mg/m2 intravenously (IV) on days 1 and 8 with P 200 mg fixed dose IV on day 1 of a 21-day cycle until unacceptable toxicity or disease progression. Primary endpoint was clinical benefit rate (CBR). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety and tolerability of the combination. Exploratory objectives included: (1) the analysis of PFS and ORR based on immune-related RECIST (irRECIST) and (2) the associations of PFS and OS to CBR/ORR, prior exposure to CDK4/6, mTOR, or PI3K inhibitors, PD-L1 status, tumor-infiltrating lymphocytes (TILs), gene signatures, mutational load, and circulating tumor cells. RESULTS: Between January 2018 and October 2018, 44 pts were enrolled in the study. The median age was 54.1 years (range: 46-60.5 years), 70.5% were ECOG 0, 90.1% had visceral disease (86.4% with liver metastases), and 54% with ≥3 involved organ sites. The median number of prior endocrine therapies was two (range: 1-6) and 52.3% of patients had previously received two chemotherapeutic regimens for treatment of locally recurrent and/or MBC. With a median follow-up of 6.64 months (mo.) (range: 1-14.2 mo.), E and P combination met primary endpoint (CBR 53.7%, 95%CI: 36.9-67.3%). ORR and median PFS were 36.4% (95%CI: 22.8-52.3%) and 6.03 mo. (95%CI: 3.7-8.4 mo.), respectively. All-cause adverse events occurred in 100% of pts (G3-4, 56.8%), without treatment-related deaths. ORR and median PFS based on irRECIST were 36.4% (95%CI: 22.8-52.3%) and 6.1 mo. (95%CI: 4.2-8.5 mo.), respectively. OS data are immature (13 deaths, 29.5%). A significant difference in median PFS has been observed between pts with and without clinical benefit (8.5 Vs. 2.2 mo., p TABLE 1Prior treatmentNEvents (%)Median PFS, mo. (95%CI)p-valueCDK4/6 inhibitorsNo2316 (69.2)6 (3.7-10.4)0.832Yes2115 (71.4)6.1 (2.5-NA)mTOR or PI3K inhibitorsNo2620 (76.9)6 (3.7-8.47)0.727Yes1811 (61.1)6 (2.5-NA) Citation Format: José Manuel Pérez-García, Antonio Llombart-Cussac, Esther Holgado, Giuseppe Curigliano, Elena López Miranda, José Luis Alonso-Romero, Begoña Bermejo, Lourdes Calvo, Vicente Carañana, Susana de la Cruz Sánchez, María Gión Cortés, Raúl Márquez Vázquez, Aleix Prat, Manuel Ruiz Borrego, Miguel Sampayo, Miguel Àngel Seguí, Jesus Soberino, Andrea Malfettone, Peter Schmid, Javier Cortés. A phase II study of pembrolizumab and eribulin in patients with HR-positive/HER2-negative metastatic breast cancer previously treated with anthracyclines and taxanes (KELLY 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 P3-09-03.

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.

Objective: To assess in situ the effect of fluoride associated with nano-hydroxyapatite for the prevention of demineralization of the enamel adjacent to orthodontic brackets. Material and Methods: Eight volunteers wore palatal devices prepared with 6 bovine enamel blocks (5x5x2 mm) with bonded brackets. The volunteers used the devices in two different moments of 14 days each. During the first 14 days, a product containing fluoride + nano-hydroxyapatite was applied twice (experimental group, GNH, n = 48), and for the other 14 days no prevention product was applied (control group, CG, n = 48). In both groups, along the experiment, the blocks were dripped with 20% sucrose eight times daily. After the experiment, all the specimens were sectioned and examined for lesion depth analysis (µm) under polarized light microscopy, and for enamel longitudinal microhardness (measured under the bracket, at 30 µm and at 130 µm from the margin), at seven different depths (10, 20, 30, 50, 70, 90, and 110 µm). Results: Under polarized light, group GNH presented significantly less demineralization depth ( X ¯= 15.01 µm, SD = 33.65) in relation to CG ( X ¯= 76.43 µm, SD = 83.75). Enamel longitudinal microhardness demonstrated significantly higher microhardness for group GNH when compared to CG. Conclusion: Fluoride + nano-hydroxyapatite can be an alternative preventive procedure for demineralization of the enamel adjacent to orthodontic brackets. RESUMO Objetivo: avaliar in situ o efeito da nano-hidroxiapatita associada ao fluoreto na prevenção da desmineralização do esmalte adjacente aos braquetes ortodônticos. Material e Métodos: oito voluntários utilizaram aparelhos palatinos preparados com seis blocos de esmalte bovino (5 x 5 x 2 mm) com braquetes colados unidos por um fio de NiTi 0,016” preso por ligaduras elásticas. Os voluntários utilizaram os dispositivos em dois tempos distintos de 14 dias. Durante os primeiros 14 dias, um produto contendo flúor + nano-hidroxiapatita foi aplicado duas vezes (grupo experimental, GNH, n = 48), e nos outros 14 dias não foi aplicado qualquer produto de prevenção (grupo controle, GC, n = 48). Em ambos os grupos, ao longo do experimento, os blocos foram gotejados com sacarose a 20%, 8 vezes ao dia. Após o experimento, todos os espécimes foram seccionados e examinados para análise de profundidade de lesão (µm), sob microscopia de luz polarizada, e para microdureza longitudinal do esmalte do braquete (a 30µm e a 130µm da margem), a 7 profundidades diferentes (10, 20, 30, 50, 70, 90 e 110µm) Resultados: sob luz polarizada, o grupo GNH apresentou significativamente menor profundidade de desmineralização ( X ¯= 15,01µm, D.P. = 33,65) em relação ao GC ( X ¯= 76,43µm, D.P. = 83,75) A microdureza longitudinal do esmalte demonstrou valor significativamente maior para o grupo GNH, quando comparado ao GC. Conclusão: a nano-hidroxiapatita associada ao fluoreto pode ser um procedimento alternativo para a prevenção da desmineralização do esmalte adjacente aos braquetes ortodônticos.

Maintaining a functional natural dentition plays an important role in keeping a satisfactory nutritional status. The aim of this study was to evaluate the relationship between oral health conditions determined by the presence of edentulism and the number of missing teeth, nutritional status and consumption of nutrients by the elderly. This cross-sectional study comprised 494 independent elderly of both genders, over 60 years of age, registered at the Brazilian public health service in Londrina, southern Brazil. The data collection included: oral examinations; anthropometric measurements by calculating the Body Mass Index (BMI); analysis of food consumption based on a multiple pass 24-hour dietary recall and a food intake frequency questionnaire; and structured interviews to obtain sociodemographic information. Multiple linear regression, the Fisher’s Exact test, chi-square and Mann‑Whitney tests, were applied at a 5% significance level. The prevalence of edentulism was 47.3%; this predominated in females, age group from 65 to 74 years, low education level and low/medium economic classification. A larger number of underweight and fewer number of overweight elderly were recorded among the edentulous versus dentate participants (< 0.0001). Significantly lower consumption of several nutrients, as well as fruit, was recorded among the edentulous group. In particular, carbohydrates, vitamins (B1, B9 and C), and the majority of the minerals studied were associated with a larger number of missing teeth. In conclusion, tooth loss was associated with the food consumption pattern of some macro- and micronutrients and the nutritional status of the Brazilian elderly.

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).

Au/SiO2 SBA-15 materials were prepared using supercritical CO2 (scCO2) and by wet impregnation. First, SiO2 SBA-15 was functionalized with thiol groups at different grafting densities using 3-(Mercaptopropyl)trimethoxysilane dissolved in scCO2. The support was then impregnated with HAuCl4·3H2O in scCO2 modified with EtOH. Wet impregnation of the supports with HAuCl4·3H2O in ethanol was also performed. Materials were calcined at 500 ºC to remove the organic matter and promote particle growth. Materials prepared on the highest thiol grafting density support showed Au NP between 2.5-5 nm homogeneously distributed within the mesopores. Slightly larger Au NPs were obtained in scCO2 modified with EtOH. Materials prepared on the low thiol grafting density support showed a bimodal particle size distribution with particles up to 7 nm located inside the mesopores and larger ones of 10-20 nm on the external surface. A possible reaction mechanism was proposed. These materials can be used in catalysis, sensing and biomedicine.

The presence of tens of Clostridium botulinum spores per gram of honey can cause infantile botulism. Thermal treatment is insufficient to inactivate these resistant forms. This study explored the effectiveness of supercritical CO2 (scCO2) on its own and combined with lemon (LEO), clove (CLEO), and cinnamon (CEO) essential oils on the inactivation of Clostridium sporogenes (CECT 553) as a surrogate of Clostridium botulinum. In water, the degree of inactivation at 10 MPa after 60 min increased with the increasing temperature, reducing the population by 90% at 40 °C and by 99.7% at 80 °C. In contrast, when applied to honey, scCO2 did not inactivate Clostridium spores satisfactorily at temperatures below 70 °C, which was related to the protective effect of honey. Meanwhile, scCO2 modified with CEO (

Purpose Because the currently available questionnaires to evaluate sexual changes on breast cancer women only address the sexual sphere with a few questions our purpose was to develop a questionnaire that assesses changes in sexual dysfunction and satisfaction in women treated for breast cancer. Methods A sample was selected of women aged between 18 and 65 who had had surgery for breast cancer, completed neoadjuvant/adjuvant chemotherapy treatment and could be receiving adjuvant hormonal treatment, with an active sex life at least 3 months before starting treatment. Metastatic disease was excluded. A questionnaire structured in 4 dimensions was developed. The MOS SF-12 and QLQ-BR23 questionnaires were also provided. The following metric properties were evaluated: item analysis; internal consistency; temporal stability; construct validity; concurrent, convergent and divergent validity; and feasibility. Results Three samples were recruited: a pilot sample of 20; a reduction sample of 152; and a validation sample of 148. The presence of 6 dimensions was confirmed: 1) Loss of sex drive; 2) worsening of body image; 3) psychological coping; 4) discomfort during intercourse; 5) satisfaction with sexual relations; and 6) satisfaction with breast reconstruction. Good goodness-of-fit statistics were obtained (χ2/df = 1.5, GFI = 0.9, AGFI = 0.84, CFI = 0.959, RMSEA = 0.062). Reliability was good (α = 0.855), as was test–retest stability (r = 0.838). The correlation with the convergent questionnaires proved to be higher than that obtained with generic measurements. Conclusions We were able to develop a short questionnaire (17 items) capable of measuring sexual satisfaction in women with breast cancer with good metric properties. Electronic supplementary material The online version of this article (10.1186/s12955-019-1197-7) contains supplementary material, which is available to authorized users.

Supercritical emulsions extraction (SEE) technology was used to encapsulate astaxanthin (AXT) in ethyl cellulose (EC). The operating parameters were 8 MPa and 311 K with an L/G ratio of 0.1 (CO2 flow rate of 1.4 kg/h). Several emulsion formulations were tested, fixing the oil-water ratio at 20:80 (ethyl acetate/water) and varying EC concentration in the oily phase from 1.0–2.5% mass and the surfactant amount in the water phase from 0.1 to 0.6% mass. Both parameters influenced carriers morphology, size and distribution; a correlation between the EC amount in oily phase and its dynamic viscosity was proposed to explain the droplets/carriers size variation observed. Carriers aggregation was monitored at surfactant concentration higher than 0.3% mass. The best emulsion formulation was obtained using 1.0% mass of EC in the oily phase and 0.1% mass of surfactant in the water phase; in these conditions spherical nanocarriers with unwrinkled and smooth surface were obtained with a size of 242 nm and Poly Dispersity Index of 0.16. EC mass recovery was of 90%. Higher carrier mean size of 363 nm (Poly Disperity Index of 0.31) was measured when AXT was encapsulated in the same conditions, achieving an encapsulation efficiency of 84%. The carriers were loaded with 21 mg/g of AXT and showed an excellent antioxidant capacity, measured as Trolox equivalent (Trolox equivalent per kg of pure AXT), and equivalent to 3900 M Trolox. In vitro release profiles obtained in a simulated intestinal fluid (SIF) at pH 7.2 and 310 K, showed a release of 70% of the total encapsulated AXT after 10 h.

The Hansen solubility theory was used to predict the best cosolvent for supercritical carbon dioxide (sc-CO2) to achieve the selective extraction of β-carotene from Dunaliella salina. Among four organic cosolvents, ethanol was predicted to be the best based on minima Ra values. The predictions were validated through equilibrium data and extraction curves from the microalgae. The addition of ethanol reduced the bubble pressures, and therefore increased the solubility of the β-carotene. With 5% mass fraction, at 318.15 K and 20 MPa, the extraction yield was 25 g carotenoids kg microalgae−1, much more than in pure sc-CO2 (6 g).

Background Copy Number Alterations (CNAs) represent changes in the copy number of genomic segments of somatic cells due to chromosomal instability. CNAs include gene amplifications or deletions and can be involved in tumorigenesis. We analyzed CNAs data in pre- and post-treatment (ttm) tumors from patients (pts) with early breast cancer (BC) in the neoadjuvant trials GEICAM/2006-03 and GEICAM/2006-14, with the aim to identify CNAs in particular genomic regions (genetic entropy) associated with treatment response. Methods GEICAM/2006-03 (NCT00432172) HER2-negative pts were selectively treated according to clinical subtypes: triple negative (TN) pts were treated with standard anthracycline/taxane -based chemotherapy (AT-CT) +/- carboplatin, while luminal patients were randomized to AT-CT vs. hormonotherapy; GEICAM/2006-14 (NCT00841828) HER2+ pts received AT-CT plus anti-HER2 therapy.Shallow-whole genome Illumina sequencing DNA data from 204 paraffin-embedded tumors (100 pre- and 104 post-ttm) were segmented to obtain CNAs and recurrent altered genomic regions were defined. We used Wilcoxon test to analyze the frequency of altered regions and logistic regression analyses to explore their association with tumor response, in terms of pathological complete response (pCR) in breast and axilla. Validation of altered genes associated with therapy response was performed in the microarray gene expression-based Hatzis dataset (GSE25066) from pts receiving neoadjuvant AT-CT (1). Results A total of 672 regions covering the whole genome were identified upon analysis of CNAs data. Regions were categorized according to their alteration status as amplified, normal and lost. Comparative analysis of alterations revealed 11 regions significantly different (p Conclusions According to our results, neoadjuvant therapy can modulate genomic aberrations landscape in BC. Our data suggest that amplification of specific genes in the genomic locus (21q22.12) is involved in the neoadjuvant therapy response in early BC. (1): Hatzis et al., JAMA 2011, 305(18) 1873-81 Citation Format: Alba E, Rueda OM, Lluch A, Albanell J, Chin S-F, Chacón JI, Calvo L, De la Haba-Rodriguez J, Bermejo B, Ribelles N, Sánchez-Rovira P, Plazaola A, Barnadas A, Cirauqul B, Ramos M, Arcusa A, Carrasco E, Herranz J, Chiesa M, Caballero R, Santonja A, Rojo F, Caldas C. Genome copy number entropy as predictor of response for neoadjuvant therapy in early 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 P5-12-03.