KEY TAKEAWAYS
- The AtezoTRIBE and AVETRIC studies analyzed LOH percentages and HRR mutations in mCRC tumor samples and explored anti-PDL1 combinations with FOLFOXIRI and bevacizumab or cetuximab.
- The study suggested that in MSS mCRC, LOH-high tumors were associated with biallelic alterations in the HRR system and a worse prognosis. However, the addition of anti-PDL1 agents to the chemotherapy showed enhanced outcomes.
Genomic LOH pertains to the disappearance of chromosomal areas and it’s linked to a deficiency in the homologous recombination repair (HRR) system (known as dHRR). In ovarian cancer, a high presence of LOH indicates a positive response to platinum-based chemotherapy and PARP inhibitors. However, in mCRC, LOH’s role hasn’t been thoroughly examined.
Using an NGS-based FoundationOne CDx assay by Foundation Medicine, Inc., researchers examined the LOH percentage in genomic regions and checked for mutations related to HRR in preserved tumor samples from mCRC patients (pts). These samples were part of both a real-world registry and the AtezoTRIBE and AVETRIC studies. These studies looked at combining anti-PDL1 (either atezolizumab or avelumab) with FOLFOXIRI and either bevacizumab or cetuximab. The cut-off established for mCRC LOH-high by Sokol et al. was used. Tumors displaying at least one biallelic modification in any of the 27 genes related to the HRR pathway, as mentioned by Riaz et al. (Nat Commun 2017) and part of the FoundationOne CDx list (including BARD1, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RBBP8, XRCC2, ABL1, ATM, ATR, BAP1, CDK12, DNMT3A, ERCC4, FANCA, FANCC, FANCG, FANCL, PARP1), are categorized as dHRR.
Out of 196 samples, none from the 7 MSI-H tumors were termed as LOH-high. Fourteen (7%) and six (3%) out of 189 MSS tumors were identified as LOH-high and dHRR, respectively. Specifically, three tumors in the LOH-high category were marked dHRR, and three dHRR tumors were marked LOH-high. LOH-high tumors often showed BRAF mutations and dHRR compared to their counterparts. An interaction was noticed between the use of a checkpoint inhibitor and LOH status in pts who had chemotherapy treatment with or without anti-PDL1. Patients not treated with anti-PDL1 and having LOH-low tumors showed a longer progression-free survival (PFS) compared to those with LOH-high tumors. The type of first-line treatment, whether oxaliplatin-based or irinotecan-based, didn’t show a variance in PFS or overall survival (OS) based on LOH status. Additionally, HRR deficiency didn’t seem to influence prognosis or predictability.
For MSS mCRC pts, having LOH-high tumors was tied to both biallelic alterations in the HRR system and worse prognosis, but also showed improved results when anti-PDL1 agents were added to the chemotherapy regimen. Due to the small sample size of LOH-high tumors in this study, further research with larger groups is necessary.
Source: https://www.annalsofoncology.org/article/S0923-7534(23)00190-4/fulltext
Clinical Trials: https://classic.clinicaltrials.gov/ct2/show/NCT03721653
https://classic.clinicaltrials.gov/ct2/show/NCT04513951
Carullo, M., Germani, M., Moretto, R., Conca, V., Minelli, A., Giordano, M., Bruno, R., Prisciandaro, M., Lonardi, S., Bensi, M., Tonini, G., Palladino, M., Ramundo, M., Tamberi, S., Antoniotti, C., Rossini, D., Ugolini, C., Marmorino, F., Fontanini, G., Cremolini, C. PD-21 EXPLORING THE PROGNOSTIC AND PREDICTIVE IMPACT OF GENOMIC LOSS OF HETEROZYGOSITY (LOH) IN METASTATIC COLORECTAL CANCER (MCRC) PATIENTS. https://doi.org/10.1016/j.annonc.2023.04.048
