bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and prognostic significance of PDGF ligands (A, B, C, and D) and PDGFR (A, B, and L) in soft-tissue sarcomas and GIST.
Authors: Lesluyes Tom , Blay Jean-Yves , Schoffski Patrick , Italiano Antoine , Le Cesne Axel , Debiec-Rychter Maria , Mir Olivier , Sciot Raf , Toulmonde Maud , Ray-Coquard Isabelle Laure , Rios Maria , Brahmi Mehdi , Chevreau Christine , Isambert Nicolas , Bonvalot Sylvie , Piperno-Neumann Sophie , Coindre Jean-Michel , Chibon Frederic
Published: September 2018

11067

Background: Sarcomas are a variety of rare connective tissue cancers. Doxorubicin and olaratumab (Ab against PDGFRA) improved survival in a recent Phase 1/2 study. Besides PDGFRA mutated gastrointestinal stroma tumor (GIST) and dermatofibrosarcoma protuberans, the role of PDGFR and the according ligands in the biology of sarcoma remain unclear. Methods: The expression levels of PDGF (A,B,C,D) and PDGFRs (A,B,L) were studied in a series of 255 sarcoma pts in localized phase using the Agilent 014850 platform. Data are available online (http://atg-sarc.sarcomabcb.org). Histologies were GIST (n = 60), myxoid liposarcoma (MLPS, n = 50), synovial sarcoma (SyS, n = 58), and sarcoma with complex genomics (SCG, n = 87). Expression levels were analyzed and tested for prognostic values for metastasis free survival (MFS) in uni- and multivariate analysis using SPSS 19.0. Results: Expression levels (ELs) of PDGFs and PDGFRs varied across histotypes: PDGFA levels were highest in SyS and lowest in MLPS (p < 0.0001). PDGFB and C levels were lower in GIST (p < 0.0001), while PDGFD ELs were similar across histological subtypes. PDGFRA ELs were highest in MLPS, while PDGFRB & L ELs were lowest in GIST and SyS (p < 0.0001 all). Complex patterns of correlation of expression between ligands and receptors were observed in each individual subtypes. PDGFA ELs above median were associated with a marginally higher risk of metastasis . Conversely, PDGFD ELs above median was associated with a reduced risk of metastasis in the whole cohort (p = 0.02). The ELs of the 3 receptors were not correlated to MFS. In multivariate analysis using Cox model on the non-GIST sarcoma cohort (histology, grade, depth, with size, PDGFA, PDGFD as continuous variables): histology, size, grade and PDGFA ELs were independent adverse prognostic factors (PF), while PDGFD ELs was a favorable PF for MFS. In the GIST cohort, testing AFIP score, PDGFA & D ELs as continuous variable, PDGFD ELs was also an independent favorable PF for MFS, in addition to AFIP score. Conclusions: The expression of PDGFs and the according receptors varies across sarcoma histological subtypes. PDGFA and D expression levels correlate independently to the risk of metastatic relapse.
Predictive role of FAS for trabectedin in second lines of advanced soft tissue sarcoma (ASTS): A Spanish group for research on sarcoma (GEIS) study.
Authors: Martin Broto Javier , Marcilla David , Ramos Rafael , Moura David Silva , Alvarez Ramiro , Hernandez Nieves , Agra Pujol Carolina , Mayordomo Empar , Romagosa Cleofe , Bague Silvia , Reguero Eugenia , Cruz Julia , Martin Francisco Javier , Gutierrez Antonio , Cruz Josefina , Alvarez Alvarez Rosa Maria , Diaz Beveridge Robert , Valverde Morales Claudia Maria , Lopez-Pousa Antonio , Martinez-Trufero Javier
Published: September 2018

11071

Background: There are currently several second-line options for the treatment of ASTS as gemcitabine combinations, trabectedin, pazopanib, eribulin or olaratumab plus doxorubicin in cases where anthracyclins are still possible. There is an unmet need for predictive biomarkers which hinders the rational selection of the best sequence in second line. We already published the prognostic value of FAS in first line of ASTS while this study analyzes its predictive role in different second line schemes. Methods: Most relevant selection criteria for this study were having received trabectedin in 2nd line or beyond for ASTS, progressive disease after at least one previous line for ASTS and signed CI. A TMA was set up for FAS staining (Cell Signaling) with blocks from diagnostic time. Two expert blinded pathologists reviewed and classified the cases as negative, weak or strong. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 198 patients accomplished selection criteria. Metastases at diagnosis occurred in 46 (24%) and median time to metastases was 18.8 months (CI 16,3; 21.3). Previous line to trabectedin consisted of gemcitabine combination 83 (42%), Doxorubicin-based 65 (33%) and others 50 (25%). Median PFS for previous and trabectedin lines were 3.5 (2.8-4.2) and 3.4 (2.8-4) months respectively. FAS positive entailed significantly better PFS for the previous trabectedin line: 4.1 (1.5-6.7) vs 3.0 (2.5-3.5) months, p = 0.01 whereas FAS positive was related with worse PFS for the trabectedin line 2.5 (2.2-2.8) vs 3.7 (2.7-4.8) months, p = 0.028. These results were more notorious for L-sarcoma cases: 7.0 (3.6-10.5) vs 4.3 (1.9-6.6) months, p = 0.017 in previous line and 2.4 (2.2-2.6) vs 6.5 (3.8-9.3) months, p < 0.001 in trabectedin. From trabectedin administration, FAS+ had significantly worse OS especially in L-sarcomas: 11.9 (5.2-18.7) vs 21.7 (12.7-30.8) months, p = 0.002. Conclusions: FAS showed predictive value in PFS and OS for trabectedin administration in ASTS. The different prognostic role of FAS across distinct lines and its relevance in L-sarcomas deserve further attention.
NY-ESO-1 antigen expression as a prognostic factor for soft tissue sarcomas.
Authors: Komarov Yuriy , Barchuk Anton , Semenova Anna Igorevna , Semiglazova Tatiana , Imianitov Evgenii , Iyevleva Aglaya , Baldueva Irina , Novik Alexey Viktorovich , Nehaeva Tatyana Leonidovna , Pipia Nino , Huhtala Heini , Ivantsov Alexander , Artemyeva Anna , Moore Malcolm , Protsenko Svetlana ,   NII
Published: September 2018

11075

Background: While a number of antigens are known to be expressed in soft tissue sarcomas, little is known about the prognosis of patients with such tumors. Recent data have demonstrated immunologic activity in sarcoma patients expressing the NY-ESO antigen, found positive in 20-80% cases. MAGE A3 has also recently attracted attention with regard to soft tissue sarcomas. In our study we aimed to assess any association between antigen expression and prognosis. Methods: In a case-control study we retrospectively collected data from a prospective database of all 137 patients with sarcomas receiving first line therapy in the Petrov Research Institute of Oncology in Saint-Petersburg. All cases were morphologically verified, with mRNA expression of NY-ESO-1, MAGE A3, PDGFR A, PDGFR B, beta-tubullin and top2alpha additionally being tested by quantitative real-time PCR in a subset of patients. The log-rank test was applied to compare Kaplan-Mayer estimates of progression-free (PFS) and overall survival (OS) by univariate analysis. Hazard ratios were derived after adjustment for age, gender, several covariates for type of chemotherapy and disease stage with two-sided probability at a significance level of 0.05. Results: The positive rate for expression of NY-ESO was 20% (11/43).Only NY-ESO was significantly associated with PFS (p < 0,001), with a median durations of 10, 4 and 7 months for positive, negative and not tested for NY-ESO expression, respectively. The adjusted hazard ratio (HR) for NY-ESO positive patients was 2.2 (95%CI, 1.2;4.2) compared with their negative counterparts, The HR for patients not tested for NY-ESO was 2.0 (95%CI, 1.3;3.0). Among other covariates, only a combination of drugs was associated with a lower risk of progression (HR, 0.7 95%CI, 0.4;0.98) , as compared to those receiving a single chemotherapy agent. Conclusions: This first report showing prognostic significance of NY-ESO expression in soft tissue sarcoma patients, suggests that research should be focused on targeting this antigen. Participation in clinical trials for patients with positive NY-ESO expression is highly recommended, because of poor survival regardless of the type of standard treatment.
Effect of mast cells on efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme b.
Authors: Wroblewski Mark , Velthaus Janna-Lisa , Bauer Raimund , Müller Volkmar , Schem Christian , Fasching Peter A. , Karn Thomas , Fehm Tanja N. , Kühn Thorsten , Rack Brigitte Kathrin , Denkert Carsten , Untch Michael , Kittel Kornelia , Janning Melanie , Minner Sarah , Sauter Guido , Bokemeyer Carsten , Von Minckwitz Gunter , Loibl Sibylle , Loges Sonja
Published: September 2018

11522

Background: Resistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. As mast cell (MC) density is known to correlate with tumor angiogenesis, we analyzed if inhibition of MC holds potential to increase efficacy of AAT in mice and cancer patients. Methods: C57BL/6J (WT), NSG or MC-deficient KitW-sh(Wsh) mice were subcutaneously injected with Panc02, EL4 or BxPC3 cells with or without bone marrow-derived MC. Tumors were treated with 20 mg/kg of anti-VEGFR2 antibodies (DC101) or 25 mg/kg cromoglicic acid. Tissue microarrays from n = 299 breast cancer patients from the GeparQuinto Phase 3 clinical trial were stained for MC and MC numbers were correlated with clinical data. Results: We observed that absence of MC reduced tumor growth and increased the efficacy of AAT in different tumor models. Intriguingly, AAT only initially reduced microvessel proliferation but this was abrogated over time as a result of MC-mediated resistance. We show that MC secrete increased amounts of granzyme b upon therapy, which mobilizes alternative pro-angiogenic factors from the tumor matrix. These factors act beside the targeted VEGFA-VEGFR2-axis and reinduce angiogenesis despite the presence of AAT. Importantly, MC-mediated resistance could be overcome using the FDA-approved MC inhibitor cromoglicic acid. In line with our preclinical data, high intratumoral MC density correlated with disease progression in HR+ breast cancer patients when Bevacizumab was added to standard neodjuvant chemotherapy (HR 8.45, p = 0.006). Accordingly, Kaplan-Meier curves indicated that disease free survival of patients with high tumoral MC density was numerically shorter in the whole cohort and significantly shorter in the HR+ cohort upon addition of AAT to chemotherapy (p = 0.168 and p = 0.004, respectively). Conclusions: Here we unravel a novel resistance mechanism, by which MC hamper efficacy of AAT in mice and cancer patients. In preclinical models this effect could be overcome by combining AAT with an FDA-approved MC inhibitor indicating high clinical relevance. Thus, combination of FDA-approved MC inhibitors with AAT might be a suitable approach to increase efficacy of AAT in the clinic.
Circulating tumor DNA profiling to reveal heterogeneity of EGFR-TKI resistance mechanisms in lung adenocarcinoma patients.
Authors: Chen Rongrong , Zhao Jun , Hu Xingsheng , Dai Pingping , Yi Yuting , Zhou Zhenzhen , Guan Yanfang , Zhao Meiru , Liu Tao , Yang Ling , Yi Xin , Xia Xuefeng
Published: September 2018

11527

Background: EGFR-TKI therapy has significantly improved prognosis of NSCLC patients with EGFR sensitive mutation. However, almost all patients ultimately develop PD while receiving TKI treatment. Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for comprehensive analysis of molecular abnormalities. Methods: A total of 254 advanced lung adenocarcinoma patients with signs of EGFR-TKI resistance were enrolled in the study. ctDNA was analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations across 59 genes. Results: ctDNA profiling was possible for all patients, 172 patients had ≥ 1 ctDNA alteration(s). Median number of plasma somatic mutations was 2, predominantly located in EGFR and TP53, with MET, ERBB2 and PIK3CA followed. Of that, 30.6% of mutations detected in ctDNA were at a frequency below 1%. In exploring the mechanisms of TKI-resistance, we found TKI-sensitizing mutations were not detected in plasma of 138 patients (54.3%). Known mechanisms such as EGFR T790M/C797S mutation, activating mutations of PI3K- AKT- mTOR signaling, amplification of MET, activating mutation / amplification of ERBB2, activating mutation of KRAS, BRAF or mutations in EGFR EX20 other than T790M/C797S were identified in 59, 16, 8, 7, 3, 2, and 2 patients respectively. T790M/C797S was detected in 50.8% of patients with plasma positive for TKI-sensitizing mutations. Of note, C797S was only detected in patients treated with AZD9291. EGFR amplification were identified in 15 patients, though whether it would result in TKI-resistance was still controversial. Co-occurrence of resistance mechanisms were observed in 22 patients including 13 patients without TKI-sensitizing mutations. Conclusions: There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after EGFR TKI therapy. ctDNA can be used as a ‘liquid biopsy’ to facilitate the broad exploration of potential resistance mechanisms.
Bim and soluble PD-L1 (sPD-L1) as predictive biomarkers of response to anti-PD-1 therapy in patients with melanoma and lung carcinoma.
Authors: Dronca Roxana Stefania , Mansfield Aaron Scott , Liu Xin , Harrington Susan , Enninga Elizabeth Ann , Kottschade Lisa A. , Koo Chi Wan , McWilliams Robert R. , Block Matthew Stephen , Nevala Wendy Kay , Markovic Svetomir , Dong Haidong
Published: September 2018

11534

Background: To date, there are no validated blood-based biomarkers of predicting response to PD-1 blockade. We previously reported that Bim is a downstream signaling molecule of the PD-1 pathway, and that measurement of Bim levels in circulating T-cells may predict and monitor responses to anti–PD-1 therapy in melanoma. We have identified the existence of sPD-L1 in cancer patients and showed that the sPD-L1 is biologically active and capable of triggering apoptosis in activated T-cells. Here we evaluated T cell Bim and sPD-L1 in the peripheral blood (PB) as biomarkers of response in a cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD1 therapy. Methods: 60 pts treated with anti-PD-1 had PB collected at baseline and at radiographic tumor evaluation. Frequencies of Bim+ T cells and Bim median fluorescence intensity (MFI) were measured by flow cytometry in gated tumor-reactive CD11ahighPD1+ CD8+ T cells. We also measured levels of sPD-L1 at baseline and serially during treatment with sPD-L1 ELISA. Baseline Bim and sPD-L1 levels and percent change in Bim levels in patients (pts) who had a radiographic response (CR/PR) were compared to those who had progressive disease (PD) at 12 wks. Results: Similarly to previously reported preliminary data, pts with objective response (CR/PR, 15/60) after 4 cycles of anti-PD1 therapy had higher frequency of Bim T cells at baseline compared to pts with PD (16/60) (mean 43% vs. 30%, P = 0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P = 0.0111). High baseline sPD-L1 were associated with progression on anti-PD1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p = 0.07, n = 13) and the levels increased by the first tumor assessment in patients resistant to anti-PD-1. Conclusions: Measurements of Bim and sPD-L1 levels may help to select patients who are likely to benefit from anti-PD1 monotherapy versus combinatorial strategies, and provide a new non-invasive way to monitor response to anti-PD-1 blockade. A larger validation study is underway.
Association of circulating tumor DNA (ctDNA) tumor mutational burden (TMB) with DNA repair mutations and response to anti-PD-1/PD-L1 therapy in non-small cell lung cancer (NSCLC).
Authors: Davis Andrew A. , Chae Young Kwang , Agte Sarita , Pan Alan , Iams Wade Thomas , Cruz Marcelo Rocha De Sousa , Mohindra Nisha Anjali , Villaflor Victoria Meucci , Giles Francis J.
Published: September 2018

11537

Background: Identifying optimal biomarkers for response to anti-PD-1/PD-L1 therapies in NSCLC is critical. TMB is a potential biomarker of genomic instability and neoantigen binding sites to activated effector T cells. The goal of this study was to derive a measure of ctDNA TMB and to examine the association between TMB and clinical variables, DNA repair mutations, and response to checkpoint blockade. Methods: We retrospectively examined 136 patients with NSCLC who had undergone ctDNA next-generation sequencing (NGS) in our institution. The ctDNA testing, performed by Guardant360, is not currently clinically indicated for TMB. We derived ctDNA TMB using coding base substitutions and indel alterations both including and excluding potentially functional variants, but excluded rearrangements, fusions, and copy number variants. In addition, survival data were obtained for 17 patients who were treated with anti-PD-1/PD-L1 therapy and had ctDNA before first line therapy or within 90 days of therapy initiation. Results: ctDNA TMB was associated with the number of direct and indirect DNA repair gene mutations (t-test, p < 0.05). Smoking was also associated with higher TMB when including functional variants (chi-square test, p = 0.034). Driver mutations (EGFR, KRAS) and prior radiation therapy were not correlated with TMB. Lower ctDNA TMB (below the median, 15 mutations/MBp) was associated with longer PFS and OS (Kaplan-Meier log-rank test, p < 0.05). Conclusions: ctDNA TMB was derived and was significantly associated with greater number of DNA repair mutations. Smoking predicted higher TMB score. However, in a small subset of patients, lower ctDNA TMB predicted response to checkpoint blockade. Potential reasons include the small sample size, the possibility of ctDNA reflecting tumor burden, and the limited length of DNA sequenced (~78,000-138,000 bp). Larger, prospective studies are necessary to validate these findings.
Progastrin: A new specific early cancer screening biomarker.
Authors: Prieur Alexandre , Mazard Thibault , Assenat Eric , Ychou Marc , Gourgou Sophie , Mariani Odette , Bronzini Thierry , Salomon Anne Vincent- , Joubert Dominique
Published: September 2018

11545

Background: One in two people will be diagnosed with cancer during his/her lifetime. Because we are lacking effective screening tests, most cancers are detected in late stages, when survival rates are very low. Here, we show the development of the first early cancer screening test for multiple cancers using progastrin (PG) as biomarker. The gene coding for PG is a target gene of the Wnt oncogenic pathway that is activated in almost all type of cancers, at the earliest stages of development. We showed that the neutralization of PG by a specific humanized antibody could be used for colorectal cancer treatment. Moreover, as PG is secreted by cancer cells, we can specifically detect it in the blood of persons having a cancer at early stage. Methods: Antibodies directed against PG were produced and selected for target specificity and affinity. ELISA is the most reliable assay to detect biomarker on the blood. Hence, selected antibodies were used to set up an ELISA sandwich to detect PG in the blood of patients with various types of cancers and at various stages. Results: We first set up a prototype ELISA using polyclonal antibodies. We validated our test using 223 blood samples from patients with polyps and colorectal cancers at various stages for which we observed an increased levels of PG. Then, we showed the presence of PG in the blood of 212 patients with other types of cancer, including liver, pancreatic and breast cancers, confirming that PG could be used as a biomarker for multiple types of cancers. Next, we set up our industrial ELISA using polyclonal and monoclonal antibodies called DECODE Lab and tested 245 new blood samples from patients with various types of cancer including early stages. Strikingly, using our test we were able to detect breast (AUC = 0.9638; sensitivity 70%), colorectal (AUC = 0.9635; sensitivity 73%), melanoma (AUC = 0.9882; sensitivity 87%) and cervix utery (AUC = 0.9827; sensitivity 84%) all stages combined with a high specificity of 97.5%. Finally, for early stage patients with melanoma and breast cancer, we had a sensitivity of 68% and 81% respectively. Conclusions: Taken together, the results presented here show that PG is a reliable biomarker for early cancer screening. The ELISA test that we developed is very efficient and now available for the clinic.
Pre-treatment hematological markers as a predictive biomarker for survival in patients with non-small cell lung cancer treated with nivolumab.
Authors: Patil Pradnya Dinkar , Khunger Monica , Rakshit Sagar , Stevenson James , Pennell Nathan A. , Elson Paul , Velcheti Vamsidhar
Published: September 2018

11547

Background: The absolute neutrophil count (ANC), absolute monocyte count (AMC) and neutrophil to lymphocyte ratio (NLR) are known markers of inflammation. We evaluated whether ANC, AMC and NLR are prognostic for overall survival (OS) and evaluated change in NLR as a predictive marker of response per RECIST in non -small cell lung cancer (NSCLC) patients treated with nivolumab. Methods: A total of 115 patients with NSCLC treated with nivolumab were included. ANC, AMC and NLR were examined at initiation of nivolumab therapy and after two cycles. The prognostic role of ANC, AMC and NLR on OS and changes in NLR ratio in responders was assessed using Cox regression model. Results: ANC > 6, AMC > 0.5 and NLR > 2.8 at baseline were independently associated with shorter OS (Hazard ratio (HR) 1.17 (1.08-1.27), p = .00001; HR 4.53 (1.99-10.31), p = 0.04 and HR 1.09 (1.04-1.13), p = 0.0002 . Responders had a decrease in NLR by (median (range) -0.93 (-14.7-52.95), p = 0.03) whereas non-responders had an increase in NLR by (median (range) 0.85 (-8.6-132.9), p = 0.03). Conclusions: ANC, AMC andNLR are independent prognostic factors in NSCLC patients treated with nivolumab. Changes in NLR can be an early biomarker for response with nivolumab in NSCLC patients. [Table: see text]
Cerebrospinal fluid circulating tumor cells (CSF CTC) for real-time patient monitoring and response to treatment.
Authors: Malani Rachna , Fleisher Martin , Lin Xuling , Omuro Antonio Marcilio Padula , Groves Morris D. , Lin Nancy U. , Melisko Michelle E. , Lassman Andrew B. , Jeyapalan Suriya A. , Briggs Samuel , DeAngelis Lisa Marie , Raizer Jeffrey J. , Pentsova Elena ,   ASCO Authors
Published: September 2018

11549

Background: The validated CellSearch system (Janssen Diagnostics, LLC), utilizing an immunomagnetic CTC selection method based on EPCAM antibody conjugated ferroparticles, is an FDA-approved methodology for enumerating CTC from blood in pts with breast, prostate and colon cancers. The CellSearch system has been used to evaluate CSF CTC of pts with leptomeningeal metastasis (LM) and has demonstrated potential as a diagnostic marker and response to cancer treatment. We explored the use of CSF CTC enumeration in the follow-up of pts with LM from HER2+ cancers receiving intrathecal (IT) therapy, aimed at characterizing changes over time as a potential biomarker of treatment response. Methods: CSF from pts participating in an IRB-approved phase I/II dose escalation trial of IT trastuzumab for LM in HER2+ cancer (NCT01325207) was evaluated by CellSearch system. 3 ml CSF from a ventricular reservoir was collected for CSF CTC enumeration at pre-treatment Day 1 of each cycle and correlated with CSF cytology from the same sample, and with clinical and radiographic response. LM progression was defined as clinical, CSF cytologic or radiographic worsening. Results: 15 pts with HER2+ LM (14 breast, 1 colon) were enrolled; 13 were women. At baseline 7 pts had positive CSF cytology, the other patients had a diagnosis by MRI. Of the 15 pts, 10 had greater than 1 cycle of treatment to be evaluable; 5 pts progressed during cycle 1 (Table). Mean CSF CTC at baseline was 82 per 3ml (range 0-200); 2 pts had no detectable CSF CTCs. A numerical decrease in CSF CTC was observed in 5 pts after cycle 1 and remained low (mean =9.5, range 0-92) while disease was stable. 3 pts (pts.3, 4 and 7) demonstrated a rise in CSF CTCs roughly 1 month prior to disease progression. Conclusions: Changes in CSF CTCs enumeration in response to treatment may allow quantitative surveillance of treatment response. CSF CTCs may serve as a platform to assess treatment response or as an early biomarker of LM progression and should be further investigated. Clinical trial information: NCT01325207. [Table: see text]
Tumor kinetic modeling and identification of predictive factors for tumor response to durvalumab in patients with non-small cell lung cancer (NSCLC).
Authors: Zheng Yanan , Narwal Rajesh , Jin Chaoyu , Wang Bing , Jin Xiaoping , Mukhopadhyay Pralay , Higgs Brandon W. , Gupta Ashok Kumar , Dennis Phillip A. , Roskos Lorin
Published: September 2018

11555

Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The primary objectives of this analysis were to describe the longitudinal tumor size profiles and identify the key factors predicting tumor growth and regression following durvalumab. Methods: Longitudinal tumor size data obtained from NSCLC patients in study 1108 (all lines of therapy) and ATLANTIC (third line and beyond) following durvalumab treatment were modeled using nonlinear mixed effect modeling. Tumor kinetics were described by four key parameters: tumor growth and killing rate constants, fraction of durvalumab-sensitive tumor cells, and delay time for tumor killing. Potential predictive factors for tumor growth and regression were evaluated in a multi-variable covariate analysis. The model was used to simulate response rates at different tumor PD-L1 expression cutoffs. Results: Tumor kinetic modeling accurately described the longitudinal tumor response profiles from NSCLC patients in both studies. The factors associated with more rapid tumor growth were liver metastases, ECOG score > 0, high neutrophil-to-lymphocyte ratio and EGFR/ALK mutation. Tumor cell PD-L1 expression, baseline tumor size and smoking history were identified as significant predictive factors for tumor killing or the fraction of sensitive tumor cells. Simulations using the tumor kinetic model showed increased response rates in patients with higher tumor cell PD-L1 expression (increased by 9-11% and 10-14% with 25% and 50% cutoff, respectively), patients receiving durvalumab as first-line therapy (increased by 12% vs. 2nd line/above), and patients with smoking histories (increased by 4-5% vs. non-smokers). Conclusions: Tumor kinetic modeling identified factors that predict tumor progression and response following durvalumab in NSCLC patients. The multivariate analysis accounts for various predictive factors within predictive biomarker strata, allowing better interpretation of different biomarker cutoffs. The modeling technique can potentially guide patient selection/enrichment, clinical trial design strategies and tumor biology. Clinical trial information: NCT02087423 and NCT01693562.
Breast cancer-related paraneoplastic neurologic disease.
Authors: Murphy Brittany L. , Zalewski Nicholas L. , Degnim Amy C. , McKeon Andrew , Flanagan Eoin P , Pittock Sean J. , Habermann Elizabeth B.
Published: September 2018

11559

Background: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by occult malignancy. Given the rarity of this disease, a paucity of data exists describing breast cancer (BC)-related PND; thus, we sought to further examine this specific population of patients. Methods: Using an institution specific clinical search tool, we identified all patients at our institution from 1997-2016 with a diagnosis of BC-related PND, verified by an international expert. Retrospective review was used to record tumor and treatment factors associated with PND and BC. A descriptive analysis was performed of the characteristics associated with BC-related PND. Results: BC-related PND was diagnosed in 58 female patients. Average age at BC diagnosis was 54.0±10.3 years. Most had invasive cancer of Stage II or higher [Stage 0 (10.3%), I (10.3%), II (44.8%), III (13.8%), IV (6.9%), unknown (13.8%)]. Most patients were hormone receptor (HR)+ (63.8%), while 4 (6.9%) were HR-, and 17 (29.3%) were unknown. Of the 34 patients where Her2/neu (Her2) data was available, 7 (20.6%) were Her2+ and 27 (79.4%) were Her2-. The majority (62.1%) had neurological symptoms prior to BC, 5.2% were concurrent, and 32.7% developed PND after initial BC. The interquartile range for time from PND to BC diagnosis was -8.5 to 10.5 months. Of the 58 patients, 29 (50%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]) (10), amphiphysin-IgG (n = 9), Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]) (n = 5), and other (n = 5). The most common syndromes were cerebellar ataxia (n = 14), myelopathy (n = 11), and myopathy (n = 11). Immunotherapy was used for PND in 53 of 58 (91.4%) patients; benefit from immunotherapy was assessed as complete 0 (0%), robust 11 (20.8%), mild to moderate 28 (52.8%), none 9 (17%), and indeterminate 5 (9.4%). Conclusions: BC-related PND is rare, with only 58 cases over 20 years at a large academic institution. Paraneoplastic symptoms often present prior to BC diagnosis and BC characteristics are typical of the general population. Over 75% of patients benefit from immunotherapy. These data may provide helpful information to providers treating this population of patients.
Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).
Authors: Obeid Elias , Zhou Chun , Macfarlane Alexander , Alpaugh R. Katherine , McAleer Cecilia , Dulaimi Essel , Campbell Kerry , Goldstein Lori J.
Published: September 2018

11563

Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.
Targeted next-generation DNA sequencing of paired tumor and normal DNA to reveal frequent actionable germline alterations.
Authors: Korn Wolfgang Michael , Yey Iwei , Van Ziffle Jessica , Grenert James P , Joseph Nancy , Solomon David A. , Laurance Megan , Talevich Eric , Onodera Courtney , Krings Gregor , Stohr Bradley A. , Blanco Amie , Bastian Boris C.
Published: September 2018

11575

Background: Targeted next-generation DNA sequencing of paired tumor and normal DNA samples allows for detection of biologically relevant variants in the tumor with significantly greater accuracy than tumor-only sequencing. In addition, this approach presents with the opportunity of unveiling previously unknown cancer predisposition traits in a patient’s germline DNA. Methods: We sought to determine the rate of pathogenic germline alterations in 546 consecutive pediatric and adult patients who underwent molecular profiling using the UCSF 500 assay, a hybrid capture-based DNA sequencing assay targeting the coding regions of ~500 cancer-related genes, TERT promoter, select introns from 40 genes (for detection of gene fusions and other structural variants), and intergenic regions at regular intervals along each chromosome (for chromosomal copy number and LOH assessment). Results: Pathogenic germline alterations were found in 89/546 patients (16.3%), including 25 pediatric and 64 adult cases. Germline variants were identified in 37 genes with MUTYH (n = 15, 17%), CHEK2 (n = 10, 11%), BRCA2 (n = 9, 10%), BRCA1 (n = 5, 6%), TP53 (n = 5, 5%), and APC (n = 4, 5%) being altered most frequently. Loss of heterozygosity of genes affected in the germline was seen in tumor DNA 37 (42%) cases, highlighting their likely role as drivers of tumorigenesis. Clinically relevant germline findings not associated with increased cancer risk were identified in 6 (7%) of the cases, for example a COL1A1 mutation associated with Ehlers-Danlos Syndrome. In In 73 (82%) of the cases, pathogenic germline alterations were new findings and genetic counseling was recommended. A possible, previously unknown, role of germline mutations was found in some instances, including a TSC2 germline mutation in a patient with hybrid oncocytoma/chromophobe tumor (HOCT) with loss of the normal TSC2 allele in the tumor. Conclusions: Our data suggest that paired tumor/normal DNA analysis uncovers actionable heritable traits in a substantial fraction of patients and represents the preferred approach to analyzing malignancies in children and adults.
Clinicopathologic features of non-small cell lung cancer (NSCLC) harboring an NTRK gene fusion.
Authors: Farago Anna F. , Taylor Martin S , Doebele Robert Charles , Spira Alexander I. , Boyle Theresa A , Haura Eric B. , Azimi Roxana S. , Shaw Alice Tsang , Mino-Kenudson Mari , Drilon Alexander E.
Published: September 2018

11580

Background: Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C, respectively. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. An estimated 0.1 – 1% of NSCLCs harbor NTRK fusions. To date, clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs (Farago et al., 2015; Hong et al., 2016). Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion NSCLCs are not well characterized. Methods: Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database. A central pathologist (M.M.) reviewed tumor histology in cases with available tissue. Results: 10 NSCLC cases with NTRK gene fusions were identified. Of these, TRK kinase domain-containing potentially activating fusions were verified by next-generation sequencing (NGS) in 7, forming the study cohort. Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners. Four (57%) patients were male. Median age at diagnosis was 47.6 years (range 27.9 – 86.0). The average smoking pack year history was 8.9 (range 0 to 30). Five (71%) presented with metastatic disease. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases. On pathologic review of 4 cases, all were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features. Of the 3 remaining non-study cohort cases, 1 was a non-kinase domain-containing NTRK1 fusion with a concurrent KRAS G12C mutation, 1 was an NTRK2 intragenic deletion disrupting the exon 18 3’ splice site, and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation. Conclusions: NTRK fusions occur in both men and women across wide ranges in age and smoking history. We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions. Notably, not all NTRK alterations are activating, requiring validation of the specific position of the fusion.
Survival profile in breast cancer molecular subtypes without systemic and locoregional treatment.
Authors: Yang Sherry X. , Polley Eric
Published: September 2018

11599

Background: It is unclear whether survival varies among breast cancer molecular subtypes without systemic and locoregional therapy. This study aims to evaluate the survival profile by molecular subtypes after surgery. Methods: In total, we evaluated 301 women with invasive breast cancer with stage I, II or III disease. Patients were classified into four major breast cancer subtypes by immunohistochemistry/FISH classifiers: luminal-A (ER+ and/or PR+/HER2-), luminal-B (ER+ and/or PR+/HER2+), HER2-enriched (HER2+/ER-/PR-) or basal-like (ER-/PR-/HER2-; triple-negative). Overall survival (OS) was analyzed by Kaplan-Meier analysis, and log-rank test for differences. Association between clinical outcome and subtype adjusting for breast cancer prognostic factors was assessed by multivariable Cox proportional hazards model. Results: All patients did not receive systemic chemotherapy and hormone therapy as well as radiation therapy. Luminal A was the most common subtype (N = 224), followed by basal-like (N = 43), luminal B (N = 21) and HER2-enriched (N = 13). Median follow-up for OS was 197 months (range: 1 – 273 months). Age at diagnosis was statistically different among the subtypes, with basal-like and luminal B having high proportions less than 50 years (P = 0.047). Patients with basal-like and HER2-enriched had more high grade tumors (P < 0.001). Notably, there was no difference in OS among the four subtypes (log-rank P = 0.983). In multivariable analysis, the adjusted hazard ratio (HR) was 1.1 for luminal A vs. luminal B (P = 0.781), 0.62 in luminal A vs. HER2-enriched (P = 0.273), or 0.67 in luminal A vs. basal-like (P = 0.158). In contrast, the adjusted HR were 2.2 in age less than 50 years (P = 0.0017), and 1.1 for number of positive nodes (P = 0.00074). Conclusions: OS, through long-term clinical follow-up, is not significantly different among molecular subtypes if not controlling for other prognostic factors in patients who only received surgery. Age and number of positive nodes are independent prognostic factors in patients with no systemic and locoregional treatments.
Effect of Wnt5a on aggressiveness of ER-positive breast cancer and cancer cell migration through JNK-ALCAM pathway.
Authors: Kobayashi Yoshie , Kadoya Takayuki , Amioka Ai , Gohda Noriko , Kono Miho , Sasada Shinsuke , Kajitani Keiko , Masumoto Norio , Okada Morihito
Published: September 2018

11614

Background: Wnt5a is a representative ligand that activates β-catenin-independent pathways and involved in cell motility and cell polarity, and the like, being mediated by JNK. We elucidated the implication of Wnt5a expression in breast cancer. Methods: One hundred seventy eight breast cancer patients (mean age ± SD: 60.0 ± 13.2 years) with clinical Stage I-III between January 2011 and February 2014, were prospectively evaluated. We examined relationships between Wnt5a expression and clinicopathological factors by immunohistochemical analyses. 5-year relapse-free survival rates and sites of recurrence were analyzed. In addition, molecules induced by Wnt5a in cultured cells were identified by DNA microarray analysis. Results: Wnt5a expression was significantly more frequent when estrogen receptor (ER) was present, 68/153 (44%) than when ER was absent, 1/25 (4%) (P <0.001) (Table). In ER-positive breast cancer, a significant interaction between expression of Wnt5a with lymph node metastasis (P<0.001), high nuclear grade (P=0.004), and lymphatic invasion (P=0.001). 5-year relapse-free survival rates were 81.1% and 100% in Wnt5a-positive and Wnt5a-negative breast cancers, respectively (P = 0.024). All recurrent breast cancer patients in this study had bone metastasis. We established MCF7 stably expressing Wnt5a (Wnt5a/MCF7 cells) and microarray analyses identified several genes induced by Wnt5a (>3.0 fold), involving activated leukocyte cell adhesion molecule (ALCAM). ALCAM is known to be related with apoptosis, invasion and prognosis of breast cancer. We focused on ALCAM and investigated its protein expression by Western blotting, and found remarkable increase of ALCAM in Wnt5a/MCF7 cells. Conclusions: Wnt5a expresses in ER-positive breast cancer and is associated with high-grade malignancy and a poor prognosis through JNK-ALCAM pathway. Wnt5a could be a novel prognostic factor of ER-positive breast cancer. [Table: see text]
Microarray analysis to identifiy novel copy number alterations in acute myeloid leukemia.
Authors: Fontana Maria Chiara , Marconi Giovanni , Papayannidis Cristina , Fonzi Eugenio , Ottaviani Emanuela , Franchini Eugenia , Ferrari Anna , Simonetti Giorgia , Padella Antonella , Bruno Samantha , Testoni Nicoletta , Baldazzi Carmen , Ghelli Luserna di Rorà Andrea , Robustelli Valentina , Abbenante Maria Chiara , Paolini Stefania , Nanni Jacopo , Bertamini Luca , Martinelli Giovanni
Published: September 2018

11622

Background: SNP microarray can detect Copy Number Alterations (CNAs) which could be predictive of response and can help define therapeutic strategies. Our aim is to improve conventional cytogenetic analysis and identify new genetic alterations relevant to leukemogenesis by a SNP array-based genotyping approach. Methods: We performed SNP 6.0/Cytoscan HD (Affymetrix) on 235 Acute Myeloid Leukemia (AML) patients at diagnosis. Seventy-eight/235 samples were also performed by Whole Exome Sequencing, WES (HiSeq,Illumina). SNP Array data were analyzed by Nexus Copy Number (BioDiscovery) and R Core Team. Results: We found several genes preferentially deleted, including MRPS5 (14.8%), PHF6 (9.3%), SCAPER (7.2%), CASK (5.9%), WNK (4.6%), STAG2 (4.2%), LRRK1 (3.4%), PALB2 (3.4%), genes preferentially amplified were RABL2B (16.1%), NF2 (10.2%), NBPF9 (7.6%), JAK2 (6.8%), RB1, NF1 and KMT2A (4.2%), PTEN (3.4%), TP73 and SMAD2 (2.5%). Single-copy losses and deletions were enriched (p < .001) for genes mapping in these pathways: aberrant PD-1 signaling, loss of function of SMAD4 in cancer and SMAD4 MH2 Domain mutants in cancer. The pathways significantly (p < .001) deregulated in our cohort with single copy gain and homozygous amplification were: regulation of transcription and nucleic acid, negative regulation of metabolic processes, constitutive signaling by aberrant PI3K in cancer and PI3K/AKT network. In order to define driver alterations, we correlate deletions and losses with mutational data. We found losses are also targeted by mutations ( BRCA2, LRRK1), while deleted genes, as CASK, CDK6 and MAPT, were involved in pathways affected by genomic mutations ( CASK deletion and MPP6 mutation, CDK6 deletion and PPM1D mutation, MAPT deletion and SPAG5mutation). Conclusions: We have identified new CNAs and pathways involving novel potential leukemia-related genes. The comparison between SNP and WES data could provide important findings on prognosis of AML patients. Minimal deleted regions of genes in deregulated pathways deserve further investigation in order to identify new genes which could be relevant AML biomarkers. Ackn: ELN, AIL, AIRC,prog. Regione-Università 2010-12 (L. Bolondi),FP7 NGS-PTL project,HARMONY.
Extended follow-up in the COGENT study: A randomized study of in-person versus telephone disclosure of cancer genetic test results.
Authors: Bradbury Angela R. , Patrick-Miller Linda J. , Egleston Brian L. , Domchek Susan M. , Olopade Olufunmilayo I. , Hall Michael J. , Daly Mary Beryl , Fleisher Linda , Grana Generosa , Ganschow Pamela , Fetzer Dominique ,   The COGENT Study Research Team
Published: September 2018

1504

Background: Alternative delivery models are needed in the era of Precision Medicine given a shortage of genetic providers and increasing utilization of genetic testing. Telephone disclosure (TD) of genetic test results, including multi-gene panel testing, is non-inferior to usual care in-person disclosure (IPD) for short-term distress but failed non-inferiority for knowledge. Longitudinal data including health behaviors are needed. Methods: 970 patients undergoing clinical genetic testing at 5 centers were randomly assigned to usual care IPD (n = 497) or TD (n = 473) of results in the COGENT Study (NCT01736345). Participants completed surveys after pre-test counseling, post-disclosure and at 6 and 12 months. We used non-inferiority tests for primary analyses and T-tests and logistic regressions for secondary analyses. Results: TD was not worse than IPD for anxiety both post-disclosure and at 6 months, but did not reach the non-inferiority threshold for knowledge at either time point. In secondary analyses there were no significant differences in anxiety, depression, or cancer worry between arms, but there was less knowledge gain at 6 (-0.41 v. +0.11 in IPD, p = 0.05) and 12 months (-0.34 v. +0.31 in IPD, p = 0.05) in the TD arm. In the TD arm, 195 (50%) returned for clinical follow-up with a physician to discuss medical management. Not returning for follow-up varied by site and was associated with a negative result, being male and non-white. Knowledge gain at 6 months was lower for those who did not return for follow-up (-0.77) compared to those who returned (-0.17, p = 0.08). There were no significant differences by arm at 6 and 12 months in performance of mammogram, breast MRI, colonoscopy or prophylactic surgeries. Conclusions: Distress is not unacceptably worse with TD, but knowledge failed the test for non-inferiority. Longitudinal knowledge declined more for those who did not return for medical follow-up, but uptake of screening and risk reducing behaviors did not differ by arm. Telephone disclosure of genetic test results, even MGPT, may be a reasonable alternative to in-person disclosure for patients who agree to return to meet with a provider for medical management recommendations. Clinical trial information: NCT01736345.