The majority of estrogen receptor-positive (ERα+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown. We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses. Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα+/PR+/HER2− tumors, was associated with poor outcome. These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα+ breast cancers.

Purpose: The optimal management of patients with metastatic germ cell tumors who achieve a complete response (CR) after first-line chemotherapy remains unsettled. This study reports long-term outcomes of patients with metastatic germ cell tumor managed with surveillance after achieving a CR to first-line chemotherapy. Materials and Methods: Patients with metastatic nonseminomatous germ cell tumor treated at Indiana University between 1990 and 2017 who achieved a CR after first-line chemotherapy and were monitored with surveillance were retrospectively analyzed. CR was defined as normalization of tumor markers AFP and hCG, and no residual mass >1 cm in long axis. Kaplan-Meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). Results: Three hundred sixty-seven patients achieved a CR and were managed with surveillance. After a median followup of 4.97 years, 34 patients had disease progression. At most recent followup, 346 (94%) patients were alive with no evidence of disease, 10 patients (2.7%) died of their disease, 5 (1.4%) died of other causes and 6 (1.6%) were lost to followup. The estimated 2-year PFS was 91% (95% CI: 87%–94%) and 2-year OS was 98% (95% CI: 96%–99%). The estimated 2-year PFS by International Germ Cell Cancer Collaborative Group risk category was 92% for good vs 90% for intermediate vs 87% for poor risk (p=0.15), and the estimated 2-year OS was 99% for good vs 96% for intermediate vs 93% for poor risk disease (p=0.001). Conclusions: Patients with metastatic nonseminomatous germ cell tumor who achieve a CR after first-line chemotherapy can be observed. Most patients who relapse can be salvaged with surgery and/or chemotherapy.

The fasting-mimicking diet (FMD) is a plant-based, calorie-restricted, low-carbohydrate, low-protein, 4- or 5-day diet that reproduces short-term fasting physiology and promotes synergy with cancer therapies. Despite established safety and feasibility, FMD data in advanced lung cancer remain lacking. This open-label, single-arm, single-center pilot study recruited metastatic non-small cell lung cancer (NSCLC) adult patients (Body mass index >18, Eastern Cooperative Oncology Group performance status [PS] 0-2) who were clinically stable on first-line therapy for ≥2 months. Patients received one 4-day FMD. Primary outcomes were feasibility (proportion completing FMD), safety (proportion completing FMD without grade 3-4 adverse events), and compliance with FMD caloric requirements. Weight and biologic measures-complete blood counts and metabolic panels-were obtained at baseline and 21 or 28 days post-FMD. Weight was also measured during FMD. The secondary outcome was self-reported willingness to repeat FMD. Ten participants initiated FMD. Median age was 57.2 years (40.5, 76.2), median baseline Body mass index 28.1 (22.6, 37.5), and baseline Eastern Cooperative Oncology Group PS 0-1. Most patients were female (70%), had adenocarcinoma (90%), and received oral targeted therapy (80%). Fifty percent were White/Caucasian, 30% Black/African American, and 20% Asian. Ninety percent completed FMD. No grade 3 to 4 adverse events occurred. Most common side effects were grades 1 to 2-nausea (30%), abdominal pain (20%), fatigue (20%), headache (20%). Weight loss remained < 10% from baseline. Biologic markers were normal. Compliance rate was 70% (95% CI, 34.8-93.3). Eighty percent of patients expressed willingness to repeat FMD. A single FMD cycle is safe and feasible in relatively young, advanced NSCLC patients on oral targeted therapy. ClinicalTrials.gov Identifier: NCT03700437.

Background/Objectives: Acute leukemias in adolescents and young adults (AYAs) with Down Syndrome (DS) are understudied. Methods: This was a single-center, retrospective cohort study. Medical records for pediatric DS (n = 41) and AYA-DS (n = 7) treated with a pediatric chemotherapy regimen for acute leukemia were evaluated. Results: Two-year event-free survival (EFS) in AYA DS acute leukemia patients was lower than that in their pediatric DS counterparts (28.6% (Confidence Interval (CI) 4.1, 61.2) vs. 84.9% (CI 69.5, 92.9); p = 0.002). Conclusions: Additional research is needed to improve outcomes in AYA DS leukemia.