Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, ...plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment.
Recent data indicate consolidative radiation therapy improves progression-free survival (PFS) for patients with oligometastatic non-small cell lung cancer (NSCLC). Data on long-term outcomes are ...limited.
This prospective, multicenter, single-arm, phase 2 trial was initiated in 2010 and enrolled patients with oligometastatic NSCLC. Oligometastatic disease was defined as a maximum of 5 metastatic lesions for all disease sites, including no more than 3 active extracranial metastatic lesions. Limited mediastinal lymph node involvement was allowed. Patients achieving a partial response or stable disease after 3 to 6 cycles of platinum-based chemotherapy were treated with CRT to the primary and metastatic sites of disease, followed by observation alone. The primary endpoint was PFS, with secondary endpoints of local control, overall survival (OS), and safety.
Twenty-nine patients were enrolled between October 2010 and October 2015, and 27 were eligible for consolidative radiation therapy. The study was closed early because of slow accrual but met its primary endpoint for success, which was PFS >6 months (P < .0001). The median PFS (95% confidence interval) was 11.2 months (7.6-15.9 months), and the median OS was 28.4 months (14.5-45.8 months). Survival outcomes were not significantly different for patients with brain metastases (P = .87 for PFS; P = .12 for OS) or lymph node involvement (P = .74 for PFS; P = .86 for OS).
For patients with oligometastatic NSCLC, chemotherapy followed by consolidative radiation therapy without maintenance chemotherapy was associated with encouraging long-term outcomes.
Small cell lung cancer (SCLC) is a common lung cancer which presents with extensive stage disease at time of diagnosis in two-thirds of patients. For treatment of advanced disease, traditional ...platinum doublet chemotherapy induces response rates up to 80% but with few durable responses. CPI-613 is a novel anti-cancer agent that selectively inhibits the altered form of mitochondrial energy metabolism in tumor cells.
We evaluated CPI-613 with a single-arm, open-label phase II study in patients with relapsed or refractory SCLC. CPI-613 was given at a dose of 3,000 mg/m2 on days 1 and 4 of weeks 1-3 of 4 week cycle. The primary outcome was response rate as assessed by CT imaging using RECIST v1.1 criteria. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and toxicity. Twelve patients were accrued (median age 57yo) who had previously received between 1 and 4 lines of chemotherapy (median 1) for SCLC with a treatment-free interval of less than 60 days in 9 of the 12 patients.
No complete or partial responses were seen. Ten patients (83%) progressed as best response and 2 (17%) were not evaluable for response. Median time to progression was 1.7 months (range 0.7 to 1.8 months). Eleven patients (92%) died with median overall survival of 4.3 months (range 1.2 to 18.2 months). The study was closed early due to lack of efficacy. Of note, three out of three patients who progressed after CPI-613 and were subsequently treated with standard topotecan then demonstrated treatment response with survival for 18.2, 7.4, and 5.1 months. We conducted laboratory studies which found synergy in-vitro for CPI-613 with topotecan.
Single agent CPI-613 had no efficacy in this study. Further study of CPI 613 in combination with a topoisomerase inhibitor is warranted.
Purpose
The purpose of this study was to retrospectively evaluate the new treatment paradigm of staged stereotactic radiosurgery (SRS) for the treatment of large brain metastases (BM) compared to the ...standard of surgical resection followed by SRS.
Methods
We evaluated 78 patients with large BM treated 2012–2017 with surgical resection and postoperative SRS (surgery + SRS) or staged SRS separated by 1 month. Overall survival (OS) was estimated using the Kaplan Meier method and compared across groups using the log-rank test. Cumulative incidence of neurologic death and local and distant brain failure (LF, DBF) were estimated using competing risk methodology.
Results
Forty patients were treated with surgery + SRS and 38 patients were treated with staged SRS. Median follow-up was 23.2 months (95% CI 20.5–39.3). Median OS was 13.2 months for staged SRS compared to surgery + SRS 9.7 months (p = 0.53). Cumulative incidence of neurologic death at 1 year was 23% after surgery + SRS, 27% after staged SRS (p = 0.69); cumulative incidence of LF at 1 year was 6% and 8% (p = 0.65) and 1-year DBF was 59% and 21% (p ≤ 0.01). Overall rates of leptomeningeal failure and radiation necrosis were similar between the groups (p = 0.63 and p = 1.0).
Conclusions
Though surgery and postoperative SRS is the standard, staged SRS represents an attractive treatment paradigm for treating large BM without sacrificing LC or survival, and potentially decreases DBF. Prospective studies are needed to validate these findings.
Las mujeres posponen su maternidad por el deseo de superación personal yprofesional. Se conoce que la cantidad y calidad de los óvulos por ciclo dependende la edad de la paciente. Las tasas de éxito ...en tratamientos de reproducciónasistida disminuyen con la edad, especialmente después de los 40 años. Se observantasas más altas de nacidos vivos en mujeres más jóvenes y las tasas disminuyensignificativamente en mujeres mayores debido a la disminución de la fertilidady el aumento de abortos espontáneos. Por ello, la edad es crucial al evaluar laposibilidad de un embarazo exitoso mediante tratamientos de reproducción asistida(TRA). Las indicaciones para realizar fertilización in vitro (FIV) con óvulos propios enmujeres mayores de 40 años incluyen iniciar lo más pronto procedimientos de altacomplejidad, buena evaluación de la reserva ovárica con análisis de la hormonaantimülleriana y conteo de folículos antrales para realizar asesoramiento genético,proponer FIV-inyección intracitoplasmática de espermatozoides (ICSI) antes de los44 años, generar expectativas realistas y realizar consentimiento informado, conestadisticas propias. En la REDLARA, de todos los procedimientos de FIV-ICSI, el 34%de las pacientes tienen más de 40 años; se prefiere transferir blastocistos con pruebagenética preimplantacional de aneuploidías (PGT-A) para seleccionar embrioneseuploides. Las tasas de éxito son bajas, inclusive cuando son tasas de embarazo portransferencia de un embrión en el grupo de mujeres ≥ 40 años (18,2% sin PGT, 42,7%con PGT en el IMRCRP). Se recomienda acumular óvulos o embriones realizandomúltiples estimulaciones ováricas. Se debe optar por transferir un solo embrión paraevitar complicaciones obstétricas con embarazos múltiples en pacientes ≥ 40 años,por el alto riesgo debido a la edad.
In this work, we study the survival outcomes of patients with lung adenocarcinoma in four independent cohorts. By classifying patients with KRAS mutations into three subgroups based on their mutation ...status of TP53 and SMARCA4, our analysis indicates that patients harboring both KRAS and SMARCA4 mutations do not benefit from the treatment with nonimmunotherapy or immune checkpoint inhibitor‐based immunotherapy. Alternative treatment strategy is requested for this subset of patients.
KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin‐remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS‐mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK‐IMPACT Clinical Sequencing (MSK‐CT) cohorts; and KRAS‐mutant patients with LUAD who received immune checkpoint inhibitor‐based immunotherapy treatment from (c) the MSK‐IMPACT (MSK‐IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS‐mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome P = 6e‐04 for disease‐free survival (DFS) and 0.031 for overall survival (OS), respectively, compared to KRAS‐TP53 comutant (KP) and KRAS‐only mutant (K) patients; in the MSK‐CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression‐free survival (PFS; P = 0.0091) in the MSK‐IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.
Improved assessment strategies are needed to individualize treatment for adults of all ages receiving palliative chemotherapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate the ...utility of the Fried Frailty Index (FFI) and a cancer-specific geriatric assessment (GA) to predict chemotherapy toxicity and overall survival (OS).
We conducted a multi-site pilot study of 50 patients with newly diagnosed advanced NSCLC, age ≥ 18 years. All participants received carboplatin AUC 6, paclitaxel 200 mg/m2 every 3 weeks. FFI and the GA were administered prior to chemotherapy. A GA toxicity risk score was calculated. Grade 3–5 toxicity was assessed during 1st two cycles of chemotherapy. OS was measured from chemotherapy initiation. Logistic regression and Cox proportional hazards models were fit to estimate the association between baseline characteristics and toxicity and OS respectively.
Among 50 participants, 48 received chemotherapy and were evaluable. The mean age was 68.5 y (range 42–86), 79% male, 85% KPS ≥80. The median OS was 8 months. Many (27%) met FFI criteria for frailty with ≥3 impairments. Impairments detected by the GA were common. In multivariable analyses both FFI ≥ 3 and GA toxicity risk score > 7 were independently associated with higher odds of toxicity (Odds ratio OR 7.0; 95% confidence interval CI 1.1–44.6 and OR 4.3; 95% CI 1.0–17.7, respectively) in first cycle chemotherapy. Neither score was associated with OS.
Frailty predicts chemotherapy toxicity during first cycle. Frailty assessment may inform toxicity risk regardless of chronologic age.
Mutations in polymerase ε (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown. Utilizing the data of 513 patients ...with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC. POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients). POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476). This benefit was not due to the high content of the tumor infiltrating lymphocytes. Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients. Our study sheds light on the molecular basis of NSCLC and adds to our understanding of responses to chemotherapy and IO therapy.
The incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but ...it is unclear if distinctive biomarkers can separate patients at risk for CNS related death.
We executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization.
We discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference.
A multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease.
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