Prospective study of a molecular selection profile for RAS wild type colorectal cancer patients receiving irinotecan-cetuximab

Background: The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed might be able to predict patients' clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild type colorectal cancer patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated into 2 groups on the basis of their profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ≥ 2.6, HER-3 Rajkumar score ≤ 8, IGF-1 immunostaining < 2) or unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible. Results: Forty-six patients were enrolled. Seventeen patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p = 0.007) respectively. The favourable group also showed an improved PFS (8months vs. 3months, p < 0.0001) and OS (15months vs. 6months, p < 0.0001). Conclusions: Our results suggest that prospective selection of optimal candidates for cetuximab treatment is feasible and may be able to improve clinical outcom

Epidermal growth factor receptor (EGFR) downstream signalling pathway in primary colorectal tumours and related metastatic sites: optimising EGFR-targeted treatment options

We analysed the expression of activated (phosphorylated) Akt and MAPK in 98 cases of paired primary colorectal tumours and metastases with the aim to define better the epidermal growth factor receptor (EGFR)-related molecular profile of colorectal cancer as a tool for treatment selection. Among 47 (48%) EGFR-negative primary tumours, 35 cases (74%) were positive for phosphorylated Akt and MAPK. Among 51 (52%) EGFR-positive primary colorectal cancers, 13 (25%) cases were negative for phosphorylated Akt and 15 (29%) were negative for phosphorylated MAPK. In EGFR-negative metastases (56 cases, 55%), phosphorylated Akt was expressed in 41 (73%) and phosphorylated MAPK was expressed in 36 (64%) samples, whereas in EGFR-positive metastases, phosphorylated Akt and MAPK were negative in 14 (31%) and in 10 (22%) cases, respectively. Phosphorylated Akt expression in primary colorectal tumours changed from positive to negative in 16 (16%) paired metastases and from negative to positive in 13 (13%) related metastatic sites. Phosphorylated MAPK expression in primary tumours changed from positive to negative in 13 (13%) paired metastases and from negative to positive in 12 (12%) related metastatic sites. Our findings suggest that phosphorylated Akt and MAPK status in primary tumours does not correlate with Akt and MAPK status in corresponding metastases. EGFR downstream signalling pathway can be overactivated even in the absence of EGFR expression in a considerable proportion of patients

Linking the genomic signatures of human beat synchronization and learned song in birds

The development of rhythmicity is foundational to communicative and social behaviours in humans and many other species, and mechanisms of synchrony could be conserved across species. The goal of the current paper is to explore evolutionary hypotheses linking vocal learning and beat synchronization through genomic approaches, testing the prediction that genetic underpinnings of birdsong also contribute to the aetiology of human interactions with musical beat structure. We combined state-of-the-art-genomic datasets that account for underlying polygenicity of these traits: birdsong genome-wide transcriptomics linked to singing in zebra finches, and a human genome-wide association study of beat synchronization. Results of competitive gene set analysis revealed that the genetic architecture of human beat synchronization is significantly enriched for birdsong genes expressed in songbird Area X (a key nucleus for vocal learning, and homologous to human basal ganglia). These findings complement ethological and neural evidence of the relationship between vocal learning and beat synchronization, supporting a framework of some degree of common genomic substrates underlying rhythm-related behaviours in two clades, humans and songbirds (the largest evolutionary radiation of vocal learners). Future cross-species approaches investigating the genetic underpinnings of beat synchronization in a broad evolutionary context are discussed

Emerging treatment evolutions and integrated molecular characteristics of biliary tract cancers

Biliary tract cancers&nbsp;(BTCs) consist of a group of highly heterogeneous malignancies that&nbsp;are&nbsp;characterized by&nbsp;genomic differences among tumors from different anatomic sites. The current&nbsp;treatment&nbsp;for&nbsp;BTC&nbsp;includes surgery,&nbsp;chemotherapy, target therapy, and immunotherapy. Although surgery remains the primary option for localized disease, representing the only potential curative treatment, a high risk of recurrence cannot be neglected.&nbsp;Chemotherapy has been considered&nbsp;the standard of care for both advanced and metastatic disease and in adjuvant settings. However, drug resistance is a major obstacle associated with chemotherapy. The development of genetic testing technologies, including next-generation sequencing, has opened the door for the identification of drug targets and candidate molecules.&nbsp;A series of preclinical studies has demonstrated the role of gene mutations, abnormal signaling pathways, and immunosuppression in the pathogenesis of BTC, laying the foundation for the application of targeted therapy and immunotherapy. A variety of molecularly targeted agents, including pemigatinib, have shown promising survival benefits in patients with advanced disease. The rapidly evolving role of multimodal therapy represents the subject of this review

Angiogenesis genotyping in the selection of first-line treatment with either sunitinib or pazopanib for advanced renal cell carcinoma

Recent data from the COMPARZ study seem to suggest a noninferiority of pazopanib confronted with sunitinib in PFS and OS. We previously reported how VEGF and VEGFR polymorphisms might have a predictive role in patients treated with first-line sunitinib. Aim of our study was to investigate whether tumour angiogenesis genotyping could influence clinical outcome in RCC patients treated with either sunitinib or pazopanib, in order to help clinicians select the appropriate treatment for each patient. Results: 19 patients were treated with pazopanib while 78 received sunitinib. VEGF A rs833061 resulted significant in PFS in sunitinib vs pazopanib patients (CC+CT > TT in sunitinib, TT > CC+CT in pazopanib; p CC in sunitinib, CC > GG+CG in pazopanib; p CC in sunitinib, CC > AA+AC in pazopanib; p < 0,0001). OS showed no statistically significant difference. Conclusions: In our analysis patients with opposite polymorphisms of rs833061, rs2010963, rs699947 of VEGF A seems to have a better PFS if treated with either sunitinib or pazopanib. Our data seem to suggest that biology could have a role choosing first line treatment for mRCC patients. Methods: A retrospective analysis on 97 histologic samples of mRCC patients was conducted for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs

Hormone Receptor-Positive/HER2-Positive Breast Cancer: Hormone Therapy and Anti-HER2 Treatment: An Update on Treatment Strategies

Hormone receptor (HR)-positive/HER2-positive breast cancer represents a distinct subtype expressing estrogen and progesterone receptors with an overexpression of HER2. Approximately 14% of female breast cancer cases are HER2-positive, with the majority being HR-positive. These tumors show a cross-talk between the hormonal and HER2 pathways; the interaction has implications for the treatment options for the disease. In this review, we analyze the biology of HR-positive/HER2-positive breast cancer and summarize the evidence concerning the standard of care options both in neoadjuvant/adjuvant settings and in advanced disease. Additionally, we focus on new trials and drugs for HR-positive/HER2-positive breast cancer and the new entity: HER2-low breast cancer

The prognostic role of hemoglobin levels in patients undergoing concurrent chemo-radiation for anal cancer

Background: Concurrent chemo-radiation (CT-RT) is a standard therapy for squamous cell carcinoma of anal canal. Different clinical and biological factors may potentially affect outcome. We investigated the prognostic role of baseline hemoglobin (Hb) in a cohort of anal cancer patients submitted to CT-RT with 5-fluorouracil and mitomycin C. Methods: Up to 161 patients with clinical stage T1-T4/N0-N3/M0 were treated. Response was assessed at 6 weeks and thereafter at 3, 6 and 12 months. Two different approaches were used:a)simultaneous integrated boost following RTOG 05-29 indications;b)first sequence of 45Gy/25 fractions to the pelvis followed by 9-14.4 Gy/5-8 fractions to the macroscopic disease. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: On multivariate analysis, pre-treatment Hb level had a significant correlation to OS (HR:0.53;95% CI:0.33-0.87; p = 0.001), but not to PFS (HR:0.78;95% CI:0.53-1.15; p = 0.12) Patients with pre-treatment Hb ≥ 12 g/dl had 5-year PFS and OS of 82.2%, compared to 29.3% and 32.8% for those below the threshold. The likelihood to achieve a complete remission increased by 5.6% for every single-unit (g/dl) increase in baseline Hb level over 11 g/dl. On multivariate analysis, response to treatment had a significant correlation to PFS (incomplete vs complete response - HR:5.43;95% CI:2.75-10.7; p < 0.0001) and OS (HR: 6.96;95% CI:2.96-16.5; p < 0.0001). Conclusions: We showed that baseline Hb level is a strong indicator for poor response to RT-CT in anal cancer patients. A close clinical monitoring for incomplete response to treatment should be advised in patients with low pre-treatment Hb. The hypothesis that the preservation of adequate Hb level during treatment may lead to a better outcome needs prospective evaluation

Low adherence to therapy and co-morbid depressive episodes are independent determinants of early death in people with cancer

Objective: The demanding nature of oncological therapies may affect treatment motivation and adherence, leading to an increased risk of premature death. Exploring the interaction between depressive episodes and treatment adherence is essential, considering how depression may influence patients' willingness to continue treatment. This study aims to investigate the association between depressive episodes, low treatment adherence, and premature death in individuals with cancer. The study also assessed whether low adherence to therapy acted as a mediator in the relationship between depression and the risk of early death. Participants and Methods: This is a 9-month cohort study in which participants were enrolled in two Italian Oncology hospital units. The Patient Health Questionnaire (PHQ-9) was used for depression screening. Stratified analyses were conducted to explore the relationship between depression, low adherence, and premature death. Results: Out of 263 subjects, depressive episode frequency was 48.2% and low adherence was 9.9%. After 9 months, 13.7% had died. There was a significative association between experiencing a depressive episode (RR=2.14, 95% CI: 1.08-4.39) and low adherence (RR=2.2, 95% CI: 1.01-4.48) upon cohort entry and being deceased at month 9 of observation. The risk associated with depression was found to persist even after accounting for the level of adherence to therapy through standardization (MH-OR=3.11; 95% CI: 1.52-6.34). Conclusions: Individuals with cancer who experience a depressive episode or demonstrate low adherence to therapy are at risk for premature death. Early intervention targeting depressive symptoms and treatment adherence may improve oncological-related outcomes

Adherence to treatment in patients with solid and hematological cancers. Could spiritual and psychological support facilitate optimal adherence?

ABSTRACT – Objective: Cancer-related diseases pose a substantial public health challenge; however, recent treatments have enhanced patient outcomes. Adherence to therapy is crucial, and research focuses on elucidating the factors that influence it. Limited information exists on medication adherence in cancer patients. This study aims to identify risk factors for non-adherence in a cohort of people with solid and hematological tumors. Participants and Methods: This is a cross-sectional study in which participants were recruited from two Oncologic hospital units in Italy. The inclusion criteria were age ≥ 18 years, confirmed malignant neoplasm, and active treatment. Data included sociodemographic and clinical-oncological factors. Treatment adherence was assessed through a clinician-based dichotomous scale. Health-related quality of life (HRQoL) was evaluated with the Short Form Health Survey – 12 items (SF-12), satisfaction with care was measured using the Treatment Perception Questionnaire. Results: A total of 263 participants (132 females, 50.2%) was involved in this study. The mean age was 61.2±13.8. Non-adherence frequency was 9.9%. Factors associated with non-adherence were shorter time since care initiation (&lt;6 months), receiving palliative care, having a solid cancer diagnosis. Non-adherence was higher in solid cancer (12.4%) compared to hematologic cancer (1.6%). In the combination of risk factors, a significant association was found between unemployment/high level of education and non-adherence. Conclusions: The study found a low non-adherence rate to oncological treatments, possibly due to strong psychological and spiritual support. However, individuals with higher education and unemployment showed specific non-adherence risk, necessitating attention to their emotional challenges while facing canc