Trastuzumab is a humanized mAb directed against the extracellular domain of the tyrosine kinase receptor HER2. Trastuzumab has shown clinical activity in HER2-overexpressing breast cancers and, at ...present, is currently approved for patients whose tumours have this abnormality, in both the metastatic and the adjuvant setting. Several issues about its optimal use, however, are still unresolved. One of the reasons for these uncertainties lies in the absence of conclusive data about its mechanism of action and possible primary or acquired resistance mechanisms. Therefore, clinical questions such as how to optimize patient selection, how to prevent resistance to trastuzumab, or what is the optimal management of those patients whose tumours progress during treatment still await convincing answers. This review summarises the current knowledge on the preclinical and clinical evidence about the mechanism of action of trastuzumab and on the mechanisms underlying the development of resistance and also briefly discusses their possible clinical implications.
Patients with brain metastases (BM) from human epidermal growth factor receptor 2 (HER2)-positive breast cancer represent a difficult-to-treat population. Trastuzumab emtansine (T-DM1) has shown ...potential activity in this subset of patients in small clinical series.
KAMILLA is an ongoing, phase IIIb study of T-DM1 in patients with HER2-positive locally advanced/metastatic breast cancer with prior HER2-targeted therapy and chemotherapy. Patients received T-DM1 3.6 mg/kg every 3 weeks (intravenously) until unacceptable toxicity, withdrawal of consent, or disease progression. Tumor response and clinical outcomes in patients with baseline BM were evaluated in this post hoc, exploratory analysis. The main outcome measures were best overall response rate (complete response + partial response) and clinical benefit rate (complete response + partial response + stable disease lasting ≥6 months) by RECIST v1.1 criteria, progression-free survival, overall survival, and safety.
Of 2002 treated patients, 398 had baseline BM. In 126 patients with measurable BM, the best overall response rate and clinical benefit rate were 21.4% 95% confidence interval (CI) 14.6–29.6 and 42.9% (95% CI 34.1–52.0), respectively. A reduction in the sum of the major diameters of BM ≥30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy to BM. In the 398 patients with baseline BM, median progression-free survival and overall survival were 5.5 (95% CI 5.3–5.6) months and 18.9 (95% CI 17.1–21.3) months, respectively. The adverse event profile was broadly similar in patients with and without baseline BM, although nervous system adverse events were more common in patients with 208 (52.3%) versus without 701 (43.7%) baseline BM.
This exploratory analysis of patients with HER2-positive metastatic breast cancer and BM enrolled in a prospective clinical trial shows that T-DM1 is active and well-tolerated in this population. T-DM1 should be explored further in this setting.
ClinicalTrials.gov identifier: NCT01702571.
•KAMILLA exploratory analysis suggests T-DM1 is active and well tolerated in HER2-positive MBC with brain metastases (BM).•Overall response rate was 21.4% (27/126) across all organs in patients with HER2-positive MBC and measurable BM.•Brain target lesion responses were observed in patients with and without prior radiotherapy.•In 398 patients with baseline BM treated with T-DM1, median progression-free survival was 5.5 (95% CI, 5.3–5.6) months.•Safety was generally similar in patients with versus without baseline BM, except for nervous system adverse events.
The use of anti-HER2 monoclonal antibodies (mAbs) has improved the clinical outcome of HER2-overexpressing breast cancers (BCs). Unfortunately, often these tumors tend to relapse and, when ...metastatic, the duration of clinical benefit is limited over time and almost invariably followed by tumor progression. Alternative approaches to this essentially passive immunotherapy are therefore needed in HER2-overexpressing BC patients. As HER2 is one of the most suitable targets for active immunotherapy in BC, manipulating the immune system is a highly attractive approach.
A computer-based literature search was carried out using PubMed (keywords: breast neoplasm, HER2 vaccine, immunology); data reported at international meetings were included.
This review provides a focus on the following active vaccinal approaches under clinical investigation against HER2-overexpressing BC: (i) peptide and protein based; (ii) DNA based; (iii) whole tumor cell based; (iv) dendritic cell based. Moreover, the review discuss future challenges in the field, trying to define the best setting for the development of this innovative strategy, considering both immunological and clinical aspects of HER2 targeting.
Development of effective vaccines for BC remains a distinct challenge but is likely to become a substantial advance for patients with HER2-overexpressing BCs.
•Low value agri-food wastes, co-products and by-products (AFWCBs) improve soil quality.•Insect frass residues suppress plant disease, increase microbial activities and immobilize N.•Digestates, ...duckweed and rice bran compost release N immediately after application.•AFWCBs play roles in closing the nitrogen and carbon cycle.
Agriculture is estimated to generate about 700 million tons of waste annually in the EU. Novel valorization technologies are developing continuously to recover and recycle valuable compounds and nutrients from waste materials. To close the nutrient loop, low-value agri-food wastes, co-products and by-products (AFWCBs) produced during the valorization process, need to be returned to the soil. However, knowledge on their reaction in soils that is needed to allow efficient and environmentally sound recycling is largely lacking. To this end, we set up a series of laboratory incubation experiments using 10 AFWCBs including insect frass residues made from three different feedstocks, anaerobic digestates from two feedstocks, potato-pulp, rice bran compost, duckweed and two reference crop residues (wheat straw and sugar beet) and measured net N release, C mineralization, dehydrogenase activity (DHA), microbial biomass C (MBC) and community structure. The suppressing potential of frasses and digestates against Rhizoctonia solani was determined using bean. The digestates released the highest net mineral N (50–70%) followed by rice bran compost (55%) and duckweed (30%), while frass made from general food waste and potato-pulp immobilized N like the reference straw for 91 days after incubation. All AFWCBs except digestates significantly increased MBC compared to the control while frasses, potato-pulp and duckweed increased DHA. Frasses and digestates significantly suppressed the development of Rhizoctonia solani in bean plants. AFWCBs from emerging valorizing technologies have the potential to improve microbial activities, C sequestration and may play a significant role in closing the nutrient loop.
Abstract Background Breast cancer (BC) subtypes have different survival and response to therapy. We studied predictors of central nervous system metastases (CNS-M) and outcome after CNS-M diagnosis ...according to tumor subtype. Patients and methods 488 patients with diagnosis of metastatic BC were retrospectively evaluated. According to the combination of hormone receptors (HR) and HER2 status, tumors were grouped in: Luminal (Lum), Luminal/HER2+, pure HER2-positive (pHER2+) and triple negative (TN). Time to CNS progression, CNS-M free interval and Overall Survival (OS) after CNS-M occurrence were compared by the log-rank test. Cox-proportional hazard models were used to study predictor factors associated with CNS progression, including tumor subtype and all potentially clinical relevant variables. Results 115 patients (pts) developed CNS-M with a median time to CNS progression of 31 months. The rate of CNS-M by subtype was: Lum 14%, Lum/HER2+ 35%, pHER2+ 49%, TN 22% ( p < 0.001). Compared with Lum tumors, Lum/HER2+ (HR 2.514, p < 0.001), pHER2+ (HR 6.799, p < 0.0001) and TN (HR = 3.179, p < 0.001) subtypes were at higher risk of CNS-M. Median OS in months after CNS-M was: Lum 7.4, Lum/HER2+ 19.2, pHER2+ 7, TN 4.9 ( p < 0.002). Belonging to the Lum/HER2+ subtype (HR 0.48, p < 0.037) and having isolated CNS (HR 0.37, p < 0.004) predicted significantly reduced risk of death. Conclusions After CNS-M, the Lum/HER2+ subtype appears associated with the longest OS. Prospective clinical trials would be required for evaluating the potential role of screening for asymptomatic CNS lesions and of more aggressive CNS-M treatment in Lum/HER2+ subtype.
Background : A growing body of real-world evidence (RWE) aims to better reflect outcomes of cancer patients treated in real-world settings. We aimed to conduct a first comprehensive mapping review of ...the RWE produced over the past 3 years in terms of tumor type, treatment strategies, setting, and data sources, focusing on targeted therapies (TT) in solid tumors.
Methods : We conducted a systematic review in PubMed of RWE studies published between 01/2020 and 12/2022. We identified non-interventional studies using observational data, focusing on solid tumors exposure to targeted therapies, excluding immunotherapies. Abstract and full-text screening were performed by 11 independent reviewers.
Results : A total of 7,774 publications were retrieved with 1,251 considered eligible and extracted. The number of publications per year progressively increased during this period (328 in 2020; 421 in 2021; 502 in 2022). Most studies (50%) were performed in Asia, followed by Europe (25%) and North America (17%). Only 8% of studies had patients treated in more than one country. Treatment effectiveness and safety were assessed in 71% and 42% of studies respectively. Main data sources were medical records.
Conclusions : RWE publications on TT for solid tumors are heterogeneous and mostly rely on retrospective data such as medical records. Population-based and international studies are rare. Collaborative efforts towards international representativeness and the use of routinely collected and/or standardized data sources must be encouraged to increase the relevance and future quality of publications and their potential impact on oncology practice.
This European phase IIIb, expanded-access multicenter trial evaluated the safety of EVE plus EXE in a patient population similar to BOLERO-2.
Post-menopausal women aged ≥18 years with hormone ...receptor-positive, human epidermal growth factor-receptor-2–negative advanced breast cancer (ABC) recurring/progressing during/after prior non-steroidal aromatase inhibitors were enrolled. The primary objective was safety of EVE plus EXE based on frequency of adverse events (AEs), and serious AEs (SAEs). The secondary objective was to evaluate AEs of grade 3/4 severity.
The median treatment duration was 5.1 months 95% confidence interval (CI) 4.8–5.6 for EVE and 5.3 months (95% CI 4.8–5.6) for EXE. Overall, 2131 patients were included in the analysis; 81.8% of patients experienced EVE- or EXE-related or EVE/EXE-related AEs (investigator assessed); 27.2% were of grade 3/4 severity. The most frequently reported non-hematologic AEs were (overall %, % EVE-related) stomatitis (52.8%; 50.8%) and asthenia (22.8%; 14.6%). The most frequently reported hematologic AEs were (overall %, % EVE-related) anemia (14.4%; 8.1%) and thrombocytopenia (5.9%; 4.6%). AE-related treatment discontinuations were higher in elderly (≥70 years) versus non-elderly patients (23.8% versus 13.0%). The incidence of EVE-related AEs in both elderly and non-elderly patients appeared to be lower in first-line ABC versus later lines. The incidence of AEs (including stomatitis/pneumonitis) was independent of BMI status (post hoc analysis). Overall, 8.5% of patients experienced at least one EVE-related SAE. Of the 121 on-treatment deaths (5.7%), 66 (3.1%) deaths were due to disease progression and 46 (2.2%) due to AEs; 4 deaths were suspected to be EVE-related.
This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. Although the patients were more heavily pretreated, the safety profile of EVE plus EXE in BALLET was consistent with BOLERO-2.
EudraCT Number: 2012-000073-23.
Patients with metastatic breast cancer (MBC) can derive clinical benefit from several subsequent lines of chemotherapy. However, in heavily pre-treated patients, agents with clinical activity, a ...favourable side effects profile and a convenient administration modality are preferred.
We retrospectively analyzed 110 patients with previously treated MBC, who received oral etoposide at the dose of 50 mg/day for 20 days in 28 days cycles, between 2003 and 2017. Because this was not a prospectively planned study, to describe the clinical performance of oral etoposide we adopted the approach suggested by Dzimitrowicz and colleagues (J Clin Oncol. 2016; 34:3511–17); Tumour Response (TR) was defined as the proportion of physician-reported clinical or imaging response; Prolonged Duration on Therapy (PDT) as the proportion of non-progressing patients whose treatment lasted more than 6 months. Furthermore, we evaluated median duration on therapy (TD) and median Overall Survival (OS) by the Kaplan Meier method.
The median number of previous chemotherapy lines was 5 (range 2–8). TR, PDT, median TD and median OS were 6.4%, 18.2% 4 (range 3.5–4.5) and 10.6 (range 8.4–12.8) months respectively. Interestingly, etoposide activity was unrelated to the number of previous lines and type of metastatic involvement. Oral etoposide was well tolerated with only two patients discontinuing therapy due to toxicity.
In this large, single Institution, real practice analysis oral etoposide is a valuable and safe option for pre-treated metastatic breast cancer patients and might be considered in patients failing other approaches, but still suitable for chemotherapy.
•Oral etoposide is a well-tolerated agent used in treatment of several types of neoplasms.•We retrospectively evaluated 110 pre-treated metastatic breast cancer patients receiving oraletoposide at our institution.•Oral etoposide was active and well tolerated in patients failing a median of 5 prior chemotherapy lines.•This real world study suggests that oral etoposide is a therapeutic option in pre-treated metastatic breast cancer patients.
Reducing inputs by promoting the recycling of energy within a cropping system is one of the principles of organic farming. To this end, the introduction and proper management of agroecological ...service crops (ASC) can play a key role. Few studies have analysed the effect of ASC introduction and compared energy flows under green manure (ASC-GM) and no-till roller crimper (ASC-NT) management. Moreover, current energy flows studies do not account for all the sources of energy that could be recycled within a cropping system, and none of them have evaluated the efficiency of cropping systems for recycling energy.
Our study, which gathered information on eight field experiments across six European countries over two years, indicates that ASC inclusion and management required, on average, a 19.73% higher input investment than systems that did not include them. Nevertheless, ASC management strategies were more prone to increase the energy that potentially could be recycled within the cropping system. Moreover, this study also provides, for the first time, evidence that ASC-NT reduces the marketable production efficiency relative to ASC-GM but improves the environmental performance by increasing the potential energy that can be recycled within the cropping system across a wide range of European pedo-climatic conditions.
•The use of agroecological service crops required 19.73% more inputs than bare soil.•Agroecological service crops increase the energy that potentially can be recycled.•No-till roller crimper needed less energy input than green manure.•No-till reduced production efficiency and fruit quality compared with green manure.•No-till increased the potentially recyclable energy within the cropping system.
The Pseudomonas fluorescens group comprises several closely related species that are involved in food contamination and spoilage. Specifically, the interest in P. fluorescens as a spoiler of dairy ...products increased after the cases of “blue mozzarella” that occurred in Italy in 2010.
A Multilocus Sequence Typing (MLST) scheme was developed and applied to characterise 136 isolates (reference strains and food borne isolates) at strain level, to reveal the genetic relationships among them and to disclose any possible genetic clustering of phenotypic markers involved in food spoilage (protease, lipase, lecithinase activities and pigmented or fluorescent molecule production). The production of dark blue diffusible pigment was evaluated on several bacterial culture media and directly on mozzarella cheese.
The MLST scheme provided precise genotyping at the strain level, and the population analyses of the concatenated sequences allowed major taxa to be defined. This approach was revealed to be suitable for tracking the strains according to their origin, such as dairy plants or food matrices. The genetic analysis revealed the presence of a connection between the blue pigment production and a specific phylogenetic cluster. The development of the online database specific to the P. fluorescens group (http://pubmlst.org/pfluorescens) will facilitate the application of the scheme and the sharing of the data.
•A MLST scheme and database were developed for Pseudomonas fluorescens.•5 phenotypic traits involved in spoilage were investigated.•The study highlighted a high heterogeneity between the strains of P. fluorescens.•The blue mozzarella causative strains belong to a single genetic cluster.•The MLST approach is applicable to track the strains involved in food spoilage.
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