Dataset Information

Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications.

ABSTRACT: Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAFV600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples, respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.

SUBMITTER: Gouda MA

PROVIDER: S-EPMC10390861 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications.

Gouda Mohamed A MA Nelson Blessie E BE Buschhorn Lars L Wahida Adam A Subbiah Vivek V

Clinical cancer research : an official journal of the American Association for Cancer Research 20230801 15

Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair/high micro ...[more]

PMID: 37061987

Similar Datasets

Project description:Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI-H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next-generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

Project description:Peritoneal metastases (PM) are common in metastatic colorectal cancer (mCRC). We aimed to characterize patients with mCRC and PM from a clinical and molecular perspective using the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange (GENIE) Biopharma Collaborative (BPC) registry. Patients' tumor samples underwent targeted next-generation sequencing. Clinical characteristics and treatment outcomes were collected retrospectively. Overall survival (OS) from advanced disease and progression-free survival (PFS) from start of cancer-directed drug regimen were estimated and adjusted for the left truncation bias. A total of 1,281 patients were analyzed, 244 (19%) had PM at time of advanced disease. PM were associated with female sex [OR: 1.67; 95% confidence interval (CI): 1.11-2.54; P = 0.014] and higher histologic grade (OR: 1.72; 95% CI: 1.08-2.71; P = 0.022), while rectal primary tumors were less frequent in patients with PM (OR: 0.51; 95% CI: 0.29-0.88; P < 0.001). APC occurred less frequently in patients with PM (N = 151, 64% vs. N = 788, 79%) while MED12 alterations occurred more frequently in patients with PM (N = 20, 10% vs. N = 32, 4%); differences in MED12 were not significant when restricting to oncogenic and likely oncogenic variants according to OncoKB. Patients with PM had worse OS (HR: 1.45; 95% CI: 1.16-1.81) after adjustment for independently significant clinical and genomic predictors. PFS from initiation of first-line treatment did not differ by presence of PM. In conclusion, PM were more frequent in females and right-sided primary tumors. Differences in frequencies of MED12 and APC alterations were identified between patients with and without PM. PM were associated with shorter OS but not with PFS from first-line treatment.SignificanceUtilizing the GENIE BPC registry, this study found that PM in patients with colorectal cancer occur more frequently in females and right-sided primary tumors and are associated with worse OS. In addition, we found a lower frequency of APC alterations and a higher frequency in MED12 alterations in patients with PM.

Dataset Information

Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications.

Publications

Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets