Predictors of Response to CDK4/6i Retrial After Prior CDK4/6i Failure in ER+ Metastatic Breast Cancer.

After disease progression on endocrine therapy (ET) plus a CDK4/6 inhibitor, there is no standardized sequence for subsequent treatment lines for estrogen receptor positive (ER+) metastatic breast cancer (MBC). CDK4/6i retrial as a treatment strategy is commonplace in modern clinical practice; however, the available prospective data investigating this strategy have had inconclusive results. To frame this data in a real-world context, we performed a retrospective analysis assessing the efficacy of CDK4/6is in 195 patients who had previous exposure to CDK4/6i in a prior treatment line at our institution. Among patients who had stopped a CDK4/6i due to toxicity, CDK4/6i retrial either immediately after with a different CDK4/6i or in a further treatment line with the same initial CDK4/6i was both safe and effective, with a median time to treatment failure (TTF) of 10.1 months (95%CI, 4.8-16.9). For patients whose disease progressed on a prior CDK4/6i, we demonstrated comparable median TTFs for patients rechallenged with the same CDK4/6i (4.3 months, 95%CI 3.2-5.5) and with a different CDK4/6i (4.7 months, 95%CI 3.7-6.0) when compared to the recent PACE, PALMIRA, and MAINTAIN trials. Exploratory genomic analysis suggested that the presence of mutations known to confer CDK4/6i resistance, such as TP53 mutations, CDK4 amplifications, and RB1 or FAT1 loss of function mutations may be molecular biomarkers predictive of CDK4/6i retrial failure.

eIF4A controls translation of estrogen receptor alpha and is a therapeutic target in advanced breast cancer.

The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial ( NCT04092673 ) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.

Molecularly Targeted Therapies for Triple Negative Breast Cancer: History, Advances, and Future Directions.

Triple negative breast cancer (TNBC) remains the subtype with poorest prognosis. Despite the subtype's heterogeneity, there is still a paucity in effective targeted therapeutics that offer both good efficacy and tolerability, and chemotherapy remains the backbone of modern TNBC therapy. In the past few years, immunotherapy as well as novel therapeutic modalities like antibody-drug conjugates (ADCs) have shown clinical benefit and have been FDA approved in various clinical stages of unselected TNBC. However, there has not been similar advancement in molecularly targeted therapies, especially when compared to advancements seen in hormone receptor (HR)-positive or HER2-positive breast cancer. PARP inhibitors have been approved for BRCA-mutated TNBC, but responses are short-lived, and resistance remains a barrier for current treatment. PI3K pathway inhibitors approved in HR+ breast cancer has not worked for TNBC and continue to have significant dose-limiting adverse effects. EGFR inhibition has been thoroughly explored in TNBC, but all trials so far have shown minimal efficacy. Nevertheless, despite these setbacks, current research in targeted therapy for TNBC holds great promise in overcoming the barriers of the past and developing novel therapeutic approaches for the future. In this review, we describe molecular targets both identified and validated in the treatment of TNBC, discuss the historical efforts towards development of targeted agents and current areas of improvement, and address promising advances that have the potential to improve outcomes in this heterogenous and aggressive breast cancer subtype. Immunotherapy, ADCs, and AR targeting will be discussed in separate reviews of this edition.

Consolidative Radiotherapy in Oligometastatic Lung Cancer: Patient Selection With a Prediction Nomogram.

BACKGROUND: Patients with stage IV oligometastatic (≤ 3 sites) non-small-cell lung cancer have a progression-free survival (PFS) and overall survival benefit when all sites of metastatic disease and the primary tumor are treated radically with consolidative radiotherapy (cRT). However, the optimal selection of patients most likely from cRT is yet to be defined. PATIENTS AND METHODS: Patients with metastatic non-small-cell lung cancer treated with definitive radiotherapy to all metastatic sites and primary tumor (2008-2019) were retrospectively identified. Univariable Cox proportional-hazards model was used to compare outcomes with demographic and clinical characteristics. A predictive nomogram model for selection of patients most likely to benefit from cRT was constructed. RESULTS: There were 91 patients identified with a total of 114 metastases treated. Median PFS from the start of cRT was 10.9 months (95% confidence interval [CI], 8.1-16.6), while the median survival time was 37.0 months (95% CI, 31.3-NR). On univariable modeling, patients with squamous histology (hazard ratio, 4.16; 95% CI, 1.99-8.71; P < .001) and those treated with non-stereotactic body radiotherapy hypofractionated therapy (hazard ratio, 5.43; 95% CI, 2.10-14.01; P < .001) had worse overall survival, while patients with targetable mutations (hazard ratio, 0.49; 95% CI, 0.25-0.98; P = .04) had a longer survival. Using a predictive nomogram model, patients with a solitary site of metastasis, targetable mutations, intracranial disease, and metachronous timing of oligometastases had a larger PFS benefit from cRT. CONCLUSION: cRT is associated with favorable outcomes in PFS and overall survival. These results may aid in patient counseling, selection for aggressive local therapy, and stratification in future prospective clinical trials.

Isolated progression of metastatic lung cancer: Clinical outcomes associated with definitive radiotherapy.

BACKGROUND: Progressive, metastatic non-small cell lung cancer (NSCLC) often requires the initiation of new systemic therapy. However, in patients with NSCLC that is oligoprogressive (≤3 lesions), local radiotherapy (RT) may allow for the eradication of resistant microclones and, therefore, the continuation of otherwise effective systemic therapy. METHODS: Patients treated from 2008 to 2019 with definitive doses of RT to all sites of intracranial or extracranial oligoprogression without a change in systemic therapy were identified. Radiographic progression-free survival (rPFS) and time to new therapy (TNT) were measured. Associations between baseline clinical and treatment-related variables were correlated with progression-free survival via Cox proportional hazards modeling. RESULTS: Among 198 unique patients, 253 oligoprogressive events were identified. Intracranial progression occurred in 51% of the patients, and extracranial progression occurred in 49%. In the entire cohort, the median rPFS was 7.9 months (95% CI, 6.5-10.0 months), and the median TNT was 8.8 months (95% CI, 7.2-10.9 months). On adjusted modeling, patients with the following disease characteristics were associated with better rPFS: better performance status (P = .003), fewer metastases (P = .03), longer time to oligoprogression (P = .009), and fewer previous systemic therapies (P = .02). Having multiple sites of oligoprogression was associated with worse rPFS (P < .001). CONCLUSIONS: In select patients with oligoprogression, definitive RT is a feasible treatment option to delay the initiation of next-line systemic therapies, which have more limited response rates and efficacy. Further randomized prospective data may help to validate these findings and identify which patients are most likely to benefit.

Propensity score adjusted analysis of patients with isolated locoregional recurrence versus de novo locally advanced NSCLC treated with definitive therapy.

OBJECTIVES: Definitive intent treatment of isolated locoregional recurrence (iLR) for non-small cell lung cancer (NSCLC) is becoming more common. This study explores outcomes associated with the definitive local treatment of iLR and compares these outcomes to newly diagnosed locally advanced NSCLC (LA-NSCLC) patients. MATERIALS AND METHODS: Patients with NSCLC treated with curative therapy between 2008 and 2019 at a tertiary academic institution were screened for iLR treated with subsequent definitive salvage therapy. Progression free survival (PFS), time to distant metastasis (TTDM), and overall survival (OS) were calculated via Kaplan-Meier methodology. Clinical outcomes were compared to a separate group of patients with de novo LA-NSCLC after adjusting for propensity score (PS). RESULTS: Sixty five cases of definitively salvaged iLR were compared to 302 patients with de novo LA-NSCLC. Most patients were treated with chemoradiotherapy (83.1% in iLR, 74.5% in LA-NSCLC). The median PFS, TTDM, and OS for the iLR cohort was 16.7 months (95% CI: 9.6-24.7), 35.8 months (95% CI: 17.1-NR), and 49.5 months (95% CI: 30.1-NR), respectively. After adjusting for PS, the iLR group was no different from the LA-NSCLC group in risk for progression (HR 0.78, 95% CI: 0.53-1.16, p = 0.22), distant metastasis (HR 0.81, 95% CI: 0.52-1.27, p = 0.36), or death (HR 0.90, 95% CI: 0.47-1.73, p = 0.75). Patterns of failure did not different significantly between groups. In the iLR cohort, patients with older age (HR 1.06, 95 CI: 1.01-1.10, p = 0.01) had a higher risk of death on multivariate analysis. CONCLUSION: To our knowledge, this is the first report that compares the definitive treatment of iLR to de novo LA-NSCLC. When treated with definitive local therapy, patients with iLR had no difference in clinical outcomes from de novo LA-NSCLC. The use of curative local therapy according to a LA-NSCLC paradigm is advisable in patients with iLR of NSCLC for whom definitive therapy is feasible.

Hospitalization and definitive radiotherapy in lung cancer: incidence, risk factors and survival impact.

BACKGROUND: Unplanned hospitalization during cancer treatment is costly, can disrupt treatment, and affect patient quality of life. However, incidence and risks factors for hospitalization during lung cancer radiotherapy are not well characterized. METHODS: Patients treated with definitive intent radiation (≥45 Gy) for lung cancer between 2008 and 2018 at a tertiary academic institution were identified. In addition to patient, tumor, and treatment related characteristics, specific baseline frailty markers (Charlson comorbidity index, ECOG, patient reported weight loss, BMI, hemoglobin, creatinine, albumin) were recorded. All cancer-related hospitalizations during or within 30 days of completing radiation were identified. Associations between baseline variables and any hospitalization, number of hospitalizations, and overall survival were identified using multivariable linear regression and multivariable Cox proportional-hazards models, respectively. RESULTS: Of 270 patients included: median age was 66.6 years (31-88), 50.4% of patients were male (n = 136), 62% were Caucasian (n = 168). Cancer-related hospitalization incidence was 17% (n = 47), of which 21% of patients hospitalized (n = 10/47) had > 1 hospitalization. On multivariable analysis, each 1 g/dL baseline drop in albumin was associated with a 2.4 times higher risk of any hospitalization (95% confidence interval (CI) 1.2-5.0, P = 0.01), and baseline hemoglobin ≤10 was associated with, on average, 2.7 more hospitalizations than having pre-treatment hemoglobin > 10 (95% CI 1.3-5.4, P = 0.01). After controlling for baseline variables, cancer-related hospitalization was associated with 1.8 times increased risk of all-cause death (95% CI: 1.02-3.1, P = 0.04). CONCLUSIONS: Our data show baseline factors can predict those who may be at increased risk for hospitalization, which was independently associated with increased mortality. Taken together, these data support the need for developing further studies aimed at early and aggressive interventions to decrease hospitalizations during treatment.

PD-L1 Immunohistochemistry Highlights Bone Marrow Involvement by Classic Hodgkin Lymphoma in Staging Biopsies: Implications for Diagnosis and Tumor Microenvironment Alterations.

Programmed cell death ligand 1 (PD-L1) is cell surface glycoprotein that regulates the cellular immune response and serves as a targetable immune checkpoint molecule. Previous studies have demonstrated consistent expression of PD-L1 by Reed-Sternberg (RS) cells, as well as nonmalignant tumor-infiltrating macrophages in classic Hodgkin lymphoma (CHL). Bone marrow involvement by CHL is uncommon, being present in 5% to 10% of cases, but indicates Ann Arbor stage IV disease. Given the mixed inflammatory infiltrate that characterizes CHL, detection of RS cells in small bone marrow biopsies may be difficult. We sought to investigate the diagnostic utility of PD-L1 expression in staging bone marrow biopsies from patients with newly diagnosed CHL. Forty-four staging bone marrow biopsies from patients with newly diagnosed CHL were examined for PD-L1 expression by immunohistochemistry. Eight bone marrow biopsies were positive for involvement by CHL (8/44, 18%) and all were positive for PD-L1 (8/8, 100%), including a case that was originally nondiagnostic. Membranous PD-L1 expression was restricted to RS cells and the adjacent nontumor inflammatory cells admixed within areas of fibrosis. Uninvolved bone marrow biopsies and normal-appearing marrow in cases positive for CHL were negative for PD-L1. In comparison, bone marrow biopsies with myelofibrosis caused by myeloproliferative or myelodysplastic disorders were negative for significant PD-L1 staining. PD-L1 expression in RS cells and surrounding inflammatory cells is a sensitive marker for bone marrow involvement by CHL. In cases where RS cells are infrequent, PD-L1 staining in regions of fibrosis may serve as a useful diagnostic clue to involvement by CHL.

Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.

Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 inhibitor (IC50=0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.

Hidradenocarcinoma presenting as soft tissue mass: Case report with cytomorphologic description, histologic correlation, and differential diagnosis.

Hidradenocarcinoma (HAC) is a rare adenexal tumor with a propensity for the head and neck region and extremities. We report a case of hidradenocarcinnoma in a 56-year-old woman with a mass on her right palm sampled by fine-needle aspiration and later confirmed on histological examination. Fine-needle aspiration cytology revealed a dual population of cells including polyhedral eosinophilic cells and glycogen containing cells with pale/clear cytoplasm. The nuclei were pleomorphic with prominent nucleoli. Occassional papillary structures were identified on the cell block material. A series of immunohistochemical stains were performed and an adnexal neoplasm was suggested. The mass was resected. On histologic sections, infiltration into the adjacent soft tissue was identified. After an additional series of immunohistochemical stains, the diagnosis was confirmed as a HAC. Herein, we present our findings and discuss the differential diagnoses.

Assessment of ankle injuries.

School nurses are faced with the challenge of identifying and treating ankle injuries in the school setting. There is little information guiding the assessment and treatment of these children when an injury occurs. It is essential for school nurses to understand ankle anatomy, pathophysiology of the acute ankle injury, general and orthopedic assessment guidelines, and various treatment options to assure proper management of students with injuries to the ankle. The benefits of adhering to these guidelines are that students will receive better, cost-effective treatment and the nurse will make appropriate referral recommendations to parents and other school personnel.

Insulin prevents oxidant-induced endothelial cell barrier dysfunction via nitric oxide-dependent pathway.

BACKGROUND: The rigorous maintenance of normoglycemia by the administration of insulin is beneficial to critically ill patients. Because insulin induces endothelial nitric oxide (NO) release, and the constitutive release of NO maintains normal microvascular permeability, the authors postulated that insulin would prevent peroxide (H(2)O(2))-induced endothelial barrier dysfunction, an effect dependent on endothelial NO synthase (eNOS) activity. METHODS: Murine lung microvascular endothelial cells (LMEC) grown to confluence on 8 micro pore polyethylene filters were exposed to media (control), H(2)O(2) (20 to 500 micromol/L), insulin (1 to 1,000 nmol/L) or insulin (100 nmol/L) + H(2)O(2) (10(-4)mol/L). Endothelial monolayer permeability was quantitated by measuring the transendothelial electrical resistance at 15-minute intervals for 120 minutes. Other cells were exposed to H(2)O(2) and insulin after pretreatment with a NO scavenger (PTIO), an eNOS inhibitor (L-NIO), or a phosphoinositol-3-kinase inhibitor (LY-294002). RESULTS: H(2)O(2) caused a concentration- and time-dependent reduction in electrical resistance consistent with an increase in monolayer permeability. This effect was prevented by insulin. Inhibiting NO release (L-NIO, LY-294002) or scavenging NO (PTIO) abolished this protective effect. CONCLUSIONS: These data suggest that insulin may modulate endothelial barrier function during oxidant stress by inducing the release of NO.