Comprehensive multiplatform biomarker analysis of 206 squamous cell anal cancers.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 603-603
Author(s):  
Patrick McKay Boland ◽  
Sherri Z. Millis ◽  
David Arguello ◽  
Zoran Gatalica ◽  
Sandeep K. Reddy ◽  
...  
Keyword(s):  
Protein Expression ◽  
Squamous Cell ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Gene Mutations ◽  
Therapeutic Options ◽  
Driver Mutations ◽  
Viral Origin ◽  
Anal Squamous Cell Carcinoma ◽  
Biomarker Analysis

603 Background: Anal squamous cell carcinoma (Anal SCC) is a rare, HPV-associated malignancy accounting for 2.4% of digestive system cancers. In most cases, these malignancies are detected in the early stages and successfully managed with chemoradiation therapy. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimen. Once beyond standard therapy, few therapeutic options exist for those patients with aggressive disease. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 206 anal SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). 6 cases were documented as positive for HPV or HIV; status was not provided on the remaining 200. Results: Key results are shown in the table below, shown as percent change/total cases. Conclusions: Multiplatform tumor profiling identified a low incidence of gene mutations. Protein expression aberrations identified potential treatment options not routinely considered, such as topoisomerase inhibitors and taxanes. Mutations in PIK3CA, Akt1, and FBXW7 as well as PTEN loss indicate potential for targeting the PI3 kinase pathway. Additionally, immunomodulatory agents may be a therapeutic option, based on PD-1 expression levels. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER - inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. It should be mentioned that differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. [Table: see text]

Genomic features of primary and recurrent anal squamous cell carcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 556-556
Author(s):  
Jonathan W Pike ◽  
Kent William Mouw ◽  
Lior Zvi Braunstein ◽  
Neil E. Martin ◽  
Harvey J. Mamon ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mutation Rate ◽  
Squamous Cell ◽  
Locally Advanced ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Anal Squamous Cell Carcinoma ◽  
Recurrent Tumors ◽  
Recurrent Mutations

556 Background: Approximately 7000 cases of anal squamous cell carcinoma (ASCC) are diagnosed annually in the US, and the incidence is increasing. Combination chemoradiotherapy (CRT) is the standard of care for locally-advanced ASCC, and the 5-year survival rate is approximately 70%. Unlike many other tumor types, no large-scale genomic studies have been reported for anal cancer. In order to characterize the mutational landscape of ASCC and identify potential therapeutic targets, we perform comprehensive genomic analysis of a pilot cohort of ASCC cases. Methods: We performed whole exome sequencing of tumor and matched germline DNA from a pilot cohort of twelve patients with locally advanced (Stage II-IVA) ASCC cases treated at Dana-Farber Cancer Institute. All patients received concurrent chemoradiotherapy (CRT): seven ‘responders’ had complete response and no evidence of recurrence with a minimum of one year follow-up, while five ‘non-responders’ had residual or recurrent disease following CRT. For non-responders, both primary and residual/recurrent tumors were analyzed. Results: The overall mutation rate was 3.7 mutations per megabase (Mb). Recurrent mutations in several known cancer genes were observed. Five of twelve cases had a hotspot mutation in FBXW7, including 3 of the 5 non-responders. Known oncogenic mutations were also observed in PIK3CA (3 tumors) and NFE2L2/KEAP1 (3 tumors). Analysis of paired primary and recurrent samples revealed surprising examples of distinct driver mutations in clonally-related tumors. Copy number analysis revealed focal amplifications of chromosome 3q. Conclusions: This study represents one of the first genome-scale analyses in ASCC. The overall mutation rate was similar to other HPV-associated squamous cell carcinomas, and recurrent mutations in several known cancer genes were observed. Analysis of paired primary and residual/recurrent tumors revealed surprising heterogeneity. To extend our findings, we are currently performing a similar analysis in a larger extension cohort of ASCC tumors.

Pembrolizumab for advanced anal squamous cell carcinoma (ASCC): Results from the multicohort, phase II KEYNOTE-158 study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 1-1 ◽  
Author(s):  
Aurelien Marabelle ◽  
Philippe Alexandre Cassier ◽  
Marwan Fakih ◽  
Tormod Kyrre Guren ◽  
Antoine Italiano ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tissue Sample ◽  
Treatment Options ◽  
Open Label ◽  
Anal Squamous Cell Carcinoma ◽  
First Line Therapy ◽  
Biomarker Analysis ◽  
Open Label Phase ◽  
Heavily Pretreated ◽  
Ecog Ps

1 Background: For patients (pts) with ASCC, second-line or later treatment options have been limited. Pembrolizumab (pembro), an anti-PD-1 monoclonal antibody, has demonstrated antitumor activity in several tumor types (including ASCC) in the multicohort phase 1b KEYNOTE-028 study. KEYNOTE-158 (NCT02628067) is an open-label, phase 2, multicohort study that evaluates antitumor activity and safety of pembro in pts with previously treated advanced cancer. Results from the ASCC cohort are presented. Methods: Eligible pts were ≥18 y with histologically/cytologically documented metastatic and/or unresectable ASCC with prior treatment failure on or intolerance to standard first-line therapy, measurable disease per RECIST v1.1, ECOG PS of ≤1, and evaluable tissue sample for PD-L1 and biomarker analysis. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Pts received pembro 200 mg Q3W until disease progression, unacceptable AE, or completion of 35 cycles. The primary endpoint was ORR per RECIST v1.1 (assessed every 9 wk for 12 mo, then every 12 wk thereafter) by independent central review. Secondary endpoints were DOR, OS, PFS and safety. Results: 112 pts with ASCC were enrolled (81.3% women; median age, 61 y [range 32–79]; ≥2 prior therapies, 73.2%). At database cutoff (Dec 6, 2018) 10 pts (8.9%) had completed 35 cycles and 102 discontinued; median follow-up was 12.0 mo (range, 0.8–33.0) Five pts had CR and 8 had PR; ORR was 11.6% (95% CI, 6.3–19.0). Median DOR was not reached (range, 6.0+ to 29.1+ mo). Responses occurred in 11/75 pts (14.7%) with PD-L1 combined positive score (CPS) ≥1 and 2/30 pts (6.7%) with PD-L1 CPS < 1. Among all pts, median OS was 12.0 mo (95% CI, 9.1–15.4), and median PFS was 2.0 mo (95% CI, 2.0–2.1). 68 (60.7%) pts had treatment-related AEs, including 21 (18.8%) who had grade 3–5 events; there were no treatment-related deaths. 4 pts (3.6%) discontinued due to treatment-related AEs. 27 pts (24.1%) had immune-mediated AEs/infusion reactions. Conclusions: Pembro demonstrated antitumor activity and manageable toxicity in pts with heavily pretreated advanced ASCC, regardless of PD-L1 status. Clinical trial information: NCT02628067.

scholarly journals A case of primary tracheal squamous cell carcinoma arising from malignant transformation of recurrent respiratory papillomatosis, with a complete response to concurrent chemoradiotherapy

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110546
Author(s):  
Aaron C Kovacs ◽  
Domagoj Vodanovich ◽  
Emily K Mogridge ◽  
Lisa Wun ◽  
June Corry
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Malignant Transformation ◽  
Squamous Cell ◽  
Metabolic Response ◽  
Therapeutic Option ◽  
Treatment Options ◽  
Complete Response ◽  
Recurrent Respiratory Papillomatosis ◽  
Positron Emission

Recurrent respiratory papillomatosis is a human papillomavirus-mediated condition characterised by the development of benign squamous papillomata of the respiratory tract. Malignant transformation of recurrent respiratory papillomatosis, while rare, carries a poor prognosis and there are limited data surrounding treatment options, particularly in inoperable disease. We present the case of a 64-year-old male who developed malignant airway obstruction secondary to primary tracheal squamous cell carcinoma in the setting of a 5-year history of recurrent laryngotracheal papillomatosis, requiring placement of tracheostomy while on veno-venous extracorporeal membranous oxygenation. He was managed with cisplatin-based definitive chemoradiotherapy and had a complete metabolic response on post-treatment positron emission tomography/computed tomography, and remains free of recurrent squamous cell carcinoma at 16 months following treatment. This case supports the use of combined chemoradiotherapy as a potential therapeutic option for patients with primary tracheal squamous cell carcinoma, and emphasises the challenges associated with the long-term management of recurrent respiratory papillomatosis.

scholarly journals Therapeutic Options in Myelodysplastic Syndromes Following Hypomethylating Agent Failure

2020 ◽  
pp. 52-64
Author(s):  
Abigail Belasen ◽  
Shyamala C. Navada
Keyword(s):  
Myelodysplastic Syndromes ◽  
Targeted Therapies ◽  
Enzyme Inhibitor ◽  
Treatment Options ◽  
Gene Mutations ◽  
Therapeutic Options ◽  
Molecular Characteristics ◽  
Therapeutic Approaches ◽  
Multikinase Inhibitor ◽  
Idh Mutations

Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for the treatment of myelodysplastic syndromes (MDS). Although HMA have revolutionised the treatment of MDS, only approximately half of patients respond to these agents with variable duration of effect, known as primary and secondary HMA failure, respectively. Therapeutic options following HMA failure remain limited; however, growing understanding of the pathogenesis underlying MDS has resulted in the development of multiple targeted therapies showing varying degrees of success in clinical trials. Drugs that target molecular alterations (such as abnormal histone regulation, IDH mutations, and spliceosome gene mutations), abnormal signalling pathways (such as the multikinase inhibitor rigosertib), cellular apoptosis (such as the Bcl2 inhibitor venetoclax), and immune checkpoint inhibition are under development. Agents recently approved for use in higher-risk acute myeloid leukaemia, such as FLT3-inhibitors and CPX-351, are also being studied in MDS. Several more agents, including two first-in-class agents, a novel immune regulator targeting CD47, and pevonedistat, a NEDD8-activating enzyme inhibitor, are under investigation. In the absence of established therapeutic approaches following HMA failure, decisions in therapy should be based on the type of HMA resistance as well as the patient’s clinical and molecular characteristics. As targeted therapies continue to be developed, a comprehensive re-evaluation of the patient including the mutational profile at the time of HMA failure may reveal new treatment options. Here, emerging therapeutic approaches to HMA failure in MDS are reviewed.

Comprehensive multiplatform biomarker analysis of 313 hepatocellular carcinoma to identify potential therapeutic options.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 283-283
Author(s):  
Ghassan K. Abou-Alfa ◽  
John Thomas Miura ◽  
T. Clark Gamblin ◽  
Joanne Xiu ◽  
Sherri Z. Millis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitors ◽  
Therapeutic Option ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Molecular Heterogeneity ◽  
Biomarker Analysis ◽  
Pi3 Kinase Pathway ◽  
Kinase Pathway

283 Background: Effective treatment strategies for hepatocellular carcinoma (HCC) remain limited. Identification of additional therapies remains paramount as currently available agents have resulted in marginal improvements in overall survival. Methods: 313 HCC sampleswere evaluated using a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ), including gene sequencing (Sanger, NGS [N=79]), protein expression (IHC) and gene amplification (ISH). Results: Biomarker changes of interest are shown. See Table. TP53 was mutated in 28%, CTNNB1 in 23%, and BRCA2 in 20%; other gene mutation rates were < 5%.TP53-mutated tumors show significantly higher TOPO2A (89% vs. 39%, p<0.0001), TS (70% vs. 32%, p=0.0067) and RRM1 expression (40% vs. 12%, p=0.017), implying high rates of proliferation and DNA synthesis. CTNNB1-mutated tumors showed significantly higher SPARC (67% vs. 21%, p=0.0013) and AR expression (53% vs. 22%, p=0.025). Primary HCC (N=209) exhibited significantly higher PD-1 (89% vs. 33%, p=0.01) and TS expression (35% vs. 13%, p<0.0001) than metastatic (N=105). Patient history/outcomes relative to biomarker status are being evaluated. Conclusions: These data suggest potential therapeutic targets, such as tyrosine kinase inhibitors, anti-PD1 agents, or PI3 kinase pathway inhibitors. Although no evidence shows that cytotoxics are effective in patients with HCC, irinotecan, alkylating agents, fluoropyrimidines, anthracyclines, nab-paclitaxel, gemcitabine, or taxanes may be therapeutically relevant. The protein changes associated with CTNNB1-mutated tumors suggest potential benefit of targeting WNT pathway in combination with nab-paclitaxel or anti-androgens. Immuno-modulatory agents may be a therapeutic option in primary HCC, based on the higher levels of PD-1. Multiplatform tumor profiling reveals molecular heterogeneity HCC, similar overall to previous reports, and identifies different potential treatment options for molecular subtypes. [Table: see text]

scholarly journals Anal Intraepithelial Neoplasia and Squamous Cell Cancer of the Anus

2018 ◽  
Vol 31 (06) ◽  
pp. 347-352 ◽  
Author(s):  
Rebecca Hoedema
Keyword(s):  
Squamous Cell ◽  
Incidental Finding ◽  
Topical Therapy ◽  
Treatment Options ◽  
Cell Cancer ◽  
High Risk Patient ◽  
Expectant Management ◽  
Intraepithelial Neoplasia ◽  
Anal Intraepithelial Neoplasia ◽  
Anal Squamous Cell Carcinoma

AbstractAnal intraepithelial neoplasia (AIN) is the premalignant condition of the anal squamous tissue. It is associated with the human papilloma virus and is considered the transition prior to the invasive anal squamous cell carcinoma. It is typically asymptomatic and can be either an incidental finding after anorectal surgery or identified when high-risk patient populations are screened. Once AIN is diagnosed, the optimal management remains controversial, partly because the natural history of the disease is unclear. Surgical management of the disease has essentially been replaced by more conservative treatment options and can range from expectant management to topical therapy to photodynamic therapy. The aim of this article is to review the varied treatment options and to briefly review prevention strategies.

Pembrolizumab for previously treated advanced anal squamous cell carcinoma: Pooled results from the KEYNOTE-028 and KEYNOTE-158 studies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4020-4020 ◽  
Author(s):  
Aurelien Marabelle ◽  
Philippe Alexandre Cassier ◽  
Marwan Fakih ◽  
Steven Chuan-Hao Kao ◽  
Dorte Nielsen ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Antitumor Activity ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Standard Therapy ◽  
Tissue Sample ◽  
Treatment Options ◽  
Anal Squamous Cell Carcinoma ◽  
Previously Treated

4020 Background: Patients (pts) with anal squamous cell carcinoma (ASCC) have poor outcomes and few treatment options. We report a pooled analysis of pembrolizumab (pembro) antitumor activity and safety in the ASCC cohorts of the multicohort studies KEYNOTE-028 (NCT02054806; phase 1b) and KEYNOTE-158 (NCT02628067; phase 2), providing a robust sample size and longer follow-up. Methods: Eligible pts were aged ≥18 y with histologically/cytologically confirmed metastatic/unresectable ASCC, had prior failure of/intolerance to standard therapy or no standard therapy options, measurable disease (RECIST v1.1), ECOG PS 0/1, and a tissue sample evaluable for PD-L1/biomarkers (KEYNOTE-028 required PD-L1 positivity). Baseline PD-L1 expression was assessed using a prototype IHC assay (QualTek) in KEYNOTE-028 and the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies) in KEYNOTE-158. Pts received pembro 10 mg/kg Q2W (KEYNOTE-028) or 200 mg Q3W (KEYNOTE-158) for 2 y or until PD/unacceptable AEs. The primary endpoint in both studies was ORR (per RECIST v1.1). Secondary endpoints were duration of response (DOR), PFS, OS, and safety. Results: 137 pts with ASCC were treated in KEYNOTE-028 (n = 25) or KEYNOTE-158 (n = 112) and were included in this analysis (median age, 61 y; 83.2% women; 73.0% had PD-L1–positive tumors). Median follow-up was 11.7 mo; 124 pts (90.5%) had discontinued treatment. ORR (95% CI) was 10.9% (6.3%–17.4%). 8 pts had CR and 7 had PR. ORR (95% CI) by PD-L1 status was 14.0% (7.9%–22.4%) in the PD-L1 positive group and 3.3% (0.1%–17.2%) in the PD-L1 negative group. Among all treated pts, median DOR was not reached (range, 6.0+ to 57.5+ mo). By Kaplan-Meier estimation, 84.6% of responders had a DOR ≥24 mo. Median PFS was 2.1 mo (95% CI, 2.0–2.1) and median OS was 11.7 mo (95% CI, 8.8–14.5). The 12-mo PFS and OS rates were 14.5% and 47.4%. 85 pts (62.0%) had +1 treatment-related AE, 24 pts (17.5%) with grade 3–4 events (no grade 5 events). 32 pts (23.4%) had immune-mediated AEs; 2 pts (1.5%) had infusion related reactions. Conclusions: In pts with previously treated advanced ASCC, pembro showed durable antitumor activity, particularly in pts with PD-L1–positive tumors, and manageable toxicity. Clinical trial information: NCT02054806 (KEYNOTE-028), NCT02628067 (KEYNOTE-158) .

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