Je tiens à exprimer mes sincères remerciements à :Monsieur le Professeur Éric Deutsch, de m'avoir fait l'honneur de présider cette thèse. Monsieur le Professeur Ahmed Idbaih et Monsieur le Professeur Keith Ligon, d'avoir pris le temps de diriger et encadrer cette thèse. Monsieur le Docteur Franck Bourdeaut, Madame la Professeure Magali Svrcek, et Monsieur le Professeur Alex Duval, d'avoir pris le temps de juger ce travail. Monsieur le Docteur Franck Bielle, et Monsieur le Professeur Marc Sanson, pour leur participation à ces travaux. Une partie importante de ces travaux a été réalisée au Dana-Farber Cancer Institute et je tiens à remercier ici très sincèrement mes collègues de Boston pour leur amitié et leurs efforts déterminants dans l'obtention de ces résultats, en particulier Keith Ligon pour son accueil au sein de son laboratoire, ses conseils et ses encouragements.
Neoantigen presentation arises as a result of tumor-specifi c mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a signifi cant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefi t from ICIs. SIGnIFICAnCE:This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a signifi cant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.
Genomic profiling of circulating tumor DNA derived from cell-free DNA (cfDNA) in blood can provide a noninvasive method for detecting genomic biomarkers to guide clinical decision making for cancer patients. We developed a hybrid capture-based next-generation sequencing assay for genomic profiling of circulating tumor DNA from blood (FoundationACT). High-sequencing coverage and molecular barcode-based error detection enabled accurate detection of genomic alterations, including short variants (base substitutions, short insertions/deletions) and genomic re-arrangements at low allele frequencies (AFs), and copy number amplifications. Analytical validation was performed on 2666 reference alterations. The assay achieved >99% overall sensitivity (95% CI, 99.1%-99.4%) for short variants at AF >0.5%, >95% sensitivity (95% CI, 94.2%-95.7%) for AF 0.25% to 0.5%, and 70% sensitivity (95% CI, 68.2%-71.5%) for AF 0.125% to 0.25%. No false positives were detected in 62 samples from healthy volunteers. Genomic alterations detected by FoundationACT demonstrated high concordance with orthogonal assays run on the same clinical cfDNA samples. In 860 routine clinical FoundationACT cases, genomic alterations were detected in cfDNA at comparable frequencies to tissue; for the subset of cases with temporally matched tissue and blood samples, 75% of genomic alterations and 83% of short variant mutations detected in tissue were also detected in cfDNA. On the basis of analytical validation results, FoundationACT has been approved for use in our Clinical Laboratory Improvement Amendments-certified/College of American Pathologists-accredited/New York State-approved laboratory.
IMPORTANCE A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. OBJECTIVE To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. DESIGN, SETTING, AND PARTICIPANTSA preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months).INTERVENTIONS Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device.MAIN OUTCOMES AND MEASURES Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). RESULTS Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). CONCLUSIONS AND RELEVANCEIn this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future pos...
PURPOSE BRCA1 or BRCA2 loss of function results in homologous recombination deficiency (HRD), which is targetable by poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damaging agents. In cancers associated with germline BRCA1/2 alterations ( BRCA1/2-associated cancers: breast, ovarian, pancreatic, prostate), BRCA1/2 alterations result in HRD and are biomarkers for PARP inhibitor use. In other (non– BRCA1/2-associated) cancer types, the association between BRCA1/2 alteration and HRD is less clear. METHODS A total of 234,154 tumor samples were sequenced by hybrid capture-based comprehensive genomic profiling. Somatic, germline, and zygosity status was determined computationally. BRCA1/2 alterations were classified as predicted germline/somatic and biallelic/monoallelic. Genome-wide loss of heterozygosity (gLOH) was evaluated as a marker of HRD. RESULTS BRCA1/2 alterations were observed at a 4.7% frequency. BRCA1/2 mutations were predicted germline in 57.4% of BRCA1/2-associated and 37.2% of non– BRCA1/2-associated cancers. The fraction of BRCA1/2-altered cases that were biallelic was 68.7%, with a higher biallelic fraction in BRCA1/2-associated (89.9%) versus non– BRCA1/2-associated cancers (43.6%). Differences in tissue distribution of biallelic BRCA1 versus BRCA2 alterations were noted, including a higher rate of biallelic BRCA2 alteration in prostate cancer. Biallelic BRCA1/2 alteration was observed at a 3.2% frequency ( BRCA1/2-associated cancers, 8.9%; non– BRCA1/2-associated cancers, 1.3%) and > 1% frequency in at least 13 cancer types. Across cancer types, biallelic BRCA1/2 alteration was associated with increased gLOH versus monoallelic or wild-type BRCA1/2; predicted germline or somatic mutations were both associated with elevated gLOH. CONCLUSION Biallelic BRCA1/2 alterations were associated with elevated gLOH in diverse cancer types, including those not traditionally associated with BRCA1/2 cancer syndromes. Biomarker development for PARP inhibitors should integrate methods to distinguish biallelic from monoallelic BRCA1/2 status, and biallelic BRCA1/2 alteration should be broadly evaluated across cancer types as a biomarker for underlying HRD and PARP inhibitor sensitivity.
NTRK fusions occur in a subset of young patients with mesenchymal or sarcoma-like tumors at a low frequency, and are eminently druggable targets via either investigational agents or approved drugs.
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