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Tumor Discovery HRD genomic alterations in Chinese NSCLC

1. Introduction known genes associated with HRD. Other genes, such as
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ataxia telangiectasia mutated (ATM), BRCA1 associated
Lung cancer is the most common type of cancer (accounting RING domain 1 (BARD1), and BRCA1 interacting protein
for 11.6% of all cancer cases) and the leading cause of cancer C-terminal helicase 1 (BRIP1), have been identified as
death worldwide (accounting for 18.4% of all cancer deaths). participants in homologous recombination and related
Lung cancer is one of the leading causes of cancer-related pathways. Numerous studies have demonstrated
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1
death in China, and its 5-year survival rate is only 19.8%. the presence of HRD in lung cancer. 18-20 However, the
Roughly 80 – 85% of lung cancers are categorized as non- expansion of PARP inhibitors into the field of lung cancer
small cell lung cancer (NSCLC), with lung adenocarcinoma through experimental and clinical studies is still limited,
(LUAD) and lung squamous cell carcinoma (LUSC) being and considerable efforts are needed before their application
the predominant subtypes of NSCLC. Recent innovations in lung cancer.
2
in NSCLC management involve the use of targeted
therapies, immunotherapies, and the synergistic pairing of Deficiency of homologous recombination, or HRD,
chemotherapy and immunotherapy. Nevertheless, around arises from defects in DNA repair pathways, particularly the
3
one-third of individuals diagnosed with LUAD and most HRR system responsible for repairing DSBs. Abnormalities
patients with LUSC lack oncogenic driver mutations that in HRR can be attributed to germline or somatic mutations
can be targeted for treatment. NSCLC patients without of some genes including BRCA1, BRCA2, ATM, RAD51,
4-6
identifiable oncogenic driver alterations can undergo and BARD1. These genetic alterations result in genomic
chemotherapy or chemo-immunotherapy, depending on instability, a hallmark of cancer development. 20,21 The
the cancer subtype and the expression of the programmed specific HRD features include large-scale state transitions,
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death ligand-1 gene (PD-L1). However, only a small loss of heterozygosity, and telomeric allelic imbalances.
percentage (<20%) of unselected NSCLC patients respond These genomic characteristics have been used to predict
to immunotherapy, and some of these patients experience response to PARP inhibitors in ovarian and breast cancers,
severe immunotoxicity. Hence, there exists an unmet need and have been associated with improved overall survival in
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to explore potential novel and effective treatment modalities patients with BRCA mutations, ovarian and breast cancers,
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to improve the therapeutic outcomes for NSCLC. and high HRD scores. However, HRD could also be both
hereditary and secondary; some tumors become HRD
Homologous recombination is pivotal for maintaining
genome stability through the repair of DNA double-strand even without BRCA mutations, but this makes it useful for
more cancer types.
breaks (DSBs) and stalled DNA replication forks. Tumors
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exhibiting deficiencies in homologous recombination still Beyond conferring sensitivity to PARP inhibitors,
require intact mechanisms for the repair of DNA lesions HRD is also linked to increased tumor immunogenicity.
that are critical for cell viability, and thus shift their reliance Several investigations have shown that the mutation rate in
to other functional DNA repair pathways. Targeting these HRD-positive tumors is higher and that these mutations
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dependent pathways in DNA damage response (DDR)- may give rise to neoantigens and increased infiltration of
deficient cancer cells induce a synthetic lethality effect, tumor tissue by immune cells. HRD is associated with
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thereby inhibiting cancer cell proliferation. Poly (ADP- increased expression of immune checkpoint proteins such
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ribose) polymerase (PARP) inhibitors selectively eradicate as PD-L1 and activation of interferon signaling pathways,
cells with homologous recombination repair (HRR) suggesting a potential interaction between HRD and
deficiencies through synthetic lethality interactions. immunotherapy. For example, in microsatellite stable
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This synthetic lethality has been extensively applied in cancers, it has been demonstrated that the utilization of
breast, ovarian, and prostate cancers with BRCA1 and HRD increases the effectiveness of immune checkpoint
BRCA2 mutations. Therefore, BRCA mutations and the inhibitors (ICI), including anti-PD-1 and anti-PD-L1
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status of homologous recombination deficiency (HRD) agents. The combination of PARP inhibitors and ICIs
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serve as biomarkers for predicting the efficacy of PARP is based on pre-clinical evidence that PARP inhibition
inhibitors. Alterations in genes of the homologous releases intracellular DNA to activate the cGAS-STING
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recombination pathway have been extensively studied, pathway, enhancing immunity against the tumor. That
leading to the development of HRD scoring algorithms is why today there are many clinical trials of such
utilizing various assays to quantify the extent of genomic combinations for various malignancies. For example, the
instability. These algorithms rely on metrics associated MEDIOLA trial exposed a relatively favorable outcome
with loss of heterozygosity, telomeric allelic imbalance, of combining olaparib and durvalumab in BRCA-mutant
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and large-scale state transitions. The breast cancer metastatic breast cancer with a high response rate and
susceptibility genes BRCA1 and BRCA2 are the most well- disease control. 26

Volume 4 Issue 3 (2025) 33 doi: 10.36922/TD025180032