Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers

Noh, Joseph J.; Kim, Min Kyu; Choi, Min Chul; Lee, Jeong‐Won; Park, Hyun; Jung, Sang Geun; Joo, Won Duk; Song, Seung Hun; Lee, Chan

doi:10.4143/crt.2021.828

Cited by 19 publications

(13 citation statements)

References 34 publications

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“…However, it is important to note that the patients in the prior meta-analysis were mainly diagnosed with NSCLC and melanoma, which are known to respond favorably to ICIs, whereas patients in the present study were diagnosed with gynecologic malignancies, which have been reported to respond to ICIs in approximately 20% of cases regardless of MMR status. 11 12 Considering this, our results are encouraging, in that the response rate to ICI rechallenge among patients with recurrent gynecologic cancers, which have a relatively limited response to ICIs, was comparable to that reported in the prior meta-analysis.…”

Section: Discussionsupporting

confidence: 75%

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies

Kim,

Chang,

Choi

et al. 2023

Yonsei Med J

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Purpose We investigated the treatment outcomes of immune checkpoint inhibitor (ICI) rechallenge in patients with recurrent gynecologic cancers. Materials and Methods We retrospectively reviewed the medical records of 20 patients who underwent rechallenge with PD-1 inhibitors for recurrent gynecologic cancers at two tertiary centers between January 2018 and September 2022. Results The median age of the patients was 56 years (range, 35–79). Seven (35%), 1 (5%), 11 (55%), and 1 (5%) patients presented with cervical, vulvar, ovarian, and endometrial cancers, respectively. Sixteen (80%) patients received pembrolizumab and 4 (20%) received nivolumab at first treatment. Eight (40%) and 12 (60%) patients received pembrolizumab and nivolumab, respectively, at second treatment. At initial ICI treatment, 1 (5%) and 4 (20%) cases of a complete response (CR) and a partial response (PR) were observed, respectively, with a median progression-free survival (PFS) of 2.8 months (range, 1.4–49.6). Reasons for first ICI discontinuation were disease progression (n=16), severe adverse events (AEs) (n=2), and treatment withdrawal (n=2). During second ICI treatment, 1 (5%) patient achieved CR, 2 (10%) showed PR, and 5 (25%) experienced stable disease. The median PFS to second ICI was 1.8 months (range, 0.4–10.4). The median overall survival was 21.3 months (range, 10.1–52.7). Neither patient who discontinued ICI treatment due to AEs experienced AE relapse during second ICI treatment. Conclusion These results suggest that responses to ICI rechallenge are not as intolerable as responses to previous ICI. Clinicians should carefully consider rechallenge with PD-1 inhibitors outside of clinical trials until there are sufficient data to routinely support this practice.

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Section: Discussionsupporting

confidence: 75%

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies

Kim,

Chang,

Choi

et al. 2023

Yonsei Med J

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“…Deficiency in DNA repair mechanisms results in a hypermutated genome, making it a surrogate marker of TMB, as well as a predictive biomarker for ICI therapy. Patients with MSI/dMMR showed a lasting response to pablizumab in multiple clinical trials ( 28 , 44 – 46 ), but the proportion of MSI mutations in cervical cancer is only approximately 3-%-11.3%, as shown in previous studies ( 47 , 48 ).…”

Section: Icis In Cervical Cancermentioning

confidence: 52%

Immune checkpoint inhibitors in cervical cancer: Current status and research progress

et al. 2022

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Cervical cancer is the second most common gynecological malignant tumor endangering the health of women worldwide. Despite advances in the therapeutic strategies available to treat cervical cancer, the long-term prognosis of patients with recurrent and metastatic cervical cancer remains unsatisfactory. In recent years, immune checkpoint inhibitors (ICIs) have shown encouraging efficacy in the treatment of cervical cancer. ICIs have been approved for use in both first- and second-line cervical cancer therapies. This review summarizes the current knowledge of ICIs and the application of ICIs in clinical trials for the treatment of cervical cancer.

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“…In our preclinical study, we observed various tumor response rates, ranging from the highest (40%) in the JC model to the lowest (23%) in the E0771 model. In patients, ICI e cacies also vary based on the types of cancers or various predictive biomarkers including PD-L1, microsatellite instability (MSI)/mismatch repair de ciency (MMRd), tumor mutation burden (TMB), tumor in ltrating lymphocytes, and cytokines [18][19][20][21]. In our preclinical study, these different tumor response rates based on the syngeneic TNBC mice models may be due to different biological features in several aspects, such as tumor in ltrating lymphocytes, T cell proliferation, and cytokines just like in patients with cancer [22].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Platform Using a Triple-negative Breast Cancer Syngeneic Murine Model to Evaluate Immune Checkpoint Inhibitors

et al. 2022

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To evaluate the feasibility of syngeneic mouse models of breast cancer by analyzing the e cacy of immune checkpoint inhibitors (ICIs) and potential predictive biomarkers. MethodsFour syngeneic mouse models of triple-negative breast cancer (TNBC) JC, 4T1, EMT6 and E0771 cells were injected subcutaneously. When the tumor reached 50-100 mm 3 , each mouse model was divided into treatment (murine PD-1 antibody) and no-treatment control. Treatment group is further divided into the responder and nonresponder groups. Potential predictive biomarkers were evaluated by analyzing serum cytokines, peripheral blood T cells and tumor in ltrating immune cells. ResultsThe JC model showed the highest tumor response rate (40%, 4/10) of syngeneic models: 4T1 (36%, 4/11), EMT6 (36%, 4/11), or E0771 model (23%, 3/13). Early change of tumor size at 7 days post PD-1 inhibitor treatment predicted the nal e cacy of PD-1 inhibitor. Peripheral blood CD8 + and CD4 + T cells with or without Ki67 expression at 7 days post-PD-1 inhibitor treatment were higher in the nally designated responder group than in the nonresponder group. At the time of sacri ce, analyses of tumor in ltrating lymphocytes consistently supported these results. Furthermore, serum IFN-γ at 7 days post-PD-1 inhibitor treatment was also higher in responders than in nonresponders, suggesting that early changes of these markers could be predictive biomarkers of the nal e cacy of ICIs. ConclusionsOur syngeneic mouse model of TNBC is a feasible preclinical platform to evaluate ICI e cacies combined with other drugs and predictive biomarkers in the screening period of immune-oncology drug development.

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Frequency of Mismatch Repair Deficiency/High Microsatellite Instability and Its Role as a Predictive Biomarker of Response to Immune Checkpoint Inhibitors in Gynecologic Cancers

Cited by 19 publications

References 34 publications

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies

Rechallenge with Anti-PD-1 Inhibitors in Patients with Recurrent Gynecologic Malignancies

Immune checkpoint inhibitors in cervical cancer: Current status and research progress

Preclinical Platform Using a Triple-negative Breast Cancer Syngeneic Murine Model to Evaluate Immune Checkpoint Inhibitors

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