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1.
Expert Rev Anticancer Ther ; 20(10): 901-908, 2020 10.
Article in English | MEDLINE | ID: mdl-32799569

ABSTRACT

OBJECTIVES: Metastatic squamous cell carcinoma anal cancer (SCCA) is rare. Prospective data recommends front-line platinum doublet combinations and second-line anti-programmed death-1 therapy. Standard therapy beyond these treatments are currently unknown. We evaluated anti-EGFR monoclonal antibody (mAb) outcomes in metastatic SCCA. METHODS: Metastatic SCCA patients given anti-EGFR mAb from Oct 2011-May 2018 were included. Primary endpoints included best response, progression-free survival, and overall survival. RESULTS: 56 patients were evaluated with a median of one prior therapy. Most patients (~90%) received anti-EGFR mAbs with chemotherapy. Response rate (any response) was 41%. Median PFS was 4.3 months with a median OS of 16 M. Seven patients with disease control proceeded onto maintenance therapy (anti-EGFR mAb ± a fluoropyrimidine) with a median PFS of 13.8 M. Next generation sequencing of 16 pts (28%) showed 4 pts had a PIK3CA mutation with 3 of these 4 patients demonstrating progression on initial restaging. CONCLUSION: Our analysis suggests anti-EGFR mAb therapy with chemotherapy provides clinical benefit in previously treated metastatic SCCA. Our maintenance therapy and the role of PIK3CA MT outcomes were thought-provoking. EXPERT OPINION: Metastatic SCCA patients have limited options; therefore, anti-EGFR mAbs may provide benefit in the treatment armamentarium and should be further explored.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Anus Neoplasms/drug therapy , Carcinoma, Squamous Cell/drug therapy , ErbB Receptors/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Anus Neoplasms/genetics , Anus Neoplasms/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Class I Phosphatidylinositol 3-Kinases/genetics , Female , Follow-Up Studies , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Progression-Free Survival , Retrospective Studies , Survival Rate
2.
Br J Cancer ; 123(8): 1262-1270, 2020 10.
Article in English | MEDLINE | ID: mdl-32733093

ABSTRACT

BACKGROUND: Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. METHODS: We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013-2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. RESULTS: Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P < 0.0001) and showed poor concordance with tissue for well-/moderately differentiated tumours. RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P < 0.0001). Appendiceal adenocarcinoma mutation profile did not resemble either right-sided CRC or any of the four CMS in CRC. High grade, but no mutation, was independently predictive of survival. CONCLUSION: Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.


Subject(s)
Adenocarcinoma/genetics , Appendiceal Neoplasms/genetics , Colorectal Neoplasms/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Appendiceal Neoplasms/mortality , Appendiceal Neoplasms/pathology , Chromogranins/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Female , GTP-Binding Protein alpha Subunits, Gs/genetics , Genes, ras , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation , Neoplasm Grading , Retrospective Studies , Tumor Suppressor Protein p53/genetics
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