Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.

COVID-19-associated cerebral microbleeds in the general population.

Cerebral microbleeds are frequent incidental findings on brain MRI and have previously been shown to occur in Coronavirus Disease 2019 (COVID-19) cohorts of critically ill patients. We aimed to determine the risk of having microbleeds on medically indicated brain MRI and compare non-hospitalized COVID-19-infected patients with non-infected controls. In this retrospective case-control study, we included patients over 18 years of age, having an MRI with a susceptibility-weighted sequence, between 1 January 2019 and 1 July 2021. Cases were identified based on a positive reverse transcriptase polymerase chain reaction test for SARS-CoV-2 and matched with three non-exposed controls, based on age, sex, body mass index and comorbidities. The number of cerebral microbleeds on each scan was determined using artificial intelligence. We included 73 cases and 219 matched non-exposed controls. COVID-19 was associated with significantly greater odds of having cerebral microbleeds on MRI [odds ratio 2.66 (1.23-5.76, 95% confidence interval)], increasingly so when patients with dementia and hospitalized patients were excluded. Our findings indicate that cerebral microbleeds may be associated with COVID-19 infections. This finding may add to the pathophysiological considerations of cerebral microbleeds and help explain cases of incidental cerebral microbleeds in patients with previous COVID-19.

Olaparib plus trastuzumab in HER2-positive advanced breast cancer patients with germline BRCA1/2 mutations: The OPHELIA phase 2 study.

PURPOSE: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). METHODS: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. RESULTS: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4-99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7-94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. CONCLUSIONS: This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive gBRCAm ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2-driven cancers.

Deep Learning to Detect Pancreatic Cystic Lesions on Abdominal Computed Tomography Scans: Development and Validation Study.

BACKGROUND: Pancreatic cystic lesions (PCLs) are frequent and underreported incidental findings on computed tomography (CT) scans and can evolve to pancreatic cancer-the most lethal cancer, with less than 5 months of life expectancy. OBJECTIVE: The aim of this study was to develop and validate an artificial deep neural network (attention gate U-Net, also named "AGNet") for automated detection of PCLs. This kind of technology can help radiologists to cope with an increasing demand of cross-sectional imaging tests and increase the number of PCLs incidentally detected, thus increasing the early detection of pancreatic cancer. METHODS: We adapted and evaluated an algorithm based on an attention gate U-Net architecture for automated detection of PCL on CTs. A total of 335 abdominal CTs with PCLs and control cases were manually segmented in 3D by 2 radiologists with over 10 years of experience in consensus with a board-certified radiologist specialized in abdominal radiology. This information was used to train a neural network for segmentation followed by a postprocessing pipeline that filtered the results of the network and applied some physical constraints, such as the expected position of the pancreas, to minimize the number of false positives. RESULTS: Of 335 studies included in this study, 297 had a PCL, including serous cystadenoma, intraductal pseudopapillary mucinous neoplasia, mucinous cystic neoplasm, and pseudocysts . The Shannon Index of the chosen data set was 0.991 with an evenness of 0.902. The mean sensitivity obtained in the detection of these lesions was 93.1% (SD 0.1%), and the specificity was 81.8% (SD 0.1%). CONCLUSIONS: This study shows a good performance of an automated artificial deep neural network in the detection of PCL on both noncontrast- and contrast-enhanced abdominal CT scans.

Pre-operative ribociclib plus letrozole versus chemotherapy: Health-related quality of life outcomes from the SOLTI CORALLEEN trial.

INTRODUCTION: In the phase II CORALLEEN trial, patients with PAM50 luminal B early breast cancer (EBC) were randomised to neoadjuvant ribociclib plus letrozole (R + L) or chemotherapy based on anthracyclines and taxanes. Results from the primary efficacy analysis showed a similar proportion of patients with response at surgery in both groups. How health-related quality of life (HRQoL) outcomes with R + L compare with chemotherapy in EBC setting is still unknown. Here, we report the results of the HRQoL analysis from the CORALLEEN study. METHODS: A total of 106 women were randomised 1:1 to receive neoadjuvant R + L (n = 52) or chemotherapy (n = 54). Patient-reported outcomes were assessed using two questionnaires: EORTC QLQ-C30 and EORTC QLQ-BR23. Change from baseline in the global health status, functional, and symptom scales was analysed using linear mixed-effect models, and between-treatment differences were estimated along with 95% confidence interval (95% CI). RESULTS: At baseline, the overall questionnaire available rate was 94.3%, and patient-reported outcomes were similar between treatment groups. At the end of the study treatment (24 weeks), patients receiving R + L showed better global health status scores with a between-treatment difference of 17.7 points (95% CI 9.2-26.2; p-value <0.001). The R + L group also presented numerically better outcomes in all functional and symptom scales. The larger between-treatment differences in symptom severity were found in fatigue (-28.9; 95% CI -38.5 to -19.3), appetite loss (-23; 95% CI -34.9 to -11.2) and systematic therapy side-effects (-11.4; 95% CI -18.3 to -4.6). CONCLUSIONS: Neoadjuvant R + L was associated with better HRQoL outcomes compared with chemotherapy in patients with luminal B EBC. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT03248427.

GDF15 and ACE2 stratify COVID-19 patients according to severity while ACE2 mutations increase infection susceptibility.

Coronavirus disease 19 (COVID-19) is a persistent global pandemic with a very heterogeneous disease presentation ranging from a mild disease to dismal prognosis. Early detection of sensitivity and severity of COVID-19 is essential for the development of new treatments. In the present study, we measured the levels of circulating growth differentiation factor 15 (GDF15) and angiotensin-converting enzyme 2 (ACE2) in plasma of severity-stratified COVID-19 patients and uninfected control patients and characterized the in vitro effects and cohort frequency of ACE2 SNPs. Our results show that while circulating GDF15 and ACE2 stratify COVID-19 patients according to disease severity, ACE2 missense SNPs constitute a risk factor linked to infection susceptibility.