Supplementary Materieal: Acquired Treatment Resistance in a Patient with Metastatic PD-L1-Positive Breast Cancer and Germline BRCA1 Mutation

 Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer associated with higher rates of relapse and mortality compared to other subtypes. Chemotherapy has been a mainstream treatment approach for TNBC due to the lack of therapeutic targets. Recent advances have led to the introduction of novel agents against specific patients with programmed death-ligand 1 (PD-L1)-positive TNBC who harbor germline BRCA mutations. However, some patients who respond to PD-L1 or poly (ADP-ribose) polymerase PARP inhibitors often develop resistance. Additionally, treatment strategies are more complicated for patients with PD-L1-positive TNBC and germline BRCA mutations. Here, we report a patient with metastatic PD-L1-positive TNBC who harbored a germline BRCA1 mutation. The patient sequentially received combination treatment regimens, including PD-L1 inhibitors with chemotherapy and the PARP inhibitor olaparib, acquiring resistance to the treatments in a couple of months. Further investigations are warranted to elucidate the mechanisms underlying resistance to PD-L1 antibodies and PARP inhibitors to improve treatment outcomes while preventing emergence of treatment resistance in patients with TNBC. </p

Complexities in Adjuvant Endocrine Therapy for Breast Cancer in Female-to-Male Transgender Patients

Introduction: Managing breast cancer in female-to-male (FtM) transgender patients is complicated and challenging. Androgens play a crucial role in the development of secondary sexual identity in FtM transgender patients, but their effectiveness in breast cancer remains unclear. Furthermore, the considerations for adjuvant endocrine therapy in this population are highly intricate and warrant thorough discussion. Case Presentation: We describe the case of a 44-year-old FtM transgender diagnosed with breast cancer 3 years after initiating androgen receptor agonist therapy as part of his gender identity transition. After mastectomy, adjuvant endocrine therapy was initiated, consisting of a combination of an aromatase inhibitor and a gonadotropin-releasing hormone agonist, along with a cross-sex hormone. Conclusion: Estradiol levels were significantly reduced, and male-typical levels of sex hormones were attained

Enrichment of Immune-Related Genes in Aggressive Primary Breast Angiosarcoma: A Case Report

Primary breast angiosarcoma is an extremely rare disease with a poor prognosis. Primary angiosarcoma is distinct from secondary angiosarcoma, which usually occurs in patients who have been previously treated for breast cancer. The low incidence of primary breast angiosarcoma has hindered the elucidation of its etiology and potential therapies. Here, we report a case of a patient with primary breast angiosarcoma who experienced recurrence after surgery. The tumor was refractory to systemic treatments, and the patient died 18 months after the surgery. We used RNA sequencing for gene expression profiling of the tumor. A high tumor inflammation signature score indicated enrichment in immune-related signaling. CIBERSORTx, a tool used to characterize the cellular composition of complex tissues based on gene expression, indicated that the immune cells in the tumor were predominantly macrophages, and this was confirmed using immunohistochemical analysis. These findings indicate the possible use of checkpoint immunotherapy for the treatment of primary breast angiosarcoma

Human Breast Cancer Tissues Contain Abundant Phosphatidylcholine(36∶1) with High Stearoyl-CoA Desaturase-1 Expression

<div><p>Breast cancer is the leading cause of cancer and mortality in women worldwide. Recent studies have argued that there is a close relationship between lipid synthesis and cancer progression because some enzymes related to lipid synthesis are overexpressed in breast cancer tissues. However, lipid distribution in breast cancer tissues has not been investigated. We aimed to visualize phosphatidylcholines (PCs) and lysoPCs (LPCs) in human breast cancer tissues by performing matrix assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS), which is a novel technique that enables the visualization of molecules comprehensively. Twenty-nine breast tissue samples were obtained during surgery and subjected to MALDI-IMS analysis. We evaluated the heterogeneity of the distribution of PCs and LPCs on the tissues. Three species [PC(32∶1), PC(34∶1), and PC(36∶1)] of PCs with 1 mono-unsaturated fatty acid chain and 1 saturated fatty acid chain (MUFA-PCs) and one [PC(34∶0)] of PCs with 2 saturated fatty acid chains (SFA-PC) were relatively localized in cancerous areas rather than the rest of the sections (named reference area). In addition, the LPCs did not show any biased distribution. The relative amounts of PC(36∶1) compared to PC(36∶0) and that of PC(36∶1) to LPC(18∶0) were significantly higher in the cancerous areas. The protein expression of stearoyl-CoA desaturase-1 (SCD1), which is a synthetic enzyme of MUFA, showed accumulation in the cancerous areas as observed by the results of immunohistochemical staining. The ratios were further analyzed considering the differences in expressions of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and Ki67. The ratios of the signal intensity of PC(36∶1) to that of PC(36∶0) was higher in the lesions with positive ER expression. The contribution of SCD1 and other enzymes to the formation of the observed phospholipid composition is discussed.</p> </div

Pathway for synthesizing MUFA-PCs catalyzed by LPCAT and LPC.

<p>Endogenously synthesized mono-unsaturated fatty acids (MUFAs) are converted from saturated fatty acids (SFA) by the catalyzing effect of stearoyl-CoA desaturase-1 (SCD1). A MUFA is added to a lyso-phosphatidylcholine (LPC) through lysophosphatidylcholine acyltransferase (LPCAT) to produce a phosphatidylcholine (PC) that contains MUFA (MUFA-PC). A MUFA-PC is degraded to a LPC and a MUFA by phospholipase A1 (PLA1) and PLA2.</p

The amount of MUFA-PCs relative to SFA-PCs was significantly higher in cancerous areas.

<p>(a) The areas that are circled with broken red lines in the hematoxylin and eosin stained image show the cancerous areas. (b) A distribution image of PC(32∶1)+K. (C) A distribution image of PC(32∶0)+K. (d) A distribution image of PC(34∶1)+K. (e) A distribution image of PC(34∶0)+K. (f) A distribution image of PC(36∶1)+K. (g) A distribution image of PC(36∶0)+K. (h) Plot of the intensities of PC(32∶1)+K. (i) Plot of the intensities of PC(32∶0)+K. (j) Plot of the intensities of PC(34∶1)+K. (k) Plot of the intensities of PC(34∶0)+K. (l) Plot of the intensities of PC(36∶1)+K. (m) Plot of the intensities of PC(36∶0)+K. (n) Plot of the ratios of PC(32∶1)+K to PC(32∶0)+K. (o) Plot of the ratios of PC(34∶1)+K to PC(34∶0)+K. (p) Plot of the ratios of PC(36∶1)+K to PC(36∶0)+K.</p

SCD1 expression and the ratios of MUFA-PCs to SFA-PCs and LPCs for differences in ER, HER2, and Ki67 expression.

<p>The intensities of SCD staining (a, h, o) and the ratios of MUFA-PC compared to SFA-PC (b–d, i–k, p–r) and LPC (e–g, l–n, s–u) were shown by the differences in ER (a–g), HER2 (h–n), and Ki67 (o–u). All of the cancer lesions were divided into two groups according to the differences in ER, HER2, and Ki67 expression and lesions with less aggressiveness are shown on the left side of each graph.</p