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The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC. • Concomitant proton pump inhibitor and palbociclib was retrospectively analyzed. • Median progression-free survival was shorter with proton pump inhibitor use. • Adverse events and dose reductions were lower with proton pump inhibitors. • These results reveal proton pump inhibitors may interact with palbociclib capsules. [ABSTRACT FROM AUTHOR]

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<0·0001 compared with the historical rate) of 227 had a pathological complete response. The most common haematological grade 3-4 adverse events were anaemia (six [9%] of 68 patients in group A vs four [1%] of 283 patients in group B), neutropenia (16 [24%] vs ten [4%]), and febrile neutropenia (14 [21%] vs 11 [4%]). Serious adverse events occurred in 20 (29%) of 68 patients in group A versus 13 (5%) of 283 patients in group B. No deaths were reported during neoadjuvant treatment. Global health status declined by at least 10% in 65·0% (95% CI 46·5-72·4) and 35·5% (29·7-41·7) of patients in groups A and B, respectively 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. [ABSTRACT FROM AUTHOR]

Background Axillary staging (pN) is considered one of the most important prognostic factors in breast cancer patients. However, the Z0011 study data drastically reduced the number of surgical axillary dissections in a selected group of patients, limiting the prognostic information relating to axillary involvement to the sentinel lymph node (SLN). It is known that there is a relationship between SLN total tumour load (TTL) and axillary involvement. The objective of this study is to analyse the relationship between the TTL and outcomes in patients with early stage breast cancer. Patients and methods clinicopathological and follow-up data were collected from 950 patients with breast cancer between 2009 and 2010 on whom SLN analysis was conducted by molecular methods (One Step Nucleic Acid Amplification, Sysmex, Kobe, Japan). Results TTL (defined as the total number of CK19 mRNA copies in all positive SLN) correlates with disease free survival (HR, 1.08; p = 0.000004), with local recurrence disease free survival (HR = 1.07; p = 0.0014) and overall survival (HR: 1.08, p = 0.0032), clearly defining a low-risk group (TTL <2.5 × 10 4 CK19 mRNA copies/μL) versus a high-risk group (>2.5 × 10 4 CK 19 mRNA copies/μL). Conclusions SLN TTL permits the differentiation between two patient groups in terms of DFS and OS, independently of axillary staging (pN), age and tumour characteristics (size, grade, lymphovascular invasion). This new data confirms the clinical value of low axillary involvement and could partially replace the information that staging of the entire axilla provides in patients on whom no axillary lymph node dissection is performed. [ABSTRACT FROM AUTHOR]

• The optimal management of severe COVID-19 represents an unmet clinical need. • Programmed cell death-1/interleukin-6 receptor blockade might restore immunocompetence and interrupt hyperinflammation. • COPERNICO assessed pembrolizumab plus tocilizumab and standard of care (SOC) compared with SOC in high-risk patients with COVID-19. • The addition of pembrolizumab plus tocilizumab to SOC reduced the hospitalization period. • The addition of pembrolizumab plus tocilizumab to SOC reduced the rate of discharge without sequelae. Severe COVID-19 is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated interleukin 6. Pembrolizumab (P; immune-activating anti-programmed cell death-1 antibody) plus tocilizumab (TCZ; anti- interleukin 6 receptor antibody) might interrupt the hyperinflammation and restore cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care (SOC) in high-risk, hospitalized patients with COVID-19 pneumonia without mechanical ventilation. Randomized, controlled, open-label, phase II trial in patients with severe SARS-CoV-2 infection to assess the hospitalization period to discharge. A total of 12 patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41-79) years. The median time to discharge for P + TCZ + SOC and SOC was 10 and 47.5 days (P = 0.03), with zero (n = 1 patient had P-related grade 5 myositis) and two COVID-19-related deaths, respectively. The addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone. [ABSTRACT FROM AUTHOR]

Axillary staging (pN) is a strong predictor of outcome in early stage breast cancer yet following the publication of the Z0011 trial there has been an increasing tendency to spare lymph node dissection. Automated molecular detection of cytokeratin 19mRNA by one-step nucleic acid amplification (OSNA) has been demonstrated to be an accurate method to assess sentinel lymph node (SLN) metastasis. In this study we compare histological and molecular methods following complete axillary lymph node dissection (cALND), determine whether molecular axillary staging affects survival, and evaluate the predictive and prognostic value of total tumor load in ALND (AD-TTL) and in all positive nodes (G-TTL). Axillary lymph nodes were collected from 102 patients with primary breast cancer with histological confirmation of axillary involvement (cN+) or positive SLN. The central 1-mm portion of each non-SLN was processed for hematoxylin-eosin staining and the remaining tissue was analyzed by OSNA. Non-SLNs were diagnosed as positive in 72 out of 102 patients (70.6 %) on OSNA compared with only 53 (52 %) on histology (p < 0.01). Thirteen patients would have changed staging if the diagnoses provided had been by molecular methods (p < 0.01), but without a change in prognosis. AD-TTL and G-TTL were predictive of recurrence and mortality. Compared to molecular detection, histological examination significantly underestimates the frequency of axillary node metastases. However, the increase in pN did not show a clinical effect on survival in those patients. [ABSTRACT FROM AUTHOR]