A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer

Masahiro Takada¹, Shigeru Imoto², Takanori Ishida³, Yoshinori Ito⁴, Hiroji Iwata⁵, Norikazu Masuda⁶, Hirofumi Mukai⁷, Shigehira Saji⁸, Takafumi Ikeda¹, Hironori Haga⁹, Toshiaki Saeki¹⁰, Kenjiro Aogi¹¹, Tomoharu Sugie¹², Takayuki Ueno⁴, Shinji Ohno⁴, Hiroshi Ishiguro¹⁰, Chizuko Kanbayashi¹³, Takeshi Miyamoto¹⁴, Yasuhiro Hagiwara¹⁵, Masakazu Toi^{16

17}

Affiliations

¹ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Breast Surgery, Kyorin University School of Medicine, Mitaka, Japan.
³ Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
⁴ Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁵ Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁶ Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁸ Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
⁹ Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
¹⁰ Breast Oncology Service, Saitama Medical University International Medical Center, Hidaka, Japan.
¹¹ Department of Breast Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹² Breast Surgery, Kansai Medical University Hospital, Hirakata, Japan.
¹³ Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan.
¹⁴ Department of Breast Oncology, Gunma Prefectural Cancer Center, Ota, Japan.
¹⁵ Department of Biostatistics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁶ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. masakazu_toi@tmhp.jp.
¹⁷ Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan. masakazu_toi@tmhp.jp.

PMID: 37676450
PMCID: PMC10564670
DOI: 10.1007/s10549-023-07099-4

A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer

Masahiro Takada et al. Breast Cancer Res Treat. 2023 Dec.

. 2023 Dec;202(3):485-496.

doi: 10.1007/s10549-023-07099-4. Epub 2023 Sep 7.

Authors

Affiliations

¹ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
² Department of Breast Surgery, Kyorin University School of Medicine, Mitaka, Japan.
³ Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan.
⁴ Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁵ Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
⁶ Department of Breast and Endocrine Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁷ Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁸ Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan.
⁹ Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
¹⁰ Breast Oncology Service, Saitama Medical University International Medical Center, Hidaka, Japan.
¹¹ Department of Breast Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
¹² Breast Surgery, Kansai Medical University Hospital, Hirakata, Japan.
¹³ Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan.
¹⁴ Department of Breast Oncology, Gunma Prefectural Cancer Center, Ota, Japan.
¹⁵ Department of Biostatistics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁶ Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan. masakazu_toi@tmhp.jp.
¹⁷ Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan. masakazu_toi@tmhp.jp.

PMID: 37676450
PMCID: PMC10564670
DOI: 10.1007/s10549-023-07099-4

Abstract

Purpose: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups.

Methods: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated.

Results: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33-0.78) and 29% (HR: 0.71, 95% CI 0.49-1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29-0.74).

Conclusions: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

Keywords: Adjuvant; Breast neoplasms; Chemotherapy; Drug therapy; Estrogen; Receptors; Recurrence.

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Conflict of interest statement

MTa received grants from Taiho (Tokyo, Japan) during the conduct of the study and has received grants from AstraZeneca (Osaka, Japan), Daiichi Sankyo (Tokyo, Japan), Eisai (Tokyo, Japan), Yakult (Tokyo, Japan), Medbis (Kyoto, Japan), the Japan Breast Cancer Research Group Association (JBCRG), the Kyoto Breast Cancer Research Network (KBCRN), ABCSG, and IQVIA Japan; and personal fees from Chugai (Tokyo, Japan), AstraZeneca, Daiichi Sankyo, Taiho, Pfizer (Tokyo, Japan), Eli Lilly (Kobe, Japan), Eisai, and MSD (Tokyo, Japan). HIw has received consulting fees from Daiichi Sankyo, Chugai, Lilly, AstraZeneca, Pfizer, MSD, and Novartis; and received personal fees from Daiichi Sankyo, Chugai, AstraZeneca, Lilly, MSD, Pfizer, and Taiho. NM has received grants from Chugai, AstraZeneca, MSD, Pfizer, Eli Lilly, Kyowa Kirin, Eisai, Novartis, Sanofi (Tokyo, Japan), Daiichi Sankyo, and Nippon Kayaku; and personal fees from Chugai, AstraZeneca, Pfizer, Elli Lilly, Eisai, and Takeda. NM is also a member of the board of directors of the Japan Breast Cancer Society (JBCS) and JBCRG. HM has received grants from Daiichi Sankyo, and Eisai; and personal fees from Taiho, Daiichi Sankyo, and Takeda. SS has received grants from AstraZeneca, Chugai, Daiichi Sankyo, MSD, and Taiho; and personal fees from AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Kyowa Kirin, MSD, Novartis, Ono (Osaka, Japan), Pfizer, Taiho, and Takeda. SS also received advisory fees from AstraZeneca, Chugai, Daiichi Sankyo, MSD, and Pfizer. TSa has received grants from Maruho, LabCorp Japan, Sanofi, Takeda, Novartis, MSD, Sawai, Covance Japan, Taiho, WJOG, Chugai, Nippon Kayaku, AstraZeneca, Eisai, Kyowa Kirin, Daiichi Sankyo, and Eli Lilly; and personal fees from Ono, Kyowa Kirin, Chugai, ASKA, Novartis, AstraZeneca, Eisai, Taiho, Takeda, Eli Lilly, Pfizer, MiRTeL, and Meiji Seika. KA has received personal fees from Chugai, Eisai, AstraZeneca, Taiho, Daiichi Sankyo, Pfizer, and Eli Lilly; and research grant from Chugai, Eisai, and Takeda. TSu has received research grants from Chugai, Eisai, and Kyoto Bridge. For Breakthrough Medicine (KBBM); and personal fees from Chugai, MSD, AstraZeneca, Pfizer, Eli Lillym Taiho, Daiichi Sankyo, and Eisai. TU has received personal fees from Chugai, Eisai, AstraZeneca, and Novartis; and research grant from Eli lilly. SO has received personal fees from Chugai, MSD, Eli Lilly, and Nippon Kayaku. HI has received personal fees from JMS, Eisai, Pfizer, Chugai, Kyowa Kirin, and Daiichi Sankyo; and research grant from Eisai, Daiichi Sankyo, Chugai, Nipro, and Takeda. MTo received grants from Taiho during the conduct of the study and has received grants from Chugai, Takeda, Pfizer, Taiho, JBCRG, KBCRN, Eisai, Eli Lilly, Daiichi Sankyo, AstraZeneca, Astellas (Tokyo, Japan), Shimadzu (Kyoto, Japan), Yakult, Nippon Kayaku, AFI technology, Luxonus (Kawasaki, Japan), Shionogi, GL Science, and Sanwa Shurui; personal fees from Chugai, Takeda, Pfizer, Kyowa Kirin, Taiho, Eisai, Daiichi Sankyo, AstraZeneca, Eli Lilly, MSD, Exact Science (Tokyo, Japan), Novartis, Shimadzu, Yakult, Nippon Kayaku, Devicore and Sysmex; and advisory fees from Daiichi Sankyo, Eli Lilly, BMS (Tokyo, Japan), Athenex Oncology, Bertis, Terumo (Tokyo, Japan), and Kansai Medical Net. MTo is also a member of the board of directors of JBCRG, KBCRN, and Organisation for Oncology and Translational Research. The other authors declare no other potential conflicts of interest.

Figures

**Fig. 1**
Flow diagram of patient selection. The full analysis cohort of the POTENT trial comprised 1,930 patients. Thirty-three patients were excluded from the analysis because of unavailable data (30 for histological grade and 3 for tumor stage); therefore, the final analysis included 1,897 patients. A continuous composite measure of recurrence risk (composite risk) was developed using the data from the control group (standard endocrine therapy only group). We divided the patients into three risk groups based on the distribution of the composite risk values in the control group: group 1, ≤ lower quartile; group 2, interquartile range; and group 3, > upper quartile. The treatment effects of S-1 in each patient group were estimated

**Fig. 2**
Kaplan–Meier estimate of invasive disease-free survival in the endocrine therapy only group according to the patient group defined by the composite risk value. Group 1, ≤ lower quartile of the composite risk value; Group 2, interquartile range; Group 3, > upper quartile. CI, confidence interval; iDFS, invasive disease-free survival; 5-y, 5-year

**Fig. 3**
Effects of S-1 treatment in each risk group. Kaplan–Meier estimate of invasive disease-free survival. A Treatment effect of S-1 in the Group 1, B Treatment effect of S-1 in the Group 2, C Treatment effect of S-1 in the Group 3. HR hazard ratio, CI confidence interval, *iDFS* invasive disease-free survival, *5-y* 5-year

**Fig. 4**
Effects of S-1 treatment in patients fulfilling monarchE criteria. Kaplan–Meier estimate of invasive disease-free survival. A patients who met monarchE criteria, B patients who did not meet monarchE criteria, C patients who met monarchE cohort 1 criteria with one to three positive nodes, D patients who met monarchE cohort 1 criteria with four or more positive nodes, E patients who met monarchE cohort 2 criteria

See this image and copyright information in PMC

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A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer

Affiliations

A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Full Text Sources

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