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In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I–IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0–1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427. Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2–206·0). At surgery, 23 (46·9%; 95% CI 32·5–61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9–61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3–4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3–4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.

Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment. Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples. 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most. Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.

Background The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. Methods Postmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. Results Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p  = 0.001) and mVNB (− 19.1%; p  < 0.001). The anti-proliferative effect of LTZ+mVNB (− 73.2%) was numerically higher compared to LTZ (− 65.7%) but did not reach statistical significance ( p  = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p  = 0.049) and LTZ+mVNB ( p  = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. Conclusions Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. Trial registration NCT02802748 , registered 16 June 2016.

Horses have inhabited Iberia (present-day Spain and Portugal) since the Middle Pleistocene, shaping a complex history in the region. Iberia has been proposed as a potential domestication centre and is renowned for producing world-class bloodlines. Here, we generate genome-wide sequence data from 87 ancient horse specimens (median coverage = 0.97X) from Iberia and the broader Mediterranean to reconstruct their genetic history over the last ~26,000 years. Here, we report that wild horses of the divergent IBE lineage inhabited Iberia from the Late Pleistocene, while domesticated DOM2 horses, native from the Pontic-Caspian steppes, already arrived ~1850 BCE. Admixture dating suggests breeding practices involving continued wild restocking until at least ~350 BCE, with IBE disappearing shortly after. Patterns of genetic affinity highlight the far-reaching influence of Iberian bloodlines across Europe and north Africa during the Iron Age and Antiquity, with continued impact extending thereafter, particularly during the colonization of the Americas. Horses have lived in Iberia since the Ice Age. Using ancient genomes to study their history, Lira Garrido et al. reveal a local wild lineage lasting until Late Iron Age, and highlight the far-reaching influence of Iberian bloodlines across Europe and north Africa during the Iron Age and beyond.

Co-occurrence of depression and a substance use disorder (SUD) in patients who present dual diagnoses has been long recognized as an important consideration in clinical practice. This review synthesizes the evidence of pharmacological and psychosocial interventions for comorbid depressive disorders and SUDs while providing clinical recommendations about the best interventions to address these patients. The best evidence from randomized controlled trials was used to evaluate treatment options. The strength of recommendations was described using the GRADE approach. Our results suggest that 1) In patients with depression and alcohol consumption, the administration of non-selective serotonin reuptake inhibitor (SSRI) antidepressants instead of SSRI is recommended for improvement of depressive symptoms (strong recommendation). Neither SSRI (strong recommendation) nor non-SSRI (weak recommendation) antidepressants are recommended for reduction in alcohol consumption. 2) In patients with depression and cannabis use, the use of venlafaxine is not recommended (weak recommendation). 3) In patients with depression and cocaine consumption, the use of SSRI antidepressants for improving depressive symptoms (weak recommendation) or to reduce cocaine use is not recommended (strong recommendation). The use of non-SSRI antidepressants is only recommended for improving depressive symptoms (strong recommendation). 4) The administration of bupropion to reduce nicotine consumption is not recommended (strong recommendation). 5) Regarding psychological treatment, in patients with depression and co-occurring alcohol disorder, both pharmacotherapy and cognitive behavioural therapy have positive effects on internalizing symptoms and in reducing alcohol consumption (weak recommendation). Our review suggests the need for more research in this area and for larger, multisite, randomized studies to provide more definite evidence.

ObjectivesInvasive meningococcal disease (IMD) is an urgent notifiable disease and its early notification is essential to prevent cases. The objective of the study was to assess the sensitivity of two independent surveillance systems and to estimate the incidence of IMD.DesignWe used capture–recapture model based on two independent surveillance systems, the statutory disease reporting (SDR) system and the microbiological reporting system (MRS) of the Public Health Agency of Catalonia, between 2011 and 2015. The capture–recapture analysis and 95% CIs were calculated using the Chapman formula. Multivariate vector generalised linear model was performed for adjusted estimation.MeasuresThe variables collected were age, sex, year of report, size of municipality (<10 000 and ≥10 000), clinical form, death, serogroup, country of birth and type of reporting centre (private and public).ResultsThe sensitivity of the two combined surveillance systems was 88.5% (85.0–92.0). SDR had greater sensitivity than the MRS (67.9%; 62.7–73.1 vs 64.7%; 59.4–70.0). In 2014–2015, the sensitivity of both systems was higher (80.6%; 73.2–87.9 vs 73.4%; 65.2–81.6) than in 2011–2013 (59.3%; 52.6–66.0 vs 58.3%; 51.6–65.1). In private centres, the sensitivity was higher for SDR than for MRS (100%; 100–100 vs 4.8%; −4.4–13.9). The adjusted estimate of IMD cases was lower than that obtained using the Chapman formula (279; 266–296 vs 313; 295–330). The estimated adjusted incidence of IMD was 0.7/100 000 persons-year.ConclusionsThe sensitivity of enhanced surveillance through the combination of two complementary sources was higher than for the sources individually. Factors associated with under-reporting in different systems should be analysed to improve IMD surveillance.

Co-occurrence of depression and a substance use disorder (SUD) in patients who present dual diagnoses has been long recognized as an important consideration in clinical practice. This review synthesizes the evidence of pharmacological and psychosocial interventions for comorbid depressive disorders and SUDs while providing clinical recommendations about the best interventions to address these patients. The best evidence from randomized controlled trials was used to evaluate treatment options. The strength of recommendations was described using the GRADE approach. Our results suggest that 1) In patients with depression and alcohol consumption, the administration of non-selective serotonin reuptake inhibitor (SSRI) antidepressants instead of SSRI is recommended for improvement of depressive symptoms (strong recommendation). Neither SSRI (strong recommendation) nor non-SSRI (weak recommendation) antidepressants are recommended for reduction in alcohol consumption. 2) In patients with depression and cannabis use, the use of venlafaxine is not recommended (weak recommendation). 3) In patients with depression and cocaine consumption, the use of SSRI antidepressants for improving depressive symptoms (weak recommendation) or to reduce cocaine use is not recommended (strong recommendation). The use of non-SSRI antidepressants is only recommended for improving depressive symptoms (strong recommendation). 4) The administration of bupropion to reduce nicotine consumption is not recommended (strong recommendation). 5) Regarding psychological treatment, in patients with depression and co-occurring alcohol disorder, both pharmacotherapy and cognitive behavioural therapy have positive effects on internalizing symptoms and in reducing alcohol consumption (weak recommendation). Our review suggests the need for more research in this area and for larger, multisite, randomized studies to provide more definite evidence.