89 research outputs found
Detection of RAS family and BRAF mutations in circulating tumor cells in patients with metastatic colorectal cancer, with or without mutations at the primary tumor, who undergo treatment with biologic agents
No full text1. Introduction: Approximately 40-50% of patients with colorectal cancer (CRC) harbor KRAS mutations and another 5-10% harbor BRAF mutations. The presence of these mutations is predictive for absence of benefit to anti-EGFR agents. Nevertheless, the emergence of resistance is inevitable due to multiple factors, such as the acquisition of KRAS mutations. As a result, proper patient selection and early therapy adaptation could lead to the optimization of patient management. Circulating tumor cell (CTC) enumeration is prognostic in metastatic CRC (mCRC), while their genotypic analysis carries predictive information. ISET (Rarecells, France) selects CTCs based on their size and it has been shown to capture diverse cellular populations in mCRC. The aim of this study was the genotypic analysis of CTCs captured by ISET. 2. Patients and methods: This prospective observational study, aiming to enumerate and characterize at the genomic level CTCs captured by ISET from patients with mCRC, was conducted at the Medical Oncology department, University Hospital of Heraklion. Following consent, CTC isolation using the ISET system was performed from prospectively collected blood samples obtained from patients with RAS and BRAF WT mCRC prior to first-line therapy initiation, at first imaging assessment and on disease progression. CTCs were enumerated based on previously published morphological criteria, using hematoxylin & eosin and CD45 double stain on a single membrane spot. DNA was extracted from 5 spots and KRAS exon 2 mutations were detected using a custom quantitative Polymerase Chain Reaction (qPCR) assay. 3. Results: In total, 28 patients were enrolled, 15 wild type (WT), 8 with a KRAS exon 2 mutation (6 harbored the G12D and 2 the G12V mutation), 1 with an exon 4 mutation (A146T), 1 NRAS and 3 with a BRAF mutation. 57 samples were collected; in all the samples, at least 1 CTC / 1 ml was identified, with a median of 6 CTCs / 1 ml (range, 1 – 32) and a mean of 8,22 CTCs / 1 ml. Both the number of CTCs and the number of clusters of 2 or more CTCs increased from baseline to response evaluation and then decreased; only differences in CTC clusters were statistically significant. Among the WT patients, 9/15 (60%) had at least one positive for a mutation sample (in total, 11/28 – 39.2% of samples). 3/11 (27%) patients had a positive baseline sample, while 3/8 (37.5%) samples at progression harbored a mutation. Out of these 3 patients, no previous mutations had been detected and 2 of them had been treated with an anti-EGFR agent. The most frequently detected mutations were G13D and G12C (n=3). Out of the 21 samples from patients with RAS mutated tumors, the G13D mutation was detected 6 times and G12V and G12C once. Finally, out of the 6 samples from 3 patients with a BRAF mutation, no such mutation could be detected in CTCs using Sanger sequencing. However, in one patient the STK11 F354L was detected in both CTCs and the primary tumor. The detection of mutations at baseline was not found to be prognostic for patient outcomes. 4. Discussion: In this study, the kinetics of CTCs isolated with ISET did not follow the disease trajectory as assessed by imaging. These results are in accordance with a published study from another group. Possible reasons are the low number of enrolled patients, the subjective nature of CTC characterization, the uncertain relative importance of the CTC populations that are captured by ISET and the phenomenon of CTC mobilization under the effect of systemic chemotherapy. This study serves as a proof-of-principle regarding the possibility for the genomic characterization of CTCs captured b ISET. The detection of mutations concerned patients with both WT and mutated primary tumors and was achieved in all the phases of first line therapy. The same point mutation identified in the primary tumor could not be identified in the patient’s CTC sample. Possible reasons could be methodology-related, due to the different methods used to detect mutations in the primary tumors and the CTCs or, lastly, this could be an accurate representation of the true molecular heterogeneity of the disease. Despite this study’s weaknesses, the genomic characterization of CTCs captured by ISET is feasible and could provide information regarding the heterogeneity and the emergent resistance while under treatment with an anti-EGFR agent before it is clinically detected. The standardization of the methodology is necessary before it is evaluated in larger scale clinical trials.1. Εισαγωγή: Περίπου 40-50% των περιπτώσεων ορθοκολικού καρκίνου (ΟΚΚ) παρουσιάζουν μεταλλάξεις στο γονίδιο KRAS και 5-10% στο γονίδιο BRAF. Η παρουσία ή μη των μεταλλάξεων έχει σημασία: μόνο οι RAS άγριου τύπου (wild type, WT) ασθενείς ωφελούνται από αντι-EGFR θεραπεία. Εντούτοις, η ανάδυση αντίστασης κατά τη θεραπεία με τα αντισώματα αυτά είναι αναπόφευκτη εξαιτίας μιας ποικιλίας μηχανισμών, όπως είναι οι νεοεμφανιζόμενες KRAS μεταλλάξεις. Έτσι, η κατάλληλη επιλογή ασθενών και η έγκαιρη τροποποίηση της θεραπείας ανάλογα με τους μηχανισμούς αντίστασης θα μπορούσε να βελτιστοποιήσει τη θεραπεία των ασθενών. Η μέτρηση των κυκλοφορούντων καρκινικών κυττάρων (ΚΚΚ) έχει σημαντική προγνωστική ισχύ σε ασθενείς με μεταστατικό ΟΚΚ (ΜΟΚΚ), ενώ η γονοτυπική τους ανάλυση παρουσιάζει προβλεπτική ισχύ για τη λήψη αντι-EGFR παραγόντων. Το σύστημα ISET (Rarecells, France) βασίζεται στην απομόνωση βάσει του μεγέθους των κυττάρων και έχει δειχθεί ότι απομονώνει ευρύ πληθυσμό ΚΚΚ από ασθενείς με ΜΟΚΚ. Στόχος της διατριβής ήταν ο γονοτυπικός χαρακτηρισμός των ΚΚΚ που απομονώνονται με το σύστημα ISET. 2. Ασθενείς και μέθοδοι: Επρόκειτο για μια προοπτική μελέτη παρατήρησης με στόχο την καταμέτρηση και μοριακό χαρακτηρισμό των ΚΚΚ που απομονώνονται από ασθενείς με ΜΟΚΚ και η οποία πραγματοποιήθηκε στην Παθολογική – Ογκολογική κλινική του Πανεπιστημιακού Νοσοκομείου Ηρακλείου. Ασθενείς με ιστολογικά επιβεβαιωμένο ΜΟΚΚ και μη προηγούμενη λήψη θεραπείας για μεταστατική νόσο εντάσσονταν κατόπιν έγγραφης συγκατάθεσης. Δείγματα 10 ml αίματος λαμβάνονταν αμέσως πριν την έναρξη θεραπείας, κατά την στιγμή της ακτινολογικής εκτίμησης της νόσου και κατά τη διαπίστωση εξέλιξης της νόσου και η επεξεργασία με το σύστημα ISET γινόταν εντός 2 ωρών. Μία θέση (spot) από τη μεμβράνη του ISET χρησιμοποιήθηκε για την καταμέτρηση των ΚΚΚ με βάση κυτταρομορφολογικά κριτήρια, χρησιμοποιώντας διπλή ανοσοϊστοχημική χρώση με αντι-CD45 αντίσωμα για την αρνητική επιλογή αιμοποιητικών κυττάρων και χρώση αιματοξυλίνης – ηωσίνης. Η απομόνωση του DNA γινόταν από 5 spot της μεμβράνης ISET κάθε δείγματος. Στο απομονωθέν γενετικό υλικό ακολούθησε ποσοτική αντίδραση αλυσωτής πολυμεράσης (qPCR) για την ανίχνευση των μεταλλάξεων KRAS εξώνιο 2. 3. Αποτελέσματα: Συνολικά εντάχθηκαν 28 ασθενείς, 15 ήταν WT, 8 είχαν μετάλλαξη στο εξώνιο 2 του KRAS (6 τη μετάλλαξη G12D και 2 τη G12V), 1 στο εξώνιο 4 (Α146Τ), 1 στο γονίδιο NRAS και 3 στο γονίδιο BRAF. Ελήφθησαν 57 δείγματα ΚΚΚ και σε όλα ανιχνεύθηκε τουλάχιστον 1 ΚΚΚ / 1 ml αίματος, με διάμεση τιμή ΚΚΚ=6 (εύρος, 1 – 32) και μέση τιμή 8.22 ΚΚΚ / 1 ml. Tόσο ο αριθμός των συνολικών ΚΚΚ όσο και των αθροίσεων 2 ή περισσοτέρων κυττάρων (διάμεση και μέση τιμή) έχουν αυξητική τάση από την 1η (baseline) στη 2η αιμοληψία, ενώ στη συνέχεια ο αριθμός τους πέφτει ξανά. Μόνο η αύξηση των αθροίσεων ήταν στατιστικά σημαντική. Μεταξύ των ασθενών με WT πρωτοπαθή όγκο, οι 9/15 (60%) είχαν τουλάχιστον 1 θετικό για μετάλλαξη δείγμα, 11/28 (39.2%) σε επίπεδο δειγμάτων. Κατά την αρχική αιμοληψία, 3/11 ασθενείς (27%) βρέθηκε να έχουν μετάλλαξη KRAS στο εξώνιο 2 ενώ κατά την εξέλιξη της νόσου, 3/8 δείγματα ήταν θετικά για την παρουσία μετάλλαξης (37.5%). Από τους 3 αυτούς ασθενείς, σε κανέναν δεν είχε ανιχνευθεί αντίστοιχη μετάλλαξη σε προηγούμενη αιμοληψία και 2 εξ αυτών είχαν λάβει θεραπεία με αντι-EGFR παράγοντα. Οι συχνότερα εντοπιζόμενες μεταλλάξεις ήταν οι G13D και G12C (n=3). Από τα 21 δείγματα ΚΚΚ από ασθενείς με RAS mutated πρωτοπαθείς, διαπιστώθηκε η μετάλλαξη G13D σε 6 δείγματα και από 1 φορά οι G12V και G12C. Τέλος, ήταν διαθέσιμα 6 δείγματα από 3 ασθενείς με τη BRAF V600E μετάλλαξη. Σε κανένα δεν διαπιστώθηκε η μετάλλαξη με τη χρήση αλληλούχισης κατά Sanger. Όμως, σε έναν ασθενή διαπιστώθηκε στο δείγμα εξέλιξης της νόσου η μετάλλαξη STK11 F354L η οποία επίσης ανευρέθηκε στον πρωτοπαθή όγκο του ασθενούς. Η ανίχνευση μετάλλαξης στο baseline δείγμα δεν προέβλεπε την έκβαση των ασθενών. 4. Συζήτηση: Στην παρούσα μελέτη φάνηκε ότι η κινητική των ΚΚΚ μετά από απομόνωση με τη μέθοδο ISET δεν ακολουθούσε την πορεία των ασθενών με ΜΟΚΚ όπως αυτή εκτιμήθηκε με τις απεικονιστικές μεθόδους. Τα αποτελέσματα αυτά έρχονται σε συμφωνία και με τα αποτελέσματα άλλης ομάδας. Πιθανές ερμηνείες αποτελούν ο μικρός αριθμός των ασθενών που εντάχθηκαν στη μελέτη, η υποκειμενική φύση του χαρακτηρισμού των ΚΚΚ βάσει μορφολογικών κριτηρίων, η αμφίβολη σημασία του ευρέος πληθυσμού ΚΚΚ που απομονώνεται με το ISET και, τέλος, το φαινόμενο της κινητοποίησης των ΚΚΚ από τους όγκους λόγω της χορηγούμενης θεραπείας. Η τρέχουσα μελέτη αποτελεί κατά βάση μία απόδειξη αρχής σχετικά με τη δυνατότητα γονοτυπικής ανάλυσης των ΚΚΚ που απομονώνονται με το σύστημα ISET. Η ανίχνευση μεταλλάξεων αφορούσε τόσο WT όσο και μεταλλαγμένους πρωτοπαθείς όγκους και επιτεύχθηκε σε όλες τις φάσεις της θεραπεία πρώτης γραμμής. Σημειακή μετάλλαξη ανιχνεύσιμη στον πρωτοπαθή όγκο δεν έγινε δυνατό να ανιχνευθεί στα ΚΚΚ. Tο γεγονός αυτό έχει πολλές πιθανές ερμηνείες: μεθοδολογικά θέματα, η ασυμφωνία να οφείλεται στην διαφορετική τεχνική με την οποία έγιναν τα δείγματα των ΚΚΚ με τον πρωτοπαθή όγκο ή, τέλος, η εικόνα αυτή να είναι αντιπροσωπευτική της αληθινής μοριακής ετερογένειας. Παρά τις αδυναμίες της μελέτης, ο μοριακός χαρακτηρισμός των ΚΚΚ που απομονώνονται με το σύστημα ISET είναι εφικτός και μπορεί να δώσει πληροφορίες σχετικά με τη γενετική ετερογένεια της νόσου και την ανάδυση αντίστασης στην αντι-EGFR θεραπεία πριν αυτή να γίνει κλινικά αντιληπτή. Η προτυποποίηση των χρησιμοποιούμενων μεθόδων είναι απαραίτητο βήμα πριν αυτές αξιολογηθούν σε μεγαλύτερης κλίμακας κλινικές μελέτες
Targeting the PD-1/PD-L1 axis in the treatment of lung cancer
No full textIn recent years major advances in the field of molecular profiling of non-small cell lung cancer led to the identification of targetable driver mutations and revolutionized the treatment of specific patient subsets. However, the majority of NSCLC tumors do not harbor these genomic events. On the other hand, current studies have confirmed an expanding role for immunotherapy in lung cancer and new agents, such as inhibitors of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis have been introduced in the treatment armamentarium. The monoclonal antibodies nivolumab and pembrolizumab targeting PD-1 resulted in superior survival when compared to standard second line chemotherapy within the context of randomized trials and received regulatory approval. Moreover, several other anti-PD-L1 antibodies have demonstrated encouraging preliminary efficacy and multiple clinical trials in various settings during the disease trajectory are currently underway. Early immunotherapy trials have also illustrated the potential of PD-1 blockade in small cell lung cancer treatment, a disease for which major advances in systemic therapy are lacking. The currently available clinical data on PD-1/PD-L1 inhibition in lung cancer are summarized in this review
PD-1 protein and gene expression as prognostic factors in early breast cancer
No full textBACKGROUND: There is a paucity of data on the prognostic value of programmed cell death protein 1 (PD-1) protein and gene expression in early breast cancer (BC) and the present study's aim was to comprehensively investigate it. METHODS: The study consisted of three parts: a correlative analysis of PD-1 protein and gene expression from an original patient cohort of 564 patients with early BC; a systematic review and trial-level meta-analysis on the association between PD-1 protein expression and disease-free survival/overall survival (OS) in early BC; and a pooled gene expression analysis from publicly available transcriptomic datasets regarding PDCD1 expression. RESULTS: In the study cohort, PD-1 protein, but not gene expression, was associated with improved OS (HRadj=0.73, 95% CI 0.55 to 0.97, p=0.027 and HRadj=0.88, 95% CI 0.68 to 1.13, p=0.312, respectively). In the trial-level meta-analysis, PD-1 protein expression was not found to be statistically significantly associated with outcomes in the overall population. Finally, in the pooled gene expression analysis, higher PDCD1 expression was associated with better OS in multivariable analysis in the entire population (HRadj=0.89, 95% CI 0.80 to 0.99, p=0.025) and in basal-like tumours. CONCLUSIONS: PD-1 protein and gene expression seem to be promising prognostic factors in early BC. Standardisation of detection and assessment methods is of utmost importance.sponsorship: This study was supported by the Swedish Cancer Society (grant number CAN 2018/846 to TF), the Cancer Society in Stockholm (174113 to TF); the Swedish Breast Cancer Association (IZ, TF); Alexios Matikas was supported by the Stockholm Region (clinical postdoctorial appointment, dnr K 2017-4577); Theodoros Foukakis is recipient of the Senior Clinical Investigator Award from the Swedish Cancer Society (grant number CAN 2017/1043); Jonas Bergh's research group receives funding from the Stockholm region, the Swedish Cancer Society, the funds at Radiumhemmet, the Swedish Research Council, the Knut and Alice Wallenberg fund. (Swedish Cancer Society|CAN 2018/846, Swedish Cancer Society|CAN 2017/1043, Cancer Society in Stockholm|174113, Swedish Breast Cancer Association, Stockholm Region|K 2017-4577, Stockholm region, Radiumhemmet, Swedish Research Council, Knut and Alice Wallenberg fund, Swedish Cancer Society)status: Publishe
Impact of Primary Breast Surgery on Overall Survival of Patients With De Novo Metastatic Breast Cancer: A Systematic Review and Meta-Analysis
No full textBreast surgery; Metastatic; Overall survivalCirurgia de mama; Metastàtic; Supervivència generalCirugía de mama; Metastásico; Supervivencia generalBackground
Breast surgery in cases of de novo metastatic breast cancer (MBC) is associated with improved outcomes in retrospective studies, although the results of randomized controlled trials (RCTs) are conflicting. We aimed to investigate whether surgery in this context prolongs patient survival.
Methods
We performed a systematic review of the literature to identify RCTs comparing surgery of primary breast cancer to no surgery in patients with de novo MBC. Cochrane Library, Embase, Medline (OVID), and Web of Science were searched with latest update in July 2023, while conference proceedings were manually searched. Data concerning patient and tumor characteristics, as well as outcomes, were extracted. A meta-analysis with random effects models was performed considering heterogeneity between trials.
Results
Overall, 3255 entries were identified and 5 RCTs fulfilled all inclusion criteria, which had enrolled 1381 patients. The overall estimation in the intention-to-treat population showed no benefit for patients who had surgical excision of the primary breast tumor (HR = 0.93; 95% CI, 0.76-1.14). No subgroups in terms of receptor status or patterns of metastasis seemed to benefit from surgery, except for younger/premenopausal patients (HR = 0.74, 95% CI, 0.58-0.94). Breast surgery was associated with improved local progression-free survival (HR = 0.37, 95% CI, 0.19-0.74).
Conclusion
Surgery of the primary tumor in patients with de novo MBC does not prolong survival, except possibly in younger/premenopausal patients. Breast surgery should be offered within the context of well-designed clinical trials examining the issue
Prognostic Implications of PD-L1 Expression in Breast Cancer: Systematic Review and Meta-analysis of Immunohistochemistry and Pooled Analysis of Transcriptomic Data
No full textPURPOSE: Conflicting data have been reported on the prognostic value of PD-L1 protein and gene expression in breast cancer.Experimental Design: Medline, Embase, Cochrane Library, and Web of Science Core Collection were searched, and data were extracted independently by two researchers. Outcomes included pooled PD-L1 protein positivity in tumor cells, immune cells, or both, per subtype and per antibody used, and its prognostic value for disease-free and overall survival. A pooled gene expression analysis of 39 publicly available transcriptomic datasets was also performed. RESULTS: Of the initial 4,184 entries, 38 retrospective studies fulfilled the predefined inclusion criteria. The overall pooled PD-L1 protein positivity rate was 24% (95% CI, 15%-33%) in tumor cells and 33% (95% CI, 14%- 56%) in immune cells. PD-L1 protein expression in tumor cells was prognostic for shorter overall survival (HR, 1.63; 95% CI, 1.07-2.46; P = 0.02); there was significant heterogeneity (I2 = 80%, P heterogeneity < 0.001). In addition, higher PD-L1 gene expression predicted better survival in multivariate analysis in the entire population (HR, 0.82; 95% CI, 0.74-0.90; P < 0.001 for OS) and in basal-like tumors (HR, 0.64; 95% CI, 0.52-0.80; P < 0.001 for OS; P interaction 0.005). CONCLUSIONS: The largest to our knowledge meta-analysis on the subject informs on PD-L1 protein positivity rates and its prognostic value in breast cancer. Standardization is needed prior to routine implementation. PD-L1 gene expression is a promising prognostic factor, especially in basal-like breast cancer. Discrepant prognostic information might be related to PD-L1 gene expression in the stroma.sponsorship: The authors acknowledge the contribution of Magdalena Svanberg, librarian, Karolinska Institutet University Library during the preparation of this manuscript. A. Matikas was supported by the Stockholm Region (clinical postdoctorial appointment). T. Foukakis is a recipient of the Senior Clinical Investigator Award from the Swedish Cancer Society (grant number CAN 2017/1043). J. Bergh's research group receives funding from the Stockholm region, the Swedish Cancer Society, the funds at Radiumhemmet, the Swedish Research Council, and the Knut and Alice Wallenberg fund. This study was supported by the Swedish Cancer Society (grant numbers CAN 2017/1043 and CAN 2018/846, to T. Foukakis), the Cancer Society in Stockholm (174113, to T. Foukakis), and the Stockholm Region (grant number K2017-4577, to A. Matikas). (Stockholm Region|K2017-4577, Swedish Cancer Society|CAN 2017/1043, Swedish Cancer Society|CAN 2018/846, Radiumhemmet, Swedish Research Council, Knut and Alice Wallenberg fund, Cancer Society in Stockholm|174113)status: Publishe
Triple-Negative Breast Cancer: One Or More Entities?
No full textCharacterized by an aggressive clinical course and relatively poor prognosis, triple-negative breast cancer (TNBC) refers to a diverse group of tumors with distinct molecular characteristics rather than to a single entity. The recognition of distinct gene expression subtypes within the group of TNBC and the description of an ever-expanding set of genetic events has led to improved understanding of the underlying biology. However, the improvement of clinical results has been incremental despite undergoing efforts to evaluate the role of molecularly targeted agents in the treatment of TNBC. The relative rarity of each one of these genetic events increases the difficulty of conducting large clinical trials, further hindering our ability to identify meaningful, personalized treatment approaches. Herein, we summarize current knowledge on TNBC, focusing on molecular pathology and emerging treatment approaches
Tackling endocrine resistance in ER-positive HER2-negative advanced breast cancer: A tale of imprecision medicine
No full textInvestigating the treatment of metastatic breast cancer : real-world evidence on treatment patterns, safety and efficacy
No full textMetastatic breast cancer is an incurable disease causing a spectrum of symptoms and leading to a continuous deterioration of performance status and quality of life. It is a heterogeneous disease, with survival being related to tumor biology and patient-related factors. Treatment of metastatic breast cancer aims at preventing cancer growth, relieving symptoms, improving quality of life and prolonging survival, and is most commonly given continuously. The choice of treatment depends on tumor subtype, performance status, organ function and comorbidities. Real world studies describe the effectiveness and safety of different therapies as well as treatment patterns in routine clinical practice, and can provide valuable information on the treatment of populations not often enrolled in randomized clinical trials. The aim of this thesis was to examine how metastatic breast cancer is treated in the real-world setting, with focus on treatment patterns as well as safety and efficacy of specific agents.Eribulin is a non-taxane microtubule inhibitor approved for the treatment of metastatic breast cancer after progression on at least two prior chemotherapy lines, including anthracyclines and taxanes. In Paper I, patients treated with eribulin were evaluated regarding efficacy and safety using data from electronic health records. The results confirmed that eribulin was safe and well tolerated, with a clinical benefit seen in half of the patients. No differences in treatment benefit were seen across histopathologic subgroups.With the aim of investigating treatment with chemotherapy near the end of life in metastatic breast cancer patients, data were collected from the Stockholm Gotland Breast Cancer Register as well as from electronic health records in Sweden and Greece for Paper II. Chemotherapy use near the end of life was common in both populations. Both orally and intravenously administered regimens were used. In the Swedish cohort, age and albumin levels were associated with the use of futile chemotherapy, with chemotherapy near the end of life being more commonly administered to younger patients.Several studies have shown a survival benefit for metastatic breast cancer patients treated with cyclin dependent kinase 4/6 inhibitors in combination with endocrine treatment. In Paper III, patients treated with cyclin dependent kinase 4/6 inhibitors were assessed regarding efficacy and safety using data from electronic health records. The treatment was well tolerated, with no new safety signals. However, there was a higher rate of treatment discontinuations than reported in randomized clinical trials. The efficacy of cyclin dependent kinase 4/6 inhibitors was significantly impaired in heavily pretreated patients.In Paper IV, data were collected from the Stockholm Gotland Breast Cancer Register as well as from electronic health records in order to investigate patients with short survival time after metastatic breast cancer diagnosis. One out of six patients with metastatic breast cancer survived less than three months following diagnosis, and out of those, nearly half did not receive any antitumor treatment. Patients with short survival time were older and had more aggressive tumor characteristics and metastatic patterns.Current treatment guidelines recommend that patients with newly diagnosed hormone receptor positive/human epidermal growth factor receptor 2 negative metastatic breast cancer are treated with endocrine therapy with or without cyclin dependent kinase 4/6 inhibitors, unless presenting with a visceral crisis. In Paper V, with the use of data from the Stockholm Gotland Breast Cancer Register and the Swedish Prescribed Drug Register, we aimed to investigate how patients with hormone receptor positive metastatic breast cancer are treated in the first line setting. Nearly half of the patients received chemotherapy, in non-adherence to guidelines. A significantly worse survival was seen in patients treated with chemotherapy, even after adjusting for menopausal status, first metastatic site and distant recurrence free interval.In summary, treatment with eribulin as well as with cyclin dependent kinase 4/6 inhibitors in routine clinical practice was safe, with greater treatment benefit seen in earlier treatment lines. Treatment of patients with first line chemotherapy instead of endocrine treatment was common. Also, use of chemotherapy treatment near the end of life was fairly common, especially in younger patients in the Swedish study population.List of scientific papersI. Luisa Kessler, Claudette Falato, Sara Margolin, Jonas Bergh, Theodoros Foukakis. A retrospective safety and efficacy analysis of the first patients treated with eribulin for metastatic breast cancer in Stockholm, Sweden. Acta Oncologica. 2015. https://doi.org/10.3109/0284186X.2014.973063 II. Luisa Edman Kessler, Johnny Sigfridsson, Dora Hatzidaki, Jonas Bergh, Theodoros Foukakis, Vasilios Georgoulias, Alexios Matikas. Chemotherapy use near the end-of-life in patients with metastatic breast cancer. Breast Cancer Research and Treatment. 2020. https://doi.org/10.1007/s10549-020-05663-w III. Luisa Edman Kessler, Oscar Wiklander, Eva Hamberg, Jonas Bergh, Theodoros Foukakis, Alexios Matikas. Efficacy and safety of cyclin dependent kinases 4/6 inhibitors in the treatment of metastatic breast cancer: a real-world experience. Acta Oncologica. 2020. https://doi.org/10.1080/0284186X.2020.1804613 IV. Caroline Boman, Luisa Edman Kessler, Jonas Bergh, Alexios Matikas, Theodoros Foukakis. Women with short survival after diagnosis of metastatic breast cancer – a population-based registry study. Breast Cancer Research and Treatment. 2022. https://doi.org/10.1007/s10549-022-06591-7 V. Luisa Edman Kessler, Jonas Bergh, Alexios Matikas, Theodoros Foukakis. Real world data of first line endocrine treatment versus chemotherapy for metastatic hormone receptor-positive breast cancer. [Manuscript]</p
Breast cancer biomarkers : dynamics during treatment and metastatic progression
No full textBreast cancer is a major global health challenge as incidence is increasing, and risk of recurrence remains a significant concern for long-term survivors. In an era of expanding therapeutic options, identifying biomarkers that can inform on prognosis and guide individualized treatment is of critical importance. This thesis explores both established and emerging biomarkers in breast cancer, examining their expression, dynamics over time and across different disease stages. In addition, it investigates key prognostic factors that influence long-term outcomes and factors associated with poor prognosis in the metastatic setting.In Paper I, a systematic review and meta-analysis was conducted to examine PD- L1 expression rates in primary breast tumors and metastatic lesions, including differences in expression according to cell type, metastasis site and the degree of discordance between primary tumors and their recurrences. The meta-analysis included 20 studies and revealed a significant discordance in PD-L1 expression between primary tumors and metastatic lesions, with overall expression rates being higher among primary tumors. Expression rates varied across metastatic sites, with the highest rates observed in lymph nodes and lungs, and the lowest in bone and liver. A substantial bidirectional discordance in PD-L1 status was observed in matched samples. Nearly half of the patients with PD-L1 positive primary tumors exhibited PD-L1 negative metastasis, while approximately one third of those with PD-L1 negative primary tumors converted to PD-L1 positive status in their metastatic lesions. The findings of the study highlight the critical importance of obtaining metastatic biopsies to accurately determine patients eligible for immune checkpoint blockade.Paper II investigated prognostic factors beyond pathologic complete response (pCR) that influence long-term outcomes in patients treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 2 487 individuals who received NACT for primary breast cancer between 2007 and 2020 in the Stockholm- Gotland region was analyzed using the National Quality Register for Breast Cancer and medical records. While pCR was confirmed as a favorable prognostic marker, it also demonstrated that patients achieving pCR are a heterogenous group with varying long-term risks. Factors independently associated with distant recurrence-free survival (DRFS) included lymph node involvement, tumor stage, estrogen receptor status, age and HER2 status. Furthermore, the study revealed a temporal dynamic of recurrence risk, with the highest risk occurring within the first two years post-surgery, though never entirely disappearing over time. Patients with residual disease consistently exhibited higher recurrence risk. These findings emphasize the importance of considering additional clinical and pathological factors beyond pCR when evaluating long-term risk, guiding treatment decisions, and designing future clinical trials.Paper III explored the distribution, temporal dynamics, and prognostic significance of HER2 status, including HER2-low, in a population-based cohort of patients with breast cancer treated with NACT. The study revealed a discordance rate of approximately 30% between untreated tumors, residual disease and metastatic lesions. HER2-low status was observed to be associated with ER expression. Notably, survival analysis revealed temporal differences in the risk curve between HER2-low and HER2 0 breast cancer. Patients with HER2 0 tumors had a higher initial peak in recurrence risk, which gradually declined over time, eventually falling below the risk observed in patients with HER2-low tumors. The likelihood of detecting a HER2-low status increased with the number of biopsies performed. The findings in paper III highlight the prognostic significance of HER2 status as well as the importance of obtaining repeated biopsies throughout the disease trajectory.In Paper IV women with very poor prognosis following a metastatic breast cancer (MBC) diagnosis were examined. The study showed that almost one in six women diagnosed with MBC died within 90 days. These patients were typically older, had more aggressive primary tumor biology, a higher clinical stage at initial diagnosis, more frequent visceral metastases, and received less chemotherapy in the primary setting. Notably, nearly half of the patients with poor prognosis never received systemic antitumoral treatment. Multivariable analysis identified age, metastasis site, adjuvant chemotherapy, primary tumor grade and period of diagnosis as independent factors of short survival. The study identified a subgroup of MBC patients with extremely poor prognosis and highlights the need for improved understanding and targeted research to enhance long-term outcomes.In conclusion, this thesis underscores the critical importance of performing repeated biopsies throughout the disease trajectory to enable more accurate and individualized treatment. It further highlights the heterogeneity of breast cancer both across time and anatomical sites. Collectively, these findings deepen our understanding of biomarkers in breast cancer and hold the potential to ultimately improve outcomes for patients with breast cancer.List of scientific papersI. Caroline Boman, Ioannis Zerdes, Kira Mårtensson, Jonas Bergh, Theodoros Foukakis, Antonios Valachis and Alexios Matikas. Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis. Cancer Treat Rev. 2021 Sep;99:102257. doi:10.1016/j.ctrv.2021.102257. PMID: 34237488https://doi.org/10.1016/j.ctrv.2021.102257II. Caroline Boman, Christian Tranchell, Xingrong Liu, Louise Eriksson Bergman, Maria Angeliki Toli, Jonas Bergh, Theodoros Foukakis and Alexios Matikas. Prognosis After Pathologic Complete Response to Neoadjuvant Therapy in Early-Stage Breast Cancer: A Population-Based Study. J Natl Compr Canc Netw. 2025 Mar 12:1- 7. doi:10.6004/jnccn.2024.7093. PMID: 40073831https://doi.org/10.6004/jnccn.2024.7093III. Caroline Boman, Xingrong Liu, Louise Eriksson Bergman, Wenwen Sun, Christian Tranchell, Maria Angeliki Toli, Balazs Acs, Jonas Bergh, Theodoros Foukakis and Alexios Matikas. A population-based study on trajectories of HER2 status during neoadjuvant chemotherapy for early breast cancer and metastatic progression. Br J Cancer. 2024 Sep;131(4):718-728. doi:https://doi.org/10.1038/s41416-024-02777-6. PMID: 38942987IV. Caroline Boman, Luisa Edman Kessler, Jonas Bergh, Alexios Matikas and Theodoros Foukakis. Women with short survival after diagnosis of metastatic breast cancer: a population-based registry study. Breast Cancer Res Treat. 2022 Jul;194(1):49-56. doi:https://doi.org/10.1007/s10549-022-06591-7. PMID: 35461374</p
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