EZH2 overexpression promotes cancer by increasing histone methylation to silence tumor suppressor genes, but how EZH2 levels become elevated in cancer is not understood. In this study, we ...investigated the mechanisms by which EZH2 expression is regulated in non-small cell lung carcinoma cells by oncogenic KRAS. In cells harboring KRAS(G12C) and KRAS(G12D) mutations, EZH2 expression was modulated by MEK-ERK and PI3K/AKT signaling, respectively. Accordingly, MEK-ERK depletion decreased EZH2 expression in cells harboring the KRAS(G12C) mutation, whereas PI3K/AKT depletion decreased EZH2 expression, EZH2 phosphorylation, and STAT3 activity in KRAS(G12D)-mutant cell lines. Combined inhibition of EZH2 and MEK-ERK or PI3K/AKT increased the sensitivity of cells with specific KRAS mutations to MEK-ERK and PI3K/AKT-targeted therapies. Our work defines EZH2 as a downstream effector of KRAS signaling and offers a rationale for combining EZH2 inhibitory strategies with MEK-ERK- or PI3K/AKT-targeted therapies to treat lung cancer patients, as stratified into distinct treatment groups based on specific KRAS mutations.
Tumor size is a known prognostic factor for early stage non–small-cell lung cancer (NSCLC), but its significance in node-positive and locally invasive NSCLC has not been extensively characterized. We ...queried the Surveillance, Epidemiology, and End Results database to evaluate the prognostic value of tumor size for early stage and node-positive and locally invasive NSCLC.
Patients in Surveillance, Epidemiology, and End Results registry with NSCLC diagnosed between 1998 and 2003 were analyzed. Tumor size was analyzed as a continuous variable. Other demographic variables included age, gender, race, histology, primary tumor extension, node status, and primary treatment modality (surgery vs. radiation). The Kaplan–Meier method was used to estimate overall survival (OS). Cox proportional hazard model was used to evaluate whether tumor size was an independent prognostic factor.
In all, 52,287 eligible patients were subgrouped based on tumor extension and node status. Tumor size had a significant effect on OS in all subgroups defined by tumor extension or node status. In addition, tumor size also had statistically significant effect on OS in 15 of 16 subgroups defined by tumor extension and nodal status after adjustment for other clinical variables. Our model incorporating tumor size had significantly better predictive accuracy than our alternative model without tumor size.
Tumor size is an independent prognostic factor, for early stage and node-positive and locally invasive disease. Prediction tools, such as nomograms, incorporating more detailed information not captured in detail by the routine tumor, node, metastasis classification, may improve prediction accuracy of OS in NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Deintensification of adjuvant therapy is being considered for older women with early-stage, biologically favorable breast cancer. Although radiation therapy (RT) can be omitted in some cases, ...toxicity from hormone therapy (HT) is not trivial, and adherence rates vary. We hypothesized that adjuvant RT alone would produce survival outcomes comparable to those with adjuvant HT alone among elderly patients treated with lumpectomy.
We searched the National Cancer Database (2010-2014) for healthy women (aged ≥70 years, Charlson/Deyo CD score 0-1) with T1N0 hormone-receptor-positive, HER-2-negative breast cancer treated with lumpectomy and adjuvant HT or RT. Propensity scores were used to match patients for analysis.
We identified 2995 patients (median age, 78 years), most (81%) with a CD score of 0, clinical stage IA (77%), of whom 65% received HT alone and 35% received RT only after lumpectomy. On multivariate analysis of the matched cohort, older age (hazard ratio HR 1.10; 95% confidence interval CI 1.07-1.13; P < .001), CD score 1 (HR 1.92; 95% CI 1.37-2.70; P = .0002), and living in a metropolitan (vs urban) area (HR 3.09; 95% CI 1.43-6.67; P = .004) were associated with inferior overall survival (OS), whereas treatment with HT (vs RT) was not (HR 1.13; 95% CI 0.85-1.49; P = .406). At a median follow-up of 45 months, no difference was found in OS between HT versus RT cohorts (85% and 86%, respectively; P = .44).
For healthy, older women with biologically favorable breast cancer treated with lumpectomy, adjuvant RT or HT is associated with equivalent 5-year OS rates. A randomized controlled trial is warranted to explore these adjuvant monotherapy options in elderly patients with hormone receptor-positive breast cancer.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
To analyze factors that predict the use of trimodality treatment (chemotherapy, surgery, and radiation therapy RT) and evaluate the impact that trimodality treatment use has on survival for patients ...with inflammatory breast cancer (IBC).
Using the National Cancer Data Base, patients who underwent surgical treatment of nonmetastatic IBC from 1998 to 2010 were identified. We collected demographic, tumor, and treatment data and analyzed treatment and survival trends over time. Logistic regression and Cox proportional hazard models were used to examine factors predicting treatment and survival.
We identified 10,197 patients who fulfilled study criteria. The use of trimodality therapy fluctuated annually (58.4% to 73.4%). Patients who were older, diagnosed earlier in the study period, lived in regions of the country outside of the Midwest, had lower incomes or public insurance, and had a higher comorbid score were significantly less likely to receive trimodality therapy (all P < .05). Five- and 10-year survival rates were highest among patients receiving trimodality treatment (55.4% and 37.3%, respectively) compared with patients who received the combination of surgery plus chemotherapy, surgery plus RT, or surgery alone. After adjusting for potential confounding variables, use of trimodality therapy remained a significant independent predictor of survival.
Underutilization of trimodality therapy negatively impacted survival for patients with IBC. The use of trimodality therapy increased marginally with time, but there remain significant factors associated with differences in use of trimodality treatment. We have identified specific barriers to care that may be targeted to improve treatment delivery and potentially improve patient outcomes.
Limited clinical activity has been seen in osteosarcoma (OS) patients treated with immune checkpoint inhibitors (ICI). To gain insights into the immunogenic potential of these tumors, we conducted ...whole genome, RNA, and T-cell receptor sequencing, immunohistochemistry and reverse phase protein array profiling (RPPA) on OS specimens from 48 pediatric and adult patients with primary, relapsed, and metastatic OS. Median immune infiltrate level was lower than in other tumor types where ICI are effective, with concomitant low T-cell receptor clonalities. Neoantigen expression in OS was lacking and significantly associated with high levels of nonsense-mediated decay (NMD). Samples with low immune infiltrate had higher number of deleted genes while those with high immune infiltrate expressed higher levels of adaptive resistance pathways. PARP2 expression levels were significantly negatively associated with the immune infiltrate. Together, these data reveal multiple immunosuppressive features of OS and suggest immunotherapeutic opportunities in OS patients.
Checkpoint inhibitors (CPIs) have revolutionized the treatment of cancer, but their use remains limited by off-target inflammatory and immune-related adverse events. Solid organ transplantation (SOT) ...recipients have been excluded from clinical trials owing to concerns about alloimmunity, organ rejection, and immunosuppressive therapy. Thus, we conducted a retrospective study and literature review to evaluate the safety of CPIs in patients with cancer and prior SOT.
Data were collected from the medical records of patients with cancer and prior SOT who received CPIs at The University of Texas MD Anderson Cancer Center from January 1, 2004, through March 31, 2018. Additionally, we systematically reviewed five databases through April 2018 to identify studies reporting CPIs to treat cancer in SOT recipients. We evaluated the safety of CPIs in terms of alloimmunity, immune-related adverse events, and mortality. We also evaluated tumor response to CPIs.
Thirty-nine patients with allograft transplantation were identified. The median age was 63 years (range 14-79 years), 74% were male, 62% had metastatic melanoma, 77% received anti-PD-1 agents, and 59% had prior renal transplantation, 28% hepatic transplantation, and 13% cardiac transplantation. Median time to CPI initiation after SOT was 9 years (range 0.92-32 years). Allograft rejection occurred in 41% of patients (11/23 renal, 4/11 hepatic, and 1/5 cardiac transplantations), at similar rates for anti-CTLA-4 and anti-PD-1 therapy. The median time to rejection was 21 days (95% confidence interval 19.3-22.8 days). There were no associations between time since SOT and frequency, timing, or type of rejection. Overall, 31% of patients permanently discontinued CPIs because of allograft rejection. Graft loss occurred in 81%, and death was reported in 46%. Of the 12 patients with transplantation biopsies, nine (75%) had acute rejection, and five of these rejections were T cell-mediated. In melanoma patients, 36% responded to CPIs.
SOT recipients had a high allograft rejection rate that was observed shortly after CPI initiation, with high mortality rates. Further studies are needed to optimize the anticancer treatment approach in these patients.
Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidated the roles of C-MYC and PVT1 involved in the pathogenesis of ...MPM.
We used small interfering RNA (siRNA)-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative polymerase chain reaction and fluorescence in situ hybridization.
Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of 12 MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with four copies or more of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between proapoptotic and antiapoptotic gene expression, whereas PVT1 and, to a lesser extent, miR-1204 up-regulate proapoptotic genes and down-regulate antiapoptotic genes. Fluorescence in situ hybridization analysis of MPM tumor specimens showed a high frequency of both CNGs (11 of 75) and trisomy (three copies; 11 of 75) for the C-MYC locus.
Our results suggest that C-MYC and PVT1 CNG promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune ...suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV
) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3
and CD8
T cell microenvironments in precancer (mostly CD3
, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in
mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and
-
codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV
HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Optimal surgical margin width for patients with phyllodes tumors (PTs) of the breast remains debated. The aim of this study was to assess the influence of margin width on long-term local recurrence ...risk.BACKGROUNDOptimal surgical margin width for patients with phyllodes tumors (PTs) of the breast remains debated. The aim of this study was to assess the influence of margin width on long-term local recurrence risk.This was a single-institution retrospective review of patients with confirmed PT treated from 2008-2015. Margins were defined as positive (ink on tumor), narrow (no tumor at inked margin but < 10mm), or widely free (>/= 10mm). LR rates were estimated by the Kaplan-Meier method.PATIENTS AND METHODSThis was a single-institution retrospective review of patients with confirmed PT treated from 2008-2015. Margins were defined as positive (ink on tumor), narrow (no tumor at inked margin but < 10mm), or widely free (>/= 10mm). LR rates were estimated by the Kaplan-Meier method.Among 117 female patients, histology included 55 (47%) benign, 29 (25%) borderline, and 33 (28%) malignant PT. Final margins were positive in 16 (14%), narrow in 32 (27%), widely free in 64 (55%), and unknown in 5 (4%) patients. Compared with margins > 10 mm, patients with positive and narrow margins had a higher LR risk HR 10.57 (95% CI 2.48-45.02) and HR 5.66 (95% CI 1.19-26.99), respectively. Among benign PTs, the 10-year LR-free rates were 100%, 94%, and 66% for widely negative, narrow, and positive margins, respectively (p = 0.056). For borderline/malignant PT, the 10-year LR-free rates were 93% and 57% for widely negative and narrow margins, respectively (p = 0.02), with no difference in LR between narrow and positive margin groups (p = 1.00).RESULTSAmong 117 female patients, histology included 55 (47%) benign, 29 (25%) borderline, and 33 (28%) malignant PT. Final margins were positive in 16 (14%), narrow in 32 (27%), widely free in 64 (55%), and unknown in 5 (4%) patients. Compared with margins > 10 mm, patients with positive and narrow margins had a higher LR risk HR 10.57 (95% CI 2.48-45.02) and HR 5.66 (95% CI 1.19-26.99), respectively. Among benign PTs, the 10-year LR-free rates were 100%, 94%, and 66% for widely negative, narrow, and positive margins, respectively (p = 0.056). For borderline/malignant PT, the 10-year LR-free rates were 93% and 57% for widely negative and narrow margins, respectively (p = 0.02), with no difference in LR between narrow and positive margin groups (p = 1.00).For benign PTs, a margin of no ink on tumor appears sufficient to optimize local control. In patients with borderline or malignant PTs, achieving a wide surgical margin may remain important as narrower margins were associated with LR rates comparable to those with positive margins.CONCLUSIONSFor benign PTs, a margin of no ink on tumor appears sufficient to optimize local control. In patients with borderline or malignant PTs, achieving a wide surgical margin may remain important as narrower margins were associated with LR rates comparable to those with positive margins.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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