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Background Endocrine resistance is a major challenge in treating patients with ER+ /HER2− metastatic breast cancer (MBC) necessitating a switch from endocrine therapy to more toxic therapies. Mutations in ESR1 constitute a key mechanism of resistance to endocrine therapy in ER+ /HER2− BC. Therapies that overcome endocrine resistance are needed. Palazestrant is a novel oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) belonging to a new class of ER-targeting agents that completely blocks estrogen-induced transcriptional activity, regardless of ESR1 mutation status. This first-in-human, open-label, multicenter, phase 1/2 dose-escalation/expansion study was designed to determine the recommended phase 2 dose (RP2D) and to evaluate safety, pharmacokinetics, and antitumor activity of palazestrant in patients with ER+ /HER2− MBC with disease progression on prior treatment. Methods Adults with ER+ /HER2‒ MBC who received ≥ 1 prior line of endocrine therapy for advanced disease and ≤ 2 prior chemotherapy regimens for metastatic disease were eligible. Patients received once-daily oral palazestrant (30–300 mg) in 28-day cycles until progression or intolerable toxicity. Results This study enrolled 146 patients. No dose-limiting toxicities were observed at doses up to 300 mg/day palazestrant. Confirmed partial responses were observed with 60 and 120 mg/day palazestrant. Both doses showed similar and tolerable safety profiles, favorable pharmacokinetics, and steady-state plasma concentrations above the predicted threshold for complete ER inhibition. Greater clinical benefit at palazestrant 120 mg/day (46%) versus 60 mg/day (19%) led to selection of 120 mg/day as RP2D and study expansion dose. At 120 mg/day, the median progression-free survival was 4.8 months (95% CI, 3.5–7.1) overall and 5.6 months (95% CI, 4.8–NE) among patients with cancers with ESR1 mutations. Most treatment-emergent adverse events (TEAEs) were grade 1–2. The most common TEAEs were nausea (62.8%), vomiting (29.1%), and fatigue (25.6%). The most common grade ≥ 3 TEAE was transient neutropenia (10.5%) managed by dose interruption and reduction. Conclusions Palazestrant demonstrated a manageable safety profile, with antitumor activity observed in patients with heavily pretreated cancers with wild-type and ESR1 -mutated BC. These data support the ongoing phase 3 study evaluating palazestrant in patients with ER+ /HER2 − MBC. Trial registration ClinicalTrials.gov, NCT04505826 . Registered August 6, 2020.

BackgroundChemoimmunotherapy is a standard treatment for triple-negative breast cancer (TNBC), however, the impacts of different chemotherapies on T-cell populations, which could correlate with clinical activity, are not known. Quantifying T-cell populations with flow cytometry and T-cell receptor (TCR) immunosequencing may improve our understanding of how chemoimmunotherapy affects T-cell subsets, and to what extent clonal shifts occur during treatment. TCR immunosequencing of intratumoral T cells may facilitate the identification and monitoring of putatively tumor-reactive T-cell clones within the blood.MethodsBlood and tumor biopsies were collected from patients with metastatic TNBC enrolled in a phase Ib clinical trial of first or second-line pembrolizumab with paclitaxel or capecitabine. Using identical biospecimen processing protocols, blood samples from a cohort of patients treated for early-stage breast cancer were obtained for comparison. Treatment-related immunological changes in peripheral blood and intratumoral T cells were characterized using flow cytometry and TCR immunosequencing. Clonal proliferation rates of T cells were compared based on intratumoral enrichment.ResultsWhen combined with pembrolizumab, paclitaxel and capecitabine resulted in similar time-dependent lymphodepletions across measured peripheral T-cell subsets. Their effects were more modest than that observed following curative-intent dose-dense anthracycline and cyclophosphamide (ddAC) (average fold-change in CD3+ cells, capecitabine: −0.42, paclitaxel: −0.56, ddAC: −1.21). No differences in T-cell clonality or richness were observed following capecitabine or paclitaxel-based treatments. Regression modeling identified differences in the emergence of novel T-cell clones that were not detected at baseline (odds compared with ddAC, capecitabine: 0.292, paclitaxel: 0.652). Pembrolizumab with paclitaxel or capecitabine expanded T-cell clones within tumors; however, these clones did not always expand within the blood. Proliferation rates within the blood were similar between clones that were enriched and those that were not enriched within tumors.ConclusionChemoimmunotherapy for metastatic TNBC with pembrolizumab and capecitabine or paclitaxel resulted in similar peripheral T-cell subset lymphodepletion without altering T-cell clonal diversity. Regression modeling methods are applicable in immune monitoring studies, such as this to identify the odds of novel T-cell clones emerging during treatment, and proliferation rates of tumor-enriched T-cell clones.

We previously showed the feasibility and immunologic effects of multivalent peri-lymphatic cytokine injection (IRX-2) in early-stage breast cancer. We now report outcomes of a pilot evaluation of IRX-2 + pembrolizumab induction preceding neoadjuvant chemo-immunotherapy in triple-negative breast cancer (TNBC). Single-cycle induction was associated with radiographic tumor regression, tumor necrosis, immune infiltration, and high pathologic complete response rate following platinum-sparing chemo-immunotherapy. Further investigation of peri-lymphatic cytokines in TNBC is warranted.

Among persons with residual invasive disease after treatment of HER2-positive early breast cancer, trastuzumab emtansine resulted in 7-year invasive disease–free survival of 80.8%, as compared with 67.1% with trastuzumab.

Residual cancer after induction therapy for HER2-positive breast cancer is associated with a worse prognosis than no residual cancer. In a randomized trial, trastuzumab emtansine was superior to trastuzumab with respect to invasive disease–free survival.

Endocrine resistance is a major challenge in treating patients with ER+ /HER2- metastatic breast cancer (MBC) necessitating a switch from endocrine therapy to more toxic therapies. Mutations in ESR1 constitute a key mechanism of resistance to endocrine therapy in ER+ /HER2- BC. Therapies that overcome endocrine resistance are needed. Palazestrant is a novel oral complete estrogen receptor (ER) antagonist (CERAN) and selective ER degrader (SERD) belonging to a new class of ER-targeting agents that completely blocks estrogen-induced transcriptional activity, regardless of ESR1 mutation status. This first-in-human, open-label, multicenter, phase 1/2 dose-escalation/expansion study was designed to determine the recommended phase 2 dose (RP2D) and to evaluate safety, pharmacokinetics, and antitumor activity of palazestrant in patients with ER+ /HER2- MBC with disease progression on prior treatment. Adults with ER+ /HER2- MBC who received [greater than or equal to] 1 prior line of endocrine therapy for advanced disease and [less than or equal to] 2 prior chemotherapy regimens for metastatic disease were eligible. Patients received once-daily oral palazestrant (30-300 mg) in 28-day cycles until progression or intolerable toxicity. This study enrolled 146 patients. No dose-limiting toxicities were observed at doses up to 300 mg/day palazestrant. Confirmed partial responses were observed with 60 and 120 mg/day palazestrant. Both doses showed similar and tolerable safety profiles, favorable pharmacokinetics, and steady-state plasma concentrations above the predicted threshold for complete ER inhibition. Greater clinical benefit at palazestrant 120 mg/day (46%) versus 60 mg/day (19%) led to selection of 120 mg/day as RP2D and study expansion dose. At 120 mg/day, the median progression-free survival was 4.8 months (95% CI, 3.5-7.1) overall and 5.6 months (95% CI, 4.8-NE) among patients with cancers with ESR1 mutations. Most treatment-emergent adverse events (TEAEs) were grade 1-2. The most common TEAEs were nausea (62.8%), vomiting (29.1%), and fatigue (25.6%). The most common grade [greater than or equal to] 3 TEAE was transient neutropenia (10.5%) managed by dose interruption and reduction. Palazestrant demonstrated a manageable safety profile, with antitumor activity observed in patients with heavily pretreated cancers with wild-type and ESR1-mutated BC. These data support the ongoing phase 3 study evaluating palazestrant in patients with ER+ /HER2 - MBC.

Over the past decade the taxanes have proved to be fundamental in the treatment of breast cancer. Initially found to have efficacy in metastatic breast cancer, the taxanes are now vital components in the treatment of early-stage disease, in which their addition to adjuvant treatment of early breast cancer has been shown to improve overall survival. In addition, the taxanes have demonstrated a role in first-line therapy for metastatic disease, with some of the highest efficacy of any class of chemotherapy. Targeted therapies in combination with the taxanes have further improved survival for both early and metastatic disease. New formulations of taxanes may both improve antitumor activity and reduce toxicity.

The ``disease-specific'' (dsp) region next to the hrp gene cluster of Erwinia amylovora is required for pathogenicity but not for elicitation of the hypersensitive reaction. A 6.6-kb apparent operon, dspEF, was found responsible for this phenotype. The operon contains genes dspE and dspF and is positively regulated by hrpL. A BLAST search revealed similarity in the dspE gene to a partial sequence of the avrE locus of Pseudomonas syringae pathovar tomato. The entire avrE locus was sequenced. Homologs of dspE and dspF were found in juxtaposed operons and were designated avrE and avrF. Introduced on a plasmid, the dspEF locus rendered P. syringae pv. glycinea race 4 avirulent on soybean. An E. amylovora dspE mutant, however, elicited a hypersensitive reaction in soybean. The avrE locus in trans restored pathogenicity to dspE strains of E. amylovora, although restored strains were low in virulence. DspE and AvrE are large (198 kDa and 195 kDa) and hydrophilic. DspF and AvrF are small (16 kDa and 14 kDa) and acidic with predicted amphipathic α helices in their C termini; they resemble chaperones for virulence factors secreted by type III secretion systems of animal pathogens.

PurposeA growing body of research suggests that inflammation plays a role in many chemotherapy-related toxicities such as fatigue, anxiety, and neuropathy. Regular exercise can change levels of individual cytokines (e.g., reducing IL-6, increasing IL-10); however, it is not known whether exercise during chemotherapy affects relationships between cytokines (i.e., whether cytokine concentrations change collectively vs. independently). This study assessed how 6 weeks of exercise during chemotherapy affected relationships between changes in concentrations of several cytokines.MethodsThis is a secondary analysis of a randomized trial studying 6 weeks of moderate-intensity walking and resistance exercise during chemotherapy compared with chemotherapy alone. At pre- and post-intervention, patients provided blood to assess serum concentrations of cytokines IL-1β, IL-6, IL-8, IL-10, and IFN-γ, and receptor sTNFR1. We investigated relationships between cytokines using the correlations between changes in cytokine concentrations from pre- to post-intervention.ResultsWe obtained complete data from 293 patients (149 randomized to exercise). Exercise strengthened the correlation between concentration changes of IL-10 and IL-6 (r = 0.44 in exercisers vs. 0.11 in controls; p = 0.001). We observed the same pattern for IL-10:IL-1β and IL-10:sTNFR1. Exercise also induced an anti-inflammatory cytokine profile, per reductions in pro-inflammatory IFN-γ (p = 0.044) and perhaps IL-1β (p = 0.099, trend-level significance).ConclusionsOur hypothesis-generating work suggests that regular exercise during 6 weeks of chemotherapy may cause certain cytokine concentrations to change collectively (not independently). This work enhances our understanding of relationships between cytokines and complements traditional analyses of cytokines in isolation. Future work should test for replication and relationships to patient outcomes.Trial registrationClinical Trials.gov, # NCT00924651, http://www.clinicaltrials.gov.

Background Insomnia is a toxicity of cancer and treatment for survivors without an objective biochemical measure. Circadian rhythms are 24-h cycles that influence physiologic processes including sleep, and disrupted rhythms may contribute to insomnia. Here, we use BloodCCD to assess circadian rhythms from RNA-sequencing of blood from cancer survivors with insomnia from the YOCAS-II trial. YOCAS-II aimed to determine whether YOCAS©® yoga or cognitive behavioral therapy for insomnia (CBT-I) improved insomnia in survivors compared with a behavioral placebo. We hypothesized that circadian rhythms are disrupted in survivors, and that insomnia severity correlates with the degree of circadian disruption. Methods BloodCCD was developed to biochemically assess circadian rhythms in blood. It was adapted from the previously published Clock Correlation Distance (CCD) and uses a correlation matrix of 42 genes known to oscillate throughout the day in blood. Results Cancer survivors had higher (worse) BloodCCD scores, indicating disrupted circadian clock, compared to healthy individuals. Furthermore, insomnia severity correlated with worse BloodCCD, and those in the YOCAS and behavioral placebo arm showed significant correlation between BloodCCD score and insomnia. Conclusions BloodCCD shows promise as a biomarker to biochemically detect disrupted circadian rhythms in cancer survivors, and as an indicator for insomnia severity. Clinical Trial Identifier NCT02613364.