bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathologic complete response and survival outcomes in patients with localized soft tissue sarcoma treated with neoadjuvant chemoradiotherapy or radiotherapy: Long-term update of NRG Oncology RTOG 9514 and 0630.
Authors: Wang Dian , Harris Jonathan , Kraybill William G. , Eisenberg Burton Larry , Kirsch David G. , Kane John Michael , Ettinger David S. , Spiro Ira J , Trotti Andy , Freeman Carolyn R. , Chen Yen-Lin , Hitchcock Ying J. , Bedi Manpreet , Salerno Kilian Elizabeth , Dundas George , Godette Karen D. , Larrier Nicole , Curran Walter John , Lucas David Robert
Published: September 2018

11012

Background: We sought to determine the prognostic significance of pathologic complete response (pCR) in soft tissue sarcoma (STS) in patients (pts) receiving neoadjuvant chemoradiotherapy (RTOG 9514) or radiotherapy (RTOG 0630) with long-term outcomes. Methods: RTOG has completed two phase II trials (RTOG 9514 and RTOG 0630) for pts with localized STS. Pts with high-grade STS ≥8 cm of extremities or body wall were enrolled to 9514 from 1997-2000 and received 3 cycles neoadjuvant chemotherapy (CT), interdigitated with RT, and 3 cycles postop CT. Pts with STS of extremities were enrolled to 0630 from 2008-2010 and received preoperative RT without CT. One pathology expert (DL) assessed pts for pCR at time of surgery without knowledge of disease outcomes. Overall and disease-free survival (OS and DFS) were calculated from the date of surgery. Pts that did not have surgery or had an amputation were excluded. Hazard ratios (HR) and p-values were estimated by multivariate Cox model stratified by study, where possible (i.e., > 0 events in both groups); otherwise p-values were calculated by stratified log-rank test. Results: Of 135 who had surgery, 123 were evaluable for pCR: 14/51 (27.5%) on 9514 and 14/72 (19.4%) on 0630 had pCR. With median follow-up of > 5 years for surviving pts, OS is 100% for pts with pCR vs. 5-year 76.5% (95% confidence interval 62.3-90.8) and 56.4% (43.3-69.5) for pts with < pCR in 9514 and 0630, respectively. pCR is associated with improved OS (p = 0.01) and DFS [HR 4.91 (1.51-15.93); p = 0.008] relative to < pCR. Local failure rate was 0% in pts with pCR vs. 5-year 11.7% (3.6-25.1) and 9.1% (3.3-18.5) for pts with < pCR in 9514 and 0630, respectively. Leiomyosarcoma/liposarcoma/myxofibrosarcoma are associated with better OS [hazard ratio 2.24 (1.12 and 4.45)] while liposarcoma/myxofibrosarcoma are associated with better DFS [hazard ratio 2.42 (1.23-4.76)]. Conclusions: Results from this analysis have demonstrated that pCR is associated with improved survival outcomes in pts with STS treated with either neoadjuvant RT or CT-RT. pCR should be considered as a survival surrogate for future STS studies. Clinical trial information: RTOG 9514 and RTOG 0630.
Immune-infiltrate characterization in localized osteosarcoma patients treated within protocol ISG-OS1.
Authors: Palmerini Emanuela , Agostinelli Claudio , Picci Piero , Pileri Stefano A , Lollini Pier-Luigi , Scotlandi Katia , Benassi Maria Serena , Marafioti Teresa , Ferrari Stefano
Published: September 2018

11025

Background: We hypothesized that immune-infiltrates were associated with survival, and examined a primary osteosarcoma tissue microarrays (TMAs) to test this hypothesis. Methods: Biopsies of patients (pts) treated from 04/2001 to 11/2006 were analyzed. TMAs from representative areas were assembled. Clinical and pathological characteristics at diagnosis, expression of CD8, CD4, CD3, FOXP3, CD20, CD68/CD163 (tumor associated macrophage), Tia-1 (cytotoxic T cell), CD303 (plamacytoid dendritic cells: pDC), Arginase-1 (myeloid derived suppressor cells: MDSC), PD-1 on immuno-cells (IC), and PD-L1 both on tumor cells (TC) and IC were correlated with patients outcome. A TMA of surgical specimens of the same cases also was assembled, and chemotherapy-induced changes analysis is ongoing. Results: 86 pts identified. Median age: 16 (range 4-39); high LDH: 36/86; high serum alkaline phosphatase (SAP): 18/86. All pts underwent neoadjuvant chemotherapy and surgery. A good pathologic response (≥90% necrosis) was achieved by 45/86 pts. IHC results are displayed in the Table. With a median follow-up of 8 years (range 1-13), the 5-year overall survival (5-yr OS) was 74% (95% CI 64-85). Univariate analysis showed better 5-yr OS for: a) good responders (good 89% vs poor 57%, p=0.0001); b) pts with CD8/Tia1 tumoral infiltrates (+/+ 81% vs +/- 60% vs -/- 45% p=0.002); c) pts with normal SAP (normal 85% vs high 44%, p=0.04). A numerically lower 5-yr OS was found in PD-L1 (IC) positive (+ 58% vs - 77%, p=0.14) and CD163 negative (+ 81% vs - 56%, p=0.17) cases. After multivariate analysis, poor histologic response (p=0.007) and lack of CD8/Tia1 infiltration (p=0.02) were independently correlated with poorer survival. In the subset of CD8+ patients, poorer (p= 0.02) OS was observed for PD-L1 (IC) + cases. Conclusions: Our findings support the hypothesis that CD8/Tia1 (cytotoxic T cells) infiltrate in tumor microenvironment at diagnosis is associated with superior survival for patients with localized osteosarcoma, while PD-L1 expression is associated with poorer survival. [Table: see text]
A phase Ib study of BGJ398 in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST).
Authors: Kelly Ciara Marie , Shoushtari Alexander Noor , Qin Li-Xuan , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Sjoberg Ana , Mcfadyen Chloe , Hwang Sinchun , Heinemann M.H. , Francis Jasmine , Singer Samuel , DeMatteo Ronald P. , Antonescu Cristina R. , Chi Ping , Tap William D.
Published: September 2018

11039

Background: Preclinical studies suggest that imatinib resistance (IR) in GIST can be mediated by MAP-kinase activation via FGF signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR inhibitor in combination with imatinib, is cytotoxic and superior to imatinib alone, or imatinib in combination with MEK-inhibition. In GIST with FGF signaling, the combination of BGJ398 and imatinib may provide a mechanism to overcome IR. Methods: This phase Ib study of BGJ398 in combination with imatinib was performed in patients (pts) with imatinib resistant advanced GIST. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose. Two treatment schedules were evaluated incorporating imatinib 400mg daily continuously in combination with (A) BGJ daily 3 wks on, 1 wk off or (B) BGJ daily 1 wk on, 3 wks off. Response was evaluated by RECIST and CHOI every 8 wks x4 and then every 12 wks. Results: 16 pts enrolled. Median age 54 (range: 44-77), 81% male, median prior therapy 4 [range: 2-6, 13/16 pts had ≥ 3 prior therapies (81%)]. 12 pts received treatment on schedule A [dose level (DL)1 (BGJ 75mg), n = 6; DL-1 (BGJ 50mg), n = 3; DL-2 (BGJ 25mg), n = 3]: 3 DLTs (myocardial infarction, grade (G)4 CPK elevation, G3 ALT elevation) were observed on schedule A at DL1, hyperphosphatemia (on target effect) was not observed raising concern for therapeutic efficacy at the maximum tolerated dose. Following protocol amendment that allowed an alternative dosing schedule, 4 pts enrolled on schedule B [DL1 (BGJ 75mg), n = 3; DL2 (BGJ 100mg), n = 1]: one DLT occurred (G3 intra-abdominal hemorrhage) at DL2. The most common non-DLT G3/4 toxicity was HTN (2/16pts) and G2 toxicity was prolonged QTc interval (3/16pts). Of the 12 pts with evaluable CT scans, stable disease (SD) was the best response observed in 7 pts by RECIST and 9 pts by CHOI. 3pts achieved SD for > 6 months. 2 pts remain on study at data cut-off (range: 1 – 67 wks). Median progression free survival is 8 weeks. Pharmacokinetic analysis of imatinib and BGJ is forthcoming. Conclusions: In heavily pre-treated pts, durable disease control was observed in 3/16 pts. This signal of efficacy suggests that further evaluation of FGF signaling in the development of IR is warranted. Clinical trial information: NCT02257541.
Tumor volume score (TVS), modified recist, and tissue damage score (TDS) as novel methods for assessing response in tenosynovial giant cell tumors (TGCT) treated with pexidartinib: Relationship with patient-reported outcomes (PROs).
Authors: Peterfy Charles , Ye Xin , Gelhorn Heather , Speck Rebecca M , Countryman Peter J. , Keedy Vicki Leigh , Wainberg Zev A. , Singh Arun S. , Chmielowski Bartosz , Von Hoff Daniel D. , Babiker Hani M. , Khemka Vivek , Cote Gregory Michael , Shapiro Geoffrey , Wagner Andrew J. , Healey John H. , Hsu Henry , Lin Paul S. , Tong Sandra , Tap William D.
Published: September 2018

11048

Background: TGCT is a locally aggressive neoplasm of joint and tendon sheath synovia that may cause pain, limit joint function and destroy bone and local tissues. Measuring TGCT with RECIST is a challenge due to irregular shape and asymmetrical growth, and local tissue damage is not assessed. We reported earlier results of a longitudinal trial of pexidartinib, a selective CSF1R kinase inhibitor, using RECIST as well as novel TVS, modified RECIST and TDS. Here we examine concordance of these MRI measures with PROs. Methods: Patients (pts) with progressive TGCT in a single-arm, multi-center trial of pexidartinib (1000 mg po daily) were assessed by MRI every 2 months by 2 central radiologists (blind to visit order). For RECIST, longest measurable dimensions of up to 2 tumors per joint or tendon sheath were summed (SLD). Modified RECIST summed short axis dimensions (SSD). TVS was based on 10% increments of the estimated maximally distended normal synovial cavity or tendon sheath. TDS scored bone erosion (ERO), cartilage loss (CAR) and bone marrow edema (BME) in multiple regions of each joint. The relationship with PROs (Worst Pain numerical rating scale [NRS] and Worst Stiffness NRS) was assessed. Results: 15 pts (7 knees, 3 hips, 2 ankles, 1 elbow, 1 wrist, 1 thigh) with PRO data and evaluable MRI scans at baseline and Month 7 were assessed. All SLD, SSD and TVS scores improved with respective median changes of -25%, -39% and -50%. Baseline ERO, CAR, and BME ranged 0-19, 0-34, and 0-15, respectively. Median change for each was 0%: ERO worsened in 1 pt, CAR did not change, and BME improved in 4 and worsened in 2. Worst Pain NRS and Worst Stiffness NRS improved in 11 and 9 pts, respectively. Conclusions: TVS demonstrated the greatest pexidartinib effect size, followed by SSD and then conventional RECIST. All had good concordance with PROs. Clinical trial information: NCT01004861. [Table: see text]
Combination of pembrolizumab and metronomic cyclophosphamide in patients with advanced sarcomas and GIST: A French Sarcoma Group phase II trial.
Authors: Toulmonde Maud , Penel Nicolas , Adam Julien , Chevreau Christine , Blay Jean-Yves , Le Cesne Axel , Bompas Emmanuelle , Piperno-Neumann Sophie , Cousin Sophie , Ryckewaert Thomas , Bessede Alban , Ghiringhelli Francois , Grellety Thomas , Pulido Marina , Italiano Antoine
Published: September 2018

11053

Background: There is a good rationale for immunotherapy in sarcoma. We report results of the first open-label multicentre phase 2 study assessing the anti-PD-1 antibody pembrolizumab in combination with metronomic cyclophosphamide (CP) in patients (pts) with advanced soft tissue sarcomas (STS) and gastro-intestinal stromal tumor (GIST). Methods: This trial included 4 cohorts of pts with advanced STS: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (Others), and GIST. All pts received CP 50 mg BID one week on, one week off, and pembrolizumab 200mg IV q21 days. The primary endpoint encompassed non-progression and objective response at 6 months per RECIST evaluation criteria v1.1 for LMS, UPS, and Others, and 6-month non-progression for GIST. Correlative studies of immune biomarkers were planned on pt’s tumor and plasma samples. Results: Between June 2015 and July 2016, 57 pts were included, and 50 were assessable for efficacy. Three pts experienced tumor shrinkage resulting in a partial response (PR) in one of them. The 6-month non-progression rate was 0%, 0%, 14.3% (95%CI 1.8-42.8), and 11.1% (95%CI 2.8-48.3) in LMS, UPS, Others, and GIST respectively. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, anemia. The only pt who experienced PR was the only one with a PD-L1-positive staining in more than 10% of immune cells on archived tumor sample. A strong macrophage infiltration was observed in tumor samples, and these macrophages largely expressed the inhibitory enzyme Indoleamine-2,3-dioxygenase-1 (IDO1). Moreover, a significant increase of the kynurenine/tryptophane ratio was observed in pts plasma samples during study treatment (p =0.0007). Conclusions: PD-1 inhibition has limited activity in advanced STS and GIST. This primary resistance may be explained by the low percent of PD-L1 positivity in these tumors, and an immune-suppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Further strategies assessing drugs such as CSF1-R inhibitors and/or IDO inhibitors combined with anti-PD-1/PD-L1 in selected sarcoma subtypes are warranted. Clinical trial information: NCT02406781.
Immune and molecular determinants of response to neoadjuvant chemotherapy in inflammatory breast cancer.
Authors: Reddy Sangeetha Meda , Wargo Jennifer Ann , Reuben Alexandre , Tetzlaff Michael T. , Roszik Jason , Reuben James M. , Woodward Wendy A. , Ueno Naoto T. , Krishnamurthy Savitri , Mittendorf Elizabeth Ann
Published: September 2018

11501

Background: Inflammatory breast cancer (IBC) is the most aggressive form of primary breast cancer and has poor responses to standard of care neoadjuvant chemotherapy (NAC). Given there is a limited understanding of the immune microenvironment of IBC, this study aims to characterize the immune and molecular profiles of stage III and IV IBC and to identify biomarkers of response to treatment and targets for future therapies. Methods: IBC patients with available pre-treatment tumor samples and with intent to take to mastectomy were identified in the IBC tumor registry and tissue bank. Tumor infiltrating lymphocyte (TIL) infiltration in the tumor stroma was quantified on H&E slides per consensus guidelines (n = 91). On a subset of patients with available samples, deeper immune profiling was performed, including quantification of CD8 T cells by immunohistochemistry (IHC) (n = 33), PD-L1 tumor expression by IHC (n = 14), myeloid cells by multiplex IHC (n = 15), T cell clonality by T cell receptor sequencing (n = 22), and total mutational load (TML) by whole exome sequencing (n = 20). Results: Mean TIL were higher in tumors from patients that achieved a pathological complete response (pCR) to NAC than from those that did not (13.79 vs 7.24%, p = 0.019) and in patients with stage III compared to stage IV disease (11.90 vs 4.79%, p < 0.001). Though no statistically significant differences in CD8 infiltrate by response, stage, or receptor status were seen, the presence of a more clonal T cell population was predictive of pCR (13.27 vs 5.70% top 5 clone frequency, p = 0.042 among stage III patients). Myeloid cell staining revealed that tryptase staining, indicative of mast cells, was inversely associated with pCR (28.26 vs 108.0 counts/mm2, p = 0.011). Three of fourteen patient tumors displayed low PD-L1 tumor positivity (range 1-2%, 1+-2+) with the others being negative. Genomic profiling showed no statistically significant differences in TML by stage, receptor status, response, or immune infiltrate. Conclusions: Higher TIL, more clonal T cells, and lower mast cell infiltration are predictive of response to NAC in IBC. Comprehensive immune characterization of a larger cohort of pre- and post-treatment samples is currently underway.
Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC.
Authors: Streicher Katie , Higgs Brandon W. , Wu Song , Coffman Karen , Damera Gautam , Durham Nick , Greenlees Lydia , Lazdun Yelena , Cheng Li , Cooper Zachary , Ranade Koustubh
Published: September 2018

11505

Background: Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood. We investigated the relationship between Methods: Flow cytometry and/or quantitative PCR were used to evaluate genes and proteins in five NSCLC EGFR mt cell lines and 6 wt lines. Anti-EGFR TKIs gefitinib and osimertinib were used at concentrations ranging from 0.001-100uM; EGF was used at 50 ng/mL. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 previously treated patients in CP1108 were enrolled. RNA sequencing was conducted on available tumor specimens from 97 patients in CP1108. CP1108 and TCGA were separated by EGFR status for genomic comparisons. Results: Median CD73 expression was increased 10-fold in EGFR mt NSCLC cell lines (n = 5) compared to wt cell lines (n = 6). EGF induced CD73 protein levels 5-40-fold in 3/6 EGFR wt lines. There was dose-dependent inhibition of CD73 expression (45-70 fold maximum) following treatment with gefitinib or osimertinib in 3/5 mt cell lines and 4/6 wt lines, suggesting a causal relationship between the EGFR pathway and CD73 expression. Consistent with these observations, EGFR mutant tumors had ≥2 fold increased expression of CD73 compared to wt (p < 0.05) in TCGA and CP1108 NSCLC adenocarcinoma patients. These EGFR mutants had significantly lower levels of IFNg signature, previously reported to be associated with enhanced benefit from durvalumab. Conclusions: Our findings identify a novel relationship in NSCLC between EGFR pathway activation, expression of the immunosuppressive molecule CD73 and reduced expression of IFNg mRNA signature. These results prompt the hypothesis that over-expression of CD73 in EGFR-mt NSCLC may explain, at least in part, the reduced benefit from anti-PD-1(L1) in this subset of NSCLC, and suggest evaluating anti-CD73 in combination with EGFR TKIs or anti-PD-L1 in EGFR-mt NSCLC.
CD4+ T cells in PBMC to predict the outcome of anti-PD-1 therapy.
Authors: Kagamu Hiroshi , Yamaguchi Ou , Shiono Ayako , Mouri Atsuto , Miyauchi Sachiko , Utsugi Harue , Nishihara Fuyumi , Uchida Takahiro , Murayama Yoshitake , Kobayashi Kunihiko
Published: September 2018

11525

Background: Antibody blockade of programmed death 1 (PD-1), has led to durable responses and significant prolongation of overall survival in metastatic cancers including non-small cell lung cancer (NSCLC). However, in clinical trials, response rates were as low as 20 %, and approximately 50 % of the patients did not achieve benefits to prolong progression free survival. These results bring us a hypothesis that there are subgroups with distinct pre-existing anti-tumor immunity resulting in different responses to anti-PD-1 therapy. We reported that effector T cells, which are capable of mediating antitumor reactivity, are primed in LNs draining growing tumors and that these T cells exclusively belong to the T cells that down-regulated CD62L (CD62Llow) subpopulation. In the absence of purified tumor antigenic proteins or peptides on many tumors, the expression of the homing molecule CD62L on T cells may serve as a surrogate marker for identifying tumor-specific immune cells. Methods: We analyzed the peripheral blood mononuclear cells (PBMC) of 50 consecutive NSCLC patients who were planned to be treated with anti-PD-1 Ab, Nivolumab after obtaining written informed consent. The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. Results: The NSCLC patients who achieved partial response (PR) or stable disease (SD) had significantly (p = 4.1x10-7) more CD62Llow CD4+ T cells in PBMC than progressive disease (PD) patients. The percentages of CD62Llow in CD4+ T cells provided sensitivity 92.9 %, and specificity 96.7 % to predict the patients who had PD. Moreover, SD patients had significantly (p = 0.0067) less regulatory T cell subpopulation than PR patients, thus, it was possible to predict PR from SD. Conclusions: These results show that the major differences in pre-existing immunity among PR, SD, and PD patients to anti-PD-1 Ab existed in CD4+ T cell balance between primed effector and regulatory T cells. Further characterization of CD62Llow CD4+ T cells including mRNA microarray, checkpoint molecules, and chemokine receptors is going on.
Algorithmic prediction of response to checkpoint inhibitors: Hyperprogressors versus responders.
Authors: Gandhi Shipra , Pabla Sarabjot , Nesline Mary , Pandey Manu , Ernstoff Marc S. , Dy Grace K. , Conroy Jeffery M. , Glenn Sean , Burgher Blake , Qin Maochun , Andreas Jonathan , Giamo Vincent , Papanicolau-Sengos Antonios , Galluzzi Lorenzo , He Ji , Gardner Mark , Morrison Carl
Published: September 2018

11565

Background: Predicting response to checkpoint inhibitors (CPIs) using biological knowledge-based decision processes with machine learning (ML) has a great potential to predict rapid progression in patients treated with checkpoint inhibitors (CPIs) (hyperprogressive disease (HPD)) as well as responders. ML models risk overfitting data and do not always evaluate the underlying biology, thus performing well in the initial training cohort but lack generalizability when extended to other cohorts. Biology-based decision may not perform as well initially due to limited understanding and a simplified rule set, but often perform equally well when extended to larger similar cohorts of patients. Methods: A custom NGS cancer immune gene expression assay compared 87 patients treated with CPIs classified as CR, PR, or SD versus 12 HPD. A ML-based polynomial regression model based on 54 immune-related genes combined with mutational burden was optimized for prediction of response. A biological 4-gene decision tree model was constructed independently based on ML. A second biological decision tree incorporated the weighted average relative rank of the expression of multiple genes in 4 different immune functions including immune cell infiltration, regulation, activation, and cytokine signaling. Bayesian model average (BMA) incorporated all three models’ results into the final prediction. Results: For87 patients classified as CR, PR, or SD the PPV >96% for responders and a NPV >90% for non-responders was achieved with the regression model, however with response indeterminate for 24% of the population. While the two biological decision tree models’ PPV were in the 70% range, they accurately revealed the critical genes’ roles in immune response with strong literature support. BMA process integrated these three models resulted in a PPV >96% and a NPV >90% and eliminated the indeterminate group. For HPD a unique biology related to priming of short term memory T-cells was identified. Conclusion: Prediction of response to CPIs is best attained by combining ML with biological knowledge. Decision tree models using a large panel of immune related genes in the context of archival samples from patients treated with CPIs can be used to better understand the biology of responders versus non-responders and provides new insights into HPD.
Restoration of tumor suppression in vivo by systemic delivery of chemically-modified PTEN mRNA nanoparticles.
Authors: Islam Mohammad Ariful , Xu Yingjie , Zope Harshal , Cao Wuji , Mahmoudi Morteza , Langer Robert , Kantoff Philip W. , Shi Jinjun , Zetter Bruce R. , Farokhzad Omid C.
Published: September 2018

11582

Background: The onset and maintenance of cancer frequently involves gain of oncogenic function along with loss of tumor suppression. PTEN is a well-characterized tumor suppressor gene that is lost or mutated in many human cancers including ~50% of metastatic castration-resistant prostate cancer (mCRPC). Reintroduction of functional PTEN for mCRPC treatment has proven difficult. Methods: PTEN mRNA was synthesized by in vitro transcription method and modified with ARCA capping and enzymatic polyadenylation, and then substituted with Pseudo-UTP, 5’-Methyl-CTP. A robust self-assembly approach was employed to prepare PTEN mRNA nanoparticles (NPs) using cationic lipid-like compound G0-C14 and PLGA polymer coated with lipid-PEG shell. PTEN expression in tumors and PI3K-AKT pathway were confirmed by IHC and western blot, respectively. Apoptosis was checked by flow cytometry and Tunel assays. In vivo toxicity was studied by hematologic and histologic tests, and immune response. Results: We successfully restored PTEN mRNA to PTEN-null prostate cancer (PCa) cells via systemic delivery of mRNA NPs. These mRNA NPs are stable in serum, demonstrate minimal toxicity, and provide highly effective transfection in PCa cells (substantially higher HA-PTEN expression than plasmid PTEN transfection) and PCa xenograft tumors, leading to ~85% inhibition of tumor cell growth in vitro and in vivo. We also confirm mRNA NP-mediated systemic restoration of PTEN function in PTEN-null PCa and delineate its tumor suppression through inhibition of the PI3K-AKT pathway and enhancement of apoptosis. Conclusions: The work provides proof of principle for the systemic reintroduction of mRNA-based tumor suppressor genes to tumors in vivo. Because PTEN loss is frequent in late-stage PCa, this approach may have feasibility in this patient population. Considering the strong potential of mRNA therapy and the lack of systemic studies of in vivo mRNA transfection of tumors, this study sheds light on the useful application of NP-mediated mRNA delivery for validating tumor suppressors (e.g., PTEN) as a therapeutic target in cancer treatment where loss of a tumor suppressor contributes to the underlying genetic mechanism of cancer.
RASA1 and NF1 co-mutated non-small cell lung carcinomas: Cancer genomic data and evaluation of sensitivity to MEK inhibition.
Authors: Hayashi Takuo , Desmeules Patrice , Smith Roger , Drilon Alexander E. , Somwar Romel , Ladanyi Marc
Published: September 2018

11600

Background: Ras-GTPase activating proteins (RasGAPs), notably NF1 and RASA1, mediate negative control of the RAS/MAPK pathway. While NF1 mutations are enriched in non-small cell lung carcinomas (NSCLC) lacking KRAS alterations, they are not completely mutually exclusive. We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases. Methods: Large genomic datasets of NSCLC [MSK-IMPACT™ dataset at MSKCC (n = 2004), TCGA combined lung cancer dataset (n = 1144)] were analyzed to define concurrent mutations and clinical features of RASA1-mutated NSCLCs. Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations, in RASA1 (RERFLCKJ), NF1 (LCLC103H and H1838), or both (EPLC272H). Results: Overall, approximately 2% of NSCLCs had RASA1 truncating mutations, and this alteration was statistically, but not completely, mutually exclusive with known activating EGFR (p = .02) and KRAS (p = .02) mutations. Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p < .001), suggesting selection for loss of more than one RasGAP. Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers, including KRAS. Knockdown of RASA1 in HBECs activated signaling downstream of RAS and promoted cell growth. Conversely, restoration of RASA1 expression in RERFLCKJ cells reduced MAPK and PI3K signaling. While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK (trametinib) or PI3K (GDC0941, PI103), EPLC272H cells (with concurrent RASA1/NF1 mutations) showed notably more profound sensitivity (IC50: 0.040µM trametinib). Finally, simultaneous silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition. Conclusions: Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC. Patients whose tumors show this distinctive genotype should be considered for trials of MEK inhibitors.
Nanomechanical profiling of human breast tumors as prognostic marker for breast cancer.
Authors: Burian Rosemarie Anne , Appenzeller Tobias , Oertle Philipp , Raez Christian , Lim Roderick Y.H. , Forte Serafino , Dellas Sophie , Obermann Ellen , Plodinec Marija
Published: September 2018

11618

Background: Assessment of tumor aggressiveness is crucial when making treatment decisions. Established prognostic markers may be insufficient to stratify cancer patients into treatment relevant risk groups. Emerging evidence indicates mechanical properties of cancer cells and their microenvironment play a vital role in cancer invasion and metastases. Detecting and measuring these nanomechanical changes could be a marker of cancer aggressiveness. Methods: We developed an atomic force microscope (AFM) based method: ARTIDIS (Automated and Reliable Tissue Diagnostics) for measuring nanomechanical properties of human tissue biopsies. These were performed on fresh, non-fixed tissue under physiological conditions. This novel method uses a micro-fabricated 20nm tip indenting and measuring stiffness of thousands of locations within 60-180minutes. This quantitative, biopsy-wide, nanomechanical profile strongly correlates to the tissue's biological composition. Post-AFM this biopsy is analyzed by pathology. We sought to differentiate benign from cancerous lesions based on nanomechanical properties; then link the cancerous nanomechanical profiles prospectively to the clinical outcomes. Results: Our results demonstrate the first AFM based nanomechanical profiling to detect aggressive breast cancer subtypes using fresh tissue in a clinical setting. We have shown that nanomechanical profiles of human breast cancer biopsies display stiffness profiles distinct from surrounding normal tissue. Breast cancer subtypes were distinguishable by their nanomechanical properties only. We have discovered specific nanomechanical profiles of tumor subtypes likely to metastasize. When the primary tumor displayed the same soft nanomechanical profile as adjacent tissue, this was associated with positive nodal status. Conclusions: Our results demontrate nanomechanical profiling is a fast and sensitive method to stratify malignant biopsies into relevant subgroups in a clinical setting. Relative stiffness and distribution values provide a nanomechanical profile indicating cancer aggressiveness. This will help optimize specific cancer diagnosis, orientate therapy choice and support patient follow up.
Variation in screening rates in a multi-ethnic population-based study in Chicago.
Authors: Aschebrook-Kilfoy Brisa , Kibriya Muhammad Ghulam , Chiu Brian C-H , Huo Dezheng , List Marcy A , Stepniak Elizabeth , Sarwar Golam , Al Shams Rabab , Gopalakrishnan Rajan , Le Beau Michelle M. , Ahsan Habibul
Published: September 2018

1509

Background: We initiated the Chicago Multiethnic Prevention and Surveillance Study (COMPASS) in 2013. Here, we present screening rates for key cancers with known disparities in risk/and or outcomes in Chicago, considering the effect health care access and race/ethnicity, and we compare the findings in COMPASS to rates reported by the CDC. Methods: COMPASS participant responses to a health interview were analyzed. The analysis of colorectal cancer screening (CRCS) was limited to persons 50-75, mammography screening (MS) was restricted to women ages 50-74, and cervical screening (CS) by pap smear testing was restricted to women ages 21-65. Frequency statistics and linear regression models were run to evaluate associations. Results: A total of 2,967 COMPASS participants were included in the analysis from 18 communities. We found ever CRCS rates in Chicago are lower than the national average (52.3% vs. 58.6%; p < .01) and that CRCS is lower in blacks (50.3%) and Hispanics (52.1%) compared to whites (65.8%), and that those with health insurance (HI) report a CRCS rate of 56.8% compared to 25.5% without insurance. Mammography within the last 2 years was 70.8% in COMPASS women compared to 72.4% nationally, with black women reporting higher rates of MS in the past 2 years (73.0%) compared to white women (65.4%) and Hispanic women (62.9%); and higher MS among women with HI (74.2%) compared to women without HI (47.2%). Pap screening within the last 5 years was 84.3% in COMPASS women compared to 83.0% nationally (last 3 years), with both black (85.3%) and Hispanic (83.2%) women reporting non-significantly higher CS compared to white women (80.9%) in COMPASS, and significantly higher CS among women with HI (86.2%) compared to women without HI (77.7%). Conclusions: Our results reinforce the fact that differences in cancer screening reflect the larger problem of access to care. We further found racial disparities in CRC screening in COMPASS to be consistent with disparities in incidence. However, our results do not support the notion that the disproportionate burden of breast and cervical cancer in black and Hispanic women in Chicago are primarily due to a lack of screening.
Identification of putative germline mutations in 10,288 patients undergoing circulating tumor DNA testing.
Authors: Slavin Thomas Paul , Banks Kimberly , Chudova Darya , Oxnard Geoffrey R. , Odegaard Justin I. , Nagy Rebecca J , Neuhausen Susan L. , Gray Stacy W. , Cristofanilli Massimo , Rodriguez Angel Augusto , Bardia Aditya , Leyland-Jones Brian , Janicek Mike , Lilly Michael B. , Sonpavde Guru , Lee Christine E. , Lanman Richard B. , Meric-Bernstam Funda , Kurzrock Razelle , Weitzel Jeffrey N.
Published: September 2018

1514

Background: No studies have yet described incidental detection of germline cancer predisposition mutations using circulating cell-free DNA (cfDNA). Methods: Deidentified cfDNA sequencing data from 10288 advanced cancer patients (pts) undergoing clinical circulating tumor DNA testing (Guardant360, 73 genes) were included in this study. CfDNA was extracted from plasma and quantified. A DNA library was prepared and sequenced to 15,000X average read depth. Using Ingenuity Variant Analysis, point mutations and small indels suspicious for germline origin (allele fraction 40-60%) were classified following American College of Medical Genetics and Genomics guidelines. Results: More than 50 cancer types were studied, including lung (40%), breast (20%), CRC (8%), prostate (6%), and pancreas (3%). Average age was 63.6 years (range:18-95), 42% were male. Of 34,873 putative germline variants identified, 520 (1.5%) were pathogenic or likely pathogenic (PV), 16,939 (49%) were of uncertain significance, and 17,414 (50%) were benign or likely benign. Of the 250 pts (2.4%) with hereditary cancer syndrome gene PVs, 83 were excluded due to high level of somatic tumor burden leaving 167 (1.6%) with putative germline PVs; rates were higher in pts <50 vs >50 overall (3.3% vs 1.4%, p=0.02) and in breast cancer pts (4.3% vs 1.5%, p=0.03). Conclusions: The observed frequency of incidentally identified putative germline PVs is expectedly lower than the true germline rate; however, these findings illustrate that detection from cfDNA is clinically feasible. Importantly, incidental germline findings could impact oncology treatment planning (e.g. PARP inhibitors for BRCA1/2 mutations) and could benefit families via increased surveillance/primary prevention. Further research is needed to explore how to report potential germline results to clinicians using a systems-based approach. [Table: see text]
Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer.
Authors: Zhou Jiaojiao , Zhang Kun , Zhu Xuan , Deng Mei , Luo Meng , Xu Chunjing , Yu Jie-Kai , Chen Yiding
Published: September 2018

1530

Background: PALB2 (Partner and Localizer of BRCA2) is recently recognized as a breast cancer predisposition gene, which plays a critical role in genome maintenance via interacting with BRCA1/2 and RAD51 when DNA break. Germline loss-of-function mutations in PALB2 lead to increased breast cancer risk. Since the germline mutation frequency of PALB2 is much less than BRCA1/2, the distinct mutation spectrum of PALB2 is still obscure. Therefore, we assessed the mutational frequency, spectrum and predictors of the PALB2 gene in a sequential series of Chinese breast cancer patients from our Research DNA Bank, to verify the utility of PALB2 genetic testing in Chinese population. Methods: We examined Chinese breast cancer cases (n = 2279) who agreed to participate in research DNA banking, recruited from 1990 through 2016. To identify the mutations, complete coding sequence and intron–exon boundaries of PALB2 were screened with Next Generation Sequencing. Personal and family histories were synchronously collected for mutation identification. Results: Among the 2279 breast cancer patients, 307 patients were familial breast cancer cases and the rest 1972 patients were sporadic breast cancer cases. PALB2 mutation carriers accounted for 7.8% (n = 24) and 4.8% (n = 95) in familial and sporadic breast cancer cohort separately. In total, 31 missense, 4 nonsense, 3 frameshift, 3 splicing and 1 codon mutations of PALB2 were identified in this study. Among the pathologic variants, PALB2 c.1744C > T, c.2748+1G > A, c.2749-1G > C, c.3114-1G > A were newly identified in sporadic breast cancer, and c.3271delC newly found in familial breast cancer. Based on in silico analysis, a total of 6 potential damaging missense variants were novelly found in this study, among which the PALB2 c.3035C > T was detected in both sporadic and familial breast cancer. Conclusions: Our data presents the germline mutation status of PALB2 in Chinese patients with breast cancer, suggesting that loss-of-function germline mutations of PALB2 are important in both familial and sporadic breast cancer. Clinically, this information may be helpful in genetic counseling of breast cancer patients with PALB2 germline mutation.
Soft palatal melanosis as a predictor for neoplasia in the upper aerodigestive tract.
Authors: Hirata Kenro , Yokoyama Akira , Nakamura Rieko , Omori Tai , Kawakubo Hirofumi , Mizukami Takeshi , Maruyama Katsuya , Kanai Takanori , Yokoyama Tetsuji
Published: September 2018

1542

Background: Squamous cell dysplasia and carcinoma in the upper aerodigestive tract (UAT) was frequently accompanied by melanosis in the UAT. Soft palatal melanosis can be detected by visual inspection during routine physical examination or even personally in a mirror. Methods: We reviewed digitalized records of high-quality endoscopic images of the soft palate of 1786 Japanese alcoholic men who underwent endoscopic screening combined with esophageal iodine staining and evaluated to what extent the presence of soft palatal melanosis combined with other risk factors can predict the risk of UAT neoplasia. Results: Soft palatal melanosis was observed in 381 (21·3%) of the subjects (mild, 15·0%; distinct, 6·3%). An older age, an inactive heterozygous aldehyde dehydrogenase-2 genotype, smoking, and a high mean corpuscular volume (MCV) were positively associated with the presence of soft palatal melanosis. The age-adjusted odds ratio (OR [95% CI]) for neoplasia in the UAT was 1·92 [1·40–2·64] in the group with melanosis and 2·51 (1·55–4·06) in the group with distinct melanosis, compared with the melanosis-free group. A multiple logistic analysis including the alcohol and aldehyde dehydrogenases genotypes and non-genetic risk factors showed that the presence of soft palatal melanosis was independently associated with a high risk of neoplasia in the UAT. We calculated the individual number of risk factors out of four easily identifiable and significant factors: age ≥55 years, current/former alcohol flushing, MCV ≥106 fl, and distinct soft palatal melanosis. Compared with the risk-factor-free condition, the OR (95% CI) values of UAT neoplasia for one, two, three and four risk factors were 1·49 (0·97–2·30), 3·14 (2·02–4·88), 4·80 (2·71–8·51) and 7·80 (2·17–28·1), respectively. Conclusions: Soft palatal melanosis combined with other simple risk assessments provides a simple new strategy for identifying heavy drinkers with a high risk for UAT neoplasia.
Safety of multiplex gene testing for inherited cancer risk in a fully accrued prospective trial.
Authors: Kurian Allison W. , Idos Gregory , Ricker Charite Nicolette , Culver Julie , Sturgeon Duveen , Kingham Kerry , Koff Rachel , Lowstuter Katrina , Chun Nicolette M. , Rowe-Teeter Courtney , Partynski Katlyn , Hartman Anne-Renee , Allen Brian , Kidd John , Mills Meredith , Hong Christine , McDonnell Kevin , Ladabaum Uri , Ford James M. , Gruber Stephen B.
Published: September 2018

1576

Background: Sequencing more genes increases the chance of finding a pathogenic mutation and/or a variant of uncertain significance (VUS). Little is known about potential harms of multiplex testing for cancer risk, such as unwarranted surgery or adverse psychological effects. Methods: We conducted a prospective trial of sequencing 25 genes : APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. Patients were eligible if they met standard testing guidelines or predictive models estimated ≥2.5% mutation probability. Participants were surveyed 3 months post-test: the Multidimensional Impact of Cancer Risk Assessment (MICRA) scale measured distress, uncertainty and positive experiences. We report on the fully accrued trial (N = 2000). Results: 1998/2000 (99.9%) participants currently have reported results: 12.1% tested positive for a pathogenic mutation (Pos), 34.5% had VUS only and 53.5% tested negative (Neg). Median age was 51, 81% were female, 40% Hispanic, and 72% had a cancer history. Self-reported preventive surgery rates were low (mastectomy 9.3%, hysterectomy 1.5%, oophorectomy 1.6%), with no difference between VUS and Neg patients (p = 0.346). Most patients never or rarely had thoughts of cancer affecting daily activities (Pos 59.5%, VUS 66.9%, Neg 71.0%), never regretted testing (Pos 84.1%, VUS 90.0%, Neg 93.6%), and wanted to know all results, even those that doctors do not fully understand (Pos 81.7%, VUS 78.8%, Neg 77.1%). Pos patients had higher MICRA distress and uncertainty scores than VUS and Neg patients, whose distress and uncertainty scores did not differ significantly (p = 0.165, p = 0.129). Relatives of Pos patients completed genetic testing (30.4%) more often than VUS (5.8%) or Neg patients (5.1%, p < 0.001). Conclusions: After multiplex testing of 2000 diverse patients, few reported preventive surgery at 3 months; VUS patients had no more distress, regret or uncertainty than Neg patients. Pos patients most often advised relatives to test, suggesting that participants understood the implications of test results. Longer-term follow-up of test-related outcomes is underway. Clinical trial information: NCT02324062.
Remote genomic consultation to support uptake of a multi-gene genomic tumor panel (MGTP) by community oncologists (COs): Results of a pilot study.
Authors: Hall Michael J. , Chertock Yana , Handorf Elizabeth , Kaczmar John M. , Innocent Julie , Wong Yu-Ning , Daly Mary Beryl
Published: September 2018

1587

Background: MGTP use in routine cancer (CA) care is likely to increase w/lower costs for NGS-based testing and growing numbers of actionable targets coupled with targeted therapeutics. Early MGPT uptake has been slow among community oncologists (COs) due to their lower confidence to order, interpret, and act upon results of MGTP. This study evaluated the provision of telephone genomic consultation (GC) via an academic clinician link to an institutional genomic tumor board to support MGTP testing of CA patients (PTs) by COs. Methods: 4 practices of COs participated: 9 COs recruited 25 PTs w/metastatic CA. All PTs/COs completed baseline and follow-up (FU) assessments. Tumor blocks were evaluated at Fox Chase Cancer Center (FCCC) and tested w/a 50-gene MGTP. 12% blocks were inadequate. MGTP results were presented when appropriate at FCCC’s Genomic Tumor Board. All MGTP yielded > 1 variant (Var) [range 1-6]: 13/22 (59%) pts tested had a clinically relevant V; 6 other Vars were potentially actionable w/ approved therapy, while 3 Vars have novel therapies in Phase I/II studies. MGTP were called out to COs (by MJH) < 2 wks of resulting. A tailored summary was provided to COs. Results: At baseline, COs (n = 9) had limited experience w/MGTP (78%, < 5 ordered). Barriers for COs were: poor understanding of MGTPs (67%), cost (89%), uncertain benefit (44%), and poor access to targeted therapies (67%). At FU, 4/8 (50%) COs found GC “very useful”, and 63% reported MGPT paired w/GC would “probably/definitely” increase their use of MGTPs. Most (88%) felt MGPTs should be offered to PTs w/incurable CA. Among PTs at baseline (n = 25), awareness of MGTP was moderate (50%), but 79% reported it would help doctors take better care of their PTs. Valuation of MGTP was mixed—30% would pay $0 out of pocket, yet 30% also said they would travel “any distance” for an MGT-targeted experimental therapy. At FU (n = 14), 86% PTs felt MGPT was valuable, yet only 46% would “definitely” retest, and only 31% would pay > $100 to retest, even for 500+ genes. Conclusions: GC can be effective to support COs to use MGTPs. PTs w/CA have high expectations of MGTPs to improve their care, and yet attribute modest value to retest or to have a larger MGTP.
Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: Efficacy and imaging analyses of the ARTE trial.
Authors: Wirsching Hans-Georg , Tabatabai Ghazaleh , Roelcke Ulrich , Hottinger Andreas Felix , Schmid Andrea , Plasswilm Ludwig , Conen Katrin Lisa , Hundsberger Thomas , Caparrotti Francesca , Von Moos Roger , Riklin Christian Alexander , Remonda Luca , Roth Patrick , Held Leonhard , Rushing Elisabeth Jane , Ochsenbein Adrian , Weller Michael
Published: September 2018

2014

Background: The addition of bevacizumab (BEV) to first-line temozolomide chemoradiotherapy prolonged progression-free survival (PFS), but not overall survival (OS) in newly diagnosed glioblastoma in two phase III trials. Elderly and frail patients are underrepresented in most clinical trials, but early uncontrolled reports of BEV treatment of glioblastoma suggested preferential benefit in this patient population. Methods: ARTE was a 2:1 randomized, multi-center, open-label trial of hypofractionated radiotherapy (RT) in combination with intravenous BEV every 2 weeks (Arm A, N = 50) versus RT alone (Arm B, N = 25) in patients with newly diagnosed glioblastoma aged 65 years or older. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Response was assessed using Response Assessment in Neuro-Oncology (RANO) criteria. Exploratory imaging studies included apparent diffusion coefficient (ADC) mapping and 18F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET). Results: Established prognostic factors including age, Karnofsky performance score (KPS), O6-methylguanine DNA methyltransferase (MGMT) gene promoter methylation and steroid intake at study entry were balanced between arms. Median PFS was longer in Arm A vs. Arm B (7.6 vs. 4.8 months, p = 0.003), but OS was similar (12.1 vs 12.2 months, p = 0.8). Prior to progression, no differences in QoL were noted, but clinical deterioration was deferred in Arm A vs. Arm B. In a Cox model that controlled for established prognostic factors, an association with prolonged PFS was detected for Arm A versus Arm B (hazard ratio [HR] 0.36, p = 0.001) and for KPS 90-100% versus 60-80% (HR 0.50, p = 0.02). Applying a similar Cox model to OS detected an association with age 65-69 vs 70+ (HR 0.52, p = 0.02) and KPS 90-100% versus 60-80% (HR 0.53, p = 0.03). Exploration of imaging predictors of OS for Arm A identified response by RANO (HR 0.52, p = 0.02), but detected no prognostic role for T2, ADC or FET signal intensity. Conclusions: Efficacy outcomes and exploratory imaging analyses of the ARTE trial do not support the notion that benefit from BEV is more pronounced in elderly glioblastoma patients. Clinical trial information: NCT01443676.