Feng H, Zhao LY, Xu Z, Xie QF, Deng HJ, Yu J, Liu H. Homologous recombination deficiency and immunotherapy response in microsatellite-stable colorectal cancer: Evidence from a cohort study in China. World J Gastrointest Oncol 2025; 17(5): 102767 [DOI: 10.4251/wjgo.v17.i5.102767]
Corresponding Author of This Article
Hao Liu, MD, PhD, Professor, Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Ave. North, Guangzhou 510515, Guangdong Province, China. liuhaofbi@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Deng HJ, Liu H and Yu J conceived and designed the study; Feng H, Xu Z, and Xie QF acquired the data; Feng H and Zhao LY implemented quality control of data and the algorithms; Feng H and Zhao LY did the statistical analyses; Feng H prepared the first draft of the manuscript. All authors analyzed and interpreted the data. All authors contributed to manuscript preparation. All authors have read and approve the final manuscript. Feng H and Zhao LY contributed equally to this work as co-first authors. Yu J and Liu H are designated as co-corresponding authors due to their significant and equal contributions to the research and manuscript. Both authors have played pivotal roles in the study design, data analysis, and interpretation of results, ensuring the integrity and accuracy of the research findings. Yu J, as a senior expert in the field of oncology, provided invaluable insights into the clinical aspects of colorectal cancer (CRC), particularly in the context of microsatellite-stable (MSS) CRC patients and homologous recombination deficiency (HRD). He has been deeply involved in the clinical trial design, patient selection, and the interpretation of immunotherapy responses in MSS CRC, making him a crucial contributor to the study. Liu H took primary responsibility for the design and execution of the molecular genetic analyses, including next-generation sequencing, and the integration of the genetic data with clinical outcomes. His expertise in bioinformatics and genomic instability further enriched the research, providing robust evidence for the potential predictive role of HRD in MSS CRC patients' response to immunotherapy. Both authors shared equal responsibility in drafting, revising, and finalizing the manuscript, ensuring its scientific rigor and coherence. Their combined expertise in both clinical and molecular aspects of CRC has been fundamental to the successful execution of this study, warranting their joint designation as co-corresponding authors.
Supported by Natural Science Foundation of Guangdong Province, No. 2021A1515011146 and No. 2023A1515010785; and Key Areas Research and Development Programs of Guangdong Province, No. 2023B1111050009.
Institutional review board statement: This retrospective study was approved by the Ethics Committee of Nanfang Hospital of Southern Medical University (Guangzhou, China) (ID: NFEC-2021-396).
Informed consent statement: Patient consent was waived because all patient data was de-identified.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement:
Pathology data and the statistical analyses for the current study are available from the corresponding author at liuhaofbi@163.com upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hao Liu, MD, PhD, Professor, Department of General Surgery, Nanfang Hospital, Southern Medical University, No. 1838 Guangzhou Ave. North, Guangzhou 510515, Guangdong Province, China. liuhaofbi@163.com
Received: November 5, 2024 Revised: February 14, 2025 Accepted: March 7, 2025 Published online: May 15, 2025 Processing time: 193 Days and 19.3 Hours
Abstract
BACKGROUND
Patients with colorectal cancer (CRC) exhibiting microsatellite instability (MSI)-high generally demonstrate a favorable response to immunotherapy. In contrast, the efficacy of immunotherapy in microsatellite-stable (MSS) CRC patients is considerably restricted. This study sought to evaluate the effectiveness of immunotherapy in MSS patients characterized by homologous recombination deficiency (HRD) as opposed to those with homologous recombination proficiency (HRP).
AIM
To investigate and compare the clinicopathological characteristics, treatment modalities, and outcomes between the HRD and HRP groups in CRC.
METHODS
Next-generation sequencing was performed on 268 CRC patients to identify tumor-associated genetic alterations and assess their HRD scores and MSI status. Patients with HRD-related gene alterations or an HRD score ≥ 30 were classified into the HRD group, while the remaining patients were assigned to the HRP group. Clinical data, including staging and treatment regimens, were collected for analysis. Cox regression and Kaplan-Meier survival curves were employed to evaluate whether the HRD group demonstrated improved survival outcomes following immunotherapy treatment.
RESULTS
Among the 268 patients, 64 were classified into the HRD group, which had a higher proportion of early-stage CRC diagnoses compared to the HRP group. Kaplan-Meier survival curves indicated significantly better survival rates in the HRD group compared to the HRP group across all cohorts, as well as among MSS patients treated with immunotherapy (P < 0.05).
CONCLUSION
This study demonstrates that CRC patients with HRD have a more favorable prognosis and suggests that HRD status could serve as a predictive marker for immunotherapy response in MSS patients.
Core Tip: This study evaluates the effectiveness of immunotherapy in microsatellite-stable (MSS) colorectal cancer (CRC) patients with homologous recombination deficiency (HRD). By analyzing 268 CRC patients through next-generation sequencing, the research identifies a significant correlation between HRD status and improved survival outcomes. Notably, MSS patients with HRD exhibited better prognoses when treated with immunotherapy compared to those with homologous recombination proficiency. These findings suggest that HRD status may serve as a critical predictive marker for immunotherapy response in MSS CRC patients.
Citation: Feng H, Zhao LY, Xu Z, Xie QF, Deng HJ, Yu J, Liu H. Homologous recombination deficiency and immunotherapy response in microsatellite-stable colorectal cancer: Evidence from a cohort study in China. World J Gastrointest Oncol 2025; 17(5): 102767
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality[1]. Metastatic CRC (mCRC) accounts for 22% of all CRC cases, with a poor 5-year survival rate of less than 15%. Patients with KRAS, NRAS, or BRAF mutations typically have a shorter median survival compared to those without these mutations[2]. Although systemic chemotherapy has shown some efficacy as the primary treatment for mCRC, a significant proportion of patients remain incurable, underscoring the urgent need for alternative therapeutic approaches[3]. In the last five years, three immunotherapy regimens, known as immune checkpoint inhibitors (ICIs), have been approved as second- or third-line treatments for mCRC with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H), including: (1) Pembrolizumab; (2) Nivolumab; and (3) Combination nivolumab plus ipilimumab[4-8]. While ICIs have significantly improved prognosis in patients with dMMR/MSI-H mCRC, their efficacy is markedly limited in patients with microsatellite-stable (MSS), who account for 95% of mCRC cases[8,9]. However, the underlying mechanisms of immunotherapy resistance in MSS patients remain poorly understood. Immunosuppression within the tumor microenvironment (TME) has been implicated in MSS mCRC, characterized by the loss of tumor antigens and the activation of immunosuppressive pathways including MAPK, PI3K, and WNT signaling. Preclinical studies have shown promising efficacy in combining ICIs with other agents that modulate the TME, aiming to overcome ICI resistance in MSS mCRC[10,11]. Additionally, a high tumor mutation burden (TMB) has been associated with favorable clinical responses to ICIs, with programmed cell death protein-1 inhibitors showing potential effectiveness in MSS CRC patients with high TMB[12-15]. This suggests that a subset of MSS CRC patients may derive significant clinical benefits from ICIs.
During tumor development and invasion, dysfunction in the DNA damage response (DDR) can lead to increased genomic mutability and instability[16]. Homologous recombination is a critical DDR pathway; deficiency in this pathway homologous recombination deficiency (HRD) can lead to DNA crosslinking, DNA double-strand breaks, and an increased reliance on error-prone alternative DDR mechanisms compared to homologous recombination proficiency (HRP) cells. HRD can lead to non-homologous end joining via poly ADP-ribose polymerase (PARP) activation, driving increased mutagenesis and genomic instability, thereby overwhelming the DNA damage repair capabilities[17-20]. HRD tumor cells may produce more peptide neoantigens or modify the tumor immune microenvironment, potentially triggering a response to ICIs. HRD-related genes have a significant impact on the prognosis and treatment of certain cancers, such as breast and ovarian cancers[21,22]. Recent research by Zhou et al[23] has indicated that HRD in non-small cell lung cancer can predict the therapeutic efficacy of neoadjuvant immunotherapy.
Despite its importance, only a limited number of studies have investigated the prognostic implications and immunotherapy outcomes of HRD in CRC patients, particularly those with MSS. This study aims to evaluate the prognosis of CRC patients with HRD or HRP status. Additionally, we assessed the microsatellite instability (MSI) status and other clinical characteristics of CRC patients with HRD through next-generation sequencing (NGS).
MATERIALS AND METHODS
Patient selection and evaluation criterion
This retrospective study was approved by the Ethics Committee of Nanfang Hospital of Southern Medical University (Guangzhou, China). Patients were enrolled at Nanfang Hospital, Southern Medical University, between June 1, 2017, and May 31, 2022, based on the following inclusion criteria: (1) Histopathologically diagnosed with CRC through biopsy or surgery, regardless of preoperative or postoperative diagnosis; (2) Absence of concurrent malignant tumors; and (3) Availability of complete demographic and clinical information. Exclusion criteria were: (1) Previous cancer-related surgery within the past 12 weeks; and (2) Loss to follow-up.
Demographic and clinicopathologic data were collected for each patient to assess their clinical characteristics. These included age, sex, weight, tumor size, histopathological type, degree of differentiation, tumor location, depth of invasion (T), lymph node metastasis (N), distant metastasis (M), tumor staging, and anti-tumor treatment. Tumor staging was defined according to the tumor-node-metastasis staging guidelines of the American Joint Committee on Cancer (8th edition). Two clinical outcomes were defined: the primary outcome, progression-free survival (PFS), was defined as the time from cancer diagnosis to the documented progression of the tumor or death from any cause; the secondary outcome, overall survival (OS), was defined as the time from cancer diagnosis to death from any cause.
Sequencing, gene, and transcriptome analyses
DNA was extracted from formalin-fixed paraffin-embedded tissues, while circulating cell-free DNA was isolated from blood samples. Indexed libraries were prepared and underwent targeted capture using a custom-designed NGS panel targeting exons of 733 cancer-related genes. The captured libraries were sequenced on the NovaSeq 6000 platform (Illumina) with 100 bp paired-end sequencing. Among the features analyzed were somatic single nucleotide variants (SNVs)[24]. Only mutations classified as pathogenic or potentially pathogenic, according to clinical trial reports and recommendations from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, were included in the study[25]. Detailed sequencing steps are provided in the Supplementary material.
To determine the MSS and MSI-H status of CRC patients, 100 microsatellite (MS) loci were selected for the MSI assay. The top 30 loci demonstrating optimal coverage were used to calculate the final MSI score. Repeat lengths were calculated for each MS site, and MS loci were classified as unstable if the cumulative distribution function for a specific length of the MS site significantly exceeded the established cutoff value. The MSI score was defined as the percentage of unstable loci, with a score ≥ 0.4 indicating MSI-H and scores below that threshold classified as MSS[26].
TMB is defined as the total number of synonymous and nonsynonymous somatic SNVs and indels in the examined coding region, excluding driver mutations. All SNVs and indels within the coding region of the target gene were considered.
Loss of heterozygosity (LOH), telomere-allele imbalance (TAI), and large-scale state transition (LST) were calculated using established methodologies[27]. TAI, which is defined as the number of allelic imbalance regions extending into a subchromosome, and LST, defined as the number of breakpoints between regions longer than 10 Mb, were determined using allelic imbalance mapping. LOH was calculated based on the number of subchromosomal LOH regions longer than 15 Mb. The HRD score was calculated as the sum of the TAI, LST, and LOH scores, providing an algorithmic assessment of three biomarkers of genomic instability.
Programmed death-ligand 1 (PD-L1) expression was assessed using immunohistochemistry with the PD-L1 antibody (22C3). The combined positive score (CPS) was calculated as the ratio of the total number of PD-L1-positive tumor cells, lymphocytes, and other cells to the total number of viable tumor cells in the sample.
Definition of HRD and HRP groups
This study focused on 33 genes involved in the homologous recombination pathways identified by Moretto and colleagues[28], as listed in Supplementary Table 1. Different experimental approaches yield varying thresholds for the HRD score when classifying patients into the HRD group. In this study, we set the HRD-score threshold at 30, a value that has been shown to identify 95% of pathogenic BRCA1/2 alterations as HRD-positive in breast and ovarian cancers. Accordingly, patients with pathogenic or likely pathogenic alterations in HRD-related genes, or with an HRD-score of ≥ 30, were classified into the HRD group, while the remaining patients were assigned to the HRP group.
Statistical analyses
Statistical analyses were performed through SPSS (version 23.0, IBM). Differences in distributions were evaluated using χ2 tests, Fisher's exact tests, or the Mann-Whitney test. Survival rates were calculated using the Kaplan-Meier method, and differences were assessed using log-rank tests. The risk of disease progression or death among groups was evaluated using hazard function curves. The Cox regression model was used to estimate hazard ratios, considering potential confounding factors. A significance level of P < 0.05 (two-sided) was considered statistically significant.
RESULTS
Participant characteristics
A total of 268 CRC patients met the inclusion criteria. The flow chart illustrating the participant selection process is shown in Figure 1. In this study cohort, the mean age was 54.9 years (SD, 53.4-56.9), with 57.05% (n = 170) being male. Adenocarcinoma (n = 216) was the most prevalent histopathological type, and the majority of tumors were located in the left colon (n = 196). Since most patients undergoing NGS testing were in advanced stages, 49 patients (18.28%) were classified as stage I or II, while 219 patients (81.72%) were classified as stage III or IV. The median PFS was 9 months (IQR, 4-15), and the median OS was 12 months (IQR, 7-18). The clinicopathological and NGS testing characteristics are summarized in Table 1.
Figure 1 The flow diagram of the study population.
CRC: Colorectal cancer; HRD: Homologous recombination deficiency; HRP: Homologous recombination proficient.
Table 1 Clinical and next-generation sequencing characteristics of colorectal cancer in the homologous recombination proficient and homologous recombination deficiency groups, n (%).
Characteristics between the HRD group and the HRP group
Out of the 268 CRC patients, 52 exhibited pathogenic or likely pathogenic somatic or germline alterations in HRD-related genes (Figure 2A). Among the 33 HRD-related genes examined, 18 were found to be altered (Figure 2B). The most frequently altered HRD-related gene was RAD50, with somatic alterations identified in 18 patients. Additionally, 15 patients had an HRD-score ≥ 30 (Figure 2C).
Figure 2 Homologous recombination deficiency-related gene alterations and homologous recombination deficiency-score distribution among colorectal cancer patients.
A: Each bar represents the number of patients carrying alterations in homologous recombination deficiency (HRD)-related genes, including germline and somatic alterations, with 52 individuals carrying the relevant alterations; B: Each bar represents the number of alterations in one HRD-related gene in the total population, including germline and somatic alterations; C: The X-axis, Y-axis, and Z-axis represent the telomere-allele imbalance, loss of heterozygosity, and large-scale state transition scores, respectively. The blue dots represent colorectal cancer patients whose sum of the three is greater than or equal to 30. HRD: Homologous recombination deficiency; LOH: Loss of heterozygosity; LST: Large-scale state transition.
Based on the presence of HRD-related alterations or an HRD-score ≥ 30, 64 patients were classified into the HRD group (n = 64, 23.9%), while the remaining 204 patients were assigned to the HRP group (n = 204, 76.1%). A comparison of clinical baseline and NGS characteristics between the two groups is summarized in Table 1. Compared to the HRP group, the HRD group exhibited a younger age at diagnosis, a higher proportion of right colon tumors, and a higher rate of early-stage diagnoses. Most patients with MSI-H and erb-B2 alterations were in the HRD group. Additionally, the HRD group demonstrated a significantly higher TMB than the HRP group (P < 0.01). No statistically significant differences were observed between the groups for other clinical features or genetic alterations. Univariate and multivariate logistic regression analyses were conducted for patients in both groups, revealing significant correlations with the HRD group for tumor location, AJCC stage, and MSI status. These factors were subsequently incorporated into the multivariable analysis, which indicated that MSI-H (OR: 118.56, 95%CI: 14.52-968.10) was independently associated with the HRD group. The detailed results of the univariate and multivariate logistic regression analyses are presented in Supplementary Table 2.
Regarding the CPS and TMB in CRC, the HRD group exhibited higher CPS and TMB levels compared to the HRP group, suggesting a potentially more favorable response to immunotherapy in the HRD group (Figure 3). Notably, even within the MSS CRC subgroup, the HRD group had higher TMB levels than the HRP group (Figure 3C).
Figure 3 Combined positive score and tumor mutation burden level distribution characteristics in colorectal cancer patients.
A: Distribution of tumor mutation burden (TMB) levels between homologous recombination deficiency (HRD) and homologous recombination proficient (HRP) groups in all patients; B: Distribution of TMB level between HRD and HRP groups in microsatellite instability-high (MSI-H) patients; C: Distribution of TMB level between HRD and HRP groups in microsatellite-stable (MSS) patients; D: Distribution of combined positive score (CPS) between HRD and HRP groups in all patients; E: Distribution of CPS between HRD and HRP groups in MSI-H patients; F: Distribution of CPS between HRD and HRP groups in MSS patients. aP < 0.05; bP < 0.01. CPS: Combined positive score; TMB: Tumor mutation burden; CRC: Colorectal cancer; HRD: Homologous recombination deficiency; HRP: Homologous recombination proficient; MSI-H: Microsatellite instability-high; MSS: Microsatellite-stable.
Differences in survival between the HRD and HRP groups
Survival analyses were conducted using Kaplan-Meier curves to compare the HRD and HRP groups. The HRD group showed significantly better PFS than the HRP group (P < 0.05, Figure 4A). However, when patients were stratified into stage I and II or stage III and IV groups, no significant differences in survival were observed between the HRD and HRP groups within each subgroup (Supplementary Figure 1).
Figure 4 Kaplan-Meier curves of progression-free survival and overall survival in homologous recombination deficiency/homologous recombination proficient cohort.
Survival curves were compared, and P values were determined using a 2-sided log-rank test. A: Progression-free survival (PFS) in all colorectal cancer (CRC) patients stratified by homologous recombination deficiency (HRD) and homologous recombination proficient (HRP) status; B: PFS in microsatellite-stable (MSS) CRC patients who received immune checkpoint inhibitors (ICIs), stratified by HRD and HRP status; C: PFS in MSS CRC patients who did not receive ICIs, stratified by HRD and HRP status; D: Overall survival (OS) in all CRC patients stratified by HRD and HRP status; E: OS in MSS CRC patients who received ICIs, stratified by HRD and HRP status; F: OS in MSS CRC patients who did not receive ICIs, stratified by HRD and HRP status. PFS: Progression-free survival; OS: Overall survival; HRD: Homologous recombination deficiency; HRP: Homologous recombination proficient; CRC: Colorectal cancer; MSS: Microsatellite-stable.
Regarding immunotherapy for CRC, in the MSI-H group, none of the patients achieved clinically relevant outcomes, preventing the generation of Kaplan-Meier curves. In the MSS group, the HRD group showed better PFS than the HRP group (P < 0.05, Figure 4B). Detailed survival data for each patient treated with ICIs in the MSS cohort are provided in Figure 5. Conversely, for MSS patients who did not receive immunotherapy, no significant survival difference was observed between the HRD and HRP groups (Figure 4C). Additionally, no significant differences in OS were observed between the HRD and HRP groups (Figure 4D-F). This may be attributed to the limited number of patients and follow-up time, as well as the influence of a few outliers. Univariable and multivariable Cox regression analyses conducted for MSS CRC patients treated with ICIs revealed an association between HRD and improved PFS (Table 2).
Figure 5 The swimmer plot of patients treated with immunotherapy in microsatellite-stable cohort.
Different colors represent the homologous recombination deficiency group and homologous recombination proficient group, respectively. The horizontal axis represents the survival time, each bar on the vertical axis represents a different patient, and symbols represent different clinical outcomes. HRD: Homologous recombination deficiency; HRP: Homologous recombination proficient.
Table 2 Univariate and multivariable Cox regression analysis of predicting progression-free survival in patients with microsatellite-stable colorectal cancer treated with immune checkpoint inhibitors.
Variable
Univariable
Multivariable
HR
95%CI
P value
HR
95%CI
P value
Gender (female vs male)
1.52
0.69-3.31
0.30
Age (> 60 vs ≤ 60 years)
1.25
0.56-2.81
0.59
BMI
< 18.5
Reference
18.5-24
2.70
0.36-20.43
0.34
> 24
3.49
0.41-29.75
0.25
Differentiation (moderately & well & chronic inflammation after neoadjuvant therapy vs poorly)
According to the 2022 NCCN guidelines and available clinical data, ICIs are recommended as the first-line treatment for advanced CRC patients with dMMR or MSI-H[6,29,30]. In contrast, the primary treatment for MSS patients remains platinum- or fluorouracil-based chemotherapy alongside targeted therapies such as bevacizumab or cetuximab[31,32]. Consequently, there is growing interest in exploring combination treatment strategies to enhance efficacy. Chen et al[33] conducted a study demonstrating that the combination of durvalumab (anti-PD-L1 antibody) and tremelimumab (anti-CTLA-4 antibody) improved OS in refractory MSS CRC patients compared to best supportive care alone, with a hazard ratio HR of 0.66 (P = 0.02). The REGONIVO/EPOC1603 phase Ib trial assessed the combination of regorafenib and nivolumab, an anti-angiogenic and immunotherapeutic agent, in refractory MSS mCRC, reporting a 36% response rate and a median PFS of 7.9 months[34]. While some phase III clinical trials have not confirmed the efficacy observed in preclinical and early clinical investigations and have shown inconsistent results in the Western population, these findings indicate that MSS is not categorically resistant to immunotherapy. This suggests that using MSS alone as a criterion for immunotherapy is incomplete. Currently, there are no established criteria or predictors for the use of ICIs in MSS CRC patients.
In this study, the researchers obtained HRD-related alterations and HRD-score levels from patients through NGS testing, subsequently dividing them into HRD and HRP groups. The threshold of 30 for distinguishing HRD from HRP in this study was carefully selected to align with the genomic characteristics of CRC. This cutoff was originally established in the context of high-grade serous ovarian cancer, primarily as a predictor of BRCA1/2 mutations and associated genomic instability. However, it has since been adapted for broader use, including other tumor types with homologous recombination repair deficiencies. In ovarian cancer, genomic instability scores (e.g., Myriad's HRD score ≥ 42) and LOH thresholds (e.g., Foundation One CDx %LOH ≥ 14%) have been widely used to predict treatment response to platinum-based chemotherapy and PARP inhibitors[35]. However, the applicability of this threshold to CRC required further validation. In this study, the selection of 30 as the HRD cutoff was not directly extrapolated from ovarian cancer models but was instead determined through a comprehensive evaluation by the sequencing company. This process incorporated genomic data specific to CRC, taking into account HRD score distributions, technical reproducibility and potential correlations with therapeutic response. By adjusting the HRD threshold to align with the distinct molecular landscape of CRC, we ensured its scientific validity and clinical relevance in this context. Future studies with larger datasets and independent validation cohorts may further refine this cutoff, but our findings support its practical utility as a stratification tool for CRC patients who may benefit from immunotherapy.
Previous studies have suggested that CRC with HRD exhibits a distinct subgroup of MSS CRCs, characterized by specific molecular and prognostic features[28]. Additionally, bioinformatics analysis of two COAD genomic datasets by Zhou et al[36] predicted that the HRD group was to have longer survival than the HRP group among CRC patients treated with ICIs. The present study found that the HRD group exhibited overall better clinical and genetic characteristics compared to the HRP group. Notably, MSS CRC patients in the HRD group had higher TMB levels than those in the HRP group, suggesting that HRD CRC patients with MSS status may still benefit from immunotherapy. Although immunotherapy is primarily utilized for CRC patients with MSI-H, some stage III or IV MSS CRC patients receiving third-line therapy showed better PFS in the HRD group compared to the HRP group. Due to the short follow-up time, the OS curves for the HRD and HRP groups did not reach statistical significance. While the response appears modest in this patient population, stratifying MSS patients based on HRD status may offer a new mechanistic explanation and research direction for immune resistance in MSS CRC patients. Moving forward, additional markers or scoring methods are needed to predict the sensitivity to ICIs in MSS CRC patients. Despite the challenges presented by MSS CRC, ongoing research and advancements in immunotherapy suggest that its future in this context remains promising.
Furthermore, this study introduces the novel concept of considering HRD status for comprehensive treatment strategies. Platinum-based regimens are commonly employed as first-line treatment for CRC[3,37,38]. Identifying HRD subgroups within CRC can enhance predictions of therapeutic efficacy of platinum-based treatments, because these agents induce covalent crosslinks within the DNA double helix[39]. Additionally, this approach may broaden the patient population that can benefit from PARP inhibitors[40]. Previous findings from a single-arm phase II study showed no superior therapeutic effect of the PARP inhibitor Olaparib in patients with chemo-resistant MSS and MSI-H mCRC[41]. However, the current study suggests that patients with chemo-resistant MSS mCRC may derive benefit from PARP inhibitors when stratified based on HRD and HRP groups.
This study had several limitations. Firstly, the researchers utilized 33 HRD-related genes and an HRD score to differentiate between the HRD and HRP groups; however, the criteria for this classification remain contentious. Secondly, while patients with germline HRD-related alterations were included in the HRD group, the distinction between somatic and germline HRD-related alterations could not be assessed at this time. Previous research has indicated that mutually exclusive bi-allelic inactivation of HR genes occurs in cancer and is associated with genomic features indicative of HR deficiency[42]. Thirdly, the data obtained from this study were sourced from a single center, necessitating future investigations with multicenter designs to validate these findings. Specifically, future studies should aim to include more stage III or IV MSS CRC patients receiving immunotherapy. Additionally, there was a selection bias in this trial, as the majority of patients undergoing NGS testing were in the mid- to late-clinical stages. Lastly, the follow-up duration in this study was relatively short, highlighting the need for future research with larger sample sizes and extended follow-up periods.
CONCLUSION
This study demonstrated that CRC patients with HRD have a better prognosis and suggested that HRD status could serve as a predictive marker for immunotherapy response in MSS CRC patients. Further research is essential to establish criteria for ICIs in MSS CRC patients and to validate these findings in larger, multicenter studies with long-term follow-up. Additionally, HRD status may enhance treatment strategies by confirming the efficacy of platinum-based regimens and expanding the patient population eligible for PARP inhibitors in MSS CRC.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade A, Grade A
Novelty: Grade A, Grade A, Grade A
Creativity or Innovation: Grade A, Grade A, Grade A
Scientific Significance: Grade A, Grade A, Grade A
P-Reviewer: Jovandaric MZ; Wang HM S-Editor: Qu XL L-Editor: A P-Editor: Zhao S
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