Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides

Journal of Clinical Oncology, Journal Year: 2024, Volume and Issue: 42(30), P. 3550 - 3560

Published: July 31, 2024

PURPOSE Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available. METHODS We trained DeepHRD, a deep learning platform predicting hematoxylin eosin (H&E)–stained histopathological slides, using primary breast (n = 1,008) ovarian 459) cancers The Cancer Genome Atlas (TCGA). DeepHRD was compared four standard 349) 141) multiple independent data sets, including platinum-treated clinical cohorts RECIST progression-free survival (PFS), complete response (CR), overall (OS) endpoints. RESULTS predicted held-out H&E-stained cancer slides in TCGA an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance confirmed two (AUC, 0.76 [95% 0.71 0.82]). In external metastatic cohort, samples as had higher CR 0.54 0.93]) 3.7-fold increase median PFS (14.4 v 3.9 months; P .0019) hazard ratio (HR) 0.45 ( .0047). There were no significant differences nonplatinum treatment outcome by status three cohorts, 0.39) (HR, 0.98, .95) taxane-treated cancer. Through transfer high-grade serous cancer, DeepHRD-predicted better OS after first-line 0.46; .030) neoadjuvant 0.49; .015) therapy cohorts. CONCLUSION predict directly routine H&E across slide scanners, tissue fixation variables. When testing, classified 1.8- 3.1-fold more patients HRD, exhibited platinum-specific

Language: Английский

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Unraveling the complexity of HRD assessment in ovarian cancer by combining genomic and functional approaches: translational analyses of MITO16-MaNGO-OV-2 trial

ESMO Open, Journal Year: 2025, Volume and Issue: 10(1), P. 104091 - 104091

Published: Jan. 1, 2025

Ovarian cancer (OvC) constitutes significant management challenges primarily due to its late-stage diagnosis and the development of resistance chemotherapy. The standard treatment regimen typically includes carboplatin paclitaxel, with addition poly (ADP-ribose) polymerase inhibitors for patients high-grade serous ovarian (HGSOC) harboring BRCA1/2 mutations. However, variability in responses suggests need investigate factors beyond mutations, such as DNA repair mechanisms epigenetic alterations. Notably, homologous recombination deficiency (HRD) is observed an additional 20% HGSOC cases, indicating a broader spectrum defects. Existing commercial HRD assays have certain limitations, prompting global effort develop new genomic functional tests through academic research.

Language: Английский

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Poly (adenosine diphosphate‐ribose) polymerase inhibitors in the treatment of triple‐negative breast cancer with homologous repair deficiency

Medicinal Research Reviews, Journal Year: 2024, Volume and Issue: 44(6), P. 2774 - 2792

Published: June 24, 2024

Breast cancer (BC) is a highly heterogeneous disease, and the presence of germline breast gene mutation (gBRCAm) associated with poor prognosis. Triple-negative (TNBC) BC subtype, characterized by absence hormone growth factor receptor expression, making therapeutic decisions difficult. Defects in DNA damage response pathway due to genes (BRCA 1/2) lead homologous recombination deficiency (HRD). However, HRD conditions, poly (adenosine diphosphate-ribose) polymerase (PARP) proteins repair tumor cell survival. Biological understanding leads development PARP inhibitors (PARPi), which trap cause genomic instability lysis. assessment can be an important biomarker identifying gBRCAm patients who could benefit from PARPi therapy. identified (HRR) gene-based assays, genomic-scarring assays mutational signatures, transcription protein expression profiles, functional assays. gold standard methodologies that are robust reliable assess not available currently. Hence, there pressing need develop accurate biomarkers tumors guide targeted therapies such as BC. has shown fruitful outcomes chemotherapy studies preliminary evidence on intervention monotherapy combination therapy HRD-stratified patients. Furthermore, ongoing trials exploring potential clinically complex TNBC settings, where testing used adjunct stratify based BRCA mutations.

Language: Английский

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Development of the NOGGO GIS v1 Assay, a Comprehensive Hybrid-Capture-Based NGS Assay for Therapeutic Stratification of Homologous Repair Deficiency Driven Tumors and Clinical Validation

Cancers, Journal Year: 2023, Volume and Issue: 15(13), P. 3445 - 3445

Published: June 30, 2023

The worldwide approval of the combination maintenance therapy olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for routine detection driver mutations homologous recombination repair (HRR) genes genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay an associated bioinformatic pipeline fulfils our institution's specific needs. assay´s target regions cover full exonic territory relevant cancer-related HRR more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow genome-wide allele copy number alterations (CNA). To determine GI status, we implemented %CNA score is across broad range cell content (25-85%) often found FFPE samples. was using which BRCA1 BRCA2 mutation status as well Myriad MyChoice deficiency (HRD) known. NOGGO (Northeastern German Society Gynecologic Oncology) GIS (GI-Score) v1 clinically validated on 400 ENGOT PAOLA-1 clinical trial part European Network Gynaecological Oncological Trial groups (ENGOT) HRD Initiative. "NOGGO assay" performed highly hazard ratios progression-free survival (PFS) overall (OS), significantly lower dropout rate supporting utility assay. also provide proof modular scalable method, can be flexibly adapted adjusted meet future needs, emerging biomarkers, further entities.

Language: Английский

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Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

Cancer Treatment Reviews, Journal Year: 2023, Volume and Issue: 121, P. 102650 - 102650

Published: Oct. 31, 2023

Breast cancer susceptibility gene 1 (BRCA1) and breast 2 (BRCA2) deleterious variants were the first and, still today, main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers individuals referred for counseling multigene panel testing, remarkable expansion approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need non-BRCA biomarkers. Significant limitations current testing assays exist. different approaches that identify causes Homologous Recombination Deficiency (HRD), such as germline somatic Repair (HRR) PVs, showing its consequences, genomic scars, or novel functional RAD51 foci are interchangeable, should be considered substitutes each other in practice guiding use PARPi non-BRCA, HRD-associated tumors. Today, deeper knowledge on significant relationship among all proteins involved HRR, limited BRCA, expands possibility successful HRD-PARPi synthetic lethality at same time, reinforces enhanced definition HRD predicting magnitude

Language: Английский

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Current HRD assays in ovarian cancer: differences, pitfalls, limitations, and novel approaches

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: Aug. 16, 2024

Ovarian carcinoma (OC) still represents an insidious and fatal malignancy, few significant results have been obtained in the last two decades to improve patient survival. Novel targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPi) successfully introduced clinical management of OC, but not all patients will benefit, drug resistance almost inevitably occurs. The identification who are likely respond PARPi-based relies on homologous recombination deficiency (HRD) tests, this condition is associated with response these treatments. This review summarizes genomic functional HRD assays currently used practice those under evaluation, implications testing their current pitfalls limitations. Special emphasis be placed development use machine learning artificial intelligence technologies novel strategies overcome limitations tests for a better-personalized treatment outcomes.

Language: Английский

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Promising new drugs and therapeutic approaches for treatment of ovarian cancer—targeting the hallmarks of cancer

BMC Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Jan. 6, 2025

Abstract Ovarian cancer remains the most lethal gynecological malignancy. Despite approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target pivotal hallmarks cancer. This review giving updated overview innovative upcoming therapies treatment ovarian that focuses specific on The constitute a broad concept to reenact complexity malignancies furthermore identify possible targets strategies. For this purpose, we analyzed approvals current clinical phase III studies (registered at ClinicalTrials.gov (National Library Medicine, National Institutes Health; U.S. Department Health Human Services, 2024)) drugs basis their mechanisms action identified approaches. A spectrum currently under investigation targeting mainly “self-sufficiency growth signals,” “genomic instability,” “angiogenesis.” benefit immune checkpoint inhibitors been demonstrated first time. Besides, tumor microenvironment growing interest. Replicative immortality, energy metabolism, promoting inflammation, microbiome are still barely by drugs. Nevertheless, precision medicine, which disease characteristics, becoming increasingly important treatment. Graphical

Language: Английский

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Opportunities for predictive proteogenomic biomarkers of drug treatment sensitivity in epithelial ovarian cancer

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 7, 2025

Genomic analysis has played a significant role in the identification of driver mutations that are linked to disease progression and response drug treatment ovarian cancer. A prominent example is stratification epithelial cancer (EOC) patients with homologous recombination deficiency (HRD) characterized by DNA damage repair genes such as BRCA1/2 for PARP inhibitors. However, recent studies have shown some tumors respond inhibitors irrespective their HRD or BRCA mutation status. An exclusive focus on genome overlooks insight can be gained from other biological analytes, including proteins, which carry out cellular functions. Proteogenomics integration genomics, transcriptomics, epigenomics proteomics data. This review paper provides novel into proteogenomics an analytical approach identify predictive biomarkers Proteogenomic facilitate response, consequently greatly improving EOC towards goal personalized medicine.

Language: Английский

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Evaluation of Homologous Recombination Deficiency in Ovarian Cancer

Current Treatment Options in Oncology, Journal Year: 2024, Volume and Issue: 25(2), P. 237 - 260

Published: Feb. 1, 2024

Language: Английский

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Novel frontiers in urogenital cancers: from molecular bases to preclinical models to tailor personalized treatments in ovarian and prostate cancer patients

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: May 15, 2024

Abstract Over the last few decades, incidence of urogenital cancers has exhibited diverse trends influenced by screening programs and geographical variations. Among women, there been a consistent or even increased occurrence endometrial ovarian cancers; conversely, prostate cancer remains one most diagnosed malignancies, with rise in reported cases, partly due to enhanced improved efforts. Simultaneously, landscape therapeutics undergone remarkable evolution, encompassing introduction targeted therapies significant advancements traditional chemotherapy. Modern treatments aim selectively address molecular aberrations driving cancer, minimizing adverse effects on normal cells. However, chemotherapy retains its crucial role, offering broad-spectrum approach that, despite wider range side effects, indispensable treatment various cancers, often working synergistically enhance overall efficacy. For especially DNA damage response inhibitors, such as PARP have emerged promising therapeutic avenues. In BRCA -mutated inhibitors like olaparib niraparib demonstrated efficacy, leading their approval for specific indications. Similarly, patients mutations shown sensitivity these agents heralding new frontier disease management. Furthermore, progression is intricately linked hormonal regulation. Ovarian development also associated prolonged exposure estrogen, while testosterone metabolite dihydrotestosterone, can fuel growth Thus, understanding interplay between hormones, repair mechanisms hold promise exploring novel tumors. addition, it primary importance use preclinical models that mirror close possible biological genetic features patients’ tumors order effectively translate findings “from bench bedside”. summary, complex underscores need innovative approaches. Targeted therapy tailored hormone regulation might offer avenues improving management outcomes affected cancers.

Language: Английский

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