Dual blockade of BRD4 and ATR/WEE1 pathways exploits ARID1A loss in clear cell ovarian cancer.

ARID1A, an epigenetic tumor suppressor, is the most common gene mutation in clear-cell ovarian cancers (CCOCs). CCOCs are often resistant to standard chemotherapy and lack effective therapies. We hypothesized that ARID1A loss would increase CCOC cell dependency on chromatin remodeling and DNA repair pathways for survival. We demonstrate that combining BRD4 inhibitor (BRD4i) with DNA damage response inhibitors (ATR or WEE1 inhibitors; e.g. BRD4i-ATRi) was synergistic at low doses leading to decreased survival, and colony formation in CCOC in an ARID1A dependent manner. BRD4i-ATRi caused significant tumor regression and increased overall survival in ARID1AMUT but not ARID1AWT patient-derived xenografts. Combination BRD4i-ATRi significantly increased γH2AX, and decreased RAD51 foci and BRCA1 expression, suggesting decreased ability to repair DNA double-strand-breaks (DSBs) by homologous-recombination in ARID1AMUT cells, and these effects were greater than monotherapies. These studies demonstrate BRD4i-ATRi is an effective treatment strategy that capitalizes on synthetic lethality with ARID1A loss in CCOC.

Association Between Availability of Molecular Genotyping Results and Overall Survival in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: Current guidelines recommend molecular genotyping for patients newly diagnosed with metastatic nonsquamous (mNSq) non-small-cell lung cancer (NSCLC). The association between availability of molecular genotyping before first line (1L) therapy and overall survival (OS) is not known. METHODS: We conducted a real-world cohort study using electronic health records in patients newly diagnosed with mNSq NSCLC. Cox proportional-hazards multivariable regression models were constructed to examine the association between OS and test result availability before 1L therapy, adjusting for covariates. Additional analyses were conducted to assess the consistency and strength of the relationship. Multivariable logistic regression models were used to examine the association between concurrent tissue and plasma testing (v tissue alone) and result availability. RESULTS: Three hundred twenty-six patients were included, 80% (261/326) with results available before 1L (available testing group), and 20% (65/326) without results available (unavailable testing group). With 14.2-month median follow-up, patients in the available testing group had significantly longer OS relative to the unavailable testing group (adjusted hazard ratio, 0.43; 95% CI, 0.30 to 0.62; P < .0001). The adjusted odds of availability of results before 1L therapy was higher with concurrent tissue and plasma testing (v tissue testing alone; adjusted odds ratio, 2.06; 95% CI, 1.09 to 3.90; P = .026). CONCLUSION: Among patients with mNSq NSCLC in a real-world cohort, availability of molecular genotyping results before 1L therapy was associated with significantly better OS. Concurrent tissue and plasma testing was associated with a higher odds of availability of results before 1L therapy. These findings warrant renewed attention to the completion of molecular genotyping before 1L therapy.

Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL) patients who achieve a complete remission (CR) to anti-CD19 chimeric antigen receptor T cells (CART-19), remissions are remarkably durable. Preclinical data suggesting synergy between CART-19 and the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib prompted us to conduct a prospective single-center phase 2 trial in which we added autologous anti-CD19 humanized binding domain T cells (huCART-19) to ibrutinib in patients with CLL not in CR despite ≥6 months of ibrutinib. The primary endpoints were safety, feasibility, and achievement of a CR within 3 months. Of 20 enrolled patients, 19 received huCART-19. The median follow-up for all infused patients was 41 months (range, 0.25-58 months). Eighteen patients developed cytokine release syndrome (CRS; grade 1-2 in 15 of 18 subjects), and 5 developed neurotoxicity (grade 1-2 in 4 patients, grade 4 in 1 patient). While the 3-month CR rate among International Working Group on CLL (iwCLL)-evaluable patients was 44% (90% confidence interval [CI], 23-67%), at 12 months, 72% of patients tested had no measurable residual disease (MRD). The estimated overall and progression-free survival at 48 months were 84% and 70%, respectively. Of 15 patients with undetectable MRD at 3 or 6 months, 13 remain in ongoing CR at the last follow-up. In patients with CLL not achieving a CR despite ≥6 months of ibrutinib, adding huCART-19 mediated a high rate of deep and durable remissions. ClinicalTrials.gov number, NCT02640209.

Outcomes in Patients With Non-small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy.

BACKGROUND: Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. PATIENTS AND METHODS: We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. RESULTS: Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. CONCLUSIONS: Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.

Long-Term Outcomes From a Randomized Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells in Relapsed Chronic Lymphocytic Leukemia.

PURPOSE: To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS: Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS: At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups (P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not (P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR (P < .0001). Toxicity was comparable in both dose groups. CONCLUSION: In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

The aryl hydrocarbon receptor mediates sex ratio distortion in the embryos sired by TCDD-exposed male mice.

Many reports describe an association between preconceptional paternal exposure to environmental chemicals, including the persistent organic pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) with an increased number of female offspring. We chronically treated wild-type C57BL/6 male mice with TCDD to investigate a role for the aryl hydrocarbon receptor (AHR) transcription factor. These mice had a 14 % lower male:female sex ratio than control mice, which was not observed in TCDD-treated Ahr knock out mice. AHR target genes Cyp1a1 and Ahrr were upregulated in the liver and testis of WT mice and Ahr expression was higher in the epididymis (2-fold) and liver (18-fold) than in whole testis tissue. The AHR protein was localized to round spermatids, elongating spermatids, and Leydig cells in the testis of WT mice. These studies demonstrate AHR involvement in the sex ratio distortion of TCDD-exposed males and the need for evaluating the molecular and genetic mechanism of this process.

Impact of KRAS and TP53 Co-Mutations on Outcomes After First-Line Systemic Therapy Among Patients With STK11-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: The STK11 gene encodes a serine/threonine protein kinase that regulates cell polarity and functions as a tumor suppressor. Patients with non-small-cell lung cancer (NSCLC) and STK11 mutations often have other co-mutations. We evaluated the impact of KRAS and TP53 co-mutations on outcomes after first-line systemic therapy for patients with metastatic or recurrent NSCLC that harbors STK11 mutations. METHODS: We conducted a retrospective review of patients with metastatic NSCLC and STK11 mutations treated at the University of Pennsylvania. STK11 mutations were identified through next-generation sequencing (NGS) in tissue or plasma. Cox proportional hazard models were used to determine the relationship between STK11 co-mutations and survival outcomes. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). RESULTS: From February 2013 to December 2016, samples from 1,385 patients with NSCLC were analyzed by NGS; of these, 77 patients (6%) harbored an STK11 mutation (n = 56, tissue; n = 21, plasma). Of the 62 patients included, 18 had an STK11 mutation alone, 19 had STK11/KRAS, 18 had STK11/TP53, and seven had STK11/KRAS/TP53. Patients with STK11/KRAS co-mutations had a worse median PFS (2.4 months) compared with STK11 alone (5.1 months; log-rank P = .048), STK11/TP53 (4.3 months; log-rank P = .043), and STK11/KRAS/ TP53 (13 months; log-rank P = .03). Patients with STK11/KRAS co-mutation experienced shorter median OS (7.1 months) compared with STK11 alone (16.1 months; log-rank P < .001), STK11/TP53 (28.3 months; log-rank P < .001), and STK11/KRAS/TP53 (22 months; log-rank P = .025). CONCLUSION: Among patients with advanced NSCLC and STK11 mutations treated with first-line systemic therapy, co-mutation with KRAS was associated with significantly worse PFS and OS. By contrast, co-mutation of STK11 with TP53 conferred a better prognosis.

Cyclin-Dependent Kinase 4/6 Inhibition for the Treatment of Unresectable Mature Teratoma: Long-Term Follow-Up of a Phase II Study.

BACKGROUND: Unresectable mature teratoma is an incurable disease associated with significant morbidity. Given the rarity of the disease, long-term outcomes for patients receiving systemic therapy have not been well described. PATIENTS AND METHODS: The present study was a retrospective analysis with long-term follow-up data of the patient cohort with unresectable mature teratoma treated in the nonrandomized phase II study of palbociclib for the treatment of metastatic, retinoblastoma protein-expressing refractory germ cell tumors. Patient clinical data were obtained from the medical records and by communication with the enrolled patients and referring medical providers. Major medical events for the treatment of germ cell tumor, including before, during, and after study treatment, were recorded. The major clinical events of interest included the initiation of systemic therapy, radiation therapy, surgical debulking, or other invasive procedures. The study endpoints included the prestudy period and study period clinical event rates, event-free survival, and radiographic progression-free survival. RESULTS: Long-term follow-up data were obtained for 12 patients with unresectable mature teratoma. The median prestudy period follow-up period was 19.7 months, and the median study follow-up period was 38.0 months. The median number of palbociclib treatment cycles was 11. The prestudy major clinical event rate was 2.27 events annually (95% confidence interval [CI], 1.66-3.13 events), and the study period event rate was 0.62 events annually (95% CI, 0.36-1.09 events). The median progression-free survival was 5.3 months (95% CI, 1.8-22.6 months), and the median event-free survival duration was 16.2 months (95% CI, 3.0-24.3 months). CONCLUSION: Unresectable mature teratoma is associated with significant long-term cumulative morbidity. The initiation of palbociclib might result in a clinically meaningful delay in disease-related major clinical events. These findings lend further support to the therapeutic activity of cyclin-dependent kinase 4/6 inhibition in this incurable patient population.

Risk-Stratified Initial Salvage Therapy for Relapsed or Refractory Metastatic Germ Cell Tumors.

BACKGROUND: Salvage treatment with either conventional-dose chemotherapy (CDCT) or high-dose chemotherapy with autologous stem cell transplantation (HDCT) offers curative potential for patients with relapsed or refractory germ cell tumor (GCT). However, the optimal initial salvage strategy remains controversial, and the criteria for appropriate patient selection are not clear. METHODS: This was a retrospective analysis of the clinical outcomes for GCT patients receiving initial salvage therapy using a risk-stratified treatment approach. In general, patients with favorable-risk disease received CDCT with 4 cycles of paclitaxel, ifosfamide, and cisplatin, while patients with unfavorable-risk disease received HDCT per institutional protocol. The prognostic validity of the International Germ Cell Cancer Collaborative Group (IGCCCG) and the International Prognostic Factors Study Group (IPFSG) risk groups were evaluated in this context. RESULTS: Thirty-seven patients received initial salvage therapy. Twenty-four patients (65%) achieved a favorable response (including complete response to chemotherapy alone, complete response after post-chemotherapy surgical resection, or partial response with negative tumor markers). The favorable response rates for the CDCT and HDCT treatment groups were 69% and 62%, respectively. After a median follow-up of 31 months, the median survival for CDCT-treated patients has not been reached, and the median survival for the HDCT-treated group was 24 months. Both the International Germ Cell Cancer Collaborative Group and the International Prognostic Factors Study Group risk groups were significantly associated with progression-free survival (log-rank P = .009 and P = .039, respectively). CONCLUSIONS: Patients with favorable prognostic features may achieve durable remissions without requiring high-dose salvage chemotherapy. However, the criteria for optimal patient selection remain unclear, and these findings further support the need for a definitive randomized trial.

Diagnosis of pernicious anemia and the risk of pancreatic cancer.

OBJECTIVES: A number of studies have demonstrated a trophic effect of gastrin on pancreatic cancer cells in vitro. Pernicious anemia (PA) is a clinical condition characterized by chronic hypergastrinemia. The aim of this study was to determine if PA is a risk factor for pancreatic cancer. METHODS: This study is a retrospective cohort study using The Health Improvement Network database, which contains comprehensive health information on 7.5 million patients in the United Kingdom from 1993 to 2009. All patients with PA in the study cohort were identified and composed of the exposed group. Each exposed patient was matched on practice site, sex, and age with up to 4 unexposed patients without PA. The outcome was incident pancreatic cancer. The hazard ratio and 95% confidence intervals were estimated using multivariable Cox regression analysis. RESULTS: We identified 15,324 patients with PA and 55,094 unexposed patients. Mean follow-up time was similar between groups (exposed 4.31 [SD, 3.38] years, unexposed 4.63 [SD, 3.44] years). The multivariable adjusted hazard ratio for pancreatic cancer associated with PA was 1.16 (95% confidence interval, 0.77-1.76; P = 0.47). CONCLUSIONS: There is no significant association between PA and the risk of pancreatic cancer.

Treatment expectations among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation.

OBJECTIVES: To understand expectations regarding treatment recommendations among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial contact with a multidisciplinary pain management clinic. Each participant completed reports of adolescent pain intensity and disability, biopsychosocial perspective of pain, and treatment expectations related to recommendations and feedback for a vignette description of an adolescent presenting at an initial multidisciplinary pain clinic evaluation. RESULTS: Descriptive findings for individual treatment expectations and adolescent-parent dyad agreement statistics were examined. Slight to fair levels of agreement occurred for 50% of the expectations assessed. The strongest shared expectations were for recommendations to return to school, pursue psychological counseling, and pursue PT/OT treatment. Stronger agreement occurred for items reflecting alternative, emotional, behavioral, and activity recommendations with weaker agreement for medical interventions (eg, medication and surgery). Correlations emerged between individual expectations and adolescent pain intensity, disability, with the greatest number of significant relationships found for adolescent and parent expectations and biopsychosocial perspectives of pain. DISCUSSION: Our results document that adolescents and parents show modest levels of agreement on expectations for treatment at the time of an initial pain clinic evaluation. This may relate to expectations being internal perspectives not clearly expressed within families; thus, the initial treatment consultation may provide an important opportunity to create and align appropriate expectations. Implications of our findings are considered with respect to education, treatment, and future research to understand factors that contribute to treatment adherence and outcomes.

Pain beliefs and readiness to change among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation.

OBJECTIVES: To understand relationships between pain-related beliefs and readiness to change among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. METHODS: A total of 102 adolescent-parent dyads were recruited at the time of initial evaluation at a multidisciplinary pain management clinic. Dyads completed self-report measures to assess pain, catastrophizing, endorsement of a biopsychosocial perspective of pain, and readiness to change/motivation to adopt a self-management approach to pain coping. RESULTS: Agreement between adolescent-parent dyad reports of pain catastrophizing and readiness to change was found; however, adolescents were less likely to view pain as "affected by feelings and emotions" than parents. The hypothesis that greater pain catastrophizing would be correlated with less readiness to change was partially supported. Adolescent and parents who reported lower levels of endorsement of a biopsychosocial perspective were less willing to adopt a self-management approach to pain coping. Endorsement of a biopsychosocial perspective of pain aligned with readiness to change stages more consistently for parents. DISCUSSION: This study documents initial relationships among pain catastrophizing, biopsychosocial perspectives of pain, and readiness to engage in a self-management approach to pain coping for adolescents with chronic pain and their parents. Although agreement exists between dyads regarding catastrophizing and readiness to change, differences were noted in biopsychosocial perspective and dominant readiness to change stage before an initial pain clinic encounter. Findings are considered in terms of future research to advance knowledge regarding the role these factors may play in treatment adherence and outcomes.

Metformin and survival in pancreatic cancer: a retrospective cohort study.

OBJECTIVES: Our aim was to determine the effect of metformin exposure on survival in patients with advanced pancreatic adenocarcinoma (PAC). METHODS: A retrospective cohort study was conducted using The Health Improvement Network, a primary care electronic medical record database from the United Kingdom (2003-2010). The study cohort included all subjects with a diagnostic code for incident PAC and a preexisting diagnosis of type 2 diabetes mellitus. Subjects were classified as exposed if they were prescribed metformin around the time of PAC diagnosis (between 6 months prior and 1 month after). A secondary analysis was performed only on exposed subjects without prior (ie, 6 months before PAC diagnosis) exposure to metformin. The primary outcome was overall survival. The analysis was performed using univariate and multivariable Cox proportional hazards models. RESULTS: The study included 516 subjects with preexisting type 2 diabetes mellitus and PAC, 247 of which were exposed to metformin. In univariate and multivariable analysis, there was no difference in survival between those exposed and those unexposed to metformin in the primary analysis (hazards ratio, 1.11 [0.89-1.38], P = 0.367) or the secondary analysis (hazards ratio, 1.09 [0.80-1.47], P = 0.585). CONCLUSIONS: Metformin use is not associated with improved survival in subjects with advanced PAC.