PURPOSE Hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer. METHODS In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2– locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. RESULTS Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%). CONCLUSION SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2– advanced breast cancer and limited treatment options.

The results suggest absence of a drug-drug interaction between ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 expression in HR+, HER2- BC (NCT01919229).

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Recycled aggregates of mixed composition (MRA) may exhibit great variability in their properties, which in turn reduces their applicability. This study intends to extend the use of MRA in a broadened scope of applications by producing recycled aggregate concretes (RAC), which were mixed using two different types of cement, ordinary Portland cement and cement incorporating blast-furnace slag, and two types of water, fresh and seawater. The testing programme included analyses of the properties of concrete in its fresh (setting time and plastic shrinkage) and hardened state (physical, mechanical and drying shrinkage). The results showed that all of the physical and several of the mechanical properties as well as drying shrinkage were negatively influenced by the use of MRA. In contrast, however, the plastic shrinkage and flexural strength were improved. The use of seawater improved the mechanical properties, reduced setting time and increased drying shrinkage, however, it was found that the cement type was more influential on most of the properties. The use of seawater and cement with blast-furnace slag improved the performances of the RAC.Peer ReviewedPostprint (author's final draft

LBA1001 Background: HR+/HER2– disease is the most common subtype of metastatic breast cancer (MBC). Treatment includes sequential endocrine therapy combined with targeted agents followed by single-agent chemotherapy, with increasingly shorter durations of benefit. SG is an anti–Trop-2 antibody-drug conjugate approved for metastatic triple-negative breast cancer with ≥2 prior therapies (≥1 for MBC). The HR+/HER2– MBC cohort of the phase 1/2 IMMU-132-01 study (n = 54) had an objective response rate (ORR) of 31.5%, median progression-free survival (PFS) of 5.5 mo, median overall survival (OS) of 12 mo, and a manageable safety profile with SG. TROPiCS-02 is a phase 3 randomized study (NCT03901339) to confirm SG outcomes in HR+/HER2– advanced breast cancer. Methods: Adults with locally determined, HR+/HER2– unresectable locally advanced or MBC, ECOG performance status of 0 or 1, and 2-4 prior chemotherapy regimens for MBC were eligible; 1 prior therapy for MBC was allowed if disease progressed ≤12 mo after (neo)adjuvant therapy. Pts must have received ≥1 prior taxane, CDK4/6 inhibitor, and endocrine therapy in any setting. Pts were randomized 1:1 to receive SG (10 mg/kg IV on d1 and 8, every 21d) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST v1.1 by blinded independent central review (final analysis) with key secondary endpoint of OS (1st planned interim analysis). Results: At data cutoff on Jan 3, 2022, 272 vs 271 pts were randomized to receive SG vs TPC, respectively. Pt characteristics in the SG vs TPC arms were similar (3 median prior chemotherapy regimens for MBC [range, 0-8]; 95% had visceral metastases, 86% had prior endocrine therapy for MBC for ≥6 mo, 60% and 38% received prior CDK4/6 inhibitors for ≤12 and > 12 mo, respectively). SG (vs TPC) improved median PFS (5.5 vs 4.0 mo; HR, 0.66; 95% CI, 0.53-0.83; P= 0.0003); PFS rates at 6 and 12 mo were 46% vs 30% and 21% vs 7%, respectively. SG vs TPC showed a numeric but nonsignificant difference in OS (13.9 vs 12.3 mo; HR, 0.84; P= 0.143); ORR (21% vs 14%) and clinical benefit rate (34% vs 22%) were higher with SG vs TPC and median duration of response was 7.4 vs 5.6 mo, respectively. Overall, 74% vs 60% of patients (SG vs TPC) had grade ≥3 treatment-emergent adverse events (AEs); neutropenia (51% vs 39%) and diarrhea (10% vs 1%) were most common. AEs leading to discontinuation of SG vs TPC were low (6% vs 4%). There was 1 treatment-related death in the SG arm; none in the TPC arm. Conclusions: SG had a statistically significant, clinically meaningful PFS benefit over single-agent chemotherapy and a manageable safety profile in pts with heavily pre-treated HR+/HER2– endocrine-resistant, unresectable locally advanced or MBC, who have limited treatment options. Clinical trial information: NCT03901339.

Metastatic breast cancer is a heterogeneous disease that presents in varying forms, and a growing number of therapeutic options makes it difficult to determine the best choice in each particular situation. When selecting a systemic treatment, it is important to consider the medication administered in the previous stages, such as acquired resistance, type of progression, time to relapse, tumor aggressiveness, age, comorbidities, pre-and post-menopausal status, and patient preferences. Moreover, tumor genomic signatures can identify different subtypes, which can be used to create patient profiles and design specific therapies. However, there is no consensus regarding the best treatment sequence for each subgroup of patients. During the SABCC Congress of 2014, specialized breast cancer oncologists from referral hospitals in Europe met to define patient profiles and to determine specific treatment sequences for each one. Conclusions were then debated in a final meeting in which a relative degree of consensus for each treatment sequence was established. Four patient profiles were defined according to established breast cancer phenotypes: pre-menopausal patients with luminal subtype, post-menopausal patients with luminal subtype, patients with triple-negative subtype, and patients with HER2-positive subtype. A treatment sequence was then defined, consisting of hormonal therapy with tamoxifen, aromatase inhibitors, fulvestrant, and mTOR inhibitors for pre-and post-menopausal patients; a chemotherapy sequence for the first, second, and further lines for luminal and triple-negative patients; and an optimal sequence for treatment with new antiHER2 therapies. Finally, a document detailing all treatment sequences, that had the agreement of all the oncologists, was drawn up as a guideline and advocacy tool for professionals treating patients with this disease.

Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment.

Introduction Mitral valve (MV) prolapse (MVP) is a primary valvular abnormality. We hypothesized that additionally there are concomitant abnormalities of the left ventricle (LV) and MV apparatus in this entity even in the absence of significant mitral regurgitation (MR). Objective To characterize MV and LV anatomic and functional features in MVP with preserved LV ejection fraction, with and without significant MR, using cardiovascular magnetic resonance (CMR). Methods Consecutive MVP patients (n = 80, mean 52 years, 37% males) with preserved LV ejection fraction, and 44 controls (46 years, 52% males) by CMR were included, as well as 13 additional patients with “borderline” MVP. From cine images we quantified LV volumes, MV and LV anatomic measurements (including angle between diastolic and systolic annular planes, annular displacement, and basal inferolateral hypertrophy) and, using feature tracking, longitudinal and circumferential peak systolic strains. Results Significant MR was found in 46 (56%) MVP patients. Compared with controls, MVP patients had LV enlargement, basal inferolateral hypertrophy, higher posterior annular excursion, and reduced shortening of the papillary muscles. LV basal strains were significantly increased, particularly in several basal segments. These differences remained significant in patients without significant MR, and many persisted in “borderline” MVP. Conclusions In patients with MVP and preserved LV ejection fraction there is LV dilatation, basal inferolateral hypertrophy, exaggerated posterior annular displacement and increased basal deformation, even in the absence of significant MR or overt MVP. These findings suggest that MVP is a disease not only of the MV but also of the adjacent myocardium.