Search

Background: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments., Patients and Methods: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test., Results: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival., Conclusions: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone., Competing Interests: Disclosure RN: Consulting from Cardinal Health, Clovis, Fujifilm, G1 Therapeutics, Genentech, Immunomedics/Gilead, iTeos, MacroGenics, Merck, OncoSec, Pfizer, Seattle Genetics; Research Funding to Institution from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Immunomedics/Gilead, Merck, OBI Pharma, Odonate Therapeutics, OncoSec, Pfizer, Seattle Genetics, Taiho. BAP: Consulting from BioAtla Inc, Samumed LLC, Dare Biosciences; Stock of Merck; Research Funding to Institution from Pfizer, GlaxoSmithKline, Novartis, Genentech/Roche, Oncternal. KSA: Grants from Seattle Genetics, Daiichi Sankyo, AstraZeneca. RKM: Participation on a Data Safety Monitoring Board or Advisory Board of Genomic Health/Exact Sciences, Genentech-Roche, Seattle Genetics/Axio; Grants from Seattle Genetics, Daiichi Sankyo, AstraZeneca; Support from Quantum Leap Healthcare Collaborative, Merck, Seattle Genetics, Amgen, Genentech-Roche. JCB: Research Funding from Eli Lilly. MCL: Funding from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, Tesaro; Support for attending meetings and/or travel from AstraZeneca, Genomic Health, Ionis; Participation on a Data Safety Monitoring Board or Advisory Board of AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. ASC: Institutional Research Funds from Novartis. HSR: Funding from Pfizer, Merck, Novartis, Lilly, Roche, Daiichi, Seattle Genetics, MacroGenics, Sermonix, Boehringer Ingelheim, AstraZeneca, Ayala, Gilead, and Ayala; Honoraria from Puma, Merck, Samsung, NAPO. JP: Honoraria from Methods in Clinical Research; Support for attending meetings from ASCO, SABCS; Participation on a Data Safety Monitoring Board or Advisory Board of University of Wisconsin Specialized Programs of Research Excellence, VIVLI, Quantum Leap Healthcare Collaborative, Patient Centered Outcomes Institute. DAB: Employee/Leadership, Stock/Ownership, and Consulting/Advisory Board of Berry Consultants; Research Funding from Daiichi Sankyo; Travel/Accommodations/Expenses from Berry Consultants. LV: part-time employee and stockholder of Agendia NV. WFS: Stock owner in Delphi Diagnostics; Patent - “Method of measuring residual cancer and predicting patient survival” (US Patent 7711494B2). LE: Research Funding from Merck; Medical Advisory Panel member of Blue Cross Blue Shield; Website Author of UpToDate. LP: Consulting fees and honoraria from Pfizer, AstraZeneca, Merck, Novartis, Genentech, Eisai, Pieris, Immunomedics, Seattle Genetics, Almac, Biotheranostics, and Natera. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Cancer treatments may improve the long-term survival rate of young patients with breast cancer, but also lead to a decrease in fertility. With the younger incidence of breast cancer in China, the fertility needs of this group have received more attention, and fertility preservation technology suitable for cancer patients is developing continuously. However, there are still many problems in the implementation of fertility preservation for young breast cancer patients in China. Patients and breast surgeons have insufficient understanding and conservative attitudes towards fertility preservation technology. And there is a lack of reproductive experts in the treatment process. What's more, the long-term follow-up and information management of patients undergoing fertility preservation are defective. In response to the above, this paper discusses how to deal with patients with potential reproductive needs in clinical practice from the perspective of breast surgeons. The first is to improve their own understanding of fertility preservation, such as the progress of relevant technologies and applicable population, when to intervene, when and how to get pregnant after cancer treatment. Secondly, education for patients must be strengthened, which should include not only fertility preservation, but also scientific contraceptive methods during cancer treatment and treatment measures for unexpected pregnancy. Finally, hospitals and relevant units should standardize the multidisciplinary team of breast cancer, and strengthen the comprehensive management of young breast cancer patients, thus to provide young breast cancer patients with more scientific cancer treatment programs and more reproductive opportunities.

Objective: To determine the most cost-effective modality for breast cancer screening in women living in Shanghai. Methods: A Markov model for breast cancer was redeveloped based on true effect which was derived from a project for detection of women at high risk of breast cancer and an organized breast cancer screening program conducted simultaneously in Minhang district, Shanghai, during 2008 to 2012. Parameters of the model were derived from literatures. General principles related to cost-effectiveness analysis were used to compare the costs and effects of 12 different screening modalities in a simulated cohort involving 100 000 women aged 45 years. Incremental cost-effectiveness ratio (ICER) was used to determine the most cost-effective modality. Sensitivity analysis was conducted to evaluate how these factors affected the estimated cost-effectiveness. Results: The modality of biennial CBE followed by ultrasonic and mammography among those with positive CBE was observed as the most cost-effective one. The costs appeared as 182 526 Yuan RMB per life year gained and 144 386 Yuan RMB per quality adjusted life-year (QALY) saved, which were within the threshold of 2-3 times of local per capita Gross Domestic Product. Results from sensitivity analysis showed that, due to higher incidence rate of breast cancer in Shanghai, the cost per QALY would be 64 836 Yuan RMB lower in Shanghai than the average level in China. Conclusion: Our research findings showed that the biennial CBE program followed by ultrasonic and mammography for those with positive CBE results might serve as the optimal breast cancer screening modality for Chinese women living in Shanghai, and thus be widely promoted in this population elsewhere.

Objective: To analyze the differences between the social support for breast cancer patients and healthy female, and to explore the correlation between social support and quality of life (QOL) in the patients. Methods: From January 2013 to December 2014, 101 patients with operable breast cancer treated at Xinyu City People's Hospital were recruited as the experimental group. They completed questionnaires in the preoperative, postoperative chemoradiotherapy and rehabilitation periods, respectively.101 healthy female volunteers recruited from the community were included as control group, whose age and level of education were matched with those of the experimental group.The general questionnaire including basic information, disease conditions and other projects, perceived social support scale (PSSS), quality of life of breast cancer patients (FACT-B) were applied to evaluate the general situation, social support and QOL of the subjects. The differences in PSSS scores between the experimental and control groups were compared. The correlation between PSSS score and FACT-B score in the experimental group was analyzed. SPSS 18.0 software was used for statistical analysis. Results: The general situations of the experimental and control groups were comparable (all P >0.05). The rates of the total social support score ≥50 in the experimental and control groups were not significantly different (93.6% vs. 94.7%, P =0.067). Compared with that of the control group (23.2±4.8), the scores of family support in the experimental group in preoperative, postoperative chemoradiotherapy and rehabilitation periods were statistically higher (25.6±3.2, 24.2±4.2 and 24.0±3.4, respectively, P =0.034). The social support scores of patients with different demographic characteristics were different. Among the demographic characteristics, years of education and place of residence had the largest impact. The scores of social support in patients with longer education years and living in the urban area were higher than those with shorter education years and living in the rural areas ( P <0.001). The scores of QOL among preoperative, postoperative chemoradiotherapy and rehabilitation periods in the experimental group were significantly different (all P <0.05). The patients gained the highest score of QOL in the preoperative period (110.7±5.1) and the lowest in the postoperative chemoradiotherapy period (95.3±18.1). The QOL of patients in the experimental group in preoperative, postoperative chemoradiotherapy and rehabilitation periods were all positively correlated with the overall social support (all P <0.01). Conclusions: The QOL of breast cancer patients at different periods of treatment is positively correlated with the social support. The quality of life can be enhanced by improving the social support for the patients.

Objective: As an invasive cancer, breast cancer is the most common tumour in women and is with high mortality. To study the mechanisms of HER2-positive breast cancer, we analyzed microarray of GSE52194., Materials and Methods: GSE52194 was downloaded from Gene Expression Omnibus including 5 HER2-positive breast cancer samples and 3 normal breast samples. Using cuffdiff software, differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DE-lncRNAs) were screened. Functions of the DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Then, protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape and modules of the PPI network were screened by CFinder. Moreover, lncRNA-DEG pairs were screened., Results: Total 209 lncRNA transcriptions were predicted, and 996 differentially expressed transcriptions were screened. Besides, FOS had interaction relationships with EGR1 and SOD2 separately in module E and F of the PPI network for the DEGs. Moreover, there were many lncRNA-DEG pairs (e.g. TCONS&#95;00003876-EGR1, TCONS&#95;00003876-FOS, lnc-HOXC4-3:1-FOS, lnc-HOXC4-3:1-BCL6B, lnc-TEAD4-1:1-FOS and lnc-TEAD4-1:1-BCL6B), meanwhile, co-expressed DEGs of TCONS&#95;00003876, lnc-HOXC4-3:1 and lnc-TEAD4-1:1 were enriched in p53 signaling pathway, MAPK signaling pathway and cancer-related pathways, respectively., Conclusions: ANXA1, EGR1, BCL6, SOD2, FOS, TCONS&#95;00003876, lnc-HOXC4-3:1 and lnc-TEAD4-1:1 might play a role in HER2-positive breast cancer.

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the number of infiltrating tumor-activated macrophages, which was highest in the more aggressive tumor subtypes. These findings indicate that human breast cancer progression and aggression, collagen linearization and stromal stiffening are linked and implicate tissue inflammation and TGF beta.

The epithelial-mesenchymal transition (EMT) induced by chemotherapeutic agents promotes malignant tumor progression; however, the mechanism underlying the drug-induced EMT remains unclear. In this study, we reported that miR-448 is the most downregulated microRNA following chemotherapy. Suppression of miR-448 correlated with EMT induction in breast cancer in vitro and in vivo. With the use of chromatin immunoprecipitation-seq analysis, we demonstrated that miR-448 suppression induces EMT by directly targeting special AT-rich sequence-binding protein-1 (SATB1) mRNA, leading to elevated levels of amphiregulin and thereby, increasing epidermal growth factor receptor (EGFR)-mediated Twist1 expression, as well as nuclear factor κB (NF-κB) activation. On the other hand, we also found that the adriamycin-activated NF-κB directly binds the promoter of miR-448 suppressing its transcription, suggesting a positive feedback loop between NF-κB and miR-448. Furthermore, all patients who received cyclophosphamide (CP), epirubicin plus taxotere/CP, epirubicin plus 5-fluorouracil chemotherapy showed miR-448 suppression, an increased SATB1, Twist1 expression and acquisition of mesenchymal phenotypes. These findings reveal an underlying regulatory pathway, in which the autoregulation between NF-κB and miR-448 is important for restrain miR-448 suppression upon chemotherapy and may have a role in the regulation of chemotherapy-induced EMT. Disruption of the NF-κB-miR-448 feedback loop during clinical treatment may improve the chemotherapy response of human breast cancers in which EMT is a critical component.

We studied 48 cases of invasive breast carcinoma for evidence of Epstein-Barr virus (EBV), which is associated with many human malignancies. In situ hybridization studies to detect the presence of EBV-encoded small nonpolyadenylated RNA (EBER)-1 were performed in paraffin sections. Immunohistochemical studies to detect EBV nuclear antigen (EBNA)-1, latent membrane protein (LMP)-1, and the transactivating immediate-early BZLF1 (ZEBRA) protein were also performed in paraffin sections. The presence of EBV genomic DNA was studied by polymerase chain reaction (PCR) amplification using sets of primers flanking the EBNA-4 and the EBV-LMP-1 genes in frozen tissues. Southern blot analysis using a probe flanking the EBV terminal repeat region was then attempted in cases that were PCR-positive. Five of 48 cases (10%) of breast carcinoma showed focal EBER-positive tumor cells. Twelve cases (25%) were positive for EBNA-1 by immunohistochemistry, all but one different from the EBER-positive cases. None of the cases were positive for LMP-1 or ZEBRA protein by immunohistochemistry. PCR studies for EBNA-4 and LMP-1 were each positive in five cases (including three cases in common). However, Southern blot studies successfully performed in all but one of the PCR-positive cases were completely negative. The identification of EBV by any methodology was not correlated with tumor size, grade, or lymph node status. This study demonstrated evidence of EBV infection in tissues involved by invasive breast carcinomas in a significant subset of cases. However, the lack of localization of EBV infection to a significant population of the tumor cells in any case, the negativity by Southern blot hybridization, and the lack of expression of multiple antigens in any case strongly argue against a significant role for EBV in the pathogenesis of breast carcinoma.

The purpose of this paper is to examine the optimal driving frequency and to configure the ultrasound energy deposition schema for a various size and location of breast tissues when a portion or the entire cylindrical ultrasound transducer is employed for breast hyperthermia treatments. This work employs a computer simulation program based on an ideal ultrasound power deposition from a cylindrical transducer. The ultrasound power within the breast is assumed to be exponentially attenuated according to the penetration depth of the ultrasound beam and a uniform absorption for the entire breast is also assumed. The distribution of the specific absorption rate (SAR) ratio is employed to determine the heating pattern of a set of given parameters. The control parameters considered are the ultrasound frequency in the breast tissue, the active portion of cylindrical transducer, and the shifting distance between the central axes of the breast and the transducer. The effect of the breast size on the SAR ratio is also considered. Simulation results demonstrate that the breast size, the ultrasound frequency in breast tissue, the shifting distance, and the active portion of the cylindrical transducer are the potential parameters for influencing the distribution of the SAR ratio. High frequencies should be used for the superficial heating treatments and the active portion of the transducer can be changed to obtain a region with an appropriate SAR ratio to cover the treatment region. Low frequencies are used for deep heating treatments and the region of the high SAR ratio can be moved by shifting the transducer and its pattern is varied with the transducer's active portion. The distribution of the SAR ratio indicates the domain of treatable tumor size and tumor depth for a given set of parameters (driving frequency, shifting distance and active portion of the transducer, as well as breast diameter). Findings of this study can be used to know whether or not the tumor is treatable as well as to select the optimal driving frequency and the appropriate active portion of the cylindrical transducer for a treatment, and hopefully to design an appropriate cylindrical ultrasound heating system for breast tumors.

The widespread use of mammography has resulted in the detection of an increasing number of small invasive breast cancers, i.e. those that are 1cm and smaller. Patients with these small cancers generally have a low incidence of axillary lymph node metastases, and this has led some to question the routine use of axillary dissection in these patients. In addition, the prognosis of these patients is generally favorable, and the routine use of adjuvant systemic therapy is difficult to justify. Nonetheless, some patients with these small invasive cancers will have axillary nodal involvement and/or develop metastatic disease. The identification of this prognostically unfavorable subset of patients within this otherwise favorable group is an important goal of clinical research. In this article, we review the available literature on prognostic factors for patients with breast cancers 1cm and smaller to help determine which of these features might be of value in the identification of patients at risk for axillary lymph node involvement and/or metastatic disease.