Precision medicine into clinical trials: the paradigm of circulating tumor DNA-based predictive biomarkers in breast cancer

Ο καρκίνος του μαστού αποτελεί την πρώτη σε συχνότητα και δεύτερη σε θνησιμότητα κακοήθεια στις γυναίκες παγκοσμίως. Στην εποχή της Ιατρικής Ακριβείας οι θεραπευτικές αποφάσεις βασίζονται στα πεδία της μεταγραφικής έρευνας: γονιδιωματικής (έκφραση γονιδίων) και πρωτεομικής (έκφραση ορμονικών και HER2 υποδοχέων) ανάλυσης των κυττάρων του όγκου, συνηθέστερα από το αρχικό δείγμα της ιστικής βιοψίας του πρωτοπαθούς όγκου, που δεν αντανακλά απαραίτητα τη δυναμική του μοριακού προφίλ της νόσου. Έτσι, η αδυναμία ελέγχου της γενετικής ετερογένειας και της εξέλιξης της νόσου, σε αληθινό χρόνο, μπορεί να εξηγήσει την αποτυχία της συστηματικής θεραπείας, στις μέρες μας, παρά την ανάπτυξη στοχευουσών θεραπειών. Αντίθετα, η ανάλυση κυκλοφορούντων καρκινικών βιοδεικτών, στο πλαίσιο των υγρών βιοψιών, συμπεριλμβανομένου του κυκλοφορούντος καρκινικού DNA (ctDNA), παρέχει μια εικόνα για το μοριακό προφίλ του πρωτοπαθούς όγκου και των μεταστατικών του εστιών, με μη παρεμβατικό τρόπο. Στη συγκεκριμένη συστηματική ανασκόπηση συνοψίζουμε τα αποτελέσματα πρόσφατα δημοσιευμένων κλινικών δοκιμών που βασίζονται σε αντίστοιχους βιοδείκτες. Είναι επιτακτική η διεξαγωγή καλά σχεδιασμένων, πολυκεντρικών, τυχαιοποιημένων κλινικών μελετών, που χρησιμοποιούν βιοδείκτες βασισμένους σε ctDNA αναλύσεις για τη διαστρωμάτωση των συμμετέχοντων ασθενών, με στόχο τον προσδιορισμό της προβλεπτικής αξίας του ctDNA στην εξατομικευμένη θεραπείων των ασθενών με καρκίνο μαστού.Breast carcinoma (BC) is the most frequent and the second leading cause of cancer mortality in women worldwide. In the era of precision medicine, therapeutic decisions are mainly based on genomic, transcriptomic (gene expression) and/or proteomic (status of HER2 and hormone receptors) profiling of cells from a single, usually archival, sample of the primary tumour, which may not necessarily represent the current disease status. Thus, the inability to capture tumour genetic heterogeneity and evolution in real-time could explain the failure of systemic therapy, nowadays, despite the advances in targeted treatment modalities. On the contrary, analysis of circulating blood markers in the field of liquid biopsies, including circulating tumour DNA (ctDNA), provides an insight into the dynamic molecular profiling of the primary tumour and its metastases, in a relatively non-invasive way. In this systematic review we summarize the results from recent and ongoing biomarker-driven clinical trials and discuss the quality and limitations of the literature. Further investigation, through the conduct of well-designed, multicenter, randomized, biomarker-stratified clinical trials, is needed to determine the potential predictive value of ctDNA analysis, with respect to tailored, personalized treatment guidance for BC patients

Κυκλοφορούντα καρκινικά κύτταρα σε ασθενείς με καρκίνο πνεύμονα

Εισαγωγή: Η προγνωστική σημασία της παρουσίας κυκλοφορούντων καρκινικών κυττάρων (ΚΚΚ) στο περιφερικό αίμα ασθενών με μη-μικροκυτταρικό καρκίνο πνεύμονα (ΜΜΚΠ) παραμένει αμφιλεγόμενη. Ο σκοπός της παρούσας μελέτης ήταν η εκτίμηση της παρουσίας και της προγνωστικής αξίας των ΚΚΚ σε ασθενείς με προχωρημένο ΜΜΚΠ, πριν και μετά τη χορήγηση 1ης γραμμής χημειοθεραπείας. Υλικά – Μέθοδοι: 43 ασθενείς με ιστολογικά ή κυτταρολογικά τεκμηριωμένο ΜΜΚΠ, σταδίου IIIB και IV, για το οποίο δεν είχαν λάβει χημειοθεραπεία και για τους οποίους υπήρχε διαθέσιμη τουλάχιστον μία μέτρηση ΚΚΚ, εντάχθηκαν σε αυτήν την μονοκεντρική, αναδρομικού χαρακτήρα, μελέτη. Η μέτρηση ΚΚΚ πραγματοποιήθηκε με τη χρήση του CellSearch System (Jannsen Diagnostics, LLC). Το σημείο διαχωρισμού (cut-off point) για τη διάκριση μεταξύ θετικών και αρνητικών δειγμάτων ορίστηκε ως ≥2 ΚΚΚ σε 7.5 ml περιφερικού αίματος. Το status των ΚΚΚ αξιολογήθηκε σε δύο διαφορετικά χρονικά σημεία (προ έναρξης θεραπείας και μετά την ολοκλήρωση του πρώτου κύκλου χημειοθεραπείας), και τα αποτελέσματα συσχετίσθηκαν με τα κλινικοπαθολογοανατομικά χαρακτηριστικά των ασθενών, την ανταπόκριση στη θεραπεία και την επιβίωση, χρησιμοποιώντας μονοπαραγοντική και πολυπαραγοντική ανάλυση παλινδρόμησης. Αποτελέσματα: 8 (18.6%) στους 43 ασθενείς (μέση ηλικία 67.1 ± 9.9 έτη ζωής, άρρενες/θήλεις 39/4) είχαν θετικό δείγμα για ΚΚΚ πριν την έναρξη της χημειοθεραπείας (μέσος αριθμός ΚΚΚ ανά ασθενή: 22.75 κύτταρα, εύρος: 2 – 108). Η παρουσία ΚΚΚ προ θεραπείας συσχετίστηκε με την παρουσία ≥5 μεταστατικών εστιών (P=0.018). Μη στατιστικά σημαντικές συσχετίσεις παρατηρήθηκαν μεταξύ της ανταπόκρισης στη θεραπεία και στο προ θεραπείας δείγμα ΚΚΚ. Αντιθέτως, η πρόοδος νόσου και το μεταστατικό φορτίο συσχετίστηκαν με την αλλαγή του αριθμού των ΚΚΚ, μεταξύ προ- και μετά- θεραπείας δείγματος (P=0.033 και P=0.035, αντίστοιχα). Το ελεύθερο προόδου νόσου διάστημα (progression-free survival, PFS) ήταν 5.9 μήνες και 2.7 μήνες για τους έχοντες αρνητικό και θετικό δείγμα ΚΚΚ, αντίστοιχα (P=0.079) και δεν επηρεάστηκε από την αλλαγή στον αριθμό των ανιχνεύσιμων ΚΚΚ μετά τη χορήγηση της χημειοθεραπείας (P=0.0116). Παρομοίως, δεν καταγράφηκε διαφορά μεταξύ της ολικής επιβίωσης (overall survival, OS) και του αριθμού των ΚΚΚ προ θεραπείας ή/και της αλλαγής στον αριθμό των ΚΚΚ με τη 2η μέτρηση (P=0.549 και P=0.275, αντίστοιχα). Στην πολυπαραγοντική ανάλυση επιβίωσης, η πτωχή κατάσταση απόδοσης (performance status, PS) του ασθενούς και η παρουσία ≥5 μεταστάσεων αναγνωρίστηκαν ως ανεξάρτητοι προγνωστικοί δείκτες για μικρότερο διάστημα PFS (HR=2.7, P=0.035 και HR=2.9, P=0.042, αντίστοιχα), ενώ το PS ήταν ο μοναδικός ανεξάρτητος προγνωστικός παράγοντας ελαττωμένης OS (HR=16.9, P<0.001). Συμπέρασμα: Στην παρούσα μελέτη τόσο ο αριθμός των ΚΚΚ όσο και η δυναμική τους μεταβολή κατά τη διάρκεια της χημειοθεραπείας συσχετίσθηκαν με αυξημένο μεταστατικό φορτίο νόσου, αλλά όχι με την επιβίωση. Τα αποτελέσματα αυτά υποστηρίζουν τον προτεινόμενο ρόλο των ΚΚΚ στη διασπορά της νεοπλασματικής νόσου και υπογραμμίζουν την ανάγκη διενέργειας μεγάλων προοπτικών πολυκεντρικών μελετών, με χρήση προτυποποιημένων μεθοδολογιών ανίχνευσης, για την ασφαλέστερη τεκμηρίωση της προγνωστικής τους σημασίας.Background: Previous studies on the clinical value of circulating tumor cells (CTCs) enumeration as a predictor of prognosis in non-small cell lung cancer (NSCLC) have yielded controversial results. The purpose of this study was to further evaluate the prognostic relevance of CTC count in patients with advanced-stage NSCLC before and after first-line chemotherapy. Methods: A total of 43 patients with chemotherapy-naïve, advanced NSCLC and at least one available measurement of CTCs were enrolled in this single-center retrospective study. The presence of CTCs was evaluated by the use of the CellSearch System; CTC positivity was defined as ≥2 CTC in 7.5 ml of whole blood. CTC status was assessed at two different time points, i.e. at baseline (before administration of chemotherapy) and after completion of the first chemotherapy cycle. Baseline CTC count and its dynamic change between the above time points were correlated with clinicopathological features of patients, treatment response and survival, using univariate and multivariate regression analysis. Results: Eight (18.6%) out of 43 patients (mean age 67.1 ± 9.9 years, male/female ratio 39/4) harbored CTCs at baseline (mean 22.75 CTCs/patient, range: 2 - 108). Positive baseline CTC count was significantly associated with the presence of five or more metastatic sites (p=0.018). Response to treatment was recorded in 40.6% of patients and disease stabilization or progression in 59.4%. No significant associations were found between response or progression rates and baseline CTC counts (p=0.067 and p=0.083, respectively). On the contrary, progressive disease status and metastatic disease burden were significantly associated with the change in CTC count, (p=0.033 and p=0.035, respectively). No significant associations were found between survival (PFS or OS) and CTC count or the dynamic change of CTC status. Worse performance status (PS) and the presence of five or more metastatic sites were recognized as independent predictors of reduced PFS [HR=2.7; 95% CI: 1.1-6.8; p=0.035 and HR=2.9; 95% CI: 1.1-8.1; p=0.042, respectively], while PS was the only variable independently associated with OS (HR=16.9; 95% CI: 4.3-65.8; p<0.001). Conclusions: In our study, CTC count and the dynamic change of CTC status following chemotherapy administration were both associated with increased metastatic disease burden but not with PFS or OS. These data support the suggested role of CTCs in the metastatic cascade and underline the need for further validation of this candidate biomarker before its implementation into routine oncology practice

Advances in Gynecological Cancers

The burden of gynecological cancer constitutes a major focus of public health efforts, as it continues to represent a significant cause of cancer mortality, exerting not only physical and emotional distress but also serious financial strain upon individuals, caregivers, and communities [...

Artificial Intelligence-Based Treatment Decisions: A New Era for NSCLC

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among women and men, in developed countries, despite the public health interventions including tobacco-free campaigns, screening and early detection methods, recent therapeutic advances, and ongoing intense research on novel antineoplastic modalities. Targeting oncogenic driver mutations and immune checkpoint inhibition has indeed revolutionized NSCLC treatment, yet there still remains the unmet need for robust and standardized predictive biomarkers to accurately inform clinical decisions. Artificial intelligence (AI) represents the computer-based science concerned with large datasets for complex problem-solving. Its concept has brought a paradigm shift in oncology considering its immense potential for improved diagnosis, treatment guidance, and prognosis. In this review, we present the current state of AI-driven applications on NSCLC management, with a particular focus on radiomics and pathomics, and critically discuss both the existing limitations and future directions in this field. The thoracic oncology community should not be discouraged by the likely long road of AI implementation into daily clinical practice, as its transformative impact on personalized treatment approaches is undeniable

Malignant Transformation of Schneiderian Papilloma Presenting With Progressive Binocular Diplopia and Blepharoptosis

Sinonasal tumors arising from Schneiderian papillomas, most frequently associated with squamous cell carcinoma (SCC), are rare and often present with non-specific symptoms, even in an advanced stage. Herein, we report the case of a 61-year-old male who presented with a four-month history of progressive binocular diplopia, blepharoptosis, and amblyopia, and upon the essential diagnostic work-up he was subsequently diagnosed with SCC arising from an SP. Surgical management was not warranted due to the extent of the disease, so induction chemotherapy with cisplatin and 5-fluorouracil (5-FU) was commenced, followed by definitive concurrent chemoradiotherapy (CRT). The patient was still alive at 25 months after his first presentation, receiving supportive care. Our case highlights the importance of early recognition of neuro-ophthalmological disorders related to sinonasal carcinomas, as diagnostic delay may lead to both functional complications and higher morbidity

Aromatase and CDK4/6 Inhibitor-Induced Musculoskeletal Symptoms: A Systematic Review

Background: Treatment with aromatase inhibitors (AIs) is fundamental in women with hormone receptor-positive breast cancer in the adjuvant as well as the metastatic setting. Even though it is considered to be a well-tolerated therapy, aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) is the most common adverse event encountered by breast cancer patients. CDK4/6 inhibitors have emerged as a new treatment strategy in metastatic hormone receptor-positive breast cancer. However, the impact of CDK4/6 inhibitors on musculoskeletal symptoms caused by AIs is not well-defined. Objectives: This systematic review aims to identify the frequency of joint symptoms induced by treatment with AIs and CDK4/6 inhibitors in the metastatic setting. Search strategy: Eligible articles were identified by a search of existing literature for the period 2005/01/01–2021/01/01; The algorithm consisted of a predefined combination of the following keywords “breast”, “cancer”, “aromatase inhibitors”, “CDK4/6”, “phase III”. Selection criteria: This study was performed in accordance with PRISMA guidelines. All randomized controlled Phase III trials (RCTs) evaluating the administration of third-generation aromatase inhibitors (AIs) and CDK4/6 inhibitors in postmenopausal women in the metastatic setting were considered eligible for this review. Data collection: Overall, 16 randomized control trials (RCTs) were retrieved, of which nine studies explored the administration of AIs in the metastatic setting and seven studies investigated the combination of CDK4/6 inhibitors and AIs. Arthralgia was reported in 1–47% of patients treated with AIs and 5.8–33.3% of patients treated with CDK4/6 inhibitors. Myalgias occurred in 2–23.7% of patients receiving AIs compared with 4.8–11.9% of patients treated with CDK4/6 inhibitors. The incidence of back pain was 7–32.9% vs. 2.9–8.5% in postmenopausal women with metastatic disease treated with AIs and CDK4/6 inhibitors, respectively. Bone pain was reported in 7–32.9% of postmenopausal women treated with AIs and 2.9–8.5% of women treated with CDK4/6 inhibitors. Conclusions: AI treatment-induced musculoskeletal syndrome is an adverse event affecting over one-third (20–47%) of postmenopausal patients treated with AIs that often leads to treatment discontinuation. Data from RCTs provide evidence that the incidence of musculoskeletal symptoms is relatively decreased upon CDK4/6 inhibitor administration. CDK4/6 inhibitors may provide a protective role against AIMSS development

Circulating tumor DNA-based predictive biomarkers in breast cancer clinical trials: a narrative review

Breast carcinoma is the most frequent and the second leading cause of cancer mortality in women worldwide. Current treatment decisions are based on tumor profiling of the initial tissue biopsy. Cancer though evolves both spatially and temporarily in a significant percentage of patients during treatment. However, sequential biopsies from the primary tumor or its metastatic sites are not either convenient or feasible in the majority of cases. In the era of precision medicine, analysis of circulating blood-based biomarkers in the field of liquid biopsies provides an insight into the dynamic molecular profiling of the primary tumor and its metastases, in a relatively non-invasive way. The latter permits not only patient stratification but also longitudinal evaluation of treatment response, when incorporated into clinical trials. This review summarizes the results from recent and ongoing circulating tumor DNA (ctDNA)based biomarker-driven clinical trials, with respect to ctDNA analysis' predictive role, both in adjuvant, neo-adjuvant, and metastatic setting. Furthermore, current challenges in ctDNA analysis applications are critically discussed, including pre-analytical and analytical issues, and future perspectives in this field, through the conduct of well-designed, multicenter, randomized, large-scale, biomarker-stratified trials, with robust statistical methods. Despite in its infancy, ctDNA analysis holds great promise as a minimally invasive tool regarding tailored, personalized treatment guidance for breast cancer patients