Search

Background: Because of the phenomenal success of treatment with monoclonal antibodies and antibody-drug conjugates targeting human epidermal growth factor receptor 2 (HER2), most patients with early-stage HER2-positive breast cancer (HER2+ BC) and some with limited metastatic diseases have been cured, and those who have not been cured have achieved significant improvements in overall survival, which has weakened the role of the TNM staging system in the prognosis of HER2+ BC today. Given that the disease is now highly curable, treatment conception, classification, and modalities should differ from those of cancer types with a poor prognosis. It is warranted to build a new paradigm for classifying and treating HER2+ BC., Recent Findings: In our personal view, we suggest that the classification system should be based not only on traditional anatomy and cancer biology but also on available treatment regimens, their exceptional outcomes, and their toxicities. In this regard, we developed a new concise classification of HER2+ BC based on the TNM staging system, a review of the literature, research results, and our clinical experience, dividing the patients into four distinct groups: curable (lymph-node negative and small (≤3 cm) early breast cancer), do our best to cure (locally advanced or tumors >3 cm early breast cancer), hope for cure (local-regional recurrent, limited metastases, and exceptional responders), and incurable (metastatic breast cancer with poor performance status or non-exceptional responders)., Conclusion: It will assist clinicians in developing an optimal treatment regimen at the outset, curing more HER2+ BC patients and improving their quality of life., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Purpose: Breast cancer and cardiovascular (CV) diseases often share the same risk factors. It is increasingly important to identify risk factors for CV events in patients with high-risk breast cancer and explore optimal treatment regimens., Experimental Design: Early HER2-positive breast cancer patients at our institution between January 1998 and October 2009 were reviewed. Primary outcome was late-severe-CV-event-free survival, and late severe CV events were defined as cardiovascular death, cardiomyopathy, symptomatic heart failure, and myocardial infarction developing 2+ years after breast cancer diagnosis. Kaplan-Meier plots, Cox proportional hazard regressions, and restricted mean survival time were used to evaluate outcomes., Results: We identified 2,448 consecutive eligible patients with a median follow-up time of 111.0 months (interquartile range, 52.0-151.8 months). One hundred and thirty-six patients had late severe CV events and 752 died of any cause [533 (70.9%) died of primary breast cancer; 12 (1.6%) died of cardiovascular disease]. Hypertension [HR, 1.546; 95% confidence interval (95% CI), 1.030-2.320; P = 0.036] and history of coronary artery disease (CAD; HR, 3.333; 95% CI, 1.669-6.656; P < 0.001) were associated with worse late-severe-CV-event-free survival. Anthracycline-containing regimens (HR, 1.536; 95% CI, 0.979-2.411; P = 0.062) was not a significant risk factor for CV events in multivariate analysis. Regimens containing both anthracycline and anti-HER2 therapy were prognostic for better OS (HR, 0.515; 95% CI, 0.412-0.643; P < 0.001)., Conclusions: Hypertension and CAD history were independent prognostic factors for late severe CV events. Adding anti-HER2 agents to anthracycline-containing regimens did not substantially increase the risk for late severe cardiotoxicity and conferred better overall survival., (©2021 American Association for Cancer Research.)

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m 2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8-11.3 months) and 28.8 months (95% CI: 17.5-59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.

Background: Although epidemiological research demonstrates that there is an association between lifestyle factors and risk of breast cancer recurrence, progression of disease, and mortality, no comprehensive lifestyle change clinical trials have been conducted to determine if changing multiple risk factors leads to changes in biobehavioral processes and clinical outcomes in women with breast cancer. This article describes the design, feasibility, adherence to the intervention and data collection, and patient experience of a comprehensive lifestyle change clinical trial (CompLife)., Methods: CompLife is a randomized, controlled trial of a multiple-behavior intervention focusing on diet, exercise, and mind-body practice along with behavioral counseling to support change. The initial exposure to the intervention takes place during the 4 to 6 weeks of radiotherapy (XRT) for women with stage III breast cancer and then across the subsequent 12 months. The intervention group will have 42 hours of in-person lifestyle counseling during XRT (7-10 hours a week) followed by up to 30 hours of counseling via video connection for the subsequent 12 months (weekly sessions for 6 months and then monthly for 6 months). The primary outcome is disease-free survival. Multiple secondary outcomes are being evaluated, including: (1) biological pathways; (2) overall survival; (3) patient-reported outcomes; (4) dietary patterns/fitness levels, anthropometrics, and body composition; and (5) economic outcomes. Qualitative data of the patient experience in the trial is collected from exit interviews, concluding remarks, direct email correspondences, and web postings from patients., Results: Fifty-five patients have been recruited and randomized to the trial to date. Accrual of eligible patients is high (72%) and dropout rates extremely low (5%). Attendance to the in-person sessions is high (95% attending greater than 80% of sessions) as well as to the 30 hours of video counseling (88% attending more than 70% of sessions). Adherence to components of the behavior change intervention is high and compliance with the intensive amount of data collection is exceptional. Qualitative data collected from the participants reveals testimonials supporting the importance of the comprehensive nature of intervention, especially the mind-body/mindfulness component and social support, and meaningful lifestyle transformations., Conclusion: Conducting a comprehensive, multicomponent, lifestyle change clinical trial for women with breast was feasible and collection of biobehavioral outcomes successful. Adherence to behavior change was high and patient experience was overwhelmingly positive.

Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.

HER2/neu oncogene is frequently deregulated in cancers, and the (PI3K)-Akt signaling is one of the major pathways in mediating HER2/neu oncogenic signal. p57 (Kip2) , an inhibitor of cyclin-depependent kinases, is pivotal in regulating cell cycle progression, but its upstream regulators remain unclear. Here we show that the HER2-Akt axis is linked to p57 (Kip2) regulation, and that Akt is a negative regulator of p57 (Kip2) . Ectopic expression of Akt can decrease the expression of p57 (Kip2) , while Akt inhibition leads to p57 (Kip2) stabilization. Mechanistic studies show that Akt interacts with p57 (Kip2) and causes cytoplasmic localization of p57 (Kip2) . Akt phosphorylates p57 on Ser 282 or Thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination. Importantly, the negative impact of HER2/Akt on p57 stability contributes to HER2-mediated cell proliferation, transformational activity and tumorigenicity. p57 restoration can attenuate these defects caused by HER2. Significantly, Kaplan-Meier analysis of tumor samples demonstrate that in tumors where HER2 expression was observed, high expression levels of p57 (Kip2) were associated with better overall survival. These data suggest that HER2/Akt is an important negative regulator of p57 (Kip2) , and that p57 restoration in HER2-overexpressing cells can reduce breast tumor growth. Our findings indicate the applicability of employing p57 regulation as a therapeutic intervention in HER2-overexpressing cancers.

Here we describe gross and microscopic sweat gland tumors found in a transgenic mouse model of breast cancer, which had transforming growth factor α under the control of mouse mammary tumor virus promoter (MMTV-TGFα). Initially, 20% of the mice in the colony were affected. Cystic lesions formed on the phalanges, palmar surfaces of the metacarpals, and plantar surfaces of the metatarsals. The lesions were multifocal and nonulcerated with straw-colored fluid, ranging in size from 1 to 30 mm at the largest dimension. The colony was monitored for 6 mo; during that time, the prevalence of lesions increased to 52% of the mice. Histologically, in most cases the cyst walls were lined by 1 or 2 layers of normal-appearing epithelial cells that resembled basal cells, indicating adenoma. However, 2 cysts from 2 different mice had papillary proliferative projections and extensive disorganized glandular structures that protruded into the cyst cavities, indicating adenocarcinoma. In these 2 cases, the neoplastic cells revealed architectural and cytologic atypia with rare mitoses. Similar findings have previously been observed in sweat gland tumors; however, multiple sweat-gland tumors have not been reported in mice.