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BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis particularly in the metastatic setting. Treatments with anti-programmed cell death protein-1/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors (ICI) in combination with chemotherapies have demonstrated promising clinical benefit in metastatic TNBC (mTNBC) but there is still an unmet need, particularly for patients with PD-L1 negative tumors. Mechanisms of resistance to ICIs in mTNBC include the presence of immunosuppressive tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). Eganelisib is a potent and selective, small molecule PI3K-γ inhibitor that was shown in preclinical studies to reshape the TME by reducing myeloid cell recruitment to tumors and reprogramming TAMs from an immune-suppressive to an immune-activating phenotype and enhancing activity of ICIs. These studies provided rationale for the clinical evaluation of eganelisib in combination with the anti-PD-L1 atezolizumab and nab-paclitaxel in firstline mTNBC in the phase 2 clinical trial MAcrophage Reprogramming in Immuno-Oncology-3 (MARIO-3, NCT03961698). We present here for the first time, in-depth translational analyses from the MARIO-3 study and supplemental data from eganelisib monotherapy Ph1/b study in solid tumors (MARIO-1, NCT02637531). METHODS: Paired pre-treatment and post-treatment tumor biopsies were analyzed for immunophenotyping by multiplex immunofluorescence (n=11), spatial transcriptomics using GeoMx digital spatial profiling (n=12), and PD-L1 immunohistochemistry, (n=18). Peripheral blood samples were analyzed using flow cytometry and multiplex cytokine analysis. RESULTS: Results from paired tumor biopsies from MARIO-3 revealed gene signatures of TAM reprogramming, immune activation and extracellular matrix (ECM) reorganization. Analysis of PD-L1 negative tumors revealed elevated ECM gene signatures at baseline that decreased after treatment. Gene signatures of immune activation were observed regardless of baseline PD-L1 status and occurred in patients having longer progression-free survival. Peripheral blood analyses revealed systemic immune activation. CONCLUSIONS: This is the first report of translational analyses including paired tumor biopsies from a phase 2 clinical study of the first-in-class PI3K-γ inhibitor eganelisib in combination with atezolizumab and nab-paclitaxel in frontline mTNBC. These results support the mechanism of action of eganelisib as a TAM-reprogramming immunotherapy and support the rationale for combining eganelisib with ICI and chemotherapy in indications with TAM-driven resistance to ICI.

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Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

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Neuroinflammation contributes to the pathogenesis of several neurodegenerative disorders. This study examined the neuroprotective effect of quercetin (QUR)-loaded poly (lactic-co-glycolic) acid (PLGA) nanoparticles (QUR NANO) against the neurotoxicity induced by lipopolysaccharide (LPS) in mice. A QUR NANO formulation was prepared and characterized by differential scanning calorimetry, X-ray diffraction, entrapment efficiency (EE), high-resolution transmission electron microscopy, field emission scanning electron microscopy, and in vitro drug release profile. Levels of glutathione, malondialdehyde, catalase, inducible nitric oxide synthase (iNOS), amyloid beta 42 (Aß42), ß-secretase, gamma-aminobutyric acid (GABA), and acetylcholine esterase (AChE) were measured in the mouse brain tissues. The gene expression of nuclear factor erythroid-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) were also determined. The prepared QUR NANO formulation showed 92.07 ± 3.21% EE and drug loading of 4.62 ± 0.55. It exhibited clusters of nano-spherical particles with smooth surface areas, and the loading process was confirmed. In vivo, the QUR NANO preserved the spatial memory of mice and protected the hippocampus from LPS-induced histological lesions. The QUR NANO significantly reduced the levels of malondialdehyde, iNOS, Aß42, ß-secretase, and AChE in brain tissue homogenates. Conversely, QUR NANO increased the glutathione, catalase, and GABA concentrations and upregulated the expression of Nrf-2 and HO-1 genes. Remarkably, the neuroprotective effect of QUR NANO was significantly greater than that of herbal QUR. In summary, the prepared QUR NANO formulation was efficient in mitigating LPS-induced neurotoxicity by reducing memory loss, oxidative stress, and amyloidogenesis while preserving neurotransmission and upregulating the expression of Nrf2 and HO-1 genes. This study addresses several key factors in neuroinflammatory disorders and explores the potential of QUR-loaded nanoparticles as a novel therapeutic approach to alleviate these factors.

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PURPOSE: HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. METHODS: A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. RESULTS: A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8 months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2 months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3 months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. CONCLUSIONS: SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

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Postprocessing is essential for improving titanium aluminide (TiAl) microstructure and part quality after using the laser powder bed fusion (L-PBF) method. It has been reported that Ti-48Al-2Cr-2Nb (%at) processed by L-PBF has internal defects and low fracture toughness. Microstructure control by heat treatment (HT) showed a significant improvement in the ductility of the material. Alternatively, hot isostatic pressing (HIPing) could be applied to reduce the residual stresses and internal defects formed during the L-PBF. Combining the benefits of these two subsequent processes into a single predetermined process is appealing for Ti-48Al-2Cr-2Nb (%at) to minimize cost. This work presents a novel strategy to postprocess L-PBF TiAl by applying combined heat treatment and hot isostatic pressing in one process, namely HT-HIP. The process includes three cycles with different conditions (i.e., temperature, time, and pressure). These conditions were determined to achieve improved part quality and microstructure. The results show that the tensile residual stresses decreased from a peak of 249 MPa in the as-built sample to compressive stresses that peaked at -90 MPa after the HT-HIP process. The number and size of internal defects could be greatly reduced. The defects were transformed into a regular spherical shape, which is good in terms of fatigue strength. Additionally, a duplex microstructure with lamellar α2/γ colonies could be introduced for better ductility. Different levels of duplex microstructure could be achieved along with the process cycles. The grain structure using EBSD analysis showed refined equiaxed grains, which demonstrate better strength after the HT-HIP process. Twinning boundaries were also observed in the HT-HIP sample. The grain orientation tendency to the build direction significantly reduced after the HT-HIP process. The nanoindentation test was applied to evaluate the nanohardness of the as-built and HT-HIP samples. It could be demonstrated that the nanohardness is dependent on the formed phases and lamellar density inside the grains. The mean hardness value was 8.19 GPa for the as-built sample, while it was 5.48 GPa for the HT-HIP sample.

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The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

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BACKGROUND: The genus Huffmanela Moravec, 1987 (Nematoda, Trichosomoididae, Huffmanelinae), represents a group of nematodes that infect both marine and freshwater fish, and the main gross feature of infection with different species of the genus is the presence of noticeable dark spots or tracks within the parasitized tissues. The purpose of this study was to describe morphologically and morphometrically the eggs of a new marine species of Huffmanela (Huffmanela persica sp. nov.), which was found in the form of black spots in the ovary and the tunica serosa of the stomach of the daggertooth pike conger (Muraenesox cinereus). The new species differs from Huffmanela hamo, another species reported from musculature of this host in Japan, in egg metrics, eggshell features and targeted organ. Molecular identification and pathological examination of the lesions caused by the new species are also reported. METHODS: Nematode eggs with varying degrees of development were separated from the infected tissues (ovary and tunica serosa of stomach) and investigated using light and scanning electron microscopy. Different species-specific markers (small subunit ribosomal DNA, 18S; large subunit ribosomal DNA, 28S; internal transcribed spacer, ITS) were used for molecular identification and phylogenetic study of the new species. Infected tissues were fixed in buffered formalin for pathological investigations. RESULTS: The fully developed eggs of H. persica sp. nov. are distinguished from those previously described from this host on the basis of their measurements (size, 54-68 × 31-43 µm; polar plugs, 6.4-9.7 × 8.4-12 µm; shell thickness, 3.5-6.1 µm) and a delicate but ornate uterine layer (UL) covering the entire eggshell including the polar plugs. Histopathological examination revealed a fibro-granulomatous inflammation in the ovary and the serosal layer of the stomach of infected fish. Maximum-likelihood (ML) phylogenetic analysis recovered a sister relationship between the new species of marine origin and Huffmanela species previously collected from freshwater hosts. CONCLUSIONS: The present study is the first to report the molecular characterization and phylogenetic position of a teleost-associated marine species of the genus Huffmanela. A comprehensive list of nominal and innominate populations of Huffmanela is also provided.

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Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855 ). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.

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AIMS: To assess the level of transesophageal echocardiography (TOE) knowledge and skills of young cardiologists. METHODS AND RESULTS: A European Association of Cardiovascular Imaging (EACVI) online study using the first fully virtual simulation-based software was conducted in two periods (9-12 December 2021 and 10-13 April 2022). All young cardiologists eligible to participate (<40 years) across the world were invited to participate. After a short survey, each participant completed two tests: a theoretical test to assess TOE knowledge and a practical test using an online TOE simulator to investigate TOE skills. Among 716 young cardiologists from 81 countries, the mean theoretical test score was 56.8 ± 20.9 points, and the mean practical test score was 47.4 ± 7.2 points (/100 points max each), including 18.4 ± 8.7 points for the acquisition test score and 29.0 ± 6.7 points for the anatomy test score (/50 points max each). Acquisition test scores were higher for four-chamber (2.3 ± 1.5 points), two-chamber (2.2 ± 1.4 points) and three-chamber views (2.3 ± 1.4 points) than for other views (all P < 0.001). Prior participation to a TOE simulation-based training session, a higher number of TOE exams performed per week, and EACVI certification for TOE were independently associated with a higher global score (all P < 0.001). CONCLUSION: Online evaluation of young cardiologists around the world showed a relatively low level of TOE skills and knowledge. Prior participation to a TOE simulation-based training session, a higher number of TOE exams performed per week, and the EACVI certification for TOE were independently associated with a higher global score.

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Compared with non-Hispanic White women, Latina women are less likely to receive genetic counseling (GC) and testing (GT) following BC diagnosis. This study used secondary data analysis to explore beliefs about GC among Latina BC survivors in and outside the US mainland. GC/GT-naïve, high-risk, Spanish-preferring Latina BC survivors (n = 52) in FL and PR completed the Behavioral Beliefs about GC scale. Participants reported high positive beliefs about GC (M = 4.19, SD = 0.92); the majority agreed that GC was beneficial to understand cancer risk (90%) and promote discussion (87%) in their family. Participants reported low-to-moderate scores for barriers (Ms = 1.53-3.40; SDs = 0.59-0.90). The most frequently endorsed barriers were desire for additional GC information (M = 3.44; SD = 0.90), and GC logistic concerns (M = 2.71; SD = 0.80). No statistically significant differences for barriers and benefits scales were identified by place of residence (all ps ≥ 0.12). These findings highlight the importance of delivering culturally sensitive GC information to high-risk Latina BC survivors.

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In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

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Among high-risk breast cancer (BC) survivors, genetic counseling (GC) and genetic testing (GT) may inform cascade testing and risk management. Compared to non-Hispanic White BC survivors, Spanish-preferring Latina BC survivors are less likely to report discussing GC with a healthcare provider. However, few studies have examined Latinas' experiences with GC/GT, particularly outside of the mainland USA. This study aimed to compare frequency of provider discussion of GC between Spanish-preferring Latina BC survivors living in Florida (FL) and Puerto Rico (PR). We conducted secondary data analysis of baseline assessments from a randomized pilot of an educational intervention for Spanish-preferring Latina BC survivors. Participants (N = 52) were GC/GT-naive, but met clinical criteria for GC/GT referral. Participants self-reported sociodemographic, clinical, and cultural variables, including previous provider discussion of GC. Descriptive statistics characterized frequency of GC discussion. Logistic regression examined the relationships between sociodemographic, clinical, and cultural characteristics and GC discussion. Only 31% of participants reported previous GC discussion. More participants from PR reported having GC discussions (43% vs. 21% in the mainland USA). In multivariable analyses, greater likelihood of GC discussion was associated with PR (vs. mainland USA) residence (odds ratio [OR] = 6.00, p = .03), older age at baseline (OR = 1.19, p = .04), and younger age at BC diagnosis (OR = 0.80, p = .03). Few high-risk Spanish-preferring Latina BC survivors in the mainland USA and PR had discussed GC with their providers. These results highlight a gap in the implementation of evidence-based genetics guidelines. Provider-directed interventions may be needed to increase uptake of GC/GT among Latina BC survivors.

Some families have changes in the BRCA genes that increase their risk for developing breast cancer compared to those who do not have these gene changes. Through genetic testing, we can identify breast cancer survivors who have these gene changes so their families can take action to prevent future cancers. Breast cancer survivors who are diagnosed at a young age, or who have a strong family history of breast and ovarian cancer, are eligible for genetic counseling and BRCA testing. Yet, compared to women from other racial and ethnic groups, fewer Latina breast cancer survivors have genetic counseling and testing. This study explored frequency of healthcare providers' discussion about genetic counseling among Spanish-preferring Latina breast cancer survivors living in Florida and Puerto Rico. Although all participants were eligible, only 3 out of 10 indicated that a provider previously discussed genetic counseling with them. Participants who were living in Puerto Rico, older at study entry, or younger at the time of their breast cancer diagnosis were more likely to have discussed genetic counseling with a healthcare provider. Healthcare providers are important for identifying and referring high-risk Spanish-preferring Latinas for genetic counseling in and outside the mainland USA.

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The treatment of metastatic breast cancer (mBC) has evolved significantly in the past several years with the approval of new targeted agents. Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate with a topoisomerase I inhibitor payload, is a new addition to the class of therapies that target the human epidermal growth factor 2 (HER2) receptor. T-DXd was approved in the US in December 2019 for patients with HER2-positive metastatic or unresectable breast cancer who have received 2 or more prior anti-HER2-based regimens in the metastatic setting. In the DESTINY-Breast01 phase II trial (NCT03248492), T-DXd demonstrated high rates of durable responses in heavily pretreated patients with HER2-positive mBC, with a confirmed objective response rate of 62%, median duration of response of 18.2 months, and median progression-free survival of 19.4 months. In addition to efficacy, successful implementation of any new anticancer therapy includes learning how to prevent, monitor, and manage treatment-related adverse events. As T-DXd becomes more widely used, information can be gained from real-world clinical practices, institutional approaches, and the collaboration of multidisciplinary oncology teams who treat patients with T-DXd. This article reviews practical insights and management of nausea and vomiting, neutropenia, interstitial lung disease, risk of cardiotoxicity, and other adverse events associated with T-DXd administration from the perspective of health care providers who have experience utilizing T-DXd.

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The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.

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Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.

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PURPOSE: PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2- advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2. PATIENTS AND METHODS: MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2- ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA. RESULTS: From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33-0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33-0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27-0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 0.37-0.79). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status. CONCLUSIONS: Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2- ABC that had progressed on ET.

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