Dataset Information

Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice.

ABSTRACT: Next-generation sequencing (NGS) followed by matched therapy has opened up new therapeutic options to patients with metastatic breast cancer (mBC). Here we report our experience with this approach in everyday clinical practice. This retrospective study included 95 patients with mBC who were genotyped with the FoundationOne® (CDx) assay in a commercial molecular pathology laboratory. Genetic alterations were identified in all tumor specimens, and 83 patients (87.4%) had a median of 2 (range, 1-6) potentially actionable alterations. A multidisciplinary tumor board recommended genomically guided therapy to 63 patients, 30 of whom received such treatment. Everolimus (n = 15) and anti-human epidermal growth factor receptor 2 (HER2) therapy (n = 6) were most frequently administered. The ratio of progression-free survival (PFS) under NGS-based therapy to PFS under the last line of standard therapy prior to NGS was >1.3 in 13 (43.3%) patients, indicative of a clinical benefit to NGS-directed therapy. One-year overall survival rates were 22.7% (95% CI, 6.5-44.4) in 65 patients allocated to the standard therapy versus 62.9% (95% CI, 41.6-78.2) in 30 patients receiving the matched therapy. In conclusion, NGS-matched treatment improved the clinical outcomes in a subgroup of mBC patients.

SUBMITTER: Bruzas S

PROVIDER: S-EPMC8468801 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice.

Bruzas Simona S Kuemmel Sherko S Harrach Hakima H Breit Elisabeth E Ataseven Beyhan B Traut Alexander A Rüland Anna A Kostara Athina A Chiari Ouafaa O Dittmer-Grabowski Christine C Reinisch Mattea M

Cancers 20210911 18

Next-generation sequencing (NGS) followed by matched therapy has opened up new therapeutic options to patients with metastatic breast cancer (mBC). Here we report our experience with this approach in everyday clinical practice. This retrospective study included 95 patients with mBC who were genotyped with the FoundationOne<sup>®</sup> (CDx) assay in a commercial molecular pathology laboratory. Genetic alterations were identified in all tumor specimens, and 83 patients (87.4%) had a median of 2 ( ...[more]

PMID: 34572791

Similar Datasets

Project description:Molecular technologies have allowed laboratories to detect and establish the profiles of human cancers by identifying a variety of somatic variants. In order to improve personalized patient care, we have established a next-generation sequencing (NGS) test to screen for somatic variants in primary or advanced cancers. In this study, we describe the laboratory quality management program for NGS testing, and also provide an overview of the somatic variants identified in over 1000 patient samples as well as their implications in clinical practice.Over the past one-and-a-half years, our laboratory received a total of 1028 formalin-fixed, paraffin-embedded (FFPE) tumor tissues, which consisted of non-small-cell lung carcinomas (NSCLCs), colon adenocarcinomas, glioma/glioblastomas, melanomas, breast carcinomas, and other tumor types. During this time period, we implemented a series of quality control (QC) checks that included (1) pre-DNA extraction, (2) DNA quantification, (3) DNA quality, (4) library quantification, (5) post-emulsification PCR, and (6) post-sequencing metrics. At least 10 ng of genomic DNA (gDNA) were used to prepare barcoded libraries using the AmpliSeq CHPv2. Samples were multiplexed and sequenced on Ion Torrent 318 chips using the Ion PGM System. Variants were identified using the Variant Caller Plugin, and annotation and functional predictions were performed using the Golden Helix SVS.A total of 1005 samples passed QC1-3, and following additional library preparation QC checkpoints, 877 samples were sequenced. Samples were classified into two categories: wild-type (127) and positive for somatic variants (750). Somatic variants were classified into clinically actionable (60%) and non-actionable (40%).The use of NGS in routine clinical laboratory practice allowed for the detection of tumor profiles that are essential for the selection of targeted therapies and identification of applicable clinical trials, contributing to the improvement of personalized patient care in oncology.

Project description:BackgroundControlled trials have consistently demonstrated the efficacy of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1 or BRCA2 alterations (BRCAalt). However, the reported efficacy of PARPi for alterations in other homologous recombination repair (HRR) genes is less consistent. We sought to evaluate the routine practice effectiveness of PARPi between and within these groups.DesignPatient-level data from a deidentified nationwide (USA-based) cancer clinico-genomic database between January 2011 and September 2023 were extracted. Patients with mCRPC and comprehensive genomic profiling by liquid biopsy [circulating tumor DNA (ctDNA)] or tissue (tumor) biopsy and who received single-agent PARPi were included and grouped by BRCAalt, ATMalt, other HRR, or no HRR. We further subcategorized BRCAalt into homozygous loss (BRCAloss) and all other deleterious BRCAalt (otherBRCAalt).ResultsA total of 445 patients met inclusion criteria: 214 with tumor and 231 with ctDNA. BRCAalt had more favorable outcomes to PARPi compared with ATM, other HRR, and no HRR groups. Within the BRCAalt subgroup, compared with other BRCAalt, BRCAloss had a more favorable time to next treatment (median 9 versus 19.4 months, P = 0.005), time to treatment discontinuation (median 8 versus 14 months, P = 0.006), and routine practice overall survival (median 14.7 versus 19.4 months, P = 0.016). Tumor BRCAloss prevalence (3.1%) was similar to ctDNA prevalence in liquid biopsy specimens with high tumor fraction (>20%). BRCAloss was not detected in orthogonal germline testing.ConclusionsPARPi routine practice effectiveness between groups mirrors prospective trials. Within the BRCAalt group, BRCAloss had the best outcomes. Unless the ctDNA tumor fraction is very high, somatic tissue testing (archival or metastatic) should be prioritized to identify patients who may benefit most from PARPi. When tissue testing is not clinically feasible, sufficient ctDNA tumor fraction levels for detection are enriched at clinical timepoints associated with tumor progression.

Project description:The aim of this study was to assess the frequency of potentially actionable genomic alterations in breast cancer that could be targeted with approved agents or investigational drugs in clinical trials using a next-generation sequencing-based genomic profiling assay performed in a Clinical Laboratory Improvement Amendments-certified and College of American Pathologists-accredited commercial laboratory. Methods. Fifty-one breast cancers were analyzed, including primary tumor biopsies of 33 stage I-II and 18 stage IV cancers (13 soft tissue, 3 liver, and 2 bone metastases). We assessed 3,230 exons in 182 cancer-related genes and 37 introns in 14 genes often rearranged in cancer for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 1,154×. Results. We observed 158 genomic alterations in 55 genes in 48 of 51 (94%) tumors (mean 3.1, range 0-9). The average number of potentially therapeutically relevant alterations was similar in primary (1.6, range 0-4) and in heavily pretreated metastatic cancers (2.0, range 0-4) (p = .24). The most common actionable alterations were in PIK3CA (n = 9, phosphatidylinositol 3-kinase [PI3K]/mammalian target of rapamycin [mTOR] inhibitors), NF1 (n = 7, PI3K/mTOR/mitogen-activated protein kinase inhibitors), v-akt murine thymoma viral oncogene homolog 1-3 (n = 7, PI3K/mTOR/AKT inhibitors), BRCA1/2 (n = 6, poly[ADP-ribose] polymerase inhibitors), and CCND1,2 and CCNE (n = 8)/cycline dependent kinase (CDK)6 (n = 1) (CDK4/6 inhibitors), KIT (n = 1, imatinib/sunitinib), ALK (n = 1, crizotinib), FGFR1,2 (n = 5, fibroblast growth factor receptor inhibitors), and EGFR (n = 2, epidermal growth factor receptor inhibitors). Our sequencing assay also correctly identified all six cases with HER2 (ERBB2) amplification by fluorescence in situ hybridization when tumor content was adequate. In addition, two known activating HER2 mutations were identified, both in unamplified cases. Conclusion. Overall, 84% of cancers harbored at least one genomic alteration linked to potential treatment options. Systematic evaluation of the predictive value of these genomic alterations is critically important for further progress in this field.

Dataset Information

Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice.

Publications

Next-Generation Sequencing-Directed Therapy in Patients with Metastatic Breast Cancer in Routine Clinical Practice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets