Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer

Tadayoshi Hashimoto, Yukinori Kurokawa, Tsuyoshi Takahashi, Yasuhiro Miyazaki, Koji Tanaka, Tomoki Makino, Makoto Yamasaki, Kiyokazu Nakajima, Jun ichiro Ikeda, Masaki Mori, Yuichiro Doki

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Abstract

Background: Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers. Methods: We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS). Results: Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%, P = 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy. Conclusions: Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.

Original languageEnglish
Pages (from-to)785-792
Number of pages8
JournalGastric Cancer
Volume22
Issue number4
DOIs
Publication statusPublished - Jul 12 2019

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Stomach Neoplasms
Ligands
Drug Therapy
Microsatellite Instability
Survival
Recurrence
MutL Protein Homolog 1
Neoplasms
DNA Mismatch Repair

All Science Journal Classification (ASJC) codes

  • Oncology
  • Gastroenterology
  • Cancer Research

Cite this

Hashimoto, T., Kurokawa, Y., Takahashi, T., Miyazaki, Y., Tanaka, K., Makino, T., ... Doki, Y. (2019). Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. Gastric Cancer, 22(4), 785-792. https://doi.org/10.1007/s10120-018-00918-4

Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. / Hashimoto, Tadayoshi; Kurokawa, Yukinori; Takahashi, Tsuyoshi; Miyazaki, Yasuhiro; Tanaka, Koji; Makino, Tomoki; Yamasaki, Makoto; Nakajima, Kiyokazu; Ikeda, Jun ichiro; Mori, Masaki; Doki, Yuichiro.

In: Gastric Cancer, Vol. 22, No. 4, 12.07.2019, p. 785-792.

Research output: Contribution to journalArticle

Hashimoto, T, Kurokawa, Y, Takahashi, T, Miyazaki, Y, Tanaka, K, Makino, T, Yamasaki, M, Nakajima, K, Ikeda, JI, Mori, M & Doki, Y 2019, 'Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer', Gastric Cancer, vol. 22, no. 4, pp. 785-792. https://doi.org/10.1007/s10120-018-00918-4
Hashimoto, Tadayoshi ; Kurokawa, Yukinori ; Takahashi, Tsuyoshi ; Miyazaki, Yasuhiro ; Tanaka, Koji ; Makino, Tomoki ; Yamasaki, Makoto ; Nakajima, Kiyokazu ; Ikeda, Jun ichiro ; Mori, Masaki ; Doki, Yuichiro. / Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer. In: Gastric Cancer. 2019 ; Vol. 22, No. 4. pp. 785-792.
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abstract = "Background: Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers. Methods: We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS). Results: Of 285 patients, 28 (9.8{\%}) and 70 (24.6{\%}) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7{\%}) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1{\%} vs. 21.0{\%}, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7{\%} vs. 61.2{\%}, P = 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9{\%} vs. 56.6{\%}, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95{\%} CI 0.09–0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95{\%} CI 0.30–1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy. Conclusions: Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.",
author = "Tadayoshi Hashimoto and Yukinori Kurokawa and Tsuyoshi Takahashi and Yasuhiro Miyazaki and Koji Tanaka and Tomoki Makino and Makoto Yamasaki and Kiyokazu Nakajima and Ikeda, {Jun ichiro} and Masaki Mori and Yuichiro Doki",
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T1 - Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer

AU - Hashimoto, Tadayoshi

AU - Kurokawa, Yukinori

AU - Takahashi, Tsuyoshi

AU - Miyazaki, Yasuhiro

AU - Tanaka, Koji

AU - Makino, Tomoki

AU - Yamasaki, Makoto

AU - Nakajima, Kiyokazu

AU - Ikeda, Jun ichiro

AU - Mori, Masaki

AU - Doki, Yuichiro

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N2 - Background: Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers. Methods: We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS). Results: Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%, P = 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy. Conclusions: Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.

AB - Background: Microsatellite instability (MSI) and programmed death-ligand 1 (PD-L1) are candidate predictors for the response to immune checkpoint inhibitors, and may predict chemotherapy sensitivity. We investigated the simultaneous expression of mutL homolog 1 (MLH1), a mismatch repair gene, and PD-L1 in gastric cancers. Methods: We examined MLH1 and PD-L1 expression in surgical specimens from 285 gastric cancer patients treated with or without preoperative chemotherapy, and assessed the relation between expression results and both histological response and recurrence-free survival (RFS). Results: Of 285 patients, 28 (9.8%) and 70 (24.6%) exhibited negative MLH1 and high PD-L1 expression, respectively. Most MLH1-negative tumors (85.7%) showed high MSI, and these tumors exhibited high PD-L1 expression more frequently than MLH1-positive tumors (57.1% vs. 21.0%, P < 0.001). MLH1-negative patients were significantly less likely to respond to preoperative chemotherapy than MLH1-positive patients (16.7% vs. 61.2%, P = 0.005), whereas there was no significant difference between high- and low-PD-L1 expression patients (55.9% vs. 56.6%, P = 0.95). RFS in patients without preoperative chemotherapy was significantly longer in the MLH1-negative group than in the MLH1-positive group (HR 0.30; 95% CI 0.09–0.95; P = 0.030), whereas in patients with preoperative chemotherapy there was no significant difference in RFS between the two groups (HR 0.70; 95% CI 0.30–1.63; P = 0.41). PD-L1 expression was not associated with RFS in patients with or without chemotherapy. Conclusions: Loss of MLH1 was associated with chemoresistance and did not prolong survival following neoadjuvant chemotherapy. The strong association between MLH1 and MSI status suggests that immune checkpoint inhibitors may be preferable to conventional chemotherapy for MLH1-negative gastric cancer.

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