Evaluation of the supply of Duddingtonia flagrans for the control of gastrointestinal parasites in sheep.

Parasitic resistance imposes alternative control methods, like nematophagous fungi. In this study, two experiments were conducted supplying Duddingtonia flagrans aiming to evaluate the biological control of parasites in sheep. In the first, 24 sheep naturally infected by gastrointestinal nematodes were allocated, in randomized blocks, following the treatments: control or treated group, 0.5g/animal product containing D. flagrans, chlamydospores. Weight, body score, Famacha©, egg count per gram of feces (EPG), and larval percentage were evaluated. In the second experiment, D. flagrans (0.25 and 0.5g product) was infested with manure, plus or not protein concentrate, in a completely randomized design. In both experiments the dose was intentionally lower than recommended. Recovery and larval identification were performed. The SAS analyzed the variables by the MIXED procedure, repeated measures in time. Weight, body score, hematocrit, and Famacha© did not show differences between treatments (p>0.05); however, EPG (p<0.001) and the percentage of larvae identified in coproculture were different. In the second experiment, the inclusion of the fungus did not influence the recovery of larvae (p>0.05). In both experiments, colonization and advancement of the fungus were visualized. Under the experimental conditions, the fungus D. flagrans was not effective in the biological control of parasitic infection in sheep.

Disseminated cancer cells in breast cancer: Mechanism of dissemination and dormancy and emerging insights on therapeutic opportunities.

Metastatic spread in breast cancer patients is the major driver of cancer-related deaths. A unique subset of cells disseminated from pre-invasive or primary tumor lesions are recognized as the main seeds for metastatic outgrowth. Disseminated cancer cells (DCCs) can migrate to distant organs and settle in a dormant state for a prolonged period until they emerge to overt metastases. Understanding the biology of breast cancer cells dissemination, dormancy and reactivation to form overt metastases has become an important focus. In this review, we discuss the recent advancements of molecular pathways involving breast cancer cell dissemination, role of chemokine-chemokine receptor networks in DCCs migration, DCCs phenotypic heterogeneity and unique genes signatures in tumor dormancy, microenvironmental regulation and specific niches that favors DCCs homing and dormancy. In addition, we also discuss recent findings relating to the role of immune response on DCC dissemination and dormancy. With recent advances in the field of immunotherapy/targeted therapy and its beneficial effects in cancer treatment, this review will focus on their impact on DCCs, reversal of stemness, tumor dormancy and metastatic relapse.

A Cohort Study of the Antitumor Efficacy and Toxicity Profile of Alpelisib for Metastatic or Locally Advanced HR+, HER2- Breast Cancer: A Single-Institution Experience.

INTRODUCTION: Alpelisib is approved in combination with endocrine therapy (ET) to treat patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) progressive metastatic breast cancer (MBC). The SOLAR-1 trial demonstrated the efficacy of this oral agent and showed that, while alpelisib improves outcomes compared to placebo, it is also associated with clinically relevant adverse events (AEs). There is a pressing need for improved knowledge on the effectiveness and tolerability of this agent in real-world patient populations. METHODS: We conducted a retrospective cohort study of patients with HR+, HER2- MBC treated with alpelisib and ET. We assessed the safety, tolerability, and effectiveness of alpelisib in a real-world population. Deidentified patient-, tumor-, and outcome-related data, including AEs, were collected and summarized. Kaplan-Meier methods were applied for survival analyses, and stratified analyses of interest were conducted. A p value <0.05 was considered statistically significant. RESULTS: A total of 76 women treated with alpelisib + ET were included in our cohort. Most had been previously treated with cyclin-dependent kinase (CDK) 4/6 inhibitors and chemotherapy for MBC. The estimated median progression-free survival was 5.2 months (95% CI, 4.1-8.0). The median overall survival was longer among patients without prior everolimus therapy (hazard ratio, 4.28 [95% CI, 1.64-11.16]; p = 0.0012), and no significant outcome differences were observed between patients treated with different starting doses of alpelisib. Approximately 31.6% of patients permanently discontinued alpelisib due to AEs, and 32.9% had at least one dose reduction. The most common grade 3/4 AEs were hyperglycemia (21%), fatigue (13.2%), and diarrhea (10.5%). CONCLUSIONS: For progressive HR+, HER2- MBC, alpelisib + ET showed effectiveness in a real-world patient population that was comparable to published clinical trial data, regardless of starting dose. However, the effectiveness of alpelisib following previous everolimus exposure may be limited and, hence, should be a consideration to decide sequencing of therapy in these patients. Patients treated with alpelisib are at risk for clinically relevant AEs and require close monitoring.

Retrospective Study of Treatment Patterns and Natural History of Patients with T1a/b N0 Triple-Negative Breast Cancers: A Single-Institution Experience.

INTRODUCTION: T1a/b, node-negative (node-), triple-negative breast cancers (TNBCs) are underrepresented in randomized drug-approving clinical trials. Given their low incidence, the clinicopathological features, natural history, and treatment patterns of these tumors remain insufficiently understood. METHODS: We conducted a single-institution retrospective cohort study of patients with T1a/b, N0, M0 TNBCs. Deidentified patient- and tumor-related data were collected and summarized. Kruskal-Wallis, χ2, or Fisher exact tests were used to evaluate associations of interest. Kaplan-Meier methods, log-rank tests, and Cox's proportional hazards models were applied for survival analyses. RESULTS: Of 108 cases of node- TNBCs measuring ≤2 cm, 34 node- T1a/b tumors were included in our analysis. All cases had an intermediate to high histological grade, and most had a Ki-67 score of ≥20%. All patients received adjuvant chemotherapy, and many underwent mastectomy (47%). Docetaxel combined with cyclophosphamide was the most common adjuvant chemotherapy regimen (75%). We did not observe significant associations between improved outcomes and treatment with anthracycline-containing regimens. Among patients with node- pT1a/b tumors, the estimated 3-year recurrence-free survival (RFS) and distant RFS rates were both 96.3% (95% CI: 76.5-99.5), and the overall survival rate was estimated to be 100% (95% CI: 100-100). There were no cases of local recurrences observed. CONCLUSIONS: In our cohort, all patients with T1a/b node- TNBCs were treated with adjuvant chemotherapy and had favorable outcomes even when treated with anthracycline-sparing regimens.

Th1 cytokine interferon gamma improves response in HER2 breast cancer by modulating the ubiquitin proteasomal pathway.

HER2 breast cancer (BC) remains a significant problem in patients with locally advanced or metastatic BC. We investigated the relationship between T helper 1 (Th1) immune response and the proteasomal degradation pathway (PDP), in HER2-sensitive and -resistant cells. HER2 overexpression is partially maintained because E3 ubiquitin ligase Cullin5 (CUL5), which degrades HER2, is frequently mutated or underexpressed, while the client-protective co-chaperones cell division cycle 37 (Cdc37) and heat shock protein 90 (Hsp90) are increased translating to diminished survival. The Th1 cytokine interferon (IFN)-γ caused increased CUL5 expression and marked dissociation of both Cdc37 and Hsp90 from HER2, causing significant surface loss of HER2, diminished growth, and induction of tumor senescence. In HER2-resistant mammary carcinoma, either IFN-γ or Th1-polarizing anti-HER2 vaccination, when administered with anti-HER2 antibodies, demonstrated increased intratumor CUL5 expression, decreased surface HER2, and tumor senescence with significant therapeutic activity. IFN-γ synergized with multiple HER2-targeted agents to decrease surface HER2 expression, resulting in decreased tumor growth. These data suggest a novel function of IFN-γ that regulates HER2 through the PDP pathway and provides an opportunity to impact HER2 responses through anti-tumor immunity.

Phenotypical categorization of indigenous ewes as resistant, resilient or susceptible to Haemonchus contortus.

The economic losses caused by parasite infections, aggravated by resistance to anthelmintics, have generated demand for alternatives involving non-chemical control, such as the selection of resistant animals. The objective of this study was to identify which characteristics best describe animals that are resistant, resilient or susceptible to Haemonchus contortus and estimate the percent number in each category. Sixty-one Morada Nova ewes were evaluated in an extensive system. The performance variables (weight, body condition score), hematological variables (packed cell volume, hemoglobin, white blood cells, segmented neutrophils, lymphocytes, eosinophils, monocytes) and fecal egg counts were measured individually every 14 days during 6 months. The variables were transformed, and analysis of variance was carried out, with construction of a correlation network. Characteristics linked to parasite infection showed variations among the categories, which helped to identify sheep resistant, resilient or susceptible to H. contortus. Based on the analyses performed, 88.3% of the animals were resistant or resilient and only 11.7% were susceptible. Presence of Trichostrongylidae eggs, body condition score, packed cell volume (PCV) and eosinophil counts were found to be good indicators of naturally infected ewes, and there were significant differences between the categories and correlations between the traits.

Growth performance, carcass traits and meat quality of lambs fed increasing level of Macadamia nut cake.

A total of 40 lambs were divided into four different treatments according to the inclusion level of the macadamia nut cake: C-control (0%), M1 (6.5%), M2 (12%) and M3 (20%). Feed was provided twice a day; animal weighing along with body condition scoring occurred within a 14-day interval. The lambs were slaughtered at the end of the performance test. Analysis of variance was performed through the Mixed procedure of the SAS, as well as linear and quadratic regression analysis. The groups presented differences between the treatments (P <0.05) for dry matter intake (DMI), ethereal extract intake (EEI), consumption in relation to live weight percentage and feed conversion ratio (FCR). The lowest mean DMI was obtained by the animals that received the M2 and differed from the C treatment, whose average was the highest. The EEI was highest for the M3 group and the FCR was also better for this group. There was a linear effect for EEI and FCR, and quadratic for crude protein intake. There was no effect for carcass characteristics, and only initial pH had a decreasing linear effect. The macadamia nut cake was effective in promoting the performance of the animals, since there was an improvement in feed conversion.

The effects of genetic group and sex on residual feed intake, performance, morphometric, testicular, and carcass traits' in lambs.

The aim of this study was to analyze the effects of genetic group and sex on residual feed intake, performance, testicular size, carcass and morphometric traits in Santa Ines purebred and Dorper ´ Santa Ines crossbred lambs. A total of 32 lambs, with initial body weight of 18±3.7 kg were used. Analysis of variance, considering the interaction between sex and genetic group of all the traits were performed. Crossbred females (-0.018±0.06) and purebred males (-0.018±0.05) were more efficient (p<0.001) in residual feed intake than crossbred males (0.018±0.04) or purebred females (0.018±0.04). The most efficient animal in residual feed intake consumed 37.9% less feed (1.179 kg/day) than the least efficient animal (1.899 kg/day). Crossbred, when compared to purebred, showed higher values for body weight, average daily gain, testicle size, carcass traits; had greater muscle accumulation, were more compact and with more aptitude to beef. Purebred were taller, but with lower body length and thoracic perimeter than crossbred. Males had greater muscle accumulation, were more compact and with more aptitude to meat. Crossing of native (Santa Ines) with exotic breed (Dorper) is an alternative to align efficiency in feed use, testicular size, compactness, aptitude for meat and ability for muscle accumulation.

Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review.

PURPOSE: Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC. RESULTS: As with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials. CONCLUSIONS: The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.

A Real-World Data Retrospective Cohort Study of HER2-positive, Early-Stage Breast Cancer in Patients 70 Years of Age or Older: Natural History, Treatment Patterns, and Outcomes.

PURPOSE: Early-stage human epidermal growth factor receptor 2-positive (HER2-positive) breast cancers (BCs) are routinely treated with intense perioperative chemotherapy combined with HER2-targeted agents. There is thus an unmet need for knowledge about treatment patterns and outcomes among patients 70 years of age or older, as this is an under-represented subset of patients in large clinical trials. METHODS: We used a deidentified cohort derived from a nationwide electronic health record database to conduct a retrospective cohort study of patients with HER2-positive BCs. Descriptive statistics were used to evaluate tumor characteristics, treatment patterns across age groups, and pathologic complete response rates. We used Kaplan-Meier survival curves to estimate recurrence-free and overall survivals; Cox proportional methods were used for adjustments with covariates of interest, including age as a categorical variable. RESULTS: We included 395 patients with HER2-positive stage I to III BCs who were 70 years of age or older. Most patients had tumors with high nuclear-grade T2 tumors, and received surgical treatment first. Most patients (61.7%) who received HER2 therapies underwent treatment in the adjuvant setting; paclitaxel and trastuzumab combination was the most commonly used adjuvant regimen. Older age was associated with increased hazard of recurrence or death. We did not detect significant evidence of decline in performance status, but there was modest weight drop after perioperative HER2 treatments. CONCLUSION: Findings suggest that patients in this older-age cohort were treated with de-escalated perioperative strategies and had poorer outcomes; our findings should be validated in future studies.

Early-Stage Triple-Negative Breast Cancer Journey: Beginning, End, and Everything in Between.

Triple-negative breast cancer (TNBC) is a very heterogeneous and aggressive breast cancer subtype with a high risk of mortality, even if diagnosed early. The mainstay of early-stage breast cancer includes systemic chemotherapy and surgery, with or without radiation therapy. More recently, immunotherapy is approved to treat TNBC, but managing immune-rated adverse events while balancing efficacy is a challenge. The purpose of this review is to highlight the current treatment recommendations for early-stage TNBC and the management of immunotherapy toxicities.

Classification Performance of Machine Learning Methods for Identifying Resistance, Resilience, and Susceptibility to Haemonchus contortus Infections in Sheep.

This study investigated the feasibility of using easy-to-measure phenotypic traits to predict sheep resistant, resilient, and susceptible to gastrointestinal nematodes, compared the classification performance of multinomial logistic regression (MLR), linear discriminant analysis (LDA), random forest (RF), and artificial neural network (ANN) methods, and evaluated the applicability of the best classification model on each farm. The database comprised 3654 records of 1250 Santa Inês sheep from 6 farms. The animals were classified into resistant (2605 records), resilient (939 records), and susceptible (110 records) according to fecal egg count and packed cell volume. A random oversampling method was performed to balance the dataset. The classification methods were fitted using the information of age class, the month of record, farm, sex, Famacha© degree, body weight, and body condition score as predictors, and the resistance, resilience, and susceptibility to gastrointestinal nematodes as the target classes to be predicted considering data from all farms randomly. An additional leave-one-farm-out cross-validation technique was used to assess prediction quality across farms. The MLR and LDA models presented good performances in predicting susceptible and resistant animals. The results suggest that the use of readily available records and easily measurable traits may provide useful information for supporting management decisions at the farm level.

A Real-World Data Retrospective Cohort Study of Low Estrogen Receptor-Positive Early Breast Cancer: Natural History and Treatment Outcomes.

Purpose: Estrogen receptor-positive (ER+) breast cancer (BC) is a heterogeneous disease, and there is an ongoing debate regarding the optimal cut point for clinically relevant ER expression. We used a real-world database to assess the prognostic and predictive values of lower ER expression levels on treatment outcomes with endocrine therapy. Methods: We used a nationwide electronic health record database. Descriptive statistics were used to evaluate the association between ER expression, tumor characteristics, and treatment patterns among patients with early-stage BC. We used Kaplan-Meier survival curves to estimate recurrence-free survival (RFS) and overall survival (OS). We assessed associations between an alternative ER expression-level cut point and clinical outcomes. Results: Among 4697 patients with early-stage HER2-negative BC, 83 (2.04%) had ER+-low BC (ER expression, 1-9.99%) and 36 (0.88%) had ER+-intermediate BC (10-19.9%). ER+-low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden than ER+-high tumors (≥20% ER expression). African Americans had a higher prevalence of both triple-negative BC (TNBC) and ER+-low BC than ER+-high BC. Patients with ER+-low and ER+-intermediate tumors had survival outcomes similar to patients with TNBC and worse survival outcomes than patients with ER+-high tumors (P < 0.001). Tumors with <20% ER expression were associated with worse outcomes. Conclusion: In our cohort, patients with BCs with ER expression levels <20% had poor clinical outcomes similar to those of patients with TNBC.

Long-Term CD4+ T-Cell and Immunoglobulin G Immune Responses in Oncology Workers following COVID-19 Vaccination: An Interim Analysis of a Prospective Cohort Study.

We conducted a prospective study to evaluate immune responses to SARS-CoV-2 in oncology workers in which we collected blood and clinical data every 6 months. Spike-specific CD4+ T-cells and immunoglobulin G responses were measured using interferon-gamma enzyme-linked immunosorbent spot and enzyme-linked immunosorbent assay, respectively. Sixty (81%) vaccinated and 14 (19%) unvaccinated individuals were enrolled. CD4+ T-cell responses of those individuals currently naturally infected were comparable to those who were 6 months from receiving their last dose of the vaccine; both responses were significantly higher than among those who were unvaccinated. Unvaccinated participants who became vaccinated while in the study showed a significant increase in both types of spike-specific immune responses. Previously vaccinated individuals who received a third dose (booster) showed a similar response to the spike protein. However, this response decreases as soon as 3 months but does not dip below the established response following two doses. Response to variants of concern B.1.617.2 (Delta) and B.1.1.529 (Omicron) also increased, with the Omicron variant having a significantly lower response when compared to Delta and the wild type. We conclude that antibody and T-cell responses increase in oncology workers after serial vaccination but can wane over time.

Transarterial Yttrium-90 Glass Microsphere Radioembolization of Chemotherapy-Refractory Breast Cancer Liver Metastases: Results of a Single Institution Retrospective Study.

PURPOSE: Our purpose was to retrospectively evaluate the safety and efficacy of transarterial hepatic radioembolization (TARE) treatment with yttrium-90 labeled glass microspheres in patients with chemotherapy-refractory breast cancer with liver-dominant metastatic disease. METHODS AND MATERIALS: This retrospective single-institution study evaluated 31 female patients (mean age of 59.6 ± 13.2 years) who were treated with TARE. All patients received and progressed on systemic chemotherapy before TARE. Twenty-one patients also had extrahepatic metastases, including 13 patients who had metastases in bones only besides the liver. Survival data were analyzed by Kaplan-Meier method and compared using log-rank test. Imaging response to treatment was determined by Response Evaluation Criteria in Solid Tumors. RESULTS: Median overall survival (OS) from the TARE was 13 months (95% confidence interval, 9.1-16.9 months). The survival probability at 1, 2, and 3 years was 60.1%, 36.7%, and 24.5%, respectively. The median hepatic progression-free survival was 7 months (95% confidence interval, 6.1-7.9 months). There was no 30-day mortality and 3 patients (9.4%) had grade 3 toxicity. Estrogen receptor (ER) positive status predicted prolonged survival (14 months for ER+ vs 9 months for ER-; P = .028). Patients who had bone-only extrahepatic disease had higher OS than patients with extraosseous metastases (23 vs 8 months, P = .02). At the 3-month follow-up the radiographic objective response rate was 46.6% and disease control rate was 70%. CONCLUSIONS: The treatment of patients with liver-dominant chemotherapy-refractory breast cancer metastases with TARE using yttrium-90 labeled glass microspheres is safe and led to promising hepatic disease control and OS especially in patients with ER+ tumors and in patients without extrahepatic extraosseous metastases.

Intratumoral delivery of dendritic cells plus anti-HER2 therapy triggers both robust systemic antitumor immunity and complete regression in HER2 mammary carcinoma.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) targeted antibodies in combination with chemotherapy has improved outcomes of HER2 positive (pos) breast cancer (BC) but toxicity of therapy remains a problem. High levels of tumor-infiltrating lymphocytes are associated with increased pathologic complete responses for patients treated with neoadjuvant therapy. Here we sought to investigate whether delivery of intratumoral (i.t.) multiepitope major histocompatibility complex (MHC) class II HER2 peptides-pulsed type I polarized dendritic cells (HER2-DC1) in combination with anti-HER2 antibodies without chemotherapy could enhance tumor regression by increasing anti-HER2 lymphocyte infiltration into the tumor. METHODS: BALB/c mice bearing orthotopic TUBO tumors, BALB/c mice bearing subcutaneous (s.c.) CT26 hHER2 tumors, or BALB-HER2/neu transgenic mice were all treated with i.t. or s.c. HER2-DC1, anti-HER2 antibodies, paclitaxel, T-DM1 or in combination. Immune response, host immune cells and effector function were analyzed using flow cytometry, interferon-γ ELISA and cytokine/chemokine arrays. The contributions of CD4+ and CD8+ T cells and antibody dependent cellular cytotoxicity (ADCC) were assessed using depleting antibodies and FcγR KO mice. Molecular changes were evaluated by immunohistochemistry and western blot. RESULTS: HER2-DC1 combined with anti-HER2 antibodies delivered i.t. compared to s.c. induced complete tumor regression in 75-80% of treated mice, with increased tumor infiltrating CD4+ and CD8+ T, B, natural killer T cells (NKT) and natural killer cells, and strong anti-HER2 responses in all HER2pos BC models tested. The therapy caused regression of untreated distant tumors. Labeled HER2-DC1 migrated prominently into the distant tumor and induced infiltration of various DC subsets into tumors. HER2-DC1 i.t. combined with anti-HER2 antibodies displayed superior antitumor response compared to standard chemotherapy with anti-HER2 antibodies. Lasting immunity was attained which prevented secondary tumor formation. The presence of CD4+ and CD8+ T cells and ADCC were required for complete tumor regression. In the HER2pos BC models, HER2-DC1 i.t. combined with anti-HER2 antibodies effectively diminished activation of HER2-mediated oncogenic signaling pathways. CONCLUSIONS: HER2-DC1 i.t. with anti-HER2 antibodies mediates tumor regression through combined activation of T and B cell compartments and provides evidence that HER2-DC1 i.t. in combination with anti-HER2 antibodies can be tested as an effective alternative therapeutic strategy to current chemotherapy and anti-HER2 antibodies in HER2pos BC.

Novel evolutionary dynamics of small populations in breast cancer adjuvant and neoadjuvant therapy.

Disseminated cancer cells (DCCs) are detected in the circulation and bone marrow of up to 40% of breast cancer (BC) patients with clinically localized disease. The formation of metastases is governed by eco-evolutionary interactions of DCCs with the tissue during the transition from microscopic populations to macroscopic disease. Here, we view BC adjuvant and neoadjuvant treatments in the context of small population extinction dynamics observed in the Anthropocene era. Specifically, the unique eco-evolutionary dynamics of small asexually reproducing cancer populations render them highly vulnerable to: (1) environmental and demographic fluctuations, (2) Allee effects, (3) genetic drift and (4) population fragmentation. Furthermore, these typically interact, producing self-reinforcing, destructive dynamics-termed the Extinction Vortex-eradicating the population even when none of the perturbations is individually capable of causing extinction. We propose that developing BC adjuvant and neoadjuvant protocols may exploit these dynamics to prevent recovery and proliferation of small cancer populations during and after treatment-termed "Eco-evolutionary rescue" in natural extinctions. We hypothesize more strategic application of currently available agents based on the extinction vulnerabilities of small populations could improve clinical outcomes.

A mixed-methods study of cyclin-dependent kinase 4 and 6 inhibitor symptom burden and quality of life among metastatic breast cancer patients and providers.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor targeted therapies dramatically improve survival outcomes for metastatic breast cancer (MBC), but they are associated with significant symptom burden that can impact patients' health-related quality of life (HRQOL) and treatment outcomes. This study is the first to describe CDK4/6 inhibitor symptoms from the lived perspectives of MBC patients taking CDK4/6 inhibitors and healthcare providers involved in MBC care. This study also explored patients' symptom management and HRQOL concerns, and gathered feedback about developing supportive interventions for MBC. METHODS: MBC patients taking CDK4/6 inhibitors (N = 20) and MBC healthcare providers (N = 12) participated in semi-structured interviews that were analyzed for qualitative themes. MBC patients completed surveys about HRQOL, symptoms, and unmet needs. RESULTS: Patient and provider perceptions of CDK4/6 inhibitor symptoms did not align with patients perceiving symptoms as more burdensome. Patients reported that supportive resources (e.g., support groups, blogs) that are not specific to MBC do not adequately meet their needs. Patients and providers were enthusiastic about developing supportive interventions specifically for MBC and offered considerations for designing such interventions. CONCLUSIONS: Findings highlight differences in perceptions of CDK4/6 inhibitor symptom burden between MBC patients and providers. Results will inform the development of supportive interventions to assist MBC patients in managing CDK4/6 inhibitor symptom burden and maintaining HRQOL. Such interventions could also improve treatment outcomes.

Real-world benefit of combination palbociclib and endocrine therapy for metastatic breast cancer and correlation with neutropenia.

BACKGROUND: Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression-free survival (PFS) in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real-world benefit of first-line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. METHODS: This study included HR-positive, HER2-negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression-free survival (PFS) was determined using Kaplan-Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil-to-lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time-dependent variable. RESULTS: In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93-NR). Median PFS for patients with bone-only metastases (n = 54) was not reached (95% CI 18.21-NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33-33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71-0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97-1.18, p = 0.203). CONCLUSION: The effectiveness of palbociclib and endocrine therapy in the treatment of HR-positive, HER2-negative mBC in the real-world setting is similar to the efficacy reported in the PALOMA-2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Nivolumab and Stereotactic Radiosurgery for Patients With Breast Cancer Brain Metastases: A Nonrandomized, Open-Label Phase 1b Study.

PURPOSE: We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated, and may improve intracranial tumor control rates compared with SRS alone. METHODS AND MATERIALS: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase 1b trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performance Status ≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. RESULTS: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. No dose limiting toxicities were noted in our patient population. The most common neurologic adverse events included grade 1 to 2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% confidence interval, 3-14 months) with 6- and 12-month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic progression free survival has not been reached with 6- and-12 month rates of 63% and 51%, respectively. CONCLUSIONS: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary data reveals activity in certain breast cancer patients to study therapy.