Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

The synthetic lethal effect observed with the use of PARP inhibitors (PARPi) with tumors characterized by the loss of key players in the homologous recombination (HR) pathway, commonly referred to as "BRCAness", is maintaining high interest in oncology. While BRCAness is a well-established feature in breast, ovarian, prostate, and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HR deficiency (HRD) from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology 500 HRD (TSO500-HRD) panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM and RAD51C immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

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Publication Details

Journal
npj Precision Oncology
Published
2024-10-14
DOI
https://doi.org/10.1038/s41698-024-00706-7
Citations
4
Primary Topic
PARP inhibition in cancer therapy
Type
article
Field-Weighted Citation Impact
1.13

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article

Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

Sara E. Bellomo, Federica Di Nicolantonio, Gianluca Mauri, Enrico Berrino et al.
4 citations
npj Precision Oncology
PARP inhibition in cancer therapy
1.13
article

Prediction of homologous recombination deficiency identifies colorectal tumors sensitive to PARP inhibition

Sara E. Bellomo, Federica Di Nicolantonio, Gianluca Mauri, Enrico Berrino, Salvatore Siena, Sabrina Arena, Giorgio Corti, Martina Miotto, Alice Bartolini, Maria Costanza Aquilano, Alberto Bardelli, Kristi Buzo, Caterina Marchiò, Mariangela Russo, Annalisa Lorenzato, Silvia Marsoni, Maria Lentini, Luca Lazzari
article en
4 citations

Abstract

The synthetic lethal effect observed with the use of PARP inhibitors (PARPi) with tumors characterized by the loss of key players in the homologous recombination (HR) pathway, commonly referred to as "BRCAness", is maintaining high interest in oncology. While BRCAness is a well-established feature in breast, ovarian, prostate, and pancreatic carcinomas, our recent findings indicate that up to 15% of colorectal cancers (CRC) also harbor defects in the HR pathway, presenting promising opportunities for innovative therapeutic strategies in CRC patients. We developed a new tool called HRDirect, which builds upon the HRDetect algorithm and is able to predict HR deficiency (HRD) from reference-free tumor samples. We validated HRDirect using matched breast cancer and CRC patient samples. Subsequently, we assessed its efficacy in predicting response to the PARP inhibitor olaparib by comparing it with two other commercial assays: AmoyDx HRD by Amoy Diagnostics and the TruSight Oncology 500 HRD (TSO500-HRD) panel by Illumina NGS technology. While all three approaches successfully identified the most PARPi-sensitive CRC models, HRDirect demonstrated superior precision in distinguishing resistant models compared to AmoyDX and TSO500-HRD, which exhibited overlapping scores between sensitive and resistant cells. Furthermore, we propose integrating HRDirect scoring with ATM and RAD51C immunohistochemical analysis as part of our "composite biomarker approach" to enhance the identification of HRD tumors, with an immediate translational and clinical impact for CRC personalized treatment.

npj Precision OncologyVol. 8(1)
Collegio Carlo Alberto (IT), University of Milan (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), IFOM (IT), Candiolo Cancer Institute (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Turin (IT)
Cancer Research UK, European Commission, Ministero della Salute, Ministero dell’Istruzione, dell’Università e della Ricerca, Associazione Italiana per la Ricerca sul Cancro, Fondazione Oncologia Niguarda Onlus
Zero hunger
Openalex Percentile: Top 18%
PARP inhibition in cancer therapy
1.13
DOIOpen Access PDFOpenAlex
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