TMPRSS-ERG fusion in men with prostate cancer (PCa) and non-prostate malignancies: Defining a role for comprehensive genomic profiling (CGP) to guide clinical care.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5037-5037 ◽  
Author(s):  
Primo Lara ◽  
Andreas Heilmann ◽  
Julia Andrea Elvin ◽  
Ralph deVere White ◽  
Regina Gandour-Edwards ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling

scholarly journals A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

2016 ◽  
Vol 9 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Siraj M. Ali ◽  
Jessica Watson ◽  
Kai Wang ◽  
Jon H. Chung ◽  
Caitlin McMahon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hospice Care ◽  
Treatment Initiation ◽  
Clinical Care ◽  
Metastatic Breast ◽  
Genomic Profiling ◽  
Treatment Resistant ◽  
Bcl2 Family ◽  
Comprehensive Genomic Profiling

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

scholarly journals Exceptional Response to Everolimus in a Patient with Metastatic Castrate-Resistant Prostate Cancer Harboring a PTEN Inactivating Mutation

2020 ◽  
Vol 13 (1) ◽  
pp. 456-461 ◽  
Author(s):  
Jamie A. Kmak ◽  
Nikita Agarwal ◽  
Yuting He ◽  
Andreas M. Heilmann ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Early Detection ◽  
Stable Disease ◽  
Medical Intervention ◽  
Genomic Profiling ◽  
Heavily Pretreated ◽  
Comprehensive Genomic Profiling ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Inactivating Mutation

Prostate cancer is among the most common types of cancer in men. Early detection and proper medical intervention is crucial to ensuring successful treatment. Here we describe a patient clinically presenting with castrate-resistant prostate carcinoma. Comprehensive genomic profiling identified a PTEN inactivating mutation in the patient’s tumor. After being heavily pretreated, the patient showed stable disease on everolimus, a PI3K-Akt-mTOR pathway inhibitor.

scholarly journals Identifying Opportunities and Challenges for Patients With Sarcoma as a Result of Comprehensive Genomic Profiling of Sarcoma Specimens

2020 ◽  
pp. 176-182 ◽  
Author(s):  
Margaret A. Hay ◽  
Eric A. Severson ◽  
Vincent A. Miller ◽  
David A. Liebner ◽  
Jo-Anne Vergilio ◽  
...  
Keyword(s):  
Decision Making ◽  
Bone Biopsy ◽  
Clinical Care ◽  
Soft Tissue Sarcomas ◽  
Treatment Decision ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Treatment Selection ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling

PURPOSE Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP. METHODS A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure. RESULTS CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; P = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival. CONCLUSION To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.

Comprehensive genomic profiling of renal cell carcinoma with sarcomatoid dedifferentiation to pinpoint recurrent genomic alterations.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 537-537
Author(s):  
Gabriel G. Malouf ◽  
Siraj Mahamed Ali ◽  
Kai Wang ◽  
Sohail Balasubramanian ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Genomic Features ◽  
Routine Clinical Care ◽  
Comprehensive Genomic Profiling ◽  
Worse Prognosis

537 Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is found in five percent of all renal cell carcinoma (RCC) cases, and has a significantly worse prognosis relative to matched highgrade RCC with only epithelial elements. The genomic features underpinning sRCC are not well understood, and at present, there are no specific or effective therapies for sRCC. Methods: We conducted comprehensive genomic profiling (CGP) on paired epithelial and sarcomatoid areas of 3 sRCC cases. In the course of routine clinical care, CGP was performed on another 23 sRCC harboring diverse epithelial components. CGP was conducted using a hybrid capture next generation DNA sequencing assay(NGS) of 236 cancer-related genes plus 19 genes frequently rearranged in cancer. Results were compared with 56 similarly sequenced cases of clear cell RCC devoid of sarcomatoid component, and with clear cell TCGA. Results: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations. Conclusions: Two of three sRCC cases that underwent CGP of both their epithelial and the sarcomatoid components demonstrated identical mutational profiles, and a third case demonstrated commonly disrupted genes. Of the 23 sRCC, TP53(43%), CDKN2A(30%), VHL(26%) and NF2(22%) were the most frequently altered genes. NF2 mutations were mutually exclusive with TP53 but not with VHL mutations.

Comprehensive genomic profiling of advanced colorectal carcinoma in the course of clinical care to identify KRAS insertions not detected by focused molecular testing.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 497-497
Author(s):  
Andrew Rankin ◽  
Alexa Betzig Schrock ◽  
Julia Andrea Elvin ◽  
Juliann Chmielecki ◽  
Rachel Erlich ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
De Novo ◽  
Clinical Care ◽  
Molecular Testing ◽  
Large Set ◽  
Genomic Profiling ◽  
Kras Mutations ◽  
Exon 2 ◽  
Nccn Guidelines ◽  
Comprehensive Genomic Profiling

497 Background: As activating RAS mutations have been shown to predict lack of benefit from anti-EGFR therapies in advanced CRC, NCCN guidelines recommend testing for KRAS exon 2 and non-exon 2 mutations; however, these alterations are thought to explain only a subset of de novo resistance to targeted therapy. In a large set of CRC assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we assessed the frequency of less common KRAS short insertions that may predict failure of anti-EGFR therapy. Methods: 4,422 CRC cases were assayed with CGP performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 650X for at least 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. All classes of genomic alterations (GA) were identified, including base pair substitutions, insertions/deletions, copy number alterations, and rearrangements. Pertinent available prior molecular testing results and clinical history was reviewed for selected cases. Results: Out of 4,422 CRC cases analyzed, KRAS short variants were identified in 50.9% of cases. A majority of cases contained a KRAS alteration at either codon G12 (35.5%) or G13 (9.1%), while alterations at codons Q61 or A146 were identified in 2.2% and 3.1% of cases, respectively. KRAS insertions were identified in 8 ( < 0.5%) cases. All KRAS insertions identified fell within codons 9-13, and 6/8 cases harbored V9_G10 insertions. Out of 6 patients with prior KRAS testing results available, 5 (83%) were negative by previous testing. Conclusions: CGP identifies KRAS insertions within or adjacent to hotspot regions in CRC cases which have previously tested negative for KRAS mutations. Given the importance of KRAS alterations in predicting lack of response to anti-EGFR therapies in CRC, accurate detection of these alterations in the course of clinical care is essential for effective treatment. CGP offers the possibility of identifying KRAS insertions that may impact efficacy of anti-EGFR targeted therapy and should be considered when previous focused testing for KRAS mutations is negative.

Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8517-8517 ◽  
Author(s):  
Young Kwang Chae ◽  
Keerthi Tamragouri ◽  
Jon Chung ◽  
Alexa Betzig Schrock ◽  
Bhaskar Kolla ◽  
...  
Keyword(s):  
Small Cell Lung Carcinoma ◽  
Clinical Care ◽  
Large Cell ◽  
Smoking History ◽  
Genomic Profiling ◽  
Wild Type ◽  
Cell Lung Carcinoma ◽  
Mutational Burden ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

8517 Background: SCLC and L-LCNEC are aggressive neoplasms that are both associated with smoking history and are thought to overlap in clinical, histogenetic, and genomic features. We reviewed the genomic profiles of >1187 patients to assess the genomic similarities of these diseases. Methods: Comprehensive genomic profiling (CGP) of tumors from 300 L-LCNEC and 887 SCLC patients in the course of clinical care was performed to suggest pathways to benefit from therapy. Results: Commonly altered genes in both diseases included TP53, RB1, MYC/MYCL1, MLL2, LRP1B and PTEN; alterations in other genes occurred at somewhat differing frequencies (table). For both diseases, RB1 mutation significantly co-occurred with TP53 mutations (p<0.001), but occurred in a mutually exclusive fashion to STK11 and CDKN2A (p<0.001). RB1 was mutually exclusive with KRAS for L-LCNEC but not for SCLC. The interquartile range for SCLC and L-LCNEC TMB is 7.9 and 12.6 with the 75% quartile being 14.4 and 17.1 respectively. Cases of both diseases will be presented with radiographic response to genomically matched targeted therapy and immunotherapy, particularly in cases of high TMB. Conclusions: Given the similar overall genomic profiles and clinical behavior of a subset of these diseases, they could be conceived of as a single disease to be further classified by genomically defined classes such as SCLC-type ( TP53/ RB1mutated) and NSCLC-like (wild type for one or both). By analogy to NSLC and melanoma, benefit from immunotherapy appears most likely for only the upper quartile of cases in TMB. [Table: see text]

Efficacy of systemic treatment for metastatic renal cell carcinoma (mRCC) guided by comprehensive genomic profiling (CGP).

2019 ◽  
Vol 37 (27_suppl) ◽  
pp. 63-63
Author(s):  
Paulo Gustavo Bergerot ◽  
Cristiane Decat Bergerot ◽  
Nazli Dizman ◽  
Nicholas Salgia ◽  
Joann Hsu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clinical Care ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling

63 Background: Comprehensive genomic profiling (CGP) has been used to guide treatment selection in metastatic renal cell carcinoma (mRCC). This study sought to determine if genomic alterations guided treatment and contributed to improved outcomes. Methods: From a single institution, patients (pts) diagnosed with mRCC who had CGP in the course of clinical care were identified. Pts were tested on a CLIAA-certified platform (FoundationOne; Cambridge, MA). Pts who died/initiated hospice within the 30 days after the test was performed or who were lost to follow-up were excluded. Duration of therapy (DOT) was measured as months between first and last day of therapy following CGP test. The Kaplan-Meier method was undertaken to estimate the association of CGP-directed therapy with overall survival (OS). Cox regression was also performed and adjusted for histologic subgroup. Results: A total of 64 patients underwent CGP between February 2014 and August 2018. From this group, 15 patients were excluded due to death/hospice within 30 d (n = 10) and lack of follow-up (n = 5). Median age at diagnosis was 60 years (range, 24-84), and 79% were male. Most patients (69%) were diagnosed with clear cell RCC. The median identified genomic alterations (GAs) was 3 (range, 0-7). The most common GAs were VHL (54%), PBRM1 (28%), TERT (21%), TP53 (15%), BAP1 (13%), and SETD2 (13%). Of the 49 patients included in this analysis, 47% had actionable mutations based on their CGP results. Of those, 13 patients received directed-therapy of whom 57% had stable disease, 28% had partial response, and 14% had progressive disease. The median time from CGP test to treatment was 1 month (range, 0-17). The median duration of directed-therapy was 12 months (range, 1-28) and of non-directed therapy was 4 months (range, 1-40) (P = 0.04). Directed-therapy was significantly associated with better OS (adjusted HR, 0.32 [95% CI, 0.13 to 0.82]; P = 0.018) compared to non-directed therapy. Conclusions: This study provides preliminary evidence to justify CGP-guided therapy in mRCC. Forthcoming studies should prospectively explore the use of CGP in treatment allocation for mRCC to validate these findings.

Cyclin pathway genomic alterations across 5,356 prostate cancers.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 179-179
Author(s):  
Denis Leonardo Fontes Jardim ◽  
Sherri Z. Millis ◽  
Michele Sue-Ann Woo ◽  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Resistance Pathway ◽  
Lower Likelihood ◽  
Ccnd1 Amplification ◽  
Comprehensive Genomic Profiling ◽  
Prostate Cancers ◽  
Copy Number Changes ◽  
Generation Sequencing

179 Background: The cyclin pathway is comprised of possible targetable alterations as well as resistant alterations that affect treatment, including hormonal agents. We describe the landscape of cyclin genomic alterations in prostate cancer. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation sequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition) and androgen receptor ( AR). Results: Alterations in any cyclin pathway genes were found in 9.7% of the 5,356 tumors analyzed. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Frequencies were substantially different according to prostate cancer histology (Table). The majority of alterations were copy number changes. Alterations in possible resistance genes, RB1 and CCNE1 were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, while AR alterations were seen in 20.9% (up to 27.3% in anaplastic). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alterations in cyclin activating and resistance pathway (odds ratio (OR), 0.44, p<0.001). Conversely, we detected a higher likelihood of co-occurrence between AR and cyclin alterations (OR 1.79, p<0.001). Conclusions: Cyclin pathway genomic abnormalities were observed in about 10% of prostate cancer tumors, and are more frequently associated with concomitant AR alterations and absence of co-alterations associated with resistance to cyclin inhibition.[Table: see text]

Integrating comprehensive genomic profiling into the clinical management of prostate cancer patients: A single institution community practice experience.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 281-281
Author(s):  
Neal D. Shore ◽  
James Haberberger ◽  
Eric Allan Severson ◽  
Brian Michael Alexander ◽  
Pratheesh Sathyan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Liquid Biopsy ◽  
Clinical Management ◽  
Additional Patient ◽  
Genomic Profiling ◽  
Data Set ◽  
Tissue Samples ◽  
Comprehensive Genomic Profiling ◽  
Germline Testing

281 Background: Prostate cancer is a leading cause of cancer-related mortality with a 5-year survival rate of 69%. In this study, we examine the role of integrating CGP, including tissue and liquid biopsy testing, into the clinical management of prostate cancer patients. Methods: We analyzed 140 cases of advanced prostate carcinoma with tissue and ctDNA based Comprehensive Genomic Profiling (CGP). CGP analysis revealed genomic alterations (GAs), TMB and MSI status. Germline testing, using multiple commercially assays was also obtained. Results: The median age of patients tested by tissue-based and liquid-based CGP was 65 years (46 to 85 yrs) and 69 years (51 to > 89 years), respectively. CGP analysis of tissue samples revealed the most commonly altered genes to be TP53 (34.6%), TMPRSS2- ERG (25.9%), PTEN (23.5%), NBN (14.8%), MYC (13.6%), BRCA2 (14.3%) and CDKN2A (13.3%). TMB analysis determined in 77 tissue samples showed a median (mean) value of 2.61 (5.00) mutations/Mb. 3.9% cases (3/77) were found to be hypermutated. MSI status was determined in 74 cases of which 2.7% (2/74) were found to be MSI-High. Of the tissue-based samples tested, 30.9% (25/81) were derived from metastatic sites. Analysis of commonly altered genes between primary vs metastatic tissue samples revealed TP53 mutations were significantly enriched in metastatic tumors. CGP analysis of the 59 liquid biopsy samples revealed the most commonly altered genes to be TP53 (37.3%), NF1 (10.2%), ATM (10.2%), CHEK2 (8.5%) and GNAS (8.5%). Germline testing was performed as described above on a clinically indicated subset of patients, which revealed alterations in BRCA, ATM, CHEK2, BRIP1 and TP53, among others. We are evaluating additional patient samples as part of the data set, which will be added to the final abstract presentation with a cutoff date of 12-31-2019. Conclusions: Genomic testing for high risk and advanced prostate cancer patients per the NCCN recommendations, with somatic testing, using tissue and liquid biopsy testing, as well as germline testing in selected cases, identifies DNA alterations which have potential clinical utility for clinical trial enrollment.

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