Granulocyte-colony-stimulating factor (G-CSF) production in carcinomas is associated with a very aggressive phenotype. Interleukin (IL)-17 secreted from tumor-infiltrating lymphocytes induces the production of G-CSF and vascular endothelial growth factor (VEGF) in cancer tissue. We present a case of a G-CSF-producing metaplastic breast carcinoma (MpBC) accompanied by systemic elevation of IL-17 and VEGF levels. A 56-year-old woman presented with a rapidly growing tumor measuring > 10 cm in her left breast. Core needle biopsy confirmed the diagnosis as MpBC with triple-negative features. Diffuse fluorodeoxyglucose uptake in the long bones and marked leukocytosis suggested that the G-CSF was produced by the primary tumor, which showed upregulated G-CSF mRNA and protein levels. Multiplex cytokine assessment identified increased serum IL-17, VEGF, and G-CSF levels. After radical mastectomy and skin grafting, the leukocyte count and serum G-CSF, IL-17, and VEGF levels were normalized. She underwent postmastectomy radiotherapy (50 Gy/25 Fr) and adjuvant chemotherapy (90 mg/m 2 of epirubicin and 600 mg/m 2 of cyclophosphamide followed by 80 mg/m 2 of paclitaxel) and is alive without recurrence. This is the first in vivo observation that describes the systemic elevation of IL-17 and VEGF levels with concomitant G-CSF production. Further research is warranted to study the IL-17/G-CSF/VEGF axis as a potential therapeutic target for this aggressive type of breast cancer.

Incidental gallbladder carcinoma (IGC), defined as unexpected malignancy identified in the surgical gallbladder specimen of a cholecystectomy performed for a benign diagnosis, can be difficult to suspect preoperatively. Furthermore, there are valid clinical reasons to defer reoperation for additional resection, particularly in elderly patients. The present study aimed to determine the long-term outcomes and prognostic factors associated with recurrence in patients with IGC. The medical records of 678 patients who underwent cholecystectomy at Toyooka Hospital between September 2011 and November 2017 were reviewed. The cases identified to be IGC were retrospectively analyzed to determine patient and histopathological characteristics, surgical details, long-term outcomes and factors associated with cancer recurrence. A total of 22 patients were diagnosed with gallbladder carcinoma following cholecystectomy by histopathological examination, and 12 of these were identified to be IGC. The median age was 80 years (range 70-89 years). Although 6 of the 12 patients with IGC had stage pT2 or pT3 tumors, only 1 patient underwent additional resection. Recurrence occurred in 3 of the 8 patients who did not undergo additional resection and were available for long-term follow-up. Recurrence was not associated with the extent of tumor invasion but may be associated with other histopathological findings, preoperative treatment history and risk factors for recurrence. Furthermore, long-term survival was observed in patients with pT2 and pT3 tumors who did not undergo additional resection. Recurrence was not associated with the extent of tumor invasion but may be associated with other histopathological findings, preoperative treatment history, and risk factors for recurrence. Furthermore, long-term survival was observed in patients with pT2 and pT3 tumors who did not undergo additional resection. Even if it is a progressive IGC case, appropriate preoperative treatment or cholecystectomy without persistence of the carcinoma cell, based on a preoperative image evaluation and a postoperative histopathological examination, may greatly influence the long-term prognosis of IGC.

Background: Abemaciclib is a selective CDK4 and CDK6 inhibitor with demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The most common adverse event across previous trials was early-onset diarrhea, affecting the patients’ quality of life and necessitating dose reductions. However, the exact mechanism for the lower rate of diarrhea in the other CDK4 and CDK6 inhibitors compared with abemaciclib is unknown. Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with the anti-tumor response; however, reported microbial signatures associated with adverse events by anti-cancer agent are inconsistent. To determine the underlying mechanism, we evaluated the correlation between diarrhea with abemaciclib and microbiota signatures in a metastatic breast cancer cohort. Methods: The KBCRN-A002 study is a multicenter, prospective cohort study, which aims to evaluate the association between gut microbiota signatures and abemaciclib-induced diarrhea in breast cancer patients. Patients with metastatic breast cancer who were receiving abemaciclib were eligible. The primary objective of this study is the correlation between diarrhea and the microbiota signatures and immune profile. Incidence and severity of diarrhea were evaluated by the Bristol stool scale at baseline, from day 1 to day 14, and at day 90 of treatment. Stool samples were collected at baseline and at day 90 after the start of abemaciclib treatment. The gut microbiota signature was evaluated by 16S rRNA analysis. Blood samples were collected at baseline and at days 14 and 90 after starting abemaciclib to evaluate the correlation between the gut microbiota signatures and the systemic immune profile in peripheral blood mononuclear cells (PBMCs). The immune profile was evaluated by mass cytometry, multi-plex cytokines assay, and RNA-sequencing of bulk PBMCs. We characterized the gut microbiota signatures, immune cell composition, immune cell signature, comprehensive cytokines, and severity of diarrhea in all patients. Results: We analyzed 39 patients, 77 stool samples, and 117 blood samples. In the preplanned interim analysis, among the 39 patients, 90% experienced diarrhea. Depleted gut microbiome α-diversity was positively associated with abemaciclib treatment and the severity of diarrhea. The relative abundances of 10 intestinal bacteria species increased and those of 18 intestinal bacteria decreased significantly after abemaciclib treatment, including bacteria known to be involved in diarrhea severity and anti-tumor immunity, such as Faecalibacterium (Table). The immune cell and cytokine profiles in PBMCs were also associated with the gut microbiota signatures. Conclusions: Gut microbiota signatures are associated with abemaciclib-induced diarrhea and the immune profile in metastatic breast cancer patients. These findings can help to elucidate the mechanism of diarrhea caused by abemaciclib and offer strategies for its management and prevention. Intestinal Microbiota Altered by Abemaciclib Citation Format: Kosuke Kawaguchi, Yurina Maeshima, Hiroshi Ishiguro, Kazuhiko Yamagami, Sachiko Takahara, Hirofumi Suwa, Masae Torii, Shigenori Nagai, Yasuaki Sagara, Wakako Tsuji, Hiroyasu Yamashiro, Takeshi Kotake, Shinji Fukuda, Kuniaki Saito, Yasuko Yamamoto, Masako Kataoka, Yuki Himoto, Atsushi Yonezawa, Yukiko Fukui, Yuki Nakamura, Wei Li, Sunao Tanaka, Satoshi Morita, Masakazu Toi. Alteration of gut microbiota signatures and its association with diarrhea during abemaciclib treatment: A multicenter prospective cohort study (KBCRN-A002 study) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-07.

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Background: Stable humanized immune mice transplanted with peripheral blood mononuclear cells (PBMCs) derived from breast cancer patients are important models for assessing the tumor immune responses and the tumor immune microenvironment in breast cancer, helping to advance both pre-clinical and clinical research. The PBMCs of breast cancer patients exhibit various differences from those of healthy individuals depending on the stage of cancer progression, subtype, and type of treatment. Recent studies indicate an association of the self-renewal signatures of T cells with successful generation of a humanized mouse model; however, the optimal T cell signature for the successful generation of a humanized mouse model derived from cancer patient cells is poorly understood. Therefore, we examined the relationship between the signature of T cell subsets, focusing on the self-renewal signatures, in PBMCs derived from patients with breast cancer and the successful generation of a humanized immune mouse model. Materials and Methods: We collected PBMCs from 12 patients with breast cancer. All samples were stimulated with interleukin-2 and beads coated with CD3 and CD28 agonist antibodies to expand T cells. After washing, 1 × 10^7 cells/mouse were intraperitoneally injected into NOD/Shi-scid IL2rgamma (null) (NOG) mice. Transplants were performed on three mice per case. Successful engraftment of immune cells into NOG mice was defined by the presence of human CD45+ cells in one or more mice. Self-renewal signatures of in vitro expanded T cells before injection into NOG mice, including the markers T cell factor-1 (TCF-1), CD45RA, CCR7, CD95, and CXCR3, were determined using flow cytometry, mass cytometry and quantitative RT-PCR. Comparisons between groups of data were evaluated by t-test. Results: The success rate of engraftment of immune cells derived from breast cancer patients into NOG mice was 66.7% (8 out of 12 patients). After expansion, the magnitude of the CD8+ stem cell memory subset and the TCF-1 expression level on the CD4+ and CD8+ T cells in the engrafted group were significantly higher than those in non-engrafted group. TCF-1 and CCR7 mRNA levels in the engrafted group were upregulated compared with those in non-engrafted group. The success of engraftment was not associated with clinical characteristics such as breast cancer progression, subtype, or prior chemotherapy treatment. Conclusion: The self-renewal signatures of T cells from breast cancer patients were associated with successful engraftment of a humanized mouse model. These results suggest that prior identification of the self-renewal signatures of the T-cell population is of direct relevance to the appropriate design of a pre-clinical model for testing immunotherapies and for elucidating the characteristics of the tumor immune microenvironment. Citation Format: Yukiko Fukui, Kosuke Kawaguchi, Ryuji Murakami, Wei Li, Yuki Nakamura, Yurina Maeshima, Sunao Tanaka, Shinpei Kawaoka, Eiji Suzuki, Masakazu Toi. Self-renewal signatures of peripheral blood T cells are associated with successful engraftment to establish a humanized mouse model of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-07.