Comparison of the Modified Immunohistochemical Marker Score and 21-Gene Recurrence Score Assay in Patients with Estrogen Receptor-Positive Breast Cancer.

INTRODUCTION: Not only the 21-gene recurrence score (RS) assay but also online prognostic tools and immunohistochemical prognostic models predict chemotherapy benefits for women with early breast cancer (BC). Multigene assays, including Oncotype DX, are expensive and not covered by insurance in some countries Methods: In this study, we retrospectively analyzed a series of 155 patients with estrogen receptor-positive primary BC for whom an Oncotype DX assay was performed between January 2016 and August 2021. The patients' modified immunohistochemical marker (mIHC4) scores were calculated on the basis of their pathological reports. The correlations of the RS with the online tool PREDICT and mIHC4 scores were evaluated. RESULTS: Of the patients, 43.9% were premenopausal, 147 (94.8%) had T1 or T2 tumor, and 55.5% had no positive lymph nodes. Low (0-10), intermediate (11-25), and high RSs (26-100) were obtained in 16.1%, 61.9%, and 21.9% of the patients, respectively. The RS showed no correlation with the PREDICT score (r = 0.2720) but correlated with the mIHC4 score (r = 0.6356). In addition, a stronger correlation was observed in the patients with no node involvement and in the postmenopausal patients (r = 0.6609 and r = 0.7277, respectively). CONCLUSIONS: A relatively strong correlation was observed between the RS and the mIHC4 score. The mIHC4 score is a potentially easy and useful tool to guide adjuvant chemotherapy decision making, especially for postmenopausal patients with no node involvement if a genomic test could not be performed for some reason.

DPYSL3 modulates mitosis, migration, and epithelial-to-mesenchymal transition in claudin-low breast cancer.

A Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteogenomic analysis prioritized dihydropyrimidinase-like-3 (DPYSL3) as a multilevel (RNA/protein/phosphoprotein) expression outlier specific to the claudin-low (CLOW) subset of triple-negative breast cancers. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive ([Formula: see text]) CLOW cell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition (EMT) markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative ([Formula: see text]) CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2 (PAK2)-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

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.

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.

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.

Long-term response to olaparib in a patient with metastatic pancreatic cancer associated with hereditary breast and ovarian cancer syndrome.

BRCA mutations are associated with an increased risk of pancreatic cancer (PC). Olaparib, an oral poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, has been approved for the treatment of metastatic PC with a germline BRCA mutation. In this report, we present the case of a metastatic PC harboring a germline BRCA2 mutation, and the daughter of the patient, who had bilateral breast cancers harboring the same germline mutation, suggesting that the PC was associated with hereditary breast and ovarian cancer syndrome. Although PC is an aggressive disease and has poor prognosis, olaparib was administered as maintenance therapy following modified FOLFIRINOX, providing clinical benefits for >12 months.

Large Breast Tumor Ulceration and Quality of Life in an 80-Year-Old Woman.

Advanced breast cancer with skin ulceration, bleeding, and odor is associated with impaired quality of life (QoL). In patients with metastatic breast cancer, treatment aims to relieve symptoms, improve QoL, and slow the progression of cancer. Occasionally, it is extremely difficult to alleviate symptoms and improve QoL in patients with breast cancer and skin ulceration, especially elderly patients. Since patient age, patient preferences, and the expected survival benefit from treatment are factors that influence the selection of therapy, physicians should provide an optimal treatment for patients with metastatic disease depending on the situation. In this study, we report the case of an elderly patient with metastatic breast cancer who had substantial skin ulceration. In this patient, multidisciplinary treatment including chemotherapy, radiotherapy, and surgery resulted in significantly improved QoL.

Pathological Complete Response to Neoadjuvant Chemotherapy in a Patient with HER2-Positive Squamous Cell Carcinoma of the Breast.

Squamous cell carcinoma (SCC) of the breast is a rare malignancy that usually has a triple-negative phenotype and poor clinical outcomes. Because HER2-positive SCC of the breast is extremely rare, its clinicopathologic features are understudied, and the effects of neoadjuvant chemotherapy including anti-HER2-targeted therapy on the tumor are unclear, although treatment resistance was described in some reports. In this study, we reported a case of HER2-positive SCC of the breast in which a pathological complete response to neoadjuvant chemotherapy was observed.

Pneumocystis Pneumonia and Acute Kidney Injury Induced by Everolimus Treatment in a Patient with Metastatic Breast Cancer.

Everolimus, an inhibitor of the rapamycin pathway, is administered with the combination of an aromatase inhibitor for the treatment of metastatic estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancers. Interstitial lung disease is a well-known major adverse event associated with everolimus treatment, but it is often difficult to distinguish between interstitial lung disease and Pneumocystis pneumonia, a lung infection. Acute kidney injury is another adverse event that is associated with everolimus use. In this article, we report a case of Pneumocystis pneumonia without respiratory symptoms and acute kidney injury induced by everolimus treatment in a patient with ER-positive and HER2-negative metastatic breast cancer.

Concurrent Bowen's Disease of the Nipple and Breast Cancer.

Bowen's disease is a squamous cell carcinoma in situ that commonly develops on the trunk, arms, or legs and has not spread beyond the top layer of skin. It seldom develops on the nipple. We report a patient who presented with Bowen's disease of the nipple and had a concurrent breast cancer identified in the ipsilateral breast after careful examination. Histopathological examination of the surgical specimen after mastectomy confirmed the diagnoses.

Preoperative concurrent endocrine therapy with chemotherapy in luminal B-like breast cancer.

PURPOSE: Luminal B-like breast cancer is sensitive to both chemotherapy and endocrine therapy. We aimed to assess the safety and efficacy of concomitant chemotherapy and endocrine therapy compared with chemotherapy alone in the preoperative setting in luminal B-like breast cancer. METHODS: This two-arm randomized clinical trial enrolled patients with luminal B-like human epithelial growth factor 2-negative breast cancer, who were randomly assigned at a 1:1 ratio to receive preoperative chemotherapy alone or preoperative endocrine therapy concurrent with chemotherapy for 24 weeks before surgery. The primary endpoint was the pathological complete response (pCR) rate. The secondary endpoints included the clinical response rate, toxicity, and health-related quality of life (HRQOL). RESULTS: Overall, 70 patients were randomly assigned to the chemotherapy and chemo-endocrine therapy groups. The pCR rates were 9.7% and 3.0% (P = 0.319), and the clinical complete response rates were 5.9% and 5.6% (P = 0.745) in the chemotherapy and chemo-endocrine therapy groups, respectively. There were no clear differences in treatment-related adverse events or HRQOL between the two groups. CONCLUSIONS: In patients with luminal B-like breast cancer, the pCR, clinical response rate, toxicity, and HRQOL with the concomitant administration of endocrine therapy and chemotherapy were not superior to chemotherapy alone in the preoperative setting.

Response of Estrogen-Receptor-Positive Metastatic Breast Cancer to Olaparib in Late-Line Therapy.

Monotherapy with olaparib provides significant benefits over standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer, who had two or fewer previous chemotherapeutic regimens for metastatic disease. Olaparib was approved on July 2, 2018, in Japan for the treatment of patients with metastatic breast cancer with a BRCA mutation and HER2-negative status. Thus, the current experience with this drug is relatively limited. In this article, we report a case of luminal-type metastatic breast cancer harboring a BRCA1 mutation detected through BRACAnalysis (Myriad Genetics). Despite the late-line treatment, in this patient, olaparib was effective against metastatic breast cancer.

Fertility preservation before neoadjuvant chemotherapy in a premenopausal breast cancer patient: a case report.

Neoadjuvant chemotherapy is now a widely accepted treatment modality for operable breast cancer and therefore fertility preservation is an important component of care for young patients with breast cancer. It is critical that oocyte retrieval is completed without delays in the initiation of neoadjuvant chemotherapy. Here we report the case of a 34-year-old woman who was diagnosed with Stage IIA triple-negative breast cancer and underwent ovarian stimulation for fertility preservation prior to the initiation of neoadjuvant chemotherapy. Oocytes were retrieved and in vitro fertilization was conducted before neoadjuvant chemotherapy was started. Upon completion of neoadjuvant chemotherapy, the patient underwent breast surgery. Subsequently, a pathological complete response was achieved. She received a frozen embryo transfer 10 months after breast surgery. The patient became pregnant and delivered a healthy baby.

Author Correction: Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair.

This corrects the article DOI: 10.1038/ncomms16102.

Functional Annotation of ESR1 Gene Fusions in Estrogen Receptor-Positive Breast Cancer.

RNA sequencing (RNA-seq) detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor-positive (ER+) breast cancer, but their role in disease pathogenesis remains unclear. We examined multiple ESR1 fusions and found that two, both identified in advanced endocrine treatment-resistant disease, encoded stable and functional fusion proteins. In both examples, ESR1-e6>YAP1 and ESR1-e6>PCDH11X, ESR1 exons 1-6 were fused in frame to C-terminal sequences from the partner gene. Functional properties include estrogen-independent growth, constitutive expression of ER target genes, and anti-estrogen resistance. Both fusions activate a metastasis-associated transcriptional program, induce cellular motility, and promote the development of lung metastasis. ESR1-e6>YAP1- and ESR1-e6>PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, and a patient-derived xenograft (PDX) naturally expressing the ESR1-e6>YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression, explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective.

Phosphorylated HBO1 at UV irradiated sites is essential for nucleotide excision repair.

HBO1, a histone acetyl transferase, is a co-activator of DNA pre-replication complex formation. We recently reported that HBO1 is phosphorylated by ATM and/or ATR and binds to DDB2 after ultraviolet irradiation. Here, we show that phosphorylated HBO1 at cyclobutane pyrimidine dimer (CPD) sites mediates histone acetylation to facilitate recruitment of XPC at the damaged DNA sites. Furthermore, HBO1 facilitates accumulation of SNF2H and ACF1, an ATP-dependent chromatin remodelling complex, to CPD sites. Depletion of HBO1 inhibited repair of CPDs and sensitized cells to ultraviolet irradiation. However, depletion of HBO1 in cells derived from xeroderma pigmentosum patient complementation groups, XPE, XPC and XPA, did not lead to additional sensitivity towards ultraviolet irradiation. Our findings suggest that HBO1 acts in concert with SNF2H-ACF1 to make the chromosome structure more accessible to canonical nucleotide excision repair factors.

UV Damage-Induced Phosphorylation of HBO1 Triggers CRL4DDB2-Mediated Degradation To Regulate Cell Proliferation.

Histone acetyltransferase binding to ORC-1 (HBO1) is a critically important histone acetyltransferase for forming the prereplicative complex (pre-RC) at the replication origin. Pre-RC formation is completed by loading of the MCM2-7 heterohexameric complex, which functions as a helicase in DNA replication. HBO1 recruited to the replication origin by CDT1 acetylates histone H4 to relax the chromatin conformation and facilitates loading of the MCM complex onto replication origins. However, the acetylation status and mechanism of regulation of histone H3 at replication origins remain elusive. HBO1 positively regulates cell proliferation under normal cell growth conditions. Whether HBO1 regulates proliferation in response to DNA damage is poorly understood. In this study, we demonstrated that HBO1 was degraded after DNA damage to suppress cell proliferation. Ser50 and Ser53 of HBO1 were phosphorylated in an ATM/ATR DNA damage sensor-dependent manner after UV treatment. ATM/ATR-dependently phosphorylated HBO1 preferentially interacted with DDB2 and was ubiquitylated by CRL4(DDB2). Replacement of endogenous HBO1 in Ser50/53Ala mutants maintained acetylation of histone H3K14 and impaired cell cycle regulation in response to UV irradiation. Our findings demonstrate that HBO1 is one of the targets in the DNA damage checkpoint. These results show that ubiquitin-dependent control of the HBO1 protein contributes to cell survival during UV irradiation.

A case of Miller Fisher syndrome during preoperative chemotherapy for breast cancer.

A 53-year-old woman with breast cancer received FEC treatment (5FU: 500 mg/m(2), epirubicin: 100 mg/m(2), and cyclophosphamide: 500 mg/m(2)) every 3 weeks as preoperative chemotherapy. Fifteen days after her third cycle of FEC, she developed a cold. Diplopia occurred 4 days after developing the cold, and progressive paresthesia of the hands and weakness of the limbs occurred. She had ophthalmoplegia, ataxia, and are flexia and was diagnosed with Miller Fisher Syndrome (MFS). The cause of MFS during chemotherapy is believed to be caused by an immunological response to infection, or drug neurotoxicity. In our case, since the patient underwent an antecedent upper respiratory infection in the period of myelosuppression, her MFS was probably induced by the immunoreaction associated with this infection. Our patient underwent intravenous immunoglobulin therapy. After initiation of the treatment, her neurological symptoms improved, then, she received a fourth cycle of FEC and her remaining neurological symptoms did not worsen. Thus, we report a rare case of MFS developed in immunosuppression by chemotherapy and remind physicians of the alarming triad of MFS symptoms.

Human breast cancer tissues contain abundant phosphatidylcholine(36∶1) with high stearoyl-CoA desaturase-1 expression.

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(34:1) to that of PC(34:0) was higher in the lesions with positive ER expression [corrected]. The contribution of SCD1 and other enzymes to the formation of the observed phospholipid composition is discussed.