bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall breast cancer survival and prognostic factors.
Authors: Benzebda Hanane , Ghomari Soumeyya Bezzar
Published: June 2023

e12525

Background: Breast cancer is a frequent and heterogeneous disease where several clinical, histological and molecular factors determine its prognosis. Our objective is to estimate the prognostic factors influencing overall survival (OS) in patients with breast cancer. Methods: We conducted our first descriptive and analytical single-center study with a retrospective collection of data on files from the Medical Oncology department in University Hospital Center Tlemcen, including patients who died in 2020-2021 and were treated for breast cancer in order to estimate overall survival and determine prognostic factors. The study of survival was carried out by the Kaplan Meier method, and the comparison between the different classes of a variable was carried out by the log rank test. The study of prognostic factors associated with survival was carried out using the Cox model. Results: One hundred twenty-four patients were included. The average age was 50 years [30-87]. The median overall survival in our study, was 48 months [37-58].Seventy-four patients (57.9%) were diagnosed at a localized stage, 50 (40.3%) at a metastatic stage (p = 0.0001; CI: 95%). More than half of the patients, were under 50 years old, 36 were between 50 and 65 years old, and 22 were ≥ 65 years old (p = 0.8; CI: 95%). Forty-seven patients (37.6%) had a tumor located in the right breast, 67 (53.6%) in the left breast and 7 patients (5.6%) had bilateral breast cancer (p = 0.8). Seventy-nine patients (63.7%) underwent a radical mastectomy type Patey, 3 (2.4%) conservative surgery, 9 (7.3%)palliative mastectomy and 33 (26.6%) were not operated (p = 0.02; CI: 95%). The histological type was non-specific infiltrating ductal carcinoma in 93 patients (75.6%) and invasive lobular carcinoma in 14 patients(11.4%) (p = 0.04). Sixty-seven patients (53.6%) had a grade 2 and 38(30.4%) grade 3 (p = 0.08). Tumor size was T0 (0.9%), T1 (8.4%), T2 (44.9%), T3 (13.1%), T4 (32.7%) (p = 0.02). Lymph node involvement was N0 (19.4%), N1 (28.7%), N2 (35.2%), N3 (16.7%) (p = 0.054). In immunohistochemistry; 22 (45.8%) patients had a Ki67 > 20% and 26 patients (54.2%) had a Ki67 ≤ 20% with (p = 0.22). Twenty patients (16%) had a positive HER2 (p = 0.7). Seventy-one patients (61.2%) had positive hormone receptors with a median OS of 57 months [34.79] (p = 0.0001). High expression of estrogen hormone receptors (≥ 50%) had no impact on overall survival (p = 0.06) while high expression of progesterone hormone receptors was associated with better overall survival (p = 0.01). Conclusions: Breast cancer is a frequent and heterogeneous disease with several factors influencing its prognosis. The initial stage of the disease, a radical surgery, the infiltrating ductal histological type, the tumor size and the level of expression of the progesterone receptors were correlated with a better survival in our study.
Use of AI-based second harmonic generation digital pathology for predicting patient survival for triple negative breast cancer patients.
Authors: Tai Dean , Ren Yayun , Chng Elaine , Akbary Kutbuddin , Kuo Wen-Hung , Huang Kai-Wen Sky
Published: June 2023

e12526

Background: Extracellular matrix (ECM) in the stromal region has been known to be associated with tumorigenesis and metastasis in breast cancers. About 10-20% of all breast cancers are triple-negative breast cancers (TNBC), considered to be more aggressive with poorer prognosis than other types of breast cancer. AI-based Second Harmonic Generation (SHG) digital pathology, which is a fully quantitative fibrosis assessment, has been widely used innon-alcoholic steatohepatitis (NASH) and is FDA approved primary endpoint in NASH phase 2 clinical trials. In oncology, AI-based SHG digital pathology has demonstrated its relevance in survival prognosis for hepatocellular carcinoma and renal cell carcinoma after surgical treatment, based on analysis of tumor and non-tumor tissue collagen parameters. In this study, we study its potential applications for survival prognosis of TNBC patients. Methods: 68 patients with TNBC were treated by breast-cancer excision surgery. Tumor and non-tumor tissue from excised mass was imaged by SHG microscope (Genesis200, HistoIndex Pte. Ltd., Singapore). Regular follow-up was performed for patients post-operatively. A total of 33 collagen morphology features for collagen strings were quantified, such as length/width of strings, number of long/short/thick/thin strings, from tumour and non-tumour tissues. We used these collagen parameters to build two survival prediction models (RFS-index and OS-index) to predict patient’s recurrence-free survival (RFS) and overall survival (OS) years. The models were validated using the leave-one-out method. Results: Both RFS-index and OS-index were created using 10 specific collagen parameters chosen by sequential selection methods from overall 33 collagen parameters evaluated. 9 out of 10 parameters were selected from non-tumour tissue. The RFS-index can differentiate patients with RFS≥3 years (n = 36) and RFS < 3 years (p < 0.001) with cut-off value of RFS-index = 0.50. The OS-index can differentiate patients with OS≥5 years (n = 42) and OS < 5 years (p < 0.001) with cut-off value of RFS-index = 0.55. The log-rank test showed RFS-index (p = 0.026) and OS-index (p < 0.001) can be used for prediction of disease-free and overall survival based on collagen parameters. Conclusions: SHG based AI-aided quantitative assessment of ECM collagen has been shown to correlate with survival rates of TNBC patients. This is a proof of concept study applying AI based digital pathology in helping predict survival rates for TNBC patients based on tumor and non-tumor tissue ECM collagen parameters. This could help identify patients with a higher risk of recurrence of disease and lower overall survival rates. Such patients can be followed-up more carefully, and be considered for earlier treatment interventions to improve their survival outcomes.
Subcutaneous versus endovenous trastuzumab: Real world data from a reference cancer center in Peru.
Authors: Otoya Iris , Valdivieso Natalia , Roque Katia , Morante Zaida , Vidaurre Tatiana , Neciosup Silvia P. , Gomez Henry Leonidas
Published: June 2023

e12527

Background: HER2 receptor amplification/overexpression is identified in approximately 20% of invasive breast neoplasms; it is characterized by biologically aggressive behavior and worse prognosis compared to HER2-negative tumors. Trastuzumab, a humanized monoclonal antibody, was approved for therapeutic use in HER2-positive breast cancer. The objective of this study is to compare the acquisition costs, costs, and preparation and application times of trastuzumab presentations. Methods: Descriptive and retrospective study in female patients aged 18 years and older with a diagnosis of HER 2 positive early breast cancer who received subcutaneous or intravenous trastuzumab during the years 2019-2021. The study setting was the National Institute of Neoplastic Diseases (INEN)- Lima/Peru. We created a simple spreadsheet model to evaluate costs (expressed in soles). The analysis included the calculation of patient time in the chemotherapy chair, preparation time and treatment administration time. Results: The cost of the subcutaneous presentation was S/4212 and S/4348 for the intravenous presentation. The cost of the complete treatment was S/75816 for the subcutaneous presentation and S/82612 for the intravenous presentation. The cost of the supplies used in the preparation of 18 cycles of treatment for the subcutaneous presentation was S/ 20.7 and for the intravenous presentation S/ 399.96; likewise, the cost of the supplies used in the administration of 18 cycles of treatment for subcutaneous trastuzumab was S/ 34.02 and for the intravenous presentation was S/ 1094.4. The cost of using a chemotherapy chair for 18 cycles for subcutaneous presentation was S/36 and for intravenous presentation S/663. The time used in the application of 1 cycle of subcutaneous presentation was 30 minutes for the first application and 15 minutes for subsequent applications; the time used in the application of each cycle for endovenous presentation was 6 hours for the first application and 2 hours for subsequent applications. The administration of 18 cycles for subcutaneous presentation was S/ 732.45 and for intravenous presentation S/ 6168. The trastuzumab formulation for subcutaneous application is a ready-to-use solution, so it did not generate preparation costs. The preparation time for one cycle of intravenous presentation was 15 minutes and meant an investment of S/693.90 for the preparation of 18 cycles (cost of preparation personnel time). Conclusions: The use of subcutaneous trastuzumab generates less costs associated with an overall savings of 16.36%, its use implies less time for preparation and application, as well as a reduction in patient chair time. These time reductions translate into economic savings, a more efficient use of resources and a reduction in waiting time for appointments in the chemotherapy service and a greater capacity of the oncology service to treat a greater number of patients.
A prospective real-world study to assess the effectiveness and safety of trastuzumab biosimilar in the adjuvant treatment of HER2-positive breast cancer: Preliminary safety results.
Authors: Cardoso Ana Carolina Ferreira , Gagliato Debora De Melo , Brito Natália Mesquita , Lapa Maura Gonzaga , Santos Renata Virgínia Cavalcanti , Magaton Erida , Castilho Vivienne Carduz
Published: June 2023

e12532

Background: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) define a biosimilar as a biological molecule product that is highly similar to and has no clinically meaningful differences from an existing approved reference product. The trastuzumab biosimilar was the first oncology biosimilar approved in Brazil for HER2-positive breast cancer (BC) and advanced gastric cancer treatment. This study aimed to assess the effectiveness and safety of trastuzumab biosimilar (named as Zedora in Brazil) in the adjuvant setting among HER2-positive BC patients. Methods: This is a national, multicentric, observational, and prospective real-world study. Patients with early-stage HER2-positive BC who received at least one dose of trastuzumab biosimilar as adjuvant therapy were eligible. At the present date, 162 of 170 planned patients were recruited. Here, we present the preliminary safety data of the first 59 patients recruited in the study. The safety endpoint is the occurrence of adverse events (AEs), and the safety population included all patients who received at least one dose of trastuzumab biosimilar. We analyzed the AEs collected from the signature of the consent form until the end of adjuvant treatment. Results: Baseline patient characteristics among the 59 evaluated patients included a mean age of 51.7 ± 12.9 years, with 79.7% of them having a node-negative disease. Most patients had hormone-receptor-positive tumors (67.8% estrogen-receptor-positive and 55.9% progesterone-receptor-positive). The number of patients undergoing conservative surgery (67.8%) was higher than mastectomy (32.2%). The most frequent histological BC subtype was invasive ductal carcinoma (98.3%). All 59 participants received adjuvant anti-HER2 therapy, that included trastuzumab biosimilar administration trastuzumab biosimilar + pertuzumab (22.0%), and only two patients were receiving reference trastuzumab, which was switched to trastuzumab biosimilar upon entry into the study. The duration of adjuvant anti-HER2 therapy was 10.2 ± 2.2 months, ranging from 5.8 to 13.9 months. This time corresponds to, on average, 14 ± 3.2 cycles of 21 days. In total, 78.0% of the patients had at least one AE, four of them were serious AEs (6.8%), including three of severe intensity and one life-threatening. Table 1 lists the most reported AEs according to SOC (System Organ Class). Conclusions: The nature and severity of AEs observed to trastuzumab biosimilar were consistent with the known safety profile of trastuzumab. Clinical trial information: NCT03892655 . [Table: see text]
Relation assessment between TAN and AR with the survival of breast cancer patients.
Authors: Moghimi Minoosh , Tavakkolian Pouria , Ahmadi Farzane , Mansouri Reza , Khodadadi Kasra
Published: June 2023

e12542

Background: Considering the importance of the relationship between biomarkers and survival in breast cancer patients, finding this relationship can play a key role in understanding disease behavior, determining prognosis and even identifying targeted treatments. This study was conducted with the aim of investigating the relationship between TAN (Tumor associated neutrophil) and AR (Androgen receptor) with survival in patients with breast cancer. Methods: In this cohort study, 83 female patients with stage I- IV breast cancer were included. we investigated the relationship between TAN and AR with the three-year survival time. Patients were diagnosed between April 2018 and March 2021. Also, the latest follow-up was performed in December 2022. The Cox-hazard model was used to determine the factors influencing the survival time of patients. Results: Out of 83, follow-up was conducted for 81 women. The mean±SD age of diagnosis was 49.5±11.1 years. Sixteen (19.75%) of them died and the mean (95% C.I) for follow-up time was 32.78 (30.97-34.58) months. The one, two, and three survival rates were 0.95, 0.89, and 0.80, respectively. The mean survival time (month) for AR-TAN-, AR+TAN-, AR+TAN+, and AR-TAN+ was 35.75, 33.50, 32.36, and 28.58 respectively. The 3-year survival in the AR-TAN-, AR+TAN-, AR+TAN+ and AR-TAN+ groups was 0.88, 0.88, 0.79, and 0.50, respectively. Conclusions: AR positivity and TAN negativity are in favor of better three-year overall survival regardless of subtypes, however the differences were not statistically significant. The Survival status was significantly lower in the AR-TAN+ group compared to AR + TAN- group. These results are a promising way to the future studies. [Table: see text]
Prevalence of low HER2 expression in breast cancer patients: An Indian experience.
Authors: Gogia Ajay , S G Nithin , Mathur Sandeep , Deo S.V.S. , Ganguly Shuvadeep , Batra Atul , Sharma Dayanand , Prasad Chandra Prakash
Published: June 2023

e12543

Background: With the recent advent of trastuzumab deruxtecan and encouraging results of the DESTINY-Breast-04 trial, low HER2 expression has emerged as a clinically significant therapeutic biomarker. The prevalence of low HER2 expression is unexplored in Indian population. Methods: This is a single center ambispective observational study conducted over a period of 4 years (1st January 2019 to 31st January 2023) at Dr. B.R.A, I.R.C.H, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Consecutive female breast cancer patients registered during the study period with available clinical-pathological details were eligible for study inclusion. The primary objective of the study was to assess the prevalence of HER2 low breast cancer. HER2 low was defined as having HER expression by immunohistochemistry (IHC) of 1+ or 2+ with no amplification of the HER2gene detected with a fluorescent in situ hybridization (FISH) assay. Patients were divided into three categories: HER-2 high (IHC3+, IHC2+/FISH+), HER-2 low (IHC 1+, IHC2+/FISH-), and HER2-0 (HER2 negative, IHC:0). Staging description of the cases were done as per anatomic TNM classification according to AJCC 7th edition. Results: A total of 2200 female breast cancer were registered during the study period, of which 1932 patients had available clinical-pathological details. Among 1932 patients, 600 patients (31%) had high HER2 expression and remaining 1332 patients had HER2 low/HER2-0 expression. Of the 1332 cases, the median age was 49 years (range 18–91 years). The stage distribution was stage I, 94 (7.06%); stage II, 409 (30.70%); stage III, 528 (39.64%); and stage IV, 301 (22.59%). Eight hundred patients (60.06%) were hormone positive, and 532 (39.94%) cases were hormone negative. The prevalence of HER2 low expression was 798 (59.9%). It was observed in 640 (80%) of hormone positive cases and 158 (29.69%) hormone-negative cases (p < 0.001). Rest 534 cases were HER2 0 [160 cases (20%) were hormone positive, and 374 cases (70.31%) were hormone negative]. Conclusions: This is the first study from India to document the prevalence of low HER2 expression in female breast cancers. We observed the prevalence to be around 60 % in our population, which is more in hormone receptor-positive breast cancer. The estimated prevalence is higher than that observed in Western population, and it underscores the need to systematically categorize these patients for therapeutic decision making at presentation.
Clinicopathologic features of early stage HER2-low breast cancer.
Authors: Nashed Rebecca , Barger Hannah , Fishman Brooke Taylor , Schlyer Dylan A. , Makani Neeharika Srivastava
Published: June 2023

e12545

Background: Breast cancer (BC) is the leading cause of cancer deaths in women worldwide. Traditionally, BC is divided into 3 categories: hormone receptor positive (HR+) if tumors overexpress either estrogen or progesterone receptors, HER2-positive (Pos) if tumors overexpress the human epidermal growth factor receptor protein (HER2), and triple negative if tumors lack overexpression of HER2, ER, or PR. 15% of all BC are HER2-Pos, which has poorer outcomes when compared to HER2-Neg. Early HER2 targeted therapies only showed benefit for treating tumors with high enough HER2 overexpression. Thus, HER2-Pos refers to tumors which stained 3+ for HER2 on immunohistochemistry (IHC) or 2+ with a positive result on amplification of the HER2 gene by fluorescence in-situ hybridization (FISH). In the recent DESTINY-Breast04 study, the drug trastuzumab deruxtecan showed benefit in treating metastatic BC patients with low levels of HER2 overexpression. HER2-Low, now a clinically relevant group, is defined as 1+ by IHC or 2+ and FISH negative. However, early stage HER2-Low BC is treated the same as HER2-Neg by the current standard of care. Large registry trials have described the HER2-Low patient population, mostly in the metastatic setting. Our study aims to describe the prevalence, pathological and clinical aspects of HER2-Low when compared to HER2-Neg BC in early stage BC patients within a community practice setting in the United States. Methods: This retrospective study analyzed 1,106 patients of which 120 were excluded due to being HER2-Pos. 986 HER2-Neg and HER2-Low patients of stages I-III were included. Patients had diagnosis dates between January 1st, 2015 and December 31st, 2022. Categorical and continuous analyses (two-proportion Z test) were performed to describe differences between HER2-Low and HER2-Neg patients at the time of diagnosis in age, tumor histology and grade, and need for chemotherapy. Results: 49% of patients (n = 1,106) were found to be HER2-Low. 91% of HER2-low patients were HR+, compared to 87% of HER2-Neg who were HR+ (p = 0.04). HER2-Low patients were more likely than HER2-Neg to have ductal carcinoma (82% vs. 75%, p = 0.01) and to be classified as grade 2 (58% vs. 48%, p = 0.001). The median age of patients with HER2-Low was 69 compared to 70 in patients with HER2-Neg disease. 36% of HER2-Low patients needed chemotherapy (neoadjuvant or adjuvant) compared to 35% who were HER2-Neg (p = 0.74). Conclusions: Our study revealed that HER2-Low patients were more likely than HER2-Neg patients to be HR+, grade 2, and to have ductal histology. In this early stage BC population, there was no difference in need for chemotherapy between HER2-Low and HER2-Neg patients. Future studies with a more racially diverse patient population looking at parameters of progression-free survival and overall survival in HER2-Low early stage BC population should be pursued.
Estrogen receptor positive breast cancer in an Afro-Caribbean cohort.
Authors: Cimpeanu Emanuela , Wu Alexander H , Lin Bo , Azam Mariam , Ventura Ana M , Chiu Edwin , Taiwo Evelyn
Published: June 2023

e12550

Background: Estrogen receptor-positive breast cancer (EBC) accounts for 78% of breast cancer (BC) cases in the United States, and with better prognosis compared to other BC subtypes. There is limited information on the incidence, presentation, and outcomes of BC in black women from the Caribbean. We describe the clinicopathologic features and treatment outcomes of EBC in this underrepresented immigrant patient population. Methods: This is a retrospective study conducted at Kings County Hospital, a public hospital in a Brooklyn, New York neighborhood with the second highest population of Afro-Caribbeans in the United States. Demographics and clinicopathological data of patients diagnosed with BC from 2015-2018 were collected from the hospital’s tumor registry. Descriptive statistics and Chi-square testing were used to analyze the data. Results: Of the 299 women with a BC diagnosis, 185 (62%) had EBC, with median age of 61, and median BMI of 29.9. Stratification by menopausal status revealed 75% of these patients were post-menopausal. 37% of pre-menopausal and 28% of post-menopausal women presented with lymph node involvement (LNI). At diagnosis, 61% of patients had localized disease, 30% regional LNI, and 9% distant metastases. Sub-analysis revealed 25%, 22%, 28%, 16% and 9% with stages 0, I, II, III and IV respectively. 39% of patients presented with Nottingham Grade 3, 50% with Grade 2, and 11% with Grade 1 disease. 25% of patients without LNI had Oncotype Dx testing. 22% of these had Recurrence Score (RS) less than 11, 50% RS 11-25, and 28% RS 26 or higher. Of the 27 patients who received neoadjuvant treatment, 22% had complete pathologic response, 37% had partial response, and 33% had disease progression. 81% of patients self-identified as Afro-Caribbean, 27% reported first- or second-degree relatives with a BC diagnosis and 22% first-degree relatives with non-breast malignancy. At time of data analysis, at median of 6 years, 75% of all patients were relapse and progression-free. Lasting response was correlated with cancer stage (p < 0.01) but independent of tumor grade and Oncotype Dx RS (p = 0.18 and p = 0.29, respectively). Conclusions: In our study, Afro-Caribbean women with EBC presented with high-grade tumors and high incidence of regional LNI. Pre-menopausal women had a higher incidence of nodal involvement. Notable was a strong family history of cancer implying inherited or familial cancer syndromes. Progression-free survival was lower than expected and correlates with disease stage, but not with low Oncotype Dx RS. Further research is warranted to investigate better prognostic tools for this population.
Comprehensive genomic profiling of Taiwanese patients with breast cancer using a novel targeted panel: Preliminary analyses from a prospective triple-negative cohort.
Authors: Huang Chi-Cheng , Yeh Yi-chen , Ho Hsiang-Ling , Liu Chun-Yu , Tsai Yi-Fang , Tseng Ling-Ming
Published: June 2023

e12553

Background: Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database to improve treatment outcomes. This study aims to determine the molecular alterations and identify potential therapeutic targets from a cohort of Taiwanese triple negative breast cancers using a novel next-generation sequencing (NGS) targeted panel. Methods: The VGH-TAYLOR study was designed to understand the genetic profiling of different subtypes of breast cancer in Taiwan. The study population comprised both early- (first-line surgery or neoadjuvant therapy) and late-stage (early/late relapse or de novo stage IV disease) of breast cancers, and we conducted molecular profiling with the illumina TruSight Oncology 500 assay using both DNA and RNA extracted from FFPE tissues from a subset of 101 prospectively enrolled breast cancers, which were previously assayed with a commercialized panel of 161 genes. Results: A total of 100 breast cancers from VGH-TAYLOR study were successfully assayed, with the majority (n = 97) being triple-negative, two HER2 over-expressed and the remaining one being HER2-low phenotypically. The most prevalent actionable alterations (more than 5% of study cohort) came from BRCA2 (24%), BRCA1 (12%), PALB2 (5%), PIK3CA (38%, both mutations and amplifications), ERBB2 (14%, both mutations and amplifications), ERBB3 (10%) and PTEN (12%). One-quarter of assayed samples were categorized into tumor mutation burden (TMB)-high cancers ( > 10 mutations per million bases), which came from 15 out of 74 (20%) early-stage and 10 out of 26 (38%) late-stage patients (chi-square test p-value: 0.06). In general, the novel panel with 500 targeted genes reported more actionable alterations than the former one with limited interrogated genes ( BRCA2: 7%, BRCA1: 12%, PALB2: 7%, PIK3CA: 45%). Conclusions: Our study ascertained the clinical applicability and feasibility of comprehensive genomic profiling from a cohort of Taiwanese breast cancers. Overall, the successful rate for NGS with QC metrics are around 90%. The novelty benefits from more investigated genes as well as multi-gene biomarkers such as TMB and microsatellite instability (MSI) status. Patients with a positive finding from the genomic assay may benefit from an immune checkpoint inhibitor (TMB-high and MSI), poly ADP- ribose polymerase (PARP) inhibitor (homologous recombination deficiency genes: BRCA1/2 and PALB2), selective estrogen receptor degrader ( ESR1), tyrosine kinase inhibitor ( ERBB2/3), phosphoinositide 3-kinase inhibitor ( PIK3CA) and so on. Further studies with more samples enrolled and longer follow up are warranted to elucidate the true value of comprehensive genomic profiling for breast cancer.
Correlation of neutrophil-to-lymphocyte ratio and stromal tumor infiltrating lymphocytes across early breast cancer subtypes.
Authors: García-Torralba Esmeralda , Ivars-Rubio Alejandra , Perez-Ramos Miguel , Navarro Manzano Esther , Blaya-Boluda Noel , de la Morena Barrio Pilar , Garcia-Garre Elisa , Marin Zafra Gema , Moya Hernandez Miguel Angel , Guirao Garcia Maria Esperanza , Chaves Benito Asuncion , Garcia Martinez Elena , Ayala Francisco
Published: June 2023

e12558

Background: The tumor microenvironment plays a key role in the treatment response and prognosis of breast cancer (BC) patients, but the integrity of the peripheral immune system is also relevant. Understanding the biological correlation of immune-related prognostic factors, such as neutrophil-to-lymphocyte ratio (NLR) and stromal tumor infiltrating lymphocytes (sTIL), is necessary to improve its clinical applicability and the possible generation of more complex biomarkers that can direct treatment. Methods: Observational and single-center cohort of 1006 early BC patients (2009-2020). Pre-treatment NLR in peripheral blood and sTIL at diagnostic biopsy were determined. The correlation between NLR and sTIL (Spearman's Rho) overall and by subtypes, as well as its prognostic value for overall (OS) or disease-free survival (DFS) by Cox regression were evaluated. Results: NLR could be determined in 965 (96%) patients; in536 (53%) patients both NLR and sTIL were available. No statistical differences in baseline characteristics between both cohorts were found. Median age: 50 (range: 24-89); 93% infiltrating ductal carcinoma; 39.4% grade 3; 42.2% stage III; subtypes: hormone receptor (HR)+/HER2- (78.2%), HER2+/HR(+/-)(9.9%), triple negative breast cancer (TNBC) (11.9%); 70.5% treated with neoadjuvant chemotherapy. Median sTIL was 5% (SD: 16.2) with higher values in grade 3 (p < 0.001), HR- (p < 0.001) and HER2+ (p = 0.001). The median NLR was 1.95 (SD: 1.20), with no differences by subtype. There was no overall relationship between NLR and sTIL (ρ:0.32, p = 0.456). Correlation was also ruled out for each molecular subtype: HR+/HER2- (ρ:0.05, p = 0.301), HER2+/HR(+/-) (ρ:0.16, p = 0.251) and TNBC (ρ:0.21, p = 0.104). In a univariate predictive model for survival (N = 965), NLR showed prognostic value for DFS (HR 0.96, 95%CI: 0.80-1.17, p = 0.711) or OS (HR 1.02, 95%CI: 0.85-1.23, p = 0.798), neither in the whole group nor in the analysis by immunochemical subtypes. Conclusions: No correlation was observed between two of the most relevant biomarkers of immune activation in the tumor (sTIL) and peripheral (NLR) compartment in a series of early BC patients. NLR was not predictor of survival in our cohort. The absence of relationship between sTIL and NLR could suggest differences in the immune response in both compartments or else the need to find more accurate peripheral immune activation markers.
Demographic characteristics of encapsulated papillary carcinoma.
Authors: Luker Andrew , Wu Xinxin , Keirns Darby , Malan Augustus , Silberstein Peter T. , Hsia Beau
Published: June 2023

e12562

Background: Encapsulated papillary carcinoma (EPC) is a very rare form of breast cancer characterized by fibrous encapsulation and expansile growth, causing 1-2% of all cases. A summary of 25 case reports found that although two-thirds of cases had invasive growth, EPC responded well to local therapy and is considered a favorable diagnosis as a result. Because classification and diagnostic criteria for EPC continues to be debated, examination of the demographics could prove useful in determining trends. Methods: A retrospective cohort study done using data from the National Cancer Database (NCDB) from 2004–2020 found 314 patients with an EPC diagnosis through histology. The following demographics were considered: age, sex, race, Hispanic identity, distance from residence to treatment facility, insurance coverage, type of facility, and Charleson-Deyo score. These variables were then analyzed through descriptive statistics. Results: 314 patients were identified with a steadily increasing number of cases diagnosed per year until 2018, when cases per year dropped from 46 to 6 or below for the remaining 3 years (2018, 2019, 2020). Of these 314 patients, 16 were male and 298 were female. (5.1% and 94.9%, respectively). The average age of diagnosis was 69.6 years with a standard deviation of 11.8 and a range of 30 to > 90 years. The majority (99.7%) were found in the breast, with the remaining found in the endometrium. The majority of individuals (82.2%) had Charlson-Deyo comorbidity scores of 0. The majority of patients were non-Hispanic White, accounting for 88.9% of the total. A higher number of patients belonged to the highest income bracket, with 35.0% in the top quartile compared to those in other quartiles. The majority of patients had Medicare insurance, making up 63.1% of the total. More patients resided in counties with over 1 million people (56.7%) compared to those living in counties with a population below 1 million (43.3%). Most patients were treated at non-academic cancer centers (65.6%). On average, patients lived 19.8 miles (SD = 74.7, range = 1.8 – 370) from the treatment facility. Conclusions: Based on our literature review, this is the first NCDB analysis on EPC and thus addresses a significant knowledge gap on the topic. With an average age of diagnosis at 69.6 years, it is not surprising that the majority of patients were insured through Medicare. Male cases, while rare, support previous literature. Most commonly, EPC patients were most diagnosed in metropolitan areas. The majority of cases were diagnosed in the breast and most patients were treated at non-academic medical centers. While the vast majority of cases occurred in non-Hispanic white patients, it is unclear how much is due to race and how much is related to disparities in healthcare access and underdiagnosis in non-white races. Thus, further research is needed to understand which demographic factors prove to be the strongest predictors of EPC.
Clustering whole-exome sequences of breast cancer and associations with staging and molecular subtype.
Authors: Man Kingson , Lim Alice , Eftekhari Zahra , Wong Chi Wah
Published: June 2023

e12563

Background: Large-scale genetic sequencing of breast cancer has enabled modern approaches to precision medicine, with the discovery of a handful of variants now known to be associated with breast cancer. However, it is critical to identify additional gene variants in breast cancer that are associated with clinically relevant features of cancers, such as staging and molecular subtype. Methods: We took an unsupervised machine learning approach that clustered the somatic whole exome sequences (WES) of 1533 breast cancers. We performed k-modes clustering on the binarized mutational state of the top 250 most frequently mutated genes. Following two rounds of clustering, 11 distinct “barcodes” for each genetic cluster’s mutation profile became apparent. We systematically tested each genetically defined cluster for associations with molecular subtypes of breast cancer. We performed non-parametric significance testing by randomly permuting cluster assignments to generate an empirical null distribution of the effect of clustering on proportions of the clinical factor of interest. Results: As an example of our set of results, two clusters showed roughly three-fold enrichment of triple-negative breast cancer (TNBC) patients, compared to the whole-group proportion. We calculated SHAP values to provide model explainability and identify the genes that placed a cancer into a particular cluster; TP53 and TTN were the strongest drivers in relation to TNBC. Genetic clusters were also found to associate with T-, N-, and M-stages. Conclusions: Our approach, which uses unsupervised machine learning on WES to create genetic groups of cancers, considers the joint mutational state – present or absent – of multiple genes for their clinical relevance. This reveals many additional variants that may have been previously overlooked or of uncertain significance.
Multicenter study to evaluate the efficacy and standardize radiofrequency ablation therapy for early breast cancer.
Authors: Kinoshita Takayuki , Takayama Shin , Takahashi Masato , Fujisawa Tomomi , Futamura Manabu , Yamamoto Naohito , Shien Tadahiko , Aogi Kenjiro , Ohnishi Tatsuya
Published: June 2023

e12570

Background: Early-stage breast cancer is increasingly detected by screening mammography, and we aim to establish radiofrequency ablation therapy (RFA) as a minimally invasive, cost-efficient, and cosmetically acceptable local treatment. In our Phase I study, localized tumors with a maximum diameter of 2 cm, preoperatively diagnosed by imaging and histopathology, were treated with RFA. A 90% complete ablation rate was confirmed histopathologically. Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Methods: From Nov. 2009 to Nov. 2012, 58 patients with early-stage breast cancer received non-surgical RFA therapy. Patients had localized solitary N0 tumors with a maximum diameter of 1 cm. In our experimental therapy, a radiofrequency electrode needle is inserted through the skin into the breast lesion under imaging guidance, followed by thermal ablation with radiofrequency waves. RFA will be conducted under general anesthesia. The Cool-tip™ RF Ablation Single Electrode Kit (Medtronic, CO, USA) will be used to standardize the evaluation of the ablation effect. They underwent RFA and SNB under general anesthesia and adjuvant therapy and breast radiation. Follow-up evaluation for residual tumor at 3, 6, and 12 months after RFA included clinical examination, diagnostic imagings and vacuum-assisted biopsy. Surgical resection was recommended for patients with suspected residual disease or incomplete ablation. The primary endpoint was the frequency of adverse events. Secondary endpoints included the complete ablation rate and ipsilateral breast relapse-free rate. Results: The follow-up period ranged from 15 to 109 months (median, 85 months). The 57 patients completed the non-surgical RFA procedure and underwent diagnostic imaging and needle biopsy after 3 months. Seven patients with suspected incomplete ablation underwent surgical resection; incomplete ablation was confirmed in 5 (8.6%, 2 with invasive and 3 with non-invasive ductal carcinoma). During subsequent follow-up, 1 patient each was diagnosed with contralateral breast cancer and ipsilateral breast tumor relapse. No distant recurrence was documented. Cosmetic results were excellent in 94% of patients. Conclusions: Our phase II multicenter study of RFA without resection for early breast cancer will evaluate the long-term safety and efficacy of RFA as well as its cosmetic results, which are a perceived advantage of this technique. Clinical trial information: UMIN000008675 .
Long term survival in patients with bony oligometastatic breast cancer treated with curative intent: An institutional case series.
Authors: Iancu Alexandra , Vinayak Shaveta , Gwin William R , Linden Hannah M. , Specht Jennifer M. , Symonds Lynn Katherine , Davidson Nancy E. , Hunter Natasha
Published: June 2023

e12574

Background: Despite recent advances in treatment, metastatic breast cancer is widely recognized as a generally incurable condition. However, oligometastatic disease remains a poorly characterized condition with few clinical trials exploring treatments and outcomes. The term itself lacks a formal definition but is often used to refer to breast cancer displaying ≤5 metastatic sites, not necessarily in the same organ. Surgical management of discrete metastases has failed to demonstrate long-term benefit, while radiotherapy for isolated bone metastases has shown promise in some retrospective studies resulting in prolonged disease-free interval. Metastatic breast tumors overexpressing HER2 represent a category where systemic therapy may offer some prolonged remission or even cure. Methods: We are conducting a retrospective review of breast cancer patients with oligometastatic disease, as defined by ≤5 sites of disease, treated at Fred Hutch Comprehensive Cancer Center (FHCC) from 2000 to 2022; we will characterize FHCC provider practices, therapies delivered, goals of treatment, and long-term outcomes. This larger ongoing effort will be reported in a separate publication. Among a cohort of patients initially identified and undergoing record review, we reviewed all patients with bone-only disease and report their outcomes here. Results: We initially identified 17 cases of oligometastatic breast cancer currently undergoing treatment at FHCC. Of these, we noted that five patients had bone-only metastases and displayed marked similarities in treatment and outcome. All presented with de novo metastatic disease, and all five had ≤2 sites of metastasis, all in the axial skeleton. Four had HER2+ tumors; of these, three were also hormone-receptor positive. The remaining patient had triple-negative disease. All were treated with curative intent, with radiation to isolated bone metastases delivered concurrently with adjuvant radiation to breast/axilla. All are living today, with a median 56 months of follow up. One remains on a systemic metastatic regimen with a CDK4/6 inhibitor, while the rest are off therapy or are completing a standard adjuvant regimen. Conclusions: Oligometastatic breast cancer represents a heterogeneous entity that may in some instances be curable, but we lack sufficient data to identify which patients may benefit from therapy with curative intent. Standard curative treatment combined with radiotherapy to isolated bone metastases produced long-term survival in five current FHCC patients, which is consistent with other reports on patients with a low burden of bone-dominant metastatic disease. Further research is needed to validate curative approaches to therapy for this understudied population.
Ozone-loaded Pt(IV) prodrug self-assembled micelles with high bioavailability, low toxicity as a novel irradiation-controlled release treatment and the immune microenvironment editor for triple-negative breast cancer.
Authors: Zheng Dan , Luo Ting , Shi Hubing , Xu Tianyue
Published: June 2023

e12575

Background: A considerable part of TNBC shows poor response to the immune checkpoint blockades (ICBs) due to the immunosuppressive microenvironment. Chemotherapy performs well in synergizing with ICBs by improving tumor immunogenicity or eliminating the immunosuppressive tumor microenvironment. However, limited bioavailability, significant systematic toxicity and immunosuppressive metastatic niche induced by chemotherapy restrict its systematic application. Methods: We constructed the Pt(IV)-prodrug self-assembled micelles of O3_PFD@PtF with an ozone-loaded perfluorodecalin as the core (O3_PFD), and Pt(IV)-fluorocarbon chains assembled micelle as the shell (PtF). Results: The particle sizes of the prodrug were about 130.5 nm of PFD@PtF and 174.7 nm of O3_PFD@PtF, and both of the two showed good stability in the environment of different pH value and temperature. The Pt(IV) in the prodrug can be reduced and released in the sodium citrate solution. In addition, ozone was well stabilized by the PFD@PtF as the ROS donor and decomposed rapidly upon the irradiation excitation. O3_PFD@PtF boosted the level of GSH by promoting the intracellular redox balance with ROS and then the Pt(IV) was reduced to Pt(II) to release only within tumor. The prodrug was efficiently endocytosed into TNBC cells. Compared to cisplatin, a higher amount of Pt(II) was detected inserted into DNA in the O3_PFD@PtF combining irradiation treating group, which was released through depleting GSH donated by ROS. Accordingly, a remarkable reduction in IC50 was recorded in TNBC cells when O3_PFD@PtF was applied synergizing with irradiation. Furthermore, a relatively low IC50 was detected in non-ozone loaded prodrug-treated TNBC cells, which was attributed to the high concentration of background GSH, whereas the IC50 of PtF in Hacat was significantly higher than in other treating groups due to the low concentration of background GSH. Excellent inhibiting rates of the TNBC cells proliferation were observed in O3_PFD@PtF plus irradiation group 96 hours after treating, outperforming the conventional cisplatin plus irradiation group. We also observed a medium proliferation rate of TNBC cells in O3_PFD@PtF treating group in the absence of irradiation, which may be attributed to the Pt(II) released by the automatic decomposition of ozone. More importantly, cisplatin was reported to induced immunogenic cell death when synergizing with irradiation, but not alone. The dual potential to enhance TNBC proliferation inhibition and edit its immune microenvironment are now continuously detected. Conclusions: As a novel nano-prodrug with high efficiency and safty, O3_PFD@PtF plus irradiation is expected to improve the response of TNBC to ICBs by editing the tumor immune microenvironment.
Defendor special: Interim analysis of TCHP with primary empegfilgrastim prophylaxis (long-acting G-CSF) for treatment outcomes in early HER2+ breast cancer.
Authors: Zhukova Lyudmila , Ibragimova Tansylu , Ganshina Inna , Filonenko Daria , Sorokina Irina
Published: June 2023

e12586

Background: TCHP is the standard regimen for neoadjuvant therapy (NAT) of HER2-positive early breast cancer (HER2+ eBC) and requires primary G-CSF prophylaxis (PP). Pathological complete response (pCR) after NAT reflects better pts outcomes. Long-acting G-CSF presents more balanced neutrophils (NEU) count vs short G-CSF. Preclinical data show tumor-associated neutrophils (TANs) as anti-tumor effector cells in eBC. There are limited data on the clinical benefit of TCHP in the subset of patients with HER2 amplification by ISH in the low-moderate of HER2 protein expression. This sub-group analysis of multicenter prospective study was designed to evaluate the pCR after TCHP with PP by empegfilgrastim (E) or filgrastim (F) in pts with HER2+ eBC. Methods: HER2+ eBC pts (n=199) with II-III stages are getting NAТ: 6 docetaxel/ carboplatin/ trastuzumab + pertuzumab + empegfilrastim/ filgrastim (TCHP+E/F). Short G-CSF (F) uses according to routine clinical practice, long-acting G-CSF (E) - 24h after each NAT cycle. This descriptive analyse were performed for pts who completed the whole NAT regimen. The study endpoints: pCR (ypT0/is, ypN0) in intention-to-treat (ITT) population and according to HER2 status: 3+ vs 2+ ISH positive (+). ClinicalTrials.gov No NCT04905329. Results: At the data cut-off (01’2023) 199 pts with HER2+ BC completed planned NAT and surgery (71 pts – TCHP+E; 128 pts – TCHP+F). pCR rate according to HER2 status and in ITT population in 2 G-CSF groups is presented. In TCHP+E group pCR rate exceeds KRISTINE trial data despite a more enriched pts’ population with poor prognosis (34% pts with IIIB - IIIC vs 17% pts in KRISTINE trial) while TCHP+F showed comparable results with historical control. The superior pCR rate under PP with E was also observed in HER2 (3+) pts sub-group vs PP with F. However, in HER2 (2+ ISH+) the results are similar in 2 G-CSF groups. The mature data are awaited. Conclusions: TCHP+E shows superior pCR rate vs TCHP+F in the ITT and HER2 (3+) population. The obtained results affirm data of preclinical research on the ability of G-CSF to switch tumor immunity from “cold” to “hot” in the eBC. We assumed that balanced NEU count under long-acting G-CSF stimulation enhances TANs infiltration is increasing therapy efficiency. In HER2 (2+ ISH+) population pCR results were comparable in 2 G-CSF groups. Discrepancies between gene amplification and protein overexpression resulted in declined amount of HER2-inhibitors-HER2 receptor active complexes. It can be TANs failure to kill anti-HER2-antibody-opsonized cancer cells by a trogoptosis. Our hypothesis requires further confirmation with translational research. Clinical trial information: NCT04905329 . [Table: see text]
Methods for selection of neoadjuvant treatment with chemotherapy for patients with hormone receptor-positive and HER2-negative with early breast cancer.
Authors: Gasol Cudos Ariadna , Morales Murillo Serafin , Tuset Der-abrain Noemí , Arbones Cid Laura , Morera Morillo Ester , Vilardell Felip , Sanchez Guzman Douglas , Canosa Morales Carles , Olivé Jordi Melé
Published: June 2023

e12591

Background: Neoadjuvant chemotherapy (NCT) in hormone receptor positive and HER2 negative early breast cancer used to achieve a poor pathological response although patients with residual tumor inferior to 10 mm had a better significant survival. Methods: We analyzed the pathologic response (complete or major response if the residual tumor is inferior to 10 mm) in a consecutive series of 333 patients treated in our center considering clinicopathological classical variables, oncotype RS score, and non-response to previous sort course of hormonotherapy measured by the decrease in the Ki67 index. Results: Median age was of 51 years (24-87), median tumor size of 32mm (9-10) and 54% had nodal involvement. Pathologic complete response (pCR) was achieved in 16,5% and pathologic response according Symmans method type 0 and I in 33,6 %. Variables associated with pCR were initial tumor size < 30 mm (OR: 0,409; p: 0,004), progesterone receptor < 100 by histoscore (OR: 0,289; p: 0,00001) and Ki67 index > 30 (OR: 2,23; p: 0,008). When these 3 variables have been associated, the pCR increases by 45%. When use the ONCOTYPE RS score to select patients to NCT the pCR found was 23,5% that increases to 42% if the RS score was superior to 32 in a series of 136 patients. Considering the RCB pathologic response, RS>32 achieved a total of 73% of RCB 0-1 response. Finally, using the hormone non-response in patients with short course of hormonotherapy with non-decreases the Ki67 index, we found a 30% of pCR and 63% of RCB type 0-1 pathologic response. Conclusions: Selecting patients with early breast cancer with positive hormone receptors for neoadjuvant treatment with chemotherapy achieves a high response rate, going from 16% and reaching 40% in selected cases. The genomic platform and hormonal testing through Ki67 changes are very useful tools to select these patients. [Table: see text]