Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

PURPOSE: Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. METHODS: 241 consecutive women (median age 58 years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24 months of follow-up. During the study period, 139 women (57.7%) received denosumab 60 mg every 6 months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. RESULTS: Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. CONCLUSIONS: TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer.

PURPOSE: HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-zero, obtained by immunohistochemistry (IHC). METHODS: Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1-10%). HER2 gene expression by ODX was negative if lower 10.7. RESULTS: The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70-9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p < 0.001] compared to the HER2-zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups. CONCLUSION: Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-zero IHC whose accurate identification is critical in the context of HER2-negative BC.

Working tables on Hormone Receptor positive (HR+), Human Epidermal growth factor Receptor 2 negative (HER2-) early stage breast cancer: Defining high risk of recurrence.

Hormone-receptor positive (HR+), Human-Epidermal-growth Factor negative (HER2-) breast cancer, including the Luminal A and the Luminal B subtypes, is the most common in women diagnosed with early-stage BC. Despite the advances in screening, surgery and therapies, recurrence still occurs. Therefore, it is important to identify early those factors that significantly impact the recurrence risk. Based on current evidence and their professional expertise, a Panel of oncologists discussed the definition of high risk of recurrence in early breast cancer. Histological grade, nodal involvement, genomic score, histological grade, tumor size, and Ki-67 proliferation index were rated as the most important factors to define the high risk in patients with early breast cancer. All these factors should be considered comprehensively to tailor the choice of treatment to the peculiar characteristics of each patient.

The importance of deep genotyping in crop breeding / La importancia de la genotipificación profunda en el mejoramiento genético

ABSTRACT One of the greatest challenges facing humanity is the development of sustainable strategies to ensure food availability in response to population growth and climate change. One approach that can contribute to increase food security is to close yield gaps and enhancing genetic gain; to such end, what is known as "molecular breeding" plays a fundamental role. Since a crop breeding program is mainly based on the quality of the germplasm, its detailed genetic characterization is mandatory to ensure the efficient use of genetic resources and accelerating development of superior varieties. Deep genotyping is an essential tool for a comprehensive characterization of the germplasm of interest and, fortunately, the technology is now accessible at a reasonable cost. What must be ensured is the correct interpretation of the genotypic information and on that basis develop efficient practical molecular crop breeding strategies that respond to the real needs of the breeding program.

RESUMEN Uno de los mayores desafíos que enfrenta la humanidad es el desarrollo de estrategias sostenibles para asegurar la disponibilidad de alimentos en respuesta al crecimiento de la población y el cambio climático. Un enfoque que puede contribuir a aumentar la seguridad alimentaria es cerrar las brechas de rendimiento y mejorar la ganancia genética; para tal fin, lo que se conoce como "mejoramiento molecular" juega un papel fundamental. Dado que un programa de mejoramiento de cultivos se basa principalmente en la calidad del germoplasma, su caracterización genética detallada es fundamental para garantizar el uso eficiente de los recursos genéticos y acelerar el desarrollo de variedades superiores. La genotipificación profunda es una herramienta esencial para una caracterización integral del germoplasma de interés y, afortunadamente, en la actualidad se puede acceder a la tecnología a un costo razonable. Lo que debe asegurarse es la interpretación correcta de la información genotípica y sobre esa base desarrollar estrategias eficientes y prácticas de mejoramiento molecular de cultivos que respondan a las necesidades reales del programa de mejoramiento.

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA).

BACKGROUND: BRCA1/2-related metastatic breast cancers (mBC) are sensitive to DNA-damage agents and show high tumor-infiltrated lymphocytes. We hypothesized that the association between pembrolizumab and carboplatin could be active in BRCA-related mBC. PATIENTS AND METHODS: In this phase II Simon's design multicenter single-arm study, BRCA1/2-related mBC patients received carboplatin at area under the curve 6 every 3 weeks for six courses associated with 200 mg pembrolizumab every 3 weeks until disease progression or unacceptable toxicity. The primary aim at first stage was overall response rate (ORR) ≥70%. Disease control rate (DCR), time to progression (TTP), duration of response (DOR), and overall survival (OS) were the secondary aims. RESULTS: Among 22 patients enrolled at the first stage, 5 BRCA1 and 17 BRCA2, 16 (76%) were luminal tumors and 6 (24%) triple-negative BC (TNBC). In 21 patients, ORR and DCR were 43% and 76% (47% and 87% in luminal, 33% and 50% in TNBC), respectively. TTP was 7.1 months, DOR was 6.3 months, and median OS was not reached. Grade ≥3 adverse events (AEs) or serious AEs occurred in 5/22 patients (22.7%). Since the primary aim was not met, the study was terminated at the first stage. CONCLUSIONS: Although the primary aim was not reached, data on efficacy and safety of pembrolizumab plus carboplatin in first-line visceral disease BRCA-related luminal mBC were provided and they need to be further investigated.

Optimizing choices and sequences in the diagnostic-therapeutic landscape of advanced triple-negative breast cancer: An Italian consensus paper and critical review.

Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.

Ontology-Driven Real World Evidence Extraction from Clinical Narratives.

Unstructured clinical notes contain a huge amount of information. We investigated the possibility of harvesting such information through an NLP-based approach. A manually curated ontology is the only resource required to handle all the steps of the process leading from clinical narrative to a structured data warehouse (i2b2). We have tested our approach at the Papa Giovanni XXIII hospital in Bergamo (Italy) on pathology reports collected since 2008.

The impact of molecular genetics in plant breeding: realities and perspectives / El impacto de la genética molecular en el mejoramiento genético vegetal: realidades y perspectivas

Even when conventional breeding was effective in achieving a continuous improvement in yield, Molecular Genetics tools applied in plant breeding contributed to maximize genetic gain. Thus, the use of DNA technology applied in agronomic improvement gave rise to Molecular Breeding, discipline which groups the different breeding strategies where genotypic selection, based on DNA markers, are used in combination with or in replacement of phenotypic selection. These strategies can be listed as: marker-assisted selection; marker-assisted backcrossing; marker assisted recurrent selection; and genomic selection. Strong arguments have been made about the potential advantages that Molecular Breeding brings, although little has been devoted to discussing its feasibility in practical applications. The consequence of the lack of a deep analysis when implementing a strategy of Molecular Breeding is its failure, leading to many undesirable outcomes and discouraging breeders from using the technology. The aim of this work is to trigger a debate about the convenience of the use of Molecular Breeding strategies in a breeding program considering the DNA technology of choice, the complexity of the trait of agronomic interest to be improved, the expected accuracy in the selection, and the demanded resources.

El mejoramiento convencional ha sido efectivo para lograr una mejora continua en el rendimiento; sin embargo las herramientas de Genética Molecular aplicadas en el fitomejoramiento han contribuido a maximizar la ganancia genética. Es así que el uso de la tecnología de ADN aplicada en la mejora agronómica dio lugar al Mejoramiento Molecular, disciplina que agrupa las diferentes estrategias en las que la selección genotípica, basada en marcadores de ADN, es utilizada en combinación con, o bien en reemplazo de, la selección fenotípica. Estas estrategias se pueden clasificar como: selección asistida por marcadores; retrocruzamiento asistido por marcadores; selección recurrente asistida por marcadores; y selección genómica. Se han presentado fuertes argumentos sobre las potenciales ventajas que aporta el mejoramiento molecular, aunque poco se ha dedicado a discutir la viabilidad de su aplicación práctica. La consecuencia de la falta de un análisis profundo al implementar una estrategia de este tipo puede ser su fracaso, lo que puede derivar en resultados indeseables, desalentando a los fitomejoradores a usar la tecnología. El objetivo de este trabajo es propiciar un debate sobre la conveniencia del uso práctico de estrategias de mejoramiento molecular teniendo en cuenta la tecnología de ADN elegida, la complejidad del rasgo de interés agronómico que se quiere mejorar, la precisión esperada en la selección y los recursos demandados.

Patient similarity by joint matrix trifactorization to identify subgroups in acute myeloid leukemia.

OBJECTIVE: Computing patients' similarity is of great interest in precision oncology since it supports clustering and subgroup identification, eventually leading to tailored therapies. The availability of large amounts of biomedical data, characterized by large feature sets and sparse content, motivates the development of new methods to compute patient similarities able to fuse heterogeneous data sources with the available knowledge. MATERIALS AND METHODS: In this work, we developed a data integration approach based on matrix trifactorization to compute patient similarities by integrating several sources of data and knowledge. We assess the accuracy of the proposed method: (1) on several synthetic data sets which similarity structures are affected by increasing levels of noise and data sparsity, and (2) on a real data set coming from an acute myeloid leukemia (AML) study. The results obtained are finally compared with the ones of traditional similarity calculation methods. RESULTS: In the analysis of the synthetic data set, where the ground truth is known, we measured the capability of reconstructing the correct clusters, while in the AML study we evaluated the Kaplan-Meier curves obtained with the different clusters and measured their statistical difference by means of the log-rank test. In presence of noise and sparse data, our data integration method outperform other techniques, both in the synthetic and in the AML data. DISCUSSION: In case of multiple heterogeneous data sources, a matrix trifactorization technique can successfully fuse all the information in a joint model. We demonstrated how this approach can be efficiently applied to discover meaningful patient similarities and therefore may be considered a reliable data driven strategy for the definition of new research hypothesis for precision oncology. CONCLUSION: The better performance of the proposed approach presents an advantage over previous methods to provide accurate patient similarities supporting precision medicine.

Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Temporal electronic phenotyping by mining careflows of breast cancer patients.

In this work we present a careflow mining approach designed to analyze heterogeneous longitudinal data and to identify phenotypes in a patient cohort. The main idea underlying our approach is to combine methods derived from sequential pattern mining and temporal data mining to derive frequent healthcare histories (careflows) in a population of patients. This approach was applied to an integrated data repository containing clinical and administrative data of more than 4000 breast cancer patients. We used the mined histories to identify sub-cohorts of patients grouped according to healthcare activities pathways, then we characterized these sub-cohorts with clinical data. In this way, we were able to perform temporal electronic phenotyping of electronic health records (EHR) data.

AurkA controls self-renewal of breast cancer-initiating cells promoting wnt3a stabilization through suppression of miR-128.

AurkA overexpression was previously found in breast cancer and associated to its ability in controlling chromosome segregation during mitosis, however whether it may affect breast cancer cells, endorsed with stem properties (BCICs), is still unclear. Surprisingly, a strong correlation between AurkA expression and ß-catenin localization in breast cancer tissues suggested a link between AurkA and Wnt signaling. In our study, AurkA knock-down reduced wnt3a mRNA and suppressed metastatic signature of MDA-MB-231 cells. As a consequence, the amount of BCICs and their migratory capability dramatically decreased. Conversely, wnt3a mRNA stabilization and increased CD44(+)/CD24(low/-) subpopulation was found in AurkA-overexpressing MCF7 cells. In vivo, AurkA-overexpressing primary breast cancer cells showed higher tumorigenic properties. Interestingly, we found that AurkA suppressed the expression of miR-128, inhibitor of wnt3a mRNA stabilization. Namely, miR-128 suppression realized after AurkA binding to Snail. Remarkably, a strong correlation between AurkA and miR-128 expression in breast cancer tissues confirmed our findings. This study provides novel insights into an undisclosed role for the kinase AurkA in self-renewal and migration of BCICs affecting response to cancer therapies, metastatic spread and recurrence. In addition, it suggests a new therapeutic strategy taking advantage of miR-128 to suppress AurkA-Wnt3a signaling.

Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: a retrospective study.

BACKGROUND: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). PATIENTS AND METHODS: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. RESULTS: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. CONCLUSIONS: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.

Targeting the EWS-FLI1 transcription factor in Ewing sarcoma.

PURPOSE: Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS-FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. METHODS: Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. RESULTS: The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. CONCLUSIONS: The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma.

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.

Long-term survival in patients with metastatic breast cancer receiving intensified chemotherapy and stem cell rescue: data from the Italian registry.

The median survival of women with metastatic breast cancer (MBC) is 18-24 months, and fewer than 5% are alive and disease free at 5 years. We report toxicity and survival in a cohort of MBC patients receiving high-dose chemotherapy (HDC) with autologous hematopoietic SCT (AHSCT) in Italy between 1990 and 2005. Data set for survival analysis has been obtained for 415 patients. Clinical parameters including probability of transplant-related mortality (TRM), PFS and OS. With a median follow-up of 27 months (range 0-172), OS and PFS at 5 and 10 years in the whole population were 47/23 and 32/14%, respectively. A total 239 patients are alive with a median follow-up of 33 months (range 2-174). Survival was significantly more pronounced in patients harboring hormone receptor positive tumors (P=0.028), without visceral metastases (P=0.009) and in women with chemosensitive disease (P<0.0001). Sixty eight patients (20.4%) who received HDC in partial response, stable or progressive disease underwent conversion to CR. TRM was 2.5% overall and 1.3% since 2000. Our findings suggest that could be a role for HDC and AHSCT in delaying disease progression and possibly cure a subset of MBC patient harboring chemosensitive tumors.