Influences of preoperative metformin on immunological factors in early breast cancer

Takahiro Tsukioki,Yukiko Kajihara,Hiroyoshi Doihara,Kengo Kawada,Shinichi Toyooka,Yoko Suzuki,Minami Hatono,Hirokuni Ikeda,Takayuki Iwamoto,Takehiro Tanaka,Naruto Taira,Mariko Kochi,Tadahiko Shien

doi:10.1007/s00280-020-04092-2

Takahiro Tsukioki, Yukiko Kajihara + Show 11 more

Open Access

https://doi.org/10.1007/s00280-020-04092-2

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Abstract

PurposeMetformin has been suggested to possibly reduce cancer risk. However, the mechanism underlying the positive effects of metformin on cancer treatment remains unclear. We conducted a prospective study to evaluate the effects of preoperative metformin in patients with early breast cancer.MethodWe evaluated the effects on immunological factors (TILs, CD4 + , CD8 + , PD-L1, IFNγ and IL-2) by comparing core needle biopsies (CNB) obtained before metformin treatment with surgical specimens. Seventeen patients were enrolled in this prospective study from January to December 2016. We also analyzed 59 patients undergoing surgery during the same period to reveal the correlation of immune factors between CNB and surgical specimen.ResultThere was a moderate correlation between CNB and surgical specimens on TILs and CD8 + lymphocyte. (TILs Rs = 0.63, CD4 + Rs = 0.224, CD8 + Rs = 0.42) In the metformin group, TILs increases were confirmed in five (29%) patients, while a decrease was confirmed in two (12%). The expressions of CD4 + and CD8 + by TILs were increased in 41% and 18% of surgical specimens, respectively. However, TILs number (p = 0.0554), CD4+ (p = 0.0613) and CD8 + (p = 0.0646) expressions did not significantly increased. Furthermore, IFNγ expression appeared to be increased in response to metformin (p = 0.08).ConclusionPreoperative metformin tends to increase TILs, as well as the numbers of CD4 and CD8 positive lymphocytes, and IFNγ levels. Metformin might improve immune function and have a possibility of chemo-sensitivity and thereby increase the effectiveness of immunotherapy, based on the results of this preliminary study.

Highlights

Breast cancer is among the major causes of cancer-related death in women worldwide
We gathered patients who had been diagnosed with breast cancer by core needle biopsies (CNB) and after that they took metformin in the preoperative period, and we compare CNB that was pre-metformin with surgical specimen that was post-metformin. Second, because of breast cancer is known to have tumor heterogeneities, it is not uncertain to compare CNB with surgical specimen on immune functions
The status of common biological markers did not differ between CNB and surgical specimens (Supplementary Table 1)

Summary

Introduction

Breast cancer is among the major causes of cancer-related death in women worldwide. While significant progress has been made in the diagnosis and treatment of breast cancer, the clinical outcomes of patients are still discouraging [1, 2]. Diabetes mellitus (DM) has an adverse impact on cancer. A systematic review indicated DM patients to have a 17% increased risk for breast cancer mortality [3]. One report has suggested that treating DM with metformin, that is one of the commonly prescribed drugs for type 2 DM, reduces the risk of breast cancer death as compared with sulfonylureas and insulin formulations [4]. The mechanism underlying the favorable effect of metformin on cancer epidemiology has yet to be investigated in detail

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