Molecular profiling and clinical characteristic of malignant melanoma in younger patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22087-e22087
Author(s):  
Jomjit Chantharasamee ◽  
Karlton Wong ◽  
Bartosz Chmielowski
Keyword(s):  
Gene Expression ◽  
General Population ◽  
Uveal Melanoma ◽  
Cutaneous Melanoma ◽  
Stage I ◽  
Stage Iii ◽  
Younger Patients ◽  
Adjuvant Immunotherapy ◽  
Better Than

e22087 Background: Combination of clinical and molecular data has not yet been well established in adolescent and younger adult patients with melanoma Methods: We performed a retrospective analysis of the molecular profiles and clinical outcome of patients diagnosed at the age younger than 40 treated at UCLA during 2010 to 2019. Patient’s molecular profile, characteristics, and treatment outcome were described using descriptive statistic. Kaplan-Meier curve was used for disease-free survival (DFS) and overall survival (OS). Results: 150 patients with a median age of 29 year (12-39) were analyzed. 101 (67.3%) patients had cutaneous melanoma, 49 (32.7%) had localized uveal melanoma. Of those 101, 23.8% had pre-existing benign or congenital nevus. 70/101 (69.3%) was stage I-II, 26/101 (25.7%) stage III and 5/101 (4.9%) stage IV. Of those 37 patients with molecularly characterized tissue, 23 (62%) had BRAF mutation including 17 V600E, 4 V600 unknown codon, 2 G469A, 2 NRAS and 1 NF-1 mutation. 11/37 were BRAF negative. 79.6% of patients who were not tested were stage I. For patients with stage III, 16/26 (61%) received adjuvant immunotherapy, none of adjuvant targeted therapy. At 35.1 months follow-up time, 27/96 (28%) localized cutaneous melanoma experienced relapse. 1-year DFS was 73% in adjuvant vs. 90% in no adjuvant immunotherapy group. Among 49 uveal melanoma patients, the median age was 27 years old. 23/49 (49%) had a T1 tumor, 18/49 (36.7%) T2, 6/49(12.2%) T3, 1/49(2%) T4. At 45 months follow-up time, three (6.1%) patients developed metastasis. 5-year DFS and OS was 90% and 100%, respectively. 45 patients had tissue for gene expression profiling and/or FISH testing. 15/45 (33%) had class IA, 13/45 (28%) had class IB, and 8/45 (17.7%) had class 2. 24 samples were analyzed by FISH: 14 with disomy 3, 5 with complex disomy 3 with gain of chromosome 6 or 8, and 5 with monosomy 3. Conclusions: Similarly to general population, most of younger patients with melanoma are diagnosed with stage I disease. Among patients with stage III melanoma treated with adjuvant immunotherapy 1-year DFS was comparable to the general population. Patients with stage III who did not receive adjuvant therapy had an excellent DFS which confirms that the decision on selecting patients for treatment was appropriate. The prognosis of younger patients with uveal melanoma was much better than predicted by molecular testing, and much better than expected regardless of gene expression profile or cytogenetic testing.

Gene expression profile signature (DecisionDx-Melanoma) to predict visceral metastatic risk in patients with stage I and stage II cutaneous melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8543-8543 ◽  
Author(s):  
Navneet Dhillon ◽  
Anna R Rogers ◽  
Keith A. Delman ◽  
Derek Maetzold ◽  
Kristen M. Oelschlager ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cutaneous Melanoma ◽  
Stage I ◽  
Partition Tree ◽  
Tree Analysis ◽  
Risk Class ◽  
Class 1 ◽  
Visceral Metastases ◽  
Metastatic Risk

8543 Background: The current AJCC TNM staging system has poor specificity for predicting visceral metastatic risk in patients diagnosed with stage I or stage II cutaneous melanoma. We, therefore, developed a gene expression profile signature (GEP) following in silico investigation of previously published microarray analyses. Methods: 60 formalin fixed paraffin embedded primary cutaneous melanoma samples from patients with stage I or II cutaneous melanoma with at least a follow up period of at least 6 years were macrodissected and analyzed blindly. RNA was isolated, converted to cDNA and RT-PCR was performed to assess the expression of the gene set. Expression data and biostatistical analysis was performed using GeNorm and JMP Genomics (SAS) Predictive modeling included Radial Basis Machine (RBM) and Partition Tree Analysis (PTA) Metastasis-free survival (MFS) was assessed using Kaplan-Meier analysis. The following clinical data was retrieved from medical records: survival, metastases, types of metastases. 20 out of 60 patients had developed visceral metastases in the follow up period. Results: GEP was developed following multiple analytical approaches.Two types of signatures emerged: Low risk (Class 1) and High risk (Class 2). Without optimizing for sensitivity, the analyses of the 60 sample cohort by radial basis machine (RBM) resulted in 92% ROC (met. accuracy = 90%, non-met. accuracy = 85%), while partition tree analysis (PTA) yielded 99% ROC (met. accuracy = 100%, non-met. accuracy = 95%). RBM classification showed 6-year MFS rates of 97% for Class 1 and 19% for predicted Class 2 of metastasis (median MFS = NR and 5.6 yrs, resp., P<0.0001 Log-Rank respectively). PTA showed 6-year MFS rates of 100% for predicted Class 1 and 14% for Class 2 of metastasis (median MFS = NR and 5.4 yrs, resp., P<0.0001 Log-Rank respectively). Conclusions: This study shows that DecisionDx-Melanoma GEP signature can provide excellent accuracy in predicting metastatic risk in stage I and II cutaneous melanoma.To our knowledge, the GEP provides the most accurate predictor to date for development of visceral metastases in patients with Stage I and II cutaneous melanoma.

scholarly journals Long-Term Outcomes in a Multicenter, Prospective Cohort Evaluating the Prognostic 31-Gene Expression Profile for Cutaneous Melanoma

2021 ◽  
pp. 589-601
Author(s):  
Eddy C. Hsueh ◽  
James R. DeBloom ◽  
Jonathan H. Lee ◽  
Jeffrey J. Sussman ◽  
Kyle R. Covington ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Distant Metastasis ◽  
Cutaneous Melanoma ◽  
Stage I ◽  
Free Survival ◽  
Metastatic Risk ◽  
Ajcc Staging

PURPOSE Current guidelines for postoperative management of patients with stage I-IIA cutaneous melanoma (CM) do not recommend routine cross-sectional imaging, yet many of these patients develop metastases. Methods that complement American Joint Committee on Cancer (AJCC) staging are needed to improve identification and treatment of these patients. A 31-gene expression profile (31-GEP) test predicts metastatic risk as low (class 1) or high (class 2). Prospective analysis of CM outcomes was performed to test the hypotheses that the 31-GEP provides prognostic value for patients with stage I-III CM, and that patients with stage I-IIA melanoma and class 2 31-GEP results have metastatic risk similar to patients for whom surveillance is recommended. MATERIALS AND METHODS Two multicenter registry studies, INTEGRATE (ClinicalTrials.gov identifier: NCT02355574 ) and EXPAND (ClinicalTrials.gov identifier: NCT02355587 ), were initiated under institutional review board approval, and 323 patients with stage I-III CM and median follow-up time of 3.2 years met inclusion criteria. Primary end points were 3-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). RESULTS The 31-GEP was significant for RFS, DMFS, and OS in a univariate analysis and was a significant, independent predictor of RFS, DMFS, and OS in a multivariable analysis. GEP class 2 results were significantly associated with lower 3-year RFS, DMFS, and OS in all patients and those with stage I-IIA disease. Patients with stage I-IIA CM and a class 2 result had recurrence, distant metastasis, and death rates similar to patients with stage IIB-III CM. Combining 31-GEP results and AJCC staging enhanced sensitivity over each approach alone. CONCLUSION These data provide a rationale for using the 31-GEP along with AJCC staging, and suggest that patients with stage I-IIA CM and a class 2 31-GEP signature may be candidates for more intense follow-up.

Single Ventricle Palliation in a Developing Sub-Saharan African Country: What Should be Improved?

2019 ◽  
Vol 10 (2) ◽  
pp. 164-170 ◽  
Author(s):  
Valdano Manuel ◽  
Humberto Morais ◽  
Aida L. R. Turquetto ◽  
Gade Miguel ◽  
Leonardo A. Miana ◽  
...  
Keyword(s):  
Confidence Interval ◽  
African Country ◽  
Single Ventricle ◽  
Hazard Ratio ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Lost To Follow Up ◽  
Single Ventricle Palliation

Introduction: Single ventricle physiology management is challenging, especially in low-income countries. Objective: To report the palliation outcomes of single ventricle patients in a developing African country. Methods: We retrospectively studied 83 consecutive patients subjected to single ventricle palliation in a single center between March 2011 and December 2017. Preoperative data, surgical factors, postoperative results, and survival outcomes were analyzed. The patients were divided by palliation stage: I (pulmonary artery banding [PAB] or Blalock–Taussig shunt [BTS]), II (Glenn procedure), or III (Fontan procedure). Results: Of the 83 patients who underwent palliation (stages I-III), 38 deaths were observed (31 after stage I, six after stage II, and one after stage III) for an overall mortality of 45.7%. The main causes of operative mortality were multiple organ dysfunction due to sepsis, shunt occlusion, and cardiogenic shock. Twenty-eight survivors were lost to follow-up (22 after stage I, six after stage II). Thirteen stage II survivors are still waiting for stage III. The mean follow-up was 366 ± 369 days. Five-year survival was 28.4 % for PAB and 30.1% for BTS, while that for stage II and III was 49.8% and 57.1%, respectively. Age (hazard ratio, 0.61; 95% confidence interval: 0.47-0.7; P = .000) and weight at surgery (hazard ratio, 0.45; 95% confidence interval: 0.31-0.64; P = .002) impacted survival. Conclusion: A high-mortality rate was observed in this initial experience, mainly in stage I patients. A large number of patients were lost to follow-up. A task force to improve outcomes is urgently required.

Primary Dermal Melanoma (PDM): Histological and Clinical Interdependence to Guide Therapy

2020 ◽  
pp. 120347542095763
Author(s):  
Hadas Zamir ◽  
Meora Feinmesser ◽  
Haim Gutman
Keyword(s):  
Mitotic Rate ◽  
Primary Treatment ◽  
Stage Iii ◽  
Sentinel Nodes ◽  
Time Period ◽  
Nodal Dissection ◽  
The Mean ◽  
Tight Correlation ◽  
Better Than

Background/purpose This study examined clinical and histological parameters of primary dermal melanoma (PDM) to aid in its distinction from dermal metastasis. Methods Retrospective analysis of a prospective cohort of PDM patients. Includes patients fulfilling the strict histologic criteria for PDM ( N = 9) and patients who did not, but clinically, unequivocally had an intradermal melanoma—clinical PDM (cPDM; N = 17). Histopathology slides were re-examined. Prognosticators and outcome measures were compared between groups. Sentinel nodes’ retrieval and wide local excision (WLE) were offered to all patients as primary treatment. Results 26 patients identified, 15 females with a median age of 69 years (range 3.5-85). Mean Breslow was 7.9 ± 5.7 mm (median 5.8, range 1.8-25.0), and the mean mitotic rate was 4.9 ± 3.8/mm2 (median 4.0, range 0-17). Initial treatment and follow-up were as for cutaneous melanoma. One patient in each group with a palpable stage III underwent primary radical dissection. Sentinel nodes were retrieved in all 20 lymphatic mappings performed and found to be metastatic in 5 (25%) patients. Treatment consisted of completion lymph-node dissection. At a median postoperative follow-up of 62 months (range 8-132), 20 patients were disease-free, including 6 of 7 patients with stage III disease at presentation. Six patients died all of cPDM; 5 of 6 patients had primary ulcerated or epidermal-abutting melanomas. Conclusions This is the first study to highlight cPDM. Diagnosis requires expert pathology review and a tight correlation to the clinical parameters. Patients seem to benefit from WLE with sentinel node retrieval and complete dissection when appropriate. However, clinical guidelines for dissection have changed since the time period of this retrospective review. Based on this series, complete nodal dissection in these melanomas is associated with better than expected outcome, for stage III disease.

scholarly journals Prospective evaluation of risk-appropriate management of uveal melanoma patients informed by gene expression profiling

2020 ◽  
Vol 7 (1) ◽  
pp. 17-25 ◽  
Author(s):  
Amy C Schefler ◽  
Alison Skalet ◽  
Scott C N Oliver ◽  
John Mason ◽  
Anthony B Daniels ◽  
...  
Keyword(s):  
Gene Expression ◽  
Uveal Melanoma ◽  
Clinical Utility ◽  
Medical Oncology ◽  
Treatment Plan ◽  
Risk Class ◽  
Class 1 ◽  
Melanoma Patients ◽  
Metastatic Risk

Aim: The Clinical Application of DecisionDx-UM Gene Expression Assay Results study aimed to evaluate the clinical utility of the prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) patients in a large, prospective multicenter cohort. Patients & methods: Nine centers prospectively enrolled 138 UM patients clinically tested with the 15-GEP. Physician-recommended specialty referrals and metastatic surveillance regimens were collected. Results: A total of 93% of high-risk class 2 patients were referred to medical oncology for follow-up, compared with 51% of class 1 patients. A majority (62%) of class 2 patients were recommended overall high-intensity metastatic surveillance, while 85% of class 1 patients were recommended low-intensity metastatic surveillance. Conclusion: Treatment plan recommendations for UM patients are aligned with GEP-informed metastatic risk, consistent with prior studies.

Combination cisplatin, vinblastine, and bleomycin chemotherapy (PVB) for malignant germ-cell tumors of the ovary.

1983 ◽  
Vol 1 (10) ◽  
pp. 645-651 ◽  
Author(s):  
R W Carlson ◽  
B I Sikic ◽  
M M Turbow ◽  
S C Ballon
Keyword(s):  
Germ Cell ◽  
Recurrent Disease ◽  
Germ Cell Tumors ◽  
Stage I ◽  
Stage Iii ◽  
Treatment Toxicity ◽  
Malignant Germ Cell Tumors ◽  
Mixed Germ Cell Tumors

Nine women with germ-cell tumors of the ovary (three endodermal sinus tumors, four immature teratomas, and two mixed germ-cell tumors) were treated with cisplatin, vinblastine, and bleomycin (PVB) chemotherapy after cytoreductive operations. Five patients were stage I, three were stage III, and one patient had recurrent disease. All nine women are alive and without evidence of disease with a median follow-up of 31 months from diagnosis and 27 months since completion of PVB. Treatment toxicity although occasionally severe was rapidly reversible.

scholarly journals Immunoexpression of Macroh2a in Uveal Melanoma

2019 ◽  
Vol 9 (16) ◽  
pp. 3244 ◽  
Author(s):  
Salvatorelli ◽  
Puzzo ◽  
Bartoloni ◽  
Palmucci ◽  
Longo ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Cutaneous Melanoma ◽  
High Expression ◽  
Melanoma Metastasis ◽  
Proper Treatment ◽  
Immunohistochemical Expression ◽  
Prognostic Role

MacroH2A is a histone variant whose expression has been studied in several neoplasms, including cutaneous melanomas (CMs). In the literature, it has been demonstrated that macroH2A.1 levels gradually decrease during CM progression, and a high expression of macroH2A.1 in CM cells relates to a better prognosis. Although both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma (UM) is biologically and genetically distinct from the more common cutaneous melanoma. Metastasis to the liver is a frequent occurrence in UM, and about 40%–50% of patients die of metastatic disease, even with early diagnosis, proper treatment, and close follow-up. We wanted to investigate macroH2A.1 immunohistochemical expression in UM. Our results demonstrated that mH2A.1 expression was higher in metastatic UM (21/23, 91.4%), while only 18/32 (56.3%). UMs without metastases showed mH2A.1 staining. These data could suggest a possible prognostic role for mH2A.1 and could form a basis for developing new pharmacological strategies for UM treatment.

QIM19-124: Does Virtual Navigation Improve Care Continuity and Compliance in Patients With Early Stage Colon Cancer?

2019 ◽  
Vol 17 (3.5) ◽  
pp. QIM19-124
Author(s):  
Dayna Crawford ◽  
Brook Blackmore ◽  
Jeremy Ortega ◽  
Erica Williams
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Early Stage ◽  
Stage I ◽  
Stage Iii ◽  
Nccn Guidelines ◽  
Care Continuity ◽  
Colon Cancers ◽  
Follow Up Care

Background: Colon cancer is the 3rd most common cancer in men and women combined, with an occurrence rate of 4.49% for men and 4.15% for women. The 2018 expectation is 50,630 deaths related to colon cancer in the United States (American Cancer Society Facts and Figures 2018). Early detection is increasing with nearly 45% of colon cancers diagnosed as stage I/II (Sarah Cannon Cancer Registry 2015). Treatment for early stage I/II colon cancer patients usually involves surgery then surveillance. On-site navigators perform their duties by patient need and barriers to care. Late stage III/IV colon cancer patients require more assistance and face more barriers, which often leaves early stage I/II patients without an advocate. This disparity can lead to lower rates of follow-up care for early stage I/II patients. Sarah Cannon created a program for virtual colon navigation (VCN) to determine if early stage I/II patients benefit from a virtual navigator who offers support by phone throughout their disease process. Objectives: The goal was to increase early stage I/II patients’ knowledge of their cancer and convey the importance of compliance with follow-up care, such as repeat colonoscopy as recommended by their physician and NCCN Guidelines. Methods: By developing software that utilizes artificial intelligence, Sarah Cannon created an automated process to identify colon cancer patients at the time of diagnosis. This technology then routes positive pathology reports to a VCN who contacts the early stage I/II patients by telephone, ensuring patient connection to the suitable physician for treatment. The VCN helps patients understand their diagnosis, provides education, assesses barriers to care, connects to resources, provides emotional support, and offers assistance with follow-up for physician visits, imaging and procedures such as colonoscopies, based upon NCCN Guidelines and physician guidelines. The VCN also connects stage III/IV patients with an on-site navigator in their region for more hands-on navigation. Results: Through September 2018, Sarah Cannon navigated 734 colon cancers, 332 stage I/II and 402 stage III/IV. With our increased capacity, Sarah Cannon/HCA maintained a 98% rate of follow-up care with new diagnoses of all stages of colon cancer. Conclusions: The VCN program allowed Sarah Cannon/HCA to improve care continuity and compliance based upon NCCN Guidelines for early stage I/II colon cancer patients throughout 5 regions and 37 facilities.

Outcomes of Nodular Lymphocyte Predominant Hodgkin's Lymphoma (NLPHL) Patients Treated with R-CHOP.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2812-2812 ◽  
Author(s):  
Michelle A. Fanale ◽  
Chao-Ming Lai ◽  
Peter McLaughlin ◽  
Jorge Romaguera ◽  
Luis Fayad ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Stage I ◽  
Hodgkin's Lymphoma ◽  
Stage Iii ◽  
Field Radiation

Abstract Abstract 2812 Introduction: Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) constitutes 5% of Hodgkin's lymphoma (HL) diagnoses. Recently gene expression profiling has shown significant overlap between NLPHL, T-cell-rich B cell lymphoma (TCRBCL), and classical HL (Brune, V et al, J Exp Med, 2008). NLPHL patients also have an approximate 7% risk of transformation at 10 years to diffuse large B-cell lymphoma (DLBCL) and TCRBCL (Al-Mansour, M et al, JCO, 2010). Data from multiple groups (Nogova, L et al, Ann Onc, 2005, Chen, RC et al, JCO, 2010, Wirth, A et al, Cancer, 2005) support extended progression-free survivals (PFS) for stage IA/IIA patients treated with radiation alone. While chemotherapy is generally recommended for patients with stage IB/IIB or III/IV disease, there is lack of guidelines on whether classical HL-directed regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), or B-cell lymphoma-directed regimens, such as R-CHOP (rituximab, cychlophosphamide, doxorubicin, vincristine, prednisone) should be used. Given the similarities between NLPHL and indolent CD20+ B-cell non-Hodgkin's lymphoma (NHL), our group started using the R-CHOP regimen for patients with NLPHL requiring systemic therapy. In order to examine the potential efficacy of this approach, we conducted a retrospective analysis of treatment outcomes in patients who received R-CHOP versus other regimens treated at UT MDACC from 1995 to 2010. Results: 83 patients were referred. 6 patients were found to have NLPHL with transformation to DLBCL or TCRBCL. 3 had alternative diagnoses. 11 lacked full immunophenotyping to confirm diagnosis. 63 patients had confirmed diagnoses of NLPHL (39 stage I/II and 24 stage III/IV). 52 NLPHL patients were evaluable (10 did not complete full treatment planning or were lost to follow-up and 1 is currently completing therapy). 7 patients had extranodal disease (thyroid, breast, lung, liver, bone marrow/cortex) and 8 had spleen involvement. Overall their median age at diagnosis was 40, male:female ratio was 2.5, and median follow-up is 46 months (range 8–149 months). 6 patients had relapse of NLPHL, 2 patients had transformation at a median of 39 months (1 to DLBCL, 1 to TCRBCL), 4 patients died (1 from acute myelogenous leukemia with deletion 7, 1 from DLBCL, 2 from unrelated causes while in remission), and 2 patients underwent autologous stem cell transplant (1 for relapsed NLPHL in 3rd complete remission and 1 for transformation to TCRBCL). Therapies for stage I/II NLPHL included: surgical excision alone (2 patients with stage IA disease declined radiation treatment), subtotal nodal irradiation (STNI), mantle field radiation, involved field radiation (IFRT), rituximab (R) alone and plus IFRT, ABVD plus STNI, R-ABVD, COPP (cyclophosphamide, vincristine, procarbazine, prednisone) plus IFRT, and R-CHOP alone and plus IFRT. Therapies for stage III/IV included: mantle field radiation (1 patient who declined chemotherapy), NOVP (mitoxantrone, vincristine, vinblastine, prednisone) plus mantle field radiation, ABVD, R-ABVD, R-CHOP alone and plus IFRT. A total of 15 patients received R-CHOP alone (4 stage I/II, 11 stage III/IV) and 5 patients received R-CHOP plus IFRT (4 stage I/II, 1 stage III/IV). Response to R-CHOP as assessed by CT scan criteria was 100% overall response rate (ORR) with 90% complete remissions (CR). No R-CHOP patients have had relapses or transformation with a median follow-up of 42 months (range 8–111 months). One patient treated with R-CHOP died of unrelated causes while in remission. However, with other therapies 19% have relapsed after median remissions of 38 months (range 4 to 72 months). R-CHOP when compared to other treatments has a trend towards improved PFS (Figures 1, 2, and 3). Survival rates for NLPHL patients at 5 years with 95% confidence intervals are: R-CHOP: PFS 0.95 (0.86, 1), OS (overall survival) 0.95 (0.86, 1) and other therapies: PFS 0.71 (0.55, 0.92), OS 0.91 (0.8, 1). Conclusions: Our data demonstrates that RCHOP is an effective regimen for the treatment of patients with NLPHL. A prospective evaluation of R-CHOP as a front-line treatment of NLPHL is under consideration. Disclosures: Fanale: Seattle Genetics: Research Funding; Novartis: Honoraria, Research Funding; Millenium: Research Funding; Genentech: Research Funding. Off Label Use: Given the CD20 positivity of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) rituximab has been evaluated previously for relapsed NLPHL and was shown to be efficacious. Rituximab however is not FDA approved for NLPHL. This is a retrospective study that evaluates the use of R-CHOP and other therapies for NLPHL. Current NCCN guidelines support consideration of R-CHOP for NLPHL treatment, and given the rarity of the disease there is no one defined preferred chemotherapy regimen. This information will be disclosed to the audience. Fayad:Genentech: Research Funding. Rodriguez:Genentech: Research Funding. Shah:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Novartis: Research Funding. Younes:Genentech: Honoraria, Research Funding; SBIO: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding.

Enhanced ETS-like Gene (ELK)-1 Expression Is a Predictor of Inferior Survival in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5670-5670
Author(s):  
Muhamed Baljevic ◽  
Baladandayuthapani Veerabhadran ◽  
Lin Heather ◽  
Leung Cheuk ◽  
Zhong Liye ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Overall Survival ◽  
Transcription Factor ◽  
Survival Curve ◽  
Proteasome Inhibitors ◽  
Stage I ◽  
Stage Iii ◽  
First Line ◽  
Overall Survival Curve

Abstract Background: We have previously reported on the putative role of c-MET/ERK-1/2/ELK1/Proteassemblin (POMP) signaling axis in enhancing proteasome assembly and capacity, which in multiple myeloma (MM) treatment may reduce sensitivity to proteasome inhibitors (PIs) such ascarfilzomib orbortezomib [ASH 2014 MeetingAbstr. 274]. The transcription factor ELK1 was found to regulate POMP expression andcarfilzomib resistance via binding to transcription initiation sites of the POMP gene promoter containing two ELK-1 consensus binding sites. Analysis of the Millennium Pharmaceuticals gene expression profile (GEP) database of patients treated withbortezomib in the relapsed and relapsed/refractory settings showed that patients who had higher expression of MUC20 had superior overall survival (OS) and progression free survival (PFS) compared to those who had lower expression. However, similar outcome was not assessed for other downstream members of this signaling cascade, including the transcription factor ELK1. Methods: We performed statistical analysis on patient and GEP data bases downloaded from the Multiple Myeloma Research Foundation Researcher Gateway website (http://research.themmrf.org),with the objective ofassessing the effects of ELK1 gene expression (gene probe ENSG00000126767) on the OS and PFSin453 patients who had data available on both demographic and clinical characteristics, as well as GEP collected during their first-line therapy.Patients were characterized by clinical variables including age, gender, race, ethnicity, therapy received and international staging system (ISS).ELK1 gene expression was dichotomized into two groups:greater than or equal to median, or less than median expression of the ELK1 gene. The distributions of OS and PFS were estimated by the Kaplan-Meier method. Results: The median patient age was 64 years (range, 27- 93), and 60% of them were male. Of 453 patients, 350 (77%) were Caucasian, 75 (17%) African-American and 11 (2%) Asian. 420 (93%) were receiving first line of therapy, while 27 (6%) and 4 (1%) were receiving second or third line therapies, respectively. Two hundred and thirty nine (53%) patients received combinedbortezomib/immunomodulatory (IMiD) based therapy, 142 (31%) receivedbortezomib-based, and a further 33 (7%) receivedIMiD-based therapy alone, while 24 (5%) patients received combinedcarfilzomib/IMiD based therapy. One hundred and forty seven (33%) patients were ISS stage I,162 (37%) stage II, and 133 (30%) stage III. There were 39 deaths, of which 19 (49%) were due to disease progression. Patents who were greater than or equal to 64 years old had inferior OS compared to those less than 64 years of age (p=0.0266), patients who had ISS stage I or II had superior OS compared to those with stage III (p=0.00983), and after adjusting for stage III, patients who had less than median ELK1 gene expression had superior OS compared to those with greater than or equal to median ELK1 gene expression (Figure 1., p=0.00309). PFS was not affected. Conclusions: Our data continue to support a role for signaling through the c-MET/ERK-1/2/ELK1/POMP axis in enhancing proteasome assembly and capacity, thereby reducing sensitivity to proteasome inhibitors likecarfilzomib orbortezomib in MM. As such, the use of drugs suppressing c-MET signaling in early phase trial design, particularly in combination with other PIs, remains a potentially attractive strategy to overcome resistance to PIs in the clinic. Figure 1 The overall survival curve for the patients who had less than median ELK1 gene expression and greater than or equal to median ELK1 gene expression. Figure 1. The overall survival curve for the patients who had less than median ELK1 gene expression and greater than or equal to median ELK1 gene expression. Disclosures No relevant conflicts of interest to declare.

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