Ryu JM, et al. J Breast Cancer. 2023 Apr;26:e17. https://doi.org/10.4048/jbc.2023.26.e17

Triple-negative breast cancer (TNBC) is known for aggressive biologic features and poor prognosis. Epidermal growth factor receptor (EGFR) overexpression in TNBC indicates poor prognosis. However, there is no previous study of the relationship between expression of the entire human epidermal growth factor receptor (HER) family genes and patient prognosis in TNBC. Accordingly, we investigated the expression profiles of HER family genes in patients with TNBC to determine the prognostic value and clinical implications of HER family expression. We used the nCounter expression assay (NanoString®) to measure the expression of EGFR, erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, and estrogen receptor 1 (ESR1) genes using mRNA extracted from paraffin-embedded tumor tissues from 203 patients diagnosed with TNBC. Our data were validated using a separate cohort of 84 TNBC patients. A total of 203 TNBC patients who received adjuvant chemotherapy after curative surgery from 2000 to 2004 formed the training set. The 84 TNBC patients in the validation consort were selected from breast cancer patients who received curative surgery since 2005 to 2010. Analysis of the expression profiles of the HER family genes in TNBC tissue specimens revealed that increased expression of ERBB4 was associated with poor prognosis according to survival analysis (5-year distant relapse free survival [5Y DRFS], low vs. high expression [cut-off: median]: 90.1 % vs. 80.2 %; p = 0.022). This trend was also observed in the validation set of TNBC patients (5Y DRFS, low vs. high: 69.4 % vs. 44.7 %; p = 0.053). In a multivariate Cox regression model, ERBB4 expression was identified as a indicator of long-term prognosis in patients with TNBC. The expression profile of ERBB4, a member of the HER family, might serve as a prognostic marker in patients with TNBC.

Background: TP53 is the most commonly mutated gene across all cancer types. R175H mutation was considered structural mutation where the mutation causes misfolding of the protein and leads to a significant conformational alterations within p53's DNA binding domain. The aim of this study was to explain the reason why R175H worse the response to immunotherapy by analyzing tumor immune microenvironment through the expression of immune cells and PD‐1.Materials and Methods: Patients diagnosed with metastatic carcinoma, including colorectal cancer (CRC), breast cancer (BRCA), gastric cancer (GC), non‐small cell lung cancer (NSCLC), and 20 other cancer types, treated in a palliative setting at Samsung Medical Center between October 2019 and April 2021, were enrolled. Of these patients, those who underwent TDS analysis (TruSight™ Oncology 500 assay [TSO 500]) were finally analyzed.Results: Of 1770 patients, 1012 (57.2%) harbored genetic alterations in TP53. All mutations were single nucleotide variants (SNVs), and the most frequent SNV was R175H (n = 84, 7.5%) which was known as one of the most common hotspot TP53 mutation. The overall survival of patients with TP53 R175H mutations was significantly worse following chemotherapy (606 vs. 456 days, p < 0.001) or immunotherapy (822 vs. 350 days, p < 0.001) compared to those with TP53 mutation in other loci. RNA sequencing indicated that the immune response‐related pathways were downregulated in tumors harboring TP53 R175H mutation. Moreover, the expression of CD8(+) T cells PD‐1 were lowered in R175H mutation tumors. In the analysis of TP53 structural domain, compared to those having TP53 mutation in other domain, patients with mutations occurring in the nuclear exporter signal (NES) and E4F1‐binding domains had significantly worse overall survival following chemotherapy (NES: 606 vs. 451 days, p = 0.043; E4F1: 606 vs. 469 days, p = 0.046) and immunotherapy (NES: 822 vs. 403 days, p < 0.001; E4F1: 822 vs. 413 days, p < 0.001). In addition, tumors with TP53 mutation and co‐existing copy number amplification of CCND1, FGF4, and FGF19 in chromosome 11 conferred worse prognosis than those with only TP53 mutation (p < 0.050).Discussion: Each TP53 mutations indicated differential treatment outcomes following chemotherapy or immunotherapy in patients with metastatic cancer. Functional analysis including RNASeq suggested that TP53 mutation downregulated immune response.Conclusion: Overall, we found each TP53 mutation to indicate different prognoses in patients with metastatic tumors undergoing chemotherapy and ICI treatment. Further validations, including a prospective cohort study or a functional study, would be particularly valuable in advancing the knowledge on this aspect and developing improved prognostic parameters.

Residual cancer burden (RCB) is a strong prognostic marker after neoadjuvant chemotherapy (NAC) in breast cancer (BC), yet some BCs defy their predicted outcomes. Using single-cell spatial transcriptomics and genomic profiling, we investigate mechanisms underlying divergent fates of BCs with high RCB across subtypes. In triple-negative BC (TNBC), CXCL9+ macrophage-CD8⁺ T cell interactions via chemokines and interferon-gamma signaling promote favorable outcomes, while SPP1+ macrophage-cancer cell interactions driven by hypoxia signaling correlate with poor prognosis. In non-TNBC, the extent of basal-like cancer cells and their proximity to scarce immune cells are linked to prognosis. Additionally, tumor-intrinsic features-such as homologous recombination deficiency in hormone receptor (HR)-positive cancers and structural variations, including extrachromosomal ERBB2 DNA in human epidermal growth factor receptor 2 (HER2)-positive cancers-predict worse outcomes. This study highlights distinct genomic and microenvironmental strategies governing BC subtype-specific fates after NAC.

PURPOSE: Current studies of the efficacy of scalp cooling are limited by short-term duration. Therefore, we conducted a randomized controlled trial to evaluate the efficacy of scalp cooling in reducing persistent chemotherapy-induced alopecia (PCIA) 6 months after chemotherapy. METHODS: We conducted an open-label randomized controlled trial comparing scalp cooling versus control in newly diagnosed patients with breast cancer stages I-III scheduled to receive neoadjuvant or adjuvant chemotherapy with curative intent between December 2020 and August 2021. Patients were randomly assigned (2:1 ratio) to scalp cooling or usual clinical practice. The primary outcome was PCIA 6 months after chemotherapy. Hair thickness and density were measured using Folliscope 5.0. CIA-related distress was assessed using the CIA distress scale (CADS), with a higher score reflecting higher stress. RESULTS: The proportion of patients with PCIA at 6 months was 13.5% (12/89) in the scalp-cooling group and 52.0% (26/50) in the control group. The average difference in the change in hair thickness from baseline between the scalp-cooling and control groups was 9.0 μm in favor of the intervention group. The average difference in the change in hair density between intervention and control at the end of the study was –3.3 hairs/cm². At 6 months after chemotherapy, the average difference in the change in CADS score between the intervention and control groups was –3.2 points, reflecting reduced CIA-related stress in the intervention group. CONCLUSION: Scalp cooling reduced the incidence of PCIA, primarily by increasing hair thickness compared with control. Scalp cooling is helpful in promoting qualitative hair regrowth. Yet, further research is necessary to observe longer-term benefits of scalp cooling.

Apocrine carcinoma is a rare breast cancer subtype. As such, the genomic characteristics of apocrine carcinoma with triple negative immunohistochemical results (TNAC), which has been treated as triple negative breast cancer (TNBC), have not been revealed. In this study, we evaluated the genomic characteristics of TNAC compared to TNBC with low Ki-67 (LK-TNBC). In the genetic analysis of 73 TNACs and 32 LK-TNBCs, the most frequently mutated driver gene in TNAC was TP53 (16/56, 28.6%), followed by PIK3CA (9/56, 16.1%), ZNF717 (8/56, 14.3%), and PIK3R1 (6/56, 10.71%). Mutational signature analysis showed enrichment of defective DNA mismatch repair (MMR)-related signatures (SBS6 and SBS21) and the SBS5 signature in TNAC, whereas an APOBEC activity-associated mutational signature (SBS13) was more prominent in LK-TNBC (Student’s t test, p < 0.05). In intrinsic subtyping, 38.4% of TNACs were classified as luminal A, 27.4% as luminal B, 26.0% as HER2-enriched (HER2-E), 2.7% as basal, and 5.5% as normal-like. The basal subtype was the most dominant subtype (43.8%) in LK-TNBC (p < 0.001), followed by luminal B (21.9%), HER2-E (21.9%), and luminal A (12.5%). In the survival analysis, TNAC had a five-year disease-free survival (DFS) rate of 92.2% compared to 59.1% for LK-TNBC (P = 0.001) and a five-year overall survival (OS) rate of 95.3% compared to 74.6% for LK-TNBC (P = 0.0099). TNAC has different genetic characteristics and better survival outcomes than LK-TNBC. In particular, normal-like and luminal A subtypes in TNAC have much better DFS and OS than other intrinsic subtypes. Our findings are expected to impact medical practice for patients diagnosed with TNAC.