Open questions, current challenges, and future perspectives in targeting human epidermal growth factor receptor 2-low breast cancer.

Approximately 60% of traditionally defined human epidermal growth factor receptor 2 (HER2)-negative breast cancers express low levels of HER2 [HER2-low; defined as immunohistochemistry (IHC) 1+ or IHC 2+/in situ hybridization (ISH)-]. HER2-low breast cancers encompass a large percentage of both hormone receptor-positive (up to 85%) and triple-negative (up to 63%) breast cancers. The DESTINY-Breast04 trial established that HER2-low tumors are targetable, leading to the approval of trastuzumab deruxtecan (T-DXd) as the first HER2-directed therapy for the treatment of HER2-low breast cancer in the United States and Europe. This change in the clinical landscape results in a number of questions and challenges-including those related to HER2 assessment and patient identification-and highlights the need for careful assessment of HER2 expression to identify patients eligible for T-DXd. This review provides context for understanding how to identify patients with HER2-low breast cancer with respect to sample types, scoring and reporting HER2 status, and testing methods and assays. It also discusses management of important T-DXd-related adverse events. Available evidence supports the efficacy of T-DXd in patients with any history of IHC 1+ or IHC 2+/ISH- scores; however, future research may further refine the population who could benefit from T-DXd or other HER2-directed therapies and identify novel methods for patient identification. Because HER2 expression can change with disease progression or treatment, and variability exists in scoring and interpretation of HER2 status, careful re-evaluation in certain scenarios may help to identify more patients who may benefit from T-DXd.

Management of patients with HER2-positive metastatic breast cancer after trastuzumab deruxtecan failure.

The current treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) has been greatly impacted in the past decade by the introduction of antibody-drug conjugates (ADCs), which represent a relatively novel therapeutic class with the peculiar ability to deliver otherwise overtly toxic chemotherapeutics to tumor sites by exploiting the specificities of monoclonal antibodies. Indeed, drug engineering refinements in ADC design, such as through the introduction of cleavable linkers and hydrophobic payloads, resulted in improved patient outcomes in recent years. Two different ADCs, namely trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), have already entered clinical practice for the treatment of HER2-positive ABC. In this scenario, T-DXd has shown to portend better survival outcomes compared to T-DM1, while leaving a large unsought area of unmet medical need upon T-DXd failure. Treatment decision and benefit of cancer drugs following T-DXd still represent an area of clinical controversy, where a preclinical investigation and clinical development should be prioritized. As the pace of innovation is currently accelerating, and with novel ADC formulations advancing in early-phase clinical trials, the whole BC field is changing at an unprecedented rate, with potential broadenings of therapeutic indications. In this review, we present the clinical landscape of HER2-positive advanced BC and discuss our vision on how to tackle T-DXd resistance, providing a perspective on the priority areas of the cancer research in this setting.

ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer has recently emerged as a targetable subset of breast tumors, based on the evidence from clinical trials of novel anti-HER2 antibody-drug conjugates. This evolution has raised several biological and clinical questions, warranting the establishment of consensus to optimally treat patients with HER2-low breast tumors. Between 2022 and 2023, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process focused on HER2-low breast cancer. The consensus included a multidisciplinary panel of 32 leading experts in the management of breast cancer from nine different countries. The aim of the consensus was to develop statements on topics that are not covered in detail in the current ESMO Clinical Practice Guideline. The main topics identified for discussion were (i) biology of HER2-low breast cancer; (ii) pathologic diagnosis of HER2-low breast cancer; (iii) clinical management of HER2-low metastatic breast cancer; and (iv) clinical trial design for HER2-low breast cancer. The expert panel was divided into four working groups to address questions relating to one of the four topics outlined above. A review of the relevant scientific literature was conducted in advance. Consensus statements were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This article presents the developed statements, including findings from the expert panel discussions, expert opinion, and a summary of evidence supporting each statement.

Targeting HER3 for cancer treatment: a new horizon for an old target.

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptors family, having as its main ligands neuregulins 1 and 2. Although its poor tyrosine kinase activity entails a weak oncogenic power on its own, HER3 can heterodimerize with HER2 and/or epidermal growth factor receptor (EGFR), leading to a drastic enhancement of transphosphorylation and activation of downstream signaling pathways, ultimately promoting oncogenesis, metastatic dissemination, and drug resistance. Given its ubiquitous expression across solid tumors, multiple efforts have been done to therapeutically target HER3 by blocking either the ligand binding domain or its dimerization with other receptors. Treatment with anti-HER3 monoclonal antibodies or bispecific antibodies, both as single agents and in combination with other compounds, unfortunately led to unsatisfactory results across several tumor types. The HER3-directed delivery of cytotoxic payloads through antibody-drug conjugates has recently demonstrated encouraging activity in several tumor types, however, suggesting a potential role for the therapeutic targeting of HER3 in cancer treatment.

Clinical development and current role of margetuximab for the treatment of breast cancer.

Up to 20% of breast cancers overexpress HER2, a molecular alteration conferring these tumors a particularly aggressive behavior. However, targeting HER2 has radically changed the prognosis of this disease in the last 2 decades, with multiple anti-HER2 compounds shown to improve disease outcomes both in the early and advanced setting. The latest anti-HER2 compound to be approved by the U.S. Food and Drug Administration (FDA) was margetuximab, an Fc-engineered monoclonal antibody with an improved binding to FcγRIIIA receptor, which leads to a greater antibody-dependent cellular cytotoxicity (ADCC) activation compared with trastuzumab. Margetuximab was shown to slightly improve progression-free survival compared with trastuzumab when combined with chemotherapy for the treatment of advanced HER2-positive breast cancer patients, and is now included among the available treatment options for pretreated HER2-positive breast cancer patients. In this monograph we recapitulate the clinical development, current role and future perspectives of margetuximab for the treatment of breast cancer.

Therapeutic cancer vaccines revamping: technology advancements and pitfalls.

Cancer vaccines (CVs) represent a long-sought therapeutic and prophylactic immunotherapy strategy to obtain antigen (Ag)-specific T-cell responses and potentially achieve long-term clinical benefit. However, historically, most CV clinical trials have resulted in disappointing outcomes, despite promising signs of immunogenicity across most formulations. In the past decade, technological advances regarding vaccine delivery platforms, tools for immunogenomic profiling, and Ag/epitope selection have occurred. Consequently, the ability of CVs to induce tumor-specific and, in some cases, remarkable clinical responses have been observed in early-phase clinical trials. It is notable that the record-breaking speed of vaccine development in response to the coronavirus disease-2019 pandemic mainly relied on manufacturing infrastructures and technological platforms already developed for CVs. In turn, research, clinical data, and infrastructures put in place for the severe acute respiratory syndrome coronavirus 2 pandemic can further speed CV development processes. This review outlines the main technological advancements as well as major issues to tackle in the development of CVs. Possible applications for unmet clinical needs will be described, putting into perspective the future of cancer vaccinology.

Benefit of adjuvant chemotherapy in patients with lobular breast cancer: A systematic review of the literature and metanalysis.

The role of adjuvant chemotherapy (aCT) for patients with localized lobular breast cancer (ILC) is still controversial. It is unclear what is the magnitude of benefit of the CT in this setting. In this systematic review of the literature and metanalysis, we aimed to estimate the benefit of aCT in addition to the standard treatments in the early ILC setting. We identified the records by searching Medline, CENTRAL, Web of Science, SCOPUS, and Google Scholar, and the meeting proceeding of the principal oncology meetings of the last 10 years, with no language or time restriction. A research strategy was developed with mapped and MeSH terms. Studies on the clinical use of aCT reporting survival outcomes in the ILC setting were double-screened and tabulated. PRISMA methodology was used for data extraction and synthesis. We extracted information on the study design and setting, eligible population and population size, histology variants, menopausal status, treatment regimens, follow-up duration. Hazard ratios (HR) and 95% confidence interval (CI) were extracted and transformed into logHR and corresponding standard error to obtain the Summary HR (SHR). Heterogeneity (I2 statistics) and publication bias (Macaskill test) were tested; a random effect models provided by SAS Proc Mixed was used for data analysis. Sensitivity analysis was conducted to examine the impact of inclusion criteria on the summary results. Disease-free (DFS), overall (OS) and cancer-specific survival (BCSS) were the primary endpoints of the investigation. The systematic review and metanalysis included 38,387 patients across 8 clinical studies. aCT was not associated with an improvement of OS (SHR 0.99; 95%CI 0.86-1.14), with low heterogeneity (I2 = 28%) and no publication bias (p = 0.43). Sensitivity analysis resulted in unchanged conclusions. We did not perform a metanalysis of the DFS estimates, as only reported in 3 studies. The value of aCT in improving DFS was unconfirmed, consistently with the OS results. Our research did not confirm a certain role of aCT for patients with ILC. Research gaps were identified, warranting the development of prospective, controlled ad hoc investigations.

Design and testing of miniaturized plasma sensor for measuring hypervelocity impact plasmas.

An increasingly notable component of the space environment pertains to the impact of meteoroids and orbital debris on spacecraft and the resulting mechanical and electrical damages. Traveling at speeds of tens of km/s, when these particles, collectively referred to as hypervelocity particles, impact a satellite, they vaporize, ionize, and produce a radially expanding plasma that can generate electrically harmful radio frequency emission or serve as a trigger for electrostatic discharge. In order to measure the flux, composition, energy distribution, and temperature of ions and electrons in this plasma, a miniaturized plasma sensor has been developed for carrying out in-situ measurements in space. The sensor comprises an array of electrostatic analyzer wells split into 16 different channels, catering to different species and energy ranges in the plasma. We present results from numerical simulation based optimization of sensor geometry. A novel approach of fabricating the sensor using printed circuit boards is implemented. We also describe the test setup used for calibrating the sensor and show results demonstrating the energy band pass characteristics of the sensor. In addition to the hypervelocity impact plasmas, the plasma sensor developed can also be used to carry out measurements of ionospheric plasma, diagnostics of plasma propulsion systems, and in other space physics experiments.

First Report of Necrotic Leaf Spot Caused by Plectosphaerella cucumerina on Lamb's Lettuce in Southern Italy.

During spring 2013, lamb's lettuce plants (Valerianella locusta) cv. Calarasi (Rijk Zwaan) in a commercial greenhouse in Sele Valley (Salerno Province, southern Italy) exhibited small, black-brown, irregular spots (1 mm2) that became necrotic, enlarged, and coalesced. The spots were mostly on the tips of leaves, and were surrounded by a yellow halo. The disease was severe under greenhouse conditions of 60 to 90% RH and maximum air temperature of 26°C, and affected up to 70% of the plants. The greenhouses covered an area of ~3,000 ha where many salad species are grown. Tissue fragments were excised from symptomatic leaves, sterilized by sequential dipping in 70% ethanol for 30 s and in 1% NaOCl for 30 s, rinsed in sterilized distilled water, and placed in 9-cm-diameter petri dishes containing potato dextrose agar (PDA) medium amended with streptomycin sulfate (0.1 g/liter). The plates were incubated at 24°C in the dark. A fungus was isolated consistently from infected leaf tissue after 4 days. Each colony was whitish to orange. Mycelium was hyaline, branched, septate, 3 to 4 µm wide, with numerous anastomosis-forming hyphal coils. Conidiophores were solitary, hyaline, smooth, thin-walled, unbranched or rarely irregularly branched. Conidiogenous cells were phialidic, determinate, discrete, smooth, solitary, and formed on hyphal coils. Phialides were aseptate or occasionally 1-septate near the base. Conidia (n = 100) were ellipsoidal, hyaline, smooth, septate or aseptate, and 6.6 ± 0.9 × 2.8 ± 0.4 µm. On the basis of morphological criteria (3), the fungus was ascribed to Plectosphaerella cucumerina (L.) Laterr. (anamorph Plectosporium tabacinum). An aliquot (50 ng) of genomic DNA extracted from mycelium of five cultures obtained by monosporic isolation on PDA was used as template for a PCR reaction with primers ITS5/ITS4, specific for the ITS 5.8S rDNA region of fungi (3). The 500-bp sequences amplified from the five isolates were identical, and the sequence of isolate Val-2 was submitted to GenBank (KF753234). Sequence analysis with BLASTn showed 100% identity of this sequence to the ITS-5.8S rDNA sequences of 11 isolates of P. cucumerina in GenBank. Three isolates were selected for pathogenicity tests on the lamb's lettuce cv. Calarasi. Before planting, seeds were surface-disinfected in 1% NaOCl and rinsed with sterilized distilled water. Plants (35 days old, 30 plants tested/isolate) were grown in 0.7-liter pots filled with a sterilized (autoclaved at 112°C for 1 h on each of two consecutive days) mixture of soil:sand:perlite (2:1:1), and inoculated by spraying the leaves with a spore suspension (106 CFU/ml, ~3 ml applied/plant) of each isolate prepared from 7-day-old cultures on PDA. As a control, five plants were sprayed with sterilized water. All plants were incubated in a growth chamber at 90% RH with a 12-h photoperiod at 24°C. Leaf spots typical of those on the original symptomatic plants appeared 7 to 10 days after inoculation on all inoculated plants. No symptoms were observed on control plants. P. cucumerina was re-isolated only from symptomatic leaves, as described for the original isolations. P. cucumerina has been associated with root and collar roots of some horticultural crops (1), and a leaf spot on Diplotaxis tenuifolia (2), often grown in rotation with lamb's lettuce in southern Italy. To our knowledge, this is the first report of P. cucumerina as a pathogen of V. locusta in Italy or elsewhere. The disease caused economic loss to lamb's lettuce, primarily used in Italy in fresh-cut, mixed salads. References: (1) A. Carlucci et al. Persoonia 28:34, 2012. (2) A. Garibaldi et al. Plant Dis. 96:1825, 2012. (3) T. J. White et al. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA, 1990.

Association study between the LINGO1 gene and Parkinson's disease in the Italian population.

Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson's disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology. In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes.

Early-onset SCA17 with 43 TBP repeats: expanding the phenotype?

The SCA17 clinical phenotype includes characteristics associated with cerebellar and cortical atrophy such as ataxia, dementia, epilepsy, chorea and parkinsonian features. Here we describe the case of a 38-year-old male presenting with ataxia, cognitive impairment and seizures, who was found to carry 43 repeats on one allele of the TATA-binding protein (TBP) gene. Therefore, genetic analysis of TBP gene triplets was performed on the patient's entire family, identifying three asymptomatic carriers of the same allele. A neuroradiological phenotype appeared to segregate with this allele, suggesting that it may play at least a contributory role in the determination of SCA17.

Met158 variant of the catechol-O-methyltransferase genotype is associated with thicker cortex in adult brain.

Cortical thickness has been proposed as a new promising brain imaging endophenotype in elucidating the nature of gene-brain relationships. Here, we define the morphological impact of the Val(158)Met polymorphism in the catechol-O-methyltransferase (COMT) gene on human brain anatomy. One hundred and forty-nine adult healthy subjects (mean age: 40.7+/-16.1; ranging from 19 to 76 years) were genotyped (38 in the homozygous Val(158) group; 80 in the Val(158)Met group; 31 in the homozygous Met(158) group) for the COMT polymorphism and underwent morphological examination. Surface-based analysis of the cortical mantle showed that the COMT genotype was associated with structural differences in the right superior temporal sulcus and inferior prefrontal sulcus, where the individuals carrying the Met(158) allele had a thicker cortex with respect to their Val(158) counterparts. Our study extends the previous evidence found on pediatric population to the adult population, demonstrating that the higher synaptic dopamine levels associated with the presence of the Met(158) allele may influence neuronal architecture in brain structures important for executive and emotional processing.

DJ-1 is a Parkinson's disease susceptibility gene in southern Italy.

Mutations in the gene DJ-1 have been shown to be a rare cause of early-onset Parkinson's disease (EOPD). Since DJ-1 mutations have been found in patients with Parkinson's disease (PD) from southern Italy, we aimed to investigate whether polymorphisms within the DJ-1 gene could represent a risk factor for sporadic PD. First, we genotyped 294 patients with PD and 298 controls coming from southern Italy to assess the distribution of the insertion/deletion (Ins/Del) polymorphism. In a second phase, we identified five single-nucleotide polymorphisms (SNPs) useful to delimit a region potentially involved and genotyped all patients and controls for these markers. All the markers analyzed were significantly associated with PD at both allelic and genotypic level. The most significant association with the disease was found at the Ins/Del polymorphism (p = 0.0001; adjusted odds ratio (OR ) = 2.05; confidence interval (CI ) = 1.36-3.08). When we considered a three-marker sliding window, we found a highly significant association between the disease and the haplotypes including markers rs17523802, Ins/Del, and rs3766606 (p = 0.0007) and markers Ins/Del, rs3766606 and rs7517357 (p = 0.0054). Our results indicate that polymorphisms located in a region spanning 3535 bp from the promoter to the intron 2 of the DJ-1 gene confer risk to sporadic PD in southern Italy.