Horizon scanning implanted biosensors in personalising breast cancer management:First pilot study of breast cancer patients views

Aims: This study aimed to explore breast cancer patients' understanding and acceptability of implanted biosensors (BS) within the primary tumour to personalise adjuvant radiotherapy, and to determine optimal design and number of BS, and evaluate potential clinical benefits as well as concerns about tolerance, toxicity, dwell time, and confidentiality of data. Patients and methods: A total of 32 patients treated by surgery (29 breast conserving, 3 mastectomy), postoperative radiotherapy and systemic therapy for early breast cancer, were recruited from a posttreatment radiotherapy clinic at a cancer centre. Patients participated in semistructured interviews. Interview transcripts were analysed using qualitative methods. Results: Participants were aged 39 to 87 years, with a median age of 62 years. Most (N = 23[72%]) were unfamiliar with biosensors. The majority (N = 29[90.6%]) were supportive of the technology's potential use in future breast cancer treatment and were willing to accept biosensors (N = 28[88%]) if they were endorsed by their breast cancer consultant. Only 3 patients expressed concerns, predominantly about uncertainties on their role in the diagnostic and treatment pathway. Patients were flexible about the size and shape of BS, but had a preference for small size (N = 28 [87.5%]). Most (N = 22[69%]) would accept implantation of more than 5 BS and were flexible (N = 22[69%]) about indefinite dwell time. Patients had a strong preference for wireless powering of the BS (N = 28[87.5%]). Few had concerns about loss of confidentiality of data collected. All patients considered biosensors to be potentially of important clinical benefit. Conclusions: While knowledge of biosensors was limited, patients were generally supportive of biosensors implanted within the primary tumour to collect data that might personalise and improve breast cancer radiotherapy in future

Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)

BACKGROUND: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC. PATIENTS AND METHODS: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m(2) capecitabine twice daily on days 1 to 14 in combination with 80 mg/m(2) bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR). RESULTS: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29-77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1-10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely. CONCLUSION: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted.The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov, (https://clinicaltrials.gov/; identifier: NCT01891227)

Predicting for activity of second-line trastuzumab-based therapy in her2-positive advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>In Her2-positive advanced breast cancer, the upfront use of trastuzumab is well established. Upon progression on first-line therapy, patients may be switched to lapatinib. Others however remain candidates for continued antibody treatment (treatment beyond progression). Here, we aimed to identify factors predicting for activity of second-line trastuzumab-based therapy.</p> <p>Methods</p> <p>Ninety-seven patients treated with > 1 line of trastuzumab-containing therapy were available for this analysis. Her2-status was determined by immunohistochemistry and re-analyzed by FISH if a score of 2+ was gained. Time to progression (TTP) on second-line therapy was defined as primary study endpoint. TTP and overall survival (OS) were estimated using the Kaplan-Meier product limit method. Multivariate analyses (Cox proportional hazards model, multinomial logistic regression) were applied in order to identify factors associated with TTP, response, OS, and incidence of brain metastases. <it>p </it>values < 0.05 were considered to indicate statistical significance.</p> <p>Results</p> <p>Median TTP on second-line trastuzumab-based therapy was 7 months (95% CI 5.74-8.26), and 8 months (95% CI 6.25-9.74) on first-line, respectively (n.s.). In the multivariate models, none of the clinical or histopthological features could reliably predict for activity of second-line trastuzumab-based treatment. OS was 43 months suggesting improved survival in patients treated with trastuzumab in multiple-lines. A significant deterioration of cardiac function was observed in three patients; 40.2% developed brain metastases while on second-line trastuzumab or thereafter.</p> <p>Conclusion</p> <p>Trastuzumab beyond progression showed considerable activity. None of the variables investigated correlated with activity of second-line therapy. In order to predict for activity of second-line trastuzumab, it appears necessary to evaluate factors known to confer trastuzumab-resistance.</p

DNA methylation signatures predicting bevacizumab efficacy in metastatic breast cancer

Background: Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Methods: Genome-wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in archival FFPE specimens of 36 patients with HER2-negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (learning set). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (>0.15 or <-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients (optimization set) and in 15 patients treated with chemotherapy alone (control set) using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the optimization set but not in the control set using Spearman rank correlation, Cox regression, and logrank test. Results: Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the optimization set, but not in the control set. Using information from the optimization set, the panel was reduced to a 9-gene signature, which could divide patients from the learning set into 2 clusters, thereby predicting response with an OR of 40 (p<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of predicted responders with longer PFS in the learning and optimization set even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Conclusion: Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab.(VLID)251037

Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer—results from an international, multicenter analysis coordinated by the AGMT Study Group

Background: Triple-negative breast cancer (TNBC) is associated with poor prognosis, and new treatment options are urgently needed. About 34%-39% of primary TNBCs show a low expression of human epidermal growth factor receptor 2 (HER2-low), which is a target for new anti-HER2 drugs. However, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC. Patients and methods: We retrospectively included patients with TNBC from five European countries for this international, multicenter analysis. Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years before metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ without ERBB2 gene amplification. Survival probabilities were calculated by the Kaplan-Meier method, and multivariable hazard ratios (HRs) were estimated by Cox regression models. Results: In total, 691 patients, diagnosed between January 2006 and February 2021, were assessable. The incidence of HER2-low was 32.0% [95% confidence interval (CI) 28.5% to 35.5%], with similar proportions in metastases (n = 265; 29.8%) and primary tumors (n = 425; 33.4%; P = 0.324). The median overall survival (OS) in HER2-low and HER2-0 TNBC was 18.6 and 16.1 months, respectively (HR 1.00; 95% CI 0.83-1.19; P = 0.969). Similarly, in multivariable analysis, HER2-low had no significant impact on OS (HR 0.95; 95% CI 0.79-1.13; P = 0.545). No difference in prognosis was observed between HER2 IHC 0/1+ and IHC 2+ tumors (HR 0.89; 95% CI 0.69-1.17; P = 0.414). Conclusions: In this large international dataset of metastatic TNBC, the frequency of HER2-low was 32.0%. Neither in univariable nor in multivariable analysis HER2-low showed any influence on OS.info:eu-repo/semantics/publishedVersio

Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry

BACKGROUND: About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody-drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC). PATIENTS AND METHODS: The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included. RESULTS: As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74-1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68-1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients. CONCLUSION: Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the prometastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy