Details of a Researcher - Hayashida, Tetsu

Papers - Hayashida, Tetsu

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増大号全領域をコンプリート!　超進化!AI時代の臨床検査各論 3章　生理学的検査乳房超音波検査

亀山友恵, 林田哲

検査と技術 (株式会社医学書院) 53 ( 8 ) 912 - 915 2025.08

Joint Work, ISSN 03012611

The Future of Breast Cancer Diagnosis in Japan with AI and Ultrasonography

Fujioka Tomoyuki, Tsukada Jitsuro, Hayashida Tetsu, Yamaga Emi, Tsukada Hiroko, Kubota Kazunori, Tateishi Ukihide

JMA Journal (Japan Medical Association / The Japanese Associaiton of Medical Sciences) 8 ( 1 ) 91 - 101 2025.01

Joint Work, ISSN 2433328X

In Japan, mammography is commonly used for breast cancer screening. However, the mortality rate has not decreased, possibly due to the low screening uptake and the high prevalence of dense breast tissue among Japanese women, which reduces mammography's effectiveness. A recent prospective study in Japan, J-START, demonstrated that combining mammography with ultrasonography increases detection rates and reduces the incidence of interval cancers, highlighting the significance of ultrasound examinations.Artificial Intelligence (AI) technologies, particularly in machine learning and deep learning, offer promising solutions to enhance the accuracy and efficiency of breast ultrasound diagnostics. This review explores AI's current capabilities in breast ultrasound imaging, emphasizing key advancements in breast lesion detection and diagnosis. Additionally, we introduce AI-based breast ultrasound diagnostic support programs approved by the Pharmaceuticals and Medical Devices Agency, which include programs for detecting lesion candidate regions and diagnosing the necessity of further examination based on detected lesion candidates. These AI tools are expected to improve diagnostic accuracy and efficiency.While AI holds significant promise, several challenges remain. It is essential for physicians to oversee its use responsibly, as there are concerns regarding patient acceptance and environmental impact. This review underscores the revolutionary potential of AI in breast cancer diagnostics and emphasizes the importance of ongoing research and development to overcome existing limitations.

A genome-wide CRISPR/Cas9 knockout screen identifies SEMA3F gene for resistance to cyclin-dependent kinase 4 and 6 inhibitors in breast cancer

Kawai Y., Nagayama A., Miyao K., Takeuchi M., Yokoe T., Kameyama T., Wang X., Seki T., Takahashi M., Hayashida T., Kitagawa Y.

Breast Cancer 32 ( 1 ) 120 - 131 2025.01

Joint Work, ISSN 13406868

Background: Palbociclib is a cell-cycle targeted small molecule agent used as one of the standards of care in combination with endocrine therapy for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Although several gene alterations such as loss of Rb gene and amplification of p16 gene are known to be conventional resistance mechanisms to cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, the comprehensive landscape of resistance is not yet fully elucidated. The purpose of this study is to identify the novel resistant genes to the CDK4/6 inhibitors in HR-positive HER2-negative breast cancer. Methods: The whole genome knockout screen using CRISPR/Cas9 genome editing was conducted in MCF7 to identify resistant genes to palbociclib. The candidate genes for resistance were selected by NGS analysis and GSEA analysis and validated by cell viability assay and mouse xenograft models. Results: We identified eight genes including RET, TIRAP, GNRH1, SEMA3F, SEMA5A, GATA4, NOD1, SSTR1 as candidate genes from the whole genome knockout screen. Among those, knockdown of SEMA3F by siRNA significantly and consistently increased the cell viability in the presence of CDK4/6 inhibitors in vitro and in vivo. Furthermore, the level of p-Rb was maintained in the palbociclib treated SEMA3F-downregulated cells, indicating that the resistance is driven by increased activity of cyclin kinases. Conclusion: Our observation provided the first evidence of SEMA3F as a regulator of sensitivity to CDK4/6 inhibitors in breast cancer. The detailed mechanisms of resistance deserve further functional studies to develop the better strategy to overcome resistance in CDK4/6 inhibitors.

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AI for Imaging Diagnosis in Breast Cancer Screening

Kataoka Masako, Fujioka Tomoyuki, Inoue Kenichi, Hayashida Tetsu, Suzuki Takashi

Nihon Nyugan Kenshin Gakkaishi (Journal of Japan Association of Breast Cancer Screening) (Japan Association of Breast Cancer Screening) 34 ( 1 ) 15 - 21 2025

Joint Work, ISSN 09180729

In breast cancer screening, AI-based computer-aided diagnosis (AI-CAD) software has been introduced into diagnostic imaging, mainly mammography (MG), with the expectation of improving sensitivity or efficiency in reading. Overseas evidence demonstrates that sensitivity and specificity of AI-CAD in diagnosing breast cancer is equivalent to those of human readers. Reducing the work load of screening by replacing one of the readers by AI-CAD has been attempted. On the other hand, pitfalls of AI-CAD include automation bias, and the fluctuation of performance by AI-CAD caused by biased training data. Furthermore, when incorporating AI into actual clinical practice, operational considerations—such as the specific conditions of each facility, feasibility of system implementation and cloud utilization, security measures, and determining who will reference the AI-CAD output and at what stage—must all be taken into account.
In the midst of the transition, it is becoming indispensable to develop guidelines at the academic society level, establish quality assurance systems, and accumulate evidence to verify AI’s usefulness over the mid to long term.

A retrospective multi-center cohort study investigating safety of sentinel lymph node biopsy for axillary staging in clinical T3-4c breast cancer

Kuba S., Sagara Y., Yano H., Maeda S., Sakai T., Kojima Y., Hattori M., Asaga S., Tokunaga E., Shien T., Bando H., Anan K., Iwakuma N., Minami S., Yamaguchi M., Harao M., Oikawa M., Sangai T., Ishitobi M., Nakayama T., Hayashida T., Tada M., Tamaki K., Kutomi G., Tomiguchi M., Harada-Shoji N., Kurashita K., Terata K., Yamanouchi K., Kubo M., Yumura C., Takahashi Y., Imoto S., Ohno S., Hayashi N.

Breast Cancer 2025

Joint Work, ISSN 13406868

Background: Sentinel lymph node biopsy (SLNB) has become a standard procedure for patients with breast cancer (BC) without clinically evident axillary metastasis. However, its role in cT3-4cN0 BC remains underexplored, leading to uncertainty regarding its safety. Methods: This retrospective, multicenter observational study included patients with cT3-4cN0M0 BC who underwent radical surgery between 2006 and 2016. Patients were divided into an SLNB group, which included those who underwent SLNB exclusively and ALND after SLNB, and an ALND group, which included those who underwent ALND exclusively. Inverse probability treatment weighting was applied to balance the patient characteristics, with recurrence-free survival (RFS) as the primary endpoint. Results: The study included 930 patients: 716 in the SLNB group and 214 in the ALND group. The ALND group had a higher proportion of patients diagnosed earlier, more T4 tumors, and more frequent use of neoadjuvant chemotherapy. During a median follow-up period of 89 months, 176 RFS events and 51 loco-regional recurrence events occurred. After adjusting for confounding factors, no significant difference was found in 10-year RFS between the groups (74.2% vs. 79.2%). Adjusted hazard ratios for RFS did not differ between the groups, even when stratified by tumor stage (cT3, cT4) or neoadjuvant chemotherapy. No significant differences were observed between the SLNB and ALND groups in loco-regional recurrence rate (LRR), with 10-year LRR rates of 93.1% and 90.8%, respectively. Conclusions: SLNB was a safe axillary staging method for patients with cT3-4cN0M0 BC and does not impact RFS or LRR negatively when compared with ALND.

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Axillary surgery in patients with breast cancer with one to three positive micro- or macrometastases in the sentinel lymph nodes: an observational study

Imoto S., Yasojima H., Nagashima T., Onishi T., Takashima T., Kitada M., Kawada M., Hayashida T., Naoi Y., Aihara T., Wada N., Kawabata H., Yoshida M., Toh U., Yoneyama K., Yamada A., Tsuda H., Masuda N., Saito-Oba M., Sakamoto J.

Breast Cancer 2025

Joint Work, ISSN 13406868

Background: The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare sentinel node biopsy (SNB) with SNB followed by axillary lymph node dissection (ALND) in breast cancer patients with positive sentinel lymph node (SLN). Patients and methods: Female patients with breast cancer with cT1-3N0-1M0 were eligible. In cases of one to three positive micro- or macrometastases in the SLN confirmed by histological or molecular diagnosis, SNB alone (SNB group) or additional ALND (ALND group) was performed under physician’s discretion. The primary endpoint was the 5-year regional node (RN) recurrence rate in the SNB group. Propensity score matching (PSM) was performed to compare the prognosis between the two groups. Results: Of the 871 eligible cases registered between 2013 and 2016, 308 underwent SNB alone. At the median follow-up of 6.3 years, 5-year RN recurrence rate was 2.7%. After PSM, 209 cases were matched in each group. Breast-conserving surgery and mastectomy were performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), two in 48 (11%), and three in 4 (1%). Macro- and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Regional nodal irradiation (RNI) was performed in 42 (20%) and 13 (6%) cases of the SNB and ALND group. The 5-year RN recurrence rate was 2.1% and 2.0%, respectively. Conclusions: ALND is not necessary for early breast cancer patients with one-positive SLN despite type of breast surgery.

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Exploring Breast Cancer Risk Management in HBOC Patients: Image Surveillance Versus Risk-reducing Surgery

Seki Tomoko, Kobayashi Yusuke, Masuda Kenta, Nakamura Kohei, Yamada Mamiko, Goto Yumiko, Misu Kumiko, Ono Ikumi, Nagayama Aiko, Hayashida Tetsu, Kitagawa Yuko

The Keio Journal of Medicine (The Keio Journal of Medicine) advpub ( 0 ) 2025

Joint Work, ISSN 00229717

In Japan, the rising incidence of hereditary breast and ovarian cancer syndrome (HBOC) follows partial insurance coverage introduced in 2020. Compared with the general population (~11% lifetime risk), individuals with HBOC face a significantly higher lifetime risk of breast cancer (48%–76%), often presenting at younger ages. BRCA1 mutations are linked to triple-negative breast cancer, whereas BRCA2 mutations typically result in luminal-type disease. Key risk management strategies include surveillance and prophylactic surgery. Annual magnetic resonance imaging and mammography are recommended at younger ages than in the general population, despite concerns regarding contrast agents, radiation exposure, and examination-related burdens. Although risk-reducing mastectomy lowers breast cancer risk by over 90%, it remains underutilized because of cosmetic and psychological considerations. Nipple-sparing or skin-sparing mastectomy combined with immediate or delayed reconstruction offers a balance between risk reduction and postoperative outcomes, although safety and procedure details still warrant careful evaluation. Managing the high breast cancer risk associated with HBOC requires ongoing efforts to refine current strategies while minimizing patient burden.

An analysis on the effect of body tissues and surgical tools on workflow recognition in first person surgical videos

Tomita H., Ienaga N., Kajita H., Hayashida T., Sugimoto M.

International Journal of Computer Assisted Radiology and Surgery 19 ( 11 ) 2195 - 2202 2024.11

Joint Work, ISSN 18616410

Purpose : Analysis of operative fields is expected to aid in estimating procedural workflow and evaluating surgeons’ procedural skills by considering the temporal transitions during the progression of the surgery. This study aims to propose an automatic recognition system for the procedural workflow by employing machine learning techniques to identify and distinguish elements in the operative field, including body tissues such as fat, muscle, and dermis, along with surgical tools. Methods : We conducted annotations on approximately 908 first-person-view images of breast surgery to facilitate segmentation. The annotated images were used to train a pixel-level classifier based on Mask R-CNN. To assess the impact on procedural workflow recognition, we annotated an additional 43,007 images. The network, structured on the Transformer architecture, was then trained with surgical images incorporating masks for body tissues and surgical tools. Results : The instance segmentation of each body tissue in the segmentation phase provided insights into the trend of area transitions for each tissue. Simultaneously, the spatial features of the surgical tools were effectively captured. In regard to the accuracy of procedural workflow recognition, accounting for body tissues led to an average improvement of 3 % over the baseline. Furthermore, the inclusion of surgical tools yielded an additional increase in accuracy by 4 % compared to the baseline. Conclusion : In this study, we revealed the contribution of the temporal transition of the body tissues and surgical tools spatial features to recognize procedural workflow in first-person-view surgical videos. Body tissues, especially in open surgery, can be a crucial element. This study suggests that further improvements can be achieved by accurately identifying surgical tools specific to each procedural workflow step.

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Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC)

Hirai I., Tanese K., Nakamura Y., Fukuda K., Ouchi T., Hayashida T., Kameyama K., Abe T., Amagai M., Funakoshi T.

Oncologist 29 ( 9 ) e1201 - e1208 2024.09

Joint Work, ISSN 10837159

Background: No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. Methods: In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. Results: All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. Conclusion: The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

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Symptom management through electronic patient-reported outcome (ePRO)-based intervention in patients with breast cancer treated with abemaciclib: Primary results from the LIBRA study, a phase II randomized controlled trial

Takano, T; Hayashida, T; Nagayama, A; Ozaki, Y; Takahashi, M; Seki, T; Yokoe, T; Aoyama, Y; Kizawa, R; Nishimura, M; Hosonaga, M; Hara, F; Kobayashi, T; Ueno, T; Kitagawa, Y

JOURNAL OF CLINICAL ONCOLOGY 42 ( 16 ) 2024.06

Joint Work, ISSN 0732-183X

Proton Pump Inhibitors and Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Breast Cancer

Takahashi K., Uozumi R., Mukohara T., Hayashida T., Iwabe M., Iihara H., Kusuhara-Mamishin K., Kitagawa Y., Tsuchiya M., Kitahora M., Nagayama A., Kosaka S., Asano-Niwa Y., Seki T., Ohnuki K., Suzuki A., Ono F., Futamura M., Kawazoe H., Nakamura T.

Oncologist 29 ( 6 ) e741 - e749 2024.06

Joint Work, ISSN 10837159

Background: Proton pump inhibitors (PPIs) reduce the bioavailability of several anticancer drugs. The impact of PPIs co-Administered with cyclin-dependent kinase 4 and 6 inhibitors is controversial. We aimed to clarify whether the concomitant use of PPIs impacts palbociclib and abemaciclib effectiveness in breast cancer treatment. Patients and Methods: This multicenter, retrospective, observational study, conducted across 4 medical institutions in Japan, consecutively included patients with endocrine-resistant metastatic breast cancer, receiving palbociclib or abemaciclib between December 2017 and August 2022. Propensity score-matched analyses were performed. Treatment efficacy and safety with and without PPIs were compared. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and compared using a log-rank test. A Cox proportional hazards model was used to estimate the hazard ratio. Results: The study included 240 patients. After 1:1 matching, 112 patients were treated with and without PPIs. The median progression-free survival period was 1.2 years in the PPI group and 1.3 years in the non-PPI group (hazard ratio, 1.19; 95% CI, 0.70-2.02). The median overall survival period was 3.6 years in the PPI group, whereas it was not reached in the non-PPI group (hazard ratio, 1.23; 95% CI, 0.61-2.47). Consistent results were obtained for subgroups receiving palbociclib (n=177) and abemaciclib (n=63) without propensity score matching. Adverse event incidence and severity were similar in both groups. Conclusion: The effectiveness of cyclin-dependent kinase 4/6 inhibitors is unlikely to be affected by concomitant PPI use. Future prospective pharmacokinetic studies are warranted.

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徹底分析シリーズ痛みのモニタリングへの挑戦 ePROを活用したがん患者の疼痛管理-ePROの現状と課題:LINE-ePROの取り組みについて

四方翔平, 林田哲, 北川雄光

LiSA ((株)メディカル・サイエンス・インターナショナル) 31 ( 5 ) 464 - 468 2024.05

Joint Work, ISSN 13408836

Clinical practice guidelines for molecular tumor marker, 2nd edition review part 2

Kikuchi Y., Shimada H., Yamasaki F., Yamashita T., Araki K., Horimoto K., Yajima S., Yashiro M., Yokoi K., Cho H., Ehira T., Nakahara K., Yasuda H., Isobe K., Hayashida T., Hatakeyama S., Akakura K., Aoki D., Nomura H., Tada Y., Yoshimatsu Y., Miyachi H., Takebayashi C., Hanamura I., Takahashi H.

International Journal of Clinical Oncology 29 ( 5 ) 512 - 534 2024.05

Joint Work, ISSN 13419625

In recent years, rapid advancement in gene/protein analysis technology has resulted in target molecule identification that may be useful in cancer treatment. Therefore, “Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition” was published in Japan in September 2021. These guidelines were established to align the clinical usefulness of external diagnostic products with the evaluation criteria of the Pharmaceuticals and Medical Devices Agency. The guidelines were scoped for each tumor, and a clinical questionnaire was developed based on a serious clinical problem. This guideline was based on a careful review of the evidence obtained through a literature search, and recommendations were identified following the recommended grades of the Medical Information Network Distribution Services (Minds). Therefore, this guideline can be a tool for cancer treatment in clinical practice. We have already reported the review portion of “Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition” as Part 1. Here, we present the English version of each part of the Clinical Practice Guidelines for Molecular Tumor Marker, Second Edition.

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PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer

Yamamoto T., Hayashida T., Masugi Y., Oshikawa K., Hayakawa N., Itoh M., Nishime C., Suzuki M., Nagayama A., Kawai Y., Hishiki T., Matsuura T., Naito Y., Kubo A., Yamamoto A., Yoshioka Y., Kurahori T., Nagasaka M., Takizawa M., Takano N., Kawakami K., Sakamoto M., Wakui M., Yamamoto T., Kitagawa Y., Kabe Y., Horisawa K., Suzuki A., Matsumoto M., Suematsu M.

Cancer Research 84 ( 7 ) 1065 - 1083 2024.04

Joint Work, ISSN 00085472

Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phos-phoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied a-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC. Significance: PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.

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増刊号 -消化器・一般外科-研修医・専攻医サバイバルブック-術者として経験すべき手技のすべて Ⅱ.体表・体壁乳腺腫瘍生検の適応と手技-吸引細胞診,針生検,マンモトーム生検,切除生検

関朋子, 林田哲, 北川雄光

臨床外科 (株式会社医学書院) 78 ( 11 ) 93 - 97 2023.10

Joint Work, ISSN 03869857

Solitary fibrous tumor of the breast: A case report.

Hirose C, Hayashida T, Saito J, Kubo A, Mikami S, Jinno H

International journal of surgery case reports 108 108369 2023.07

Joint Work, ISSN 2210-2612

Introduction: Solitary fibrous tumors (SFTs) are uncommon mesenchymal neoplasms that comprise <2 % of all soft tissue tumors. They are a diagnostically challenging group of neoplasms that can occur essentially anywhere. Molecular or genetic testing of soft tissue tumors will increasingly add to the foundation of distinctive histologic features, as accurate diagnosis is critical for appropriate treatment. Case presentation: A 28-year-old woman was referred to our hospital for a left breast mass. Ultrasonography showed an oval hypoechoic mass with partially obscured boundaries. Surgical specimens revealed spindle tumor cells surrounding the mammary ducts and were immunoreactive for both CD34 and STAT6, suggesting SFTs. However, the infiltration of spindle tumor cells into the surrounding fat, and the storiform-like pattern made us consider dermatofibrosarcoma protuberans (DFSP) as a differential diagnosis. Lack of amplification of the COL1A1-PDGFB fusion gene, a characteristic feature of DFSP, led to our definitive diagnosis of breast SFT. Discussion: The presence of STAT6 in tumor cell nuclei is a highly sensitive immunohistochemical marker for SFT. In our case, morphological features evoked the differential diagnosis of DFSP and we investigated the COL1A1-PDGFB fusion gene. The diagnostic process of reliably performing careful morphological examination and immunohistochemical marker test, and then obtain conviction by molecular cytogenetic technique is more and more important for soft tissue tumors. Conclusions: We report a quite uncommon case of breast SFT and excluded DFSP as a differential diagnosis. If it is difficult to distinguish between these diseases, molecular cytogenetic analysis would be required for accurate diagnosis.

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Copy number alteration is an independent prognostic biomarker in triple-negative breast cancer patients.

Nagahashi M, Ling Y, Toshikawa C, Hayashida T, Kitagawa Y, Futamura M, Kuwayama T, Nakamura S, Yamauchi H, Yamauchi T, Kaneko K, Kanbayashi C, Sato N, Tsuchida J, Moro K, Nakajima M, Shimada Y, Ichikawa H, Lyle S, Miyoshi Y, Takabe K, Okuda S, Wakai T

Breast cancer (Tokyo, Japan) 30 ( 4 ) 584 - 595 2023.07

Joint Work, ISSN 1340-6868

Background: Next-generation sequencing (NGS) has enabled comprehensive genomic profiling to identify gene alterations that play important roles in cancer biology. However, the clinical significance of these genomic alterations in triple-negative breast cancer (TNBC) patients has not yet been fully elucidated. The aim of this study was to clarify the clinical significance of genomic profiling data, including copy number alterations (CNA) and tumor mutation burden (TMB), in TNBC patients. Methods: A total of 47 patients with Stage I–III TNBC with genomic profiling of 435 known cancer genes by NGS were enrolled in this study. Disease-free survival (DFS) and overall survival (OS) were evaluated for their association to gene profiling data. Results: CNA-high patients showed significantly worse DFS and OS than CNA-low patients (p = 0.0009, p = 0.0041, respectively). TMB was not associated with DFS or OS in TNBC patients. Patients with TP53 alterations showed a tendency of worse DFS (p = 0.0953) and significantly worse OS (p = 0.0338) compared with patients without TP53 alterations. Multivariable analysis including CNA and other clinicopathological parameters revealed that CNA was an independent prognostic factor for DFS (p = 0.0104) and OS (p = 0.0306). Finally, multivariable analysis also revealed the combination of CNA-high and TP53 alterations is an independent prognostic factor for DFS (p = 0.0005) and OS (p = 0.0023). Conclusions: We revealed that CNA, but not TMB, is significantly associated with DFS and OS in TNBC patients. The combination of CNA-high and TP53 alterations may be a promising biomarker that can inform beyond standard clinicopathologic factors to identify a subgroup of TNBC patients with significantly worse prognosis.

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今月の臨床乳腺-産婦人科医が知っておくべき必須知識乳がんの治療と管理初期治療-外科治療,化学療法・放射線療法

林田哲, 北川雄光

臨床婦人科産科 (株式会社医学書院) 77 ( 3 ) 347 - 352 2023.04

Joint Work, ISSN 03869865

Clinicopathological features, genetic alterations, and BRCA1 promoter methylation in Japanese male patients with breast cancer.

Shimomura A, Yoshida M, Kubo T, Yamashita S, Noguchi E, Nagayama A, Hanamura T, Okazaki M, Mukohara T, Tsuruga A, Tanaka K, Kawamura Y, Higuchi T, Takahashi Y, Kurozumi S, Hayashida T, Ichikawa H, Ushijima T, Suto A

Breast cancer research and treatment 197 ( 3 ) 593 - 602 2023.02

Joint Work, ISSN 0167-6806

Purpose: Male breast cancer (MBC) is a rare cancer accounting for only 1% of all male cancers and is, therefore, poorly studied. We aimed to characterize the subtypes of MBC in Japanese patients based on genetic profiling, the presence of tumor-infiltrating cells, and the expression of immunohistochemical markers. Methods: This retrospective study included 103 patients with MBC diagnosed between January 2009 and December 2019 at various hospitals in Japan. Clinicopathological patient characteristics were obtained from medical records, and formalin-fixed paraffin-embedded tissue specimens were analyzed for histological markers, mutations of 126 genes, BRCA1 methylation, and stromal tumor-infiltrating lymphocytes. Results: The median patient age was 71 (range 31–92) years. T1-stage tumors were the most frequent (47.6%), and most were node negative (77.7%). The majority of tumors were positive for estrogen receptor (98.1%), progesterone receptor (95.1%), and androgen receptor (96.1%), and BRCA2 was the most frequently mutated gene (12.6%). The most common treatment was surgery (99.0%), either total mastectomy (91.1%) or partial mastectomy (7.0%). Survival analysis showed a 5-year recurrence-free survival rate of 64.4% (95% confidence interval [CI] 46.7–88.8) and a 5-year overall survival rate of 54.3% (95% CI 24.1–100.0). Conclusion: Japanese MBC is characterized by a high rate of hormonal receptor positivity and BRCA2 somatic mutation. Due to the observed clinicopathological differences in MBC between the Western countries and Japan, further prospective studies are needed to evaluate the most suitable treatment strategies.

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Polysulfide Serves as a Hallmark of Desmoplastic Reaction to Differentially Diagnose Ductal Carcinoma In Situ and Invasive Breast Cancer by SERS Imaging.

Kubo A, Masugi Y, Hase T, Nagashima K, Kawai Y, Takizawa M, Hishiki T, Shiota M, Wakui M, Kitagawa Y, Kabe Y, Sakamoto M, Yachie A, Hayashida T, Suematsu M

Antioxidants (Basel, Switzerland) 12 ( 2 ) 2023.01

Joint Work, ISSN 2076-3921

Pathological examination of formalin-fixed paraffin-embedded (FFPE) needle-biopsied samples by certified pathologists represents the gold standard for differential diagnosis between ductal carcinoma in situ (DCIS) and invasive breast cancers (IBC), while information of marker metabolites in the samples is lost in the samples. Infrared laser-scanning large-area surface-enhanced Raman spectroscopy (SERS) equipped with gold-nanoparticle-based SERS substrate enables us to visualize metabolites in fresh-frozen needle-biopsied samples with spatial matching between SERS and HE staining images with pathological annotations. DCIS (n = 14) and IBC (n = 32) samples generated many different SERS peaks in finger-print regions of SERS spectra among pathologically annotated lesions including cancer cell nests and the surrounding stroma. The results showed that SERS peaks in IBC stroma exhibit significantly increased polysulfide that coincides with decreased hypotaurine as compared with DCIS, suggesting that alterations of these redox metabolites account for fingerprints of desmoplastic reactions to distinguish IBC from DCIS. Furthermore, the application of supervised machine learning to the stroma-specific multiple SERS signals enables us to support automated differential diagnosis with high accuracy. The results suggest that SERS-derived biochemical fingerprints derived from redox metabolites account for a hallmark of desmoplastic reaction of IBC that is absent in DCIS, and thus, they serve as a useful method for precision diagnosis in breast cancer.

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