Role of ctDNA in Breast Cancer Sant, Marta; Bernat-Peguera, Adrià; Felip, Eudald ...
Cancers,
01/2022, Volume:
14, Issue:
2
Journal Article
Peer reviewed
Open access
Breast cancer is currently classified by immunohistochemistry. However, technological advances in the detection of circulating tumor DNA (ctDNA) have made new options available for diagnosis, ...classification, biological knowledge, and treatment selection. Breast cancer is a heterogeneous disease and ctDNA can accurately reflect this heterogeneity, allowing us to detect, monitor, and understand the evolution of the disease. Breast cancer patients have higher levels of circulating DNA than healthy subjects, and ctDNA can be used for different objectives at different timepoints of the disease, ranging from screening and early detection to monitoring for resistance mutations in advanced disease. In early breast cancer, ctDNA clearance has been associated with higher rates of complete pathological response after neoadjuvant treatment and with fewer recurrences after radical treatments. In metastatic disease, ctDNA can help select the optimal sequencing of treatments. In the future, thanks to new bioinformatics tools, the use of ctDNA in breast cancer will become more frequent, enhancing our knowledge of the biology of tumors. Moreover, deep learning algorithms may also be able to predict breast cancer evolution or treatment sensitivity. In the coming years, continued research and the improvement of liquid biopsy techniques will be key to the implementation of ctDNA analysis in routine clinical practice.
Besides its prominent role in cell proliferation, cyclin-dependent kinases (CDKs) are key players in viral infections as both DNA and RNA viruses modify CDK function to favor viral replication. ...Recently, a number of specific pharmacological CDK inhibitors have been developed and approved for cancer treatment. The repurposing of these specific CDK inhibitors for the treatment of viral infections may represent a novel effective therapeutic strategy to combat old and emergent viruses. In this review, we describe the role, mechanisms of action, and potential of CDKs as antiviral drug targets. We also discuss the current clinical state of novel specific CDK inhibitors, focusing on their putative use as antivirals, especially against new emerging viruses.
Drug repurposing is an effective strategy to develop new antiviral therapies as the identification of new uses for already approved drugs is highly efficient, time-saving, cost-effective, and minimizes the risk of failure, while maximizing the therapeutic value of a drug.Viruses use a variety of strategies to usurp and control cellular activities, with the manipulation of the host cell cycle being one of the most frequent. Meeting the timely clinical needs presented by emerging viruses will be best achieved by the development of broad-spectrum antiviral therapies that target enzymatic functions shared by multiple viruses and the host–cell machinery, such as cell cycle control through modification of CDK function.The advent of novel specific CDK inhibitors with better toxicity profiles in cancer clinical trials, together with accumulating preclinical data that shed light on the antiviral and immunomodulatory properties of CDK inhibitors, opens new avenues to enable the rapid development of a new class of broad-spectrum antivirals.
Digital counting methods were developed to decrease the high intra- and inter-observer variability of immunohistochemical markers such as Ki67, with most presenting a good correlation coefficient ...(CC). Since Ki67 is one of the major contributors to Oncotype DX, it is conceivable that Ki67 expression and the recurrence score (RS) obtained by the multigene panel are positively correlated. We decided first to test to what extent conventional and digital Ki67 quantification methods correlate in daily practice and, second, to determine which of these methods correlates better with the prognostic capacity of the Oncotype DX test. Both Ki67 evaluations were performed in 89 core biopsies with a diagnosis of estrogen receptor (ER) positive HER2-negative breast cancer (BC). Cases were, thus, classified twice for surrogate subtype: first by conventional analysis and then by digital evaluation. The Oncotype RS was obtained in 55 cases that were subsequently correlated to Ki67 evaluation by both methods. Conventional and digital Ki67 evaluation showed good concordance and correlation (CC = 0.81 (95% CI 0.73-0.89)). The correlation of Oncotype DX risk groups and surrogate derived subtypes was slightly higher for the digital technique (r
= 0.46, p < 0.01) compared to the conventional method (r
= 0.39, p < 0.01), even though both were statistically significant. In conclusion, we show that digital evaluation could be an alternative to conventional counting, and also has advantages for predicting the risk established by the Oncotype DX test in ER-positive BC. This study also supports the importance of an accurate Ki67 analysis which can influence the decision to submit ER-positive HER2-negative BC to prognostic molecular platforms.
Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for ...node-positive early BC.
Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m(2), respectively, × four cycles), followed by docetaxel (100 mg/m(2) × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m(2), respectively, × four cycles), followed by capecitabine (1,250 mg/m(2) twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS).
After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months).
Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.
SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase which has been proposed as a putative prognostic factor in haematological cancers and certain solid tumours, although with ...controversial data. Here, we evaluate SAMHD1 function in ovarian cancer, both
and in ovarian cancer patients.
SAMHD1 expression was downregulated in ovarian cancer cell lines OVCAR3 and SKOV3 by RNA interference. Gene and protein expression changes in immune signalling pathways were assessed. SAMHD1 expression in ovarian cancer patients was evaluated by immunohistochemistry and survival analysis was performed according to SAMHD1 expression.
SAMHD1 knockdown induced a significant upregulation of proinflammatory cytokines concomitant to increased expression of the main RNA-sensors, MDA5 and RIG-I, and interferon-stimulated genes, supporting the idea that the absence of SAMHD1 promotes innate immune activation
. To assess the contribution of SAMHD1 in ovarian cancer patients, tumours were stratified in SAMHD1-low and SAMHD1-high expressing tumours, resulting in significantly shorter progression free survival (PFS) and overall survival (OS) in SAMHD1-high expression subgroup (
=0.01 and 0.04, respectively).
SAMHD1 depletion correlates with increased innate immune cell signalling in ovarian cancer cells. In clinical samples, SAMHD1-low expressing tumors showed increased progression free survival and overall survival irrespective of BRCA mutation status. These results point towards SAMHD1 modulation as a new therapeutic strategy, able to enhance innate immune activation directly in tumour cells, leading to improved prognosis in ovarian cancer.
To confirm the efficacy of a risk-adapted treatment approach for patients with clinical stage I seminoma. The aim was to reduce both the risk of relapse and the proportion of patients receiving ...adjuvant chemotherapy while maintaining a high cure rate.
From 2004 to 2008, 227 patients were included after orchiectomy in a multicenter study. Eighty-four patients (37%) presented no local risk factors, 44 patients (19%) had tumors larger than 4 cm, 25 patients (11%) had rete testis involvement, and 74 patients (33%) had both criteria. Only the latter group received two courses of adjuvant carboplatin, whereas the rest were managed by surveillance.
After a median follow-up time of 34 months, 16 relapses (7%) have been documented (15 9.8% among patients on surveillance and one 1.4% among those treated with carboplatin). All relapses occurred in retroperitoneal lymph nodes, except for one case in pelvic nodes. Median node size was 25 mm, and median time to recurrence was 14 months. All patients were rendered disease-free with chemotherapy. The actuarial 3-year disease-free survival rate was 88.1% (95% CI, 82.3% to 93.9%) for patients on surveillance and 98.0% (95% CI, 94.0% to 100%) for those treated with adjuvant chemotherapy. Overall 3-year survival was 100%.
With the limitations of the short follow-up duration, we confirm that a risk-adapted approach is effective for stage I seminoma. Adjuvant carboplatin seems adequate treatment for patients with 2 risk criteria, as is active surveillance for those with 0 to one risk factors. More reliable predictive factors are needed to improve the applicability of this model.
Neoadjuvant treatment (NAT) is one of the most widely used options for HER2+ and triple negative (TN) early breast cancer (BC). Since around half of the patients treated with NAT do not achieve a ...pathologically complete response (pCR), biomarkers to predict resistance are urgently needed. The correlation of clinicopathological factors with pCR was studied in 150 patients (HER2 = 81; TN = 69) and pre- and post-NAT differences in tumour biomarkers were compared. Low estrogen receptor (ER) expression, high tumour-infiltrating lymphocytes (TILs) and low cT-stage were associated with pCR in HER2+ tumours (
= 0.022;
= 0.032 and
= 0.005, respectively). Furthermore, ER expression was also associated with residual cancer burden (RCB;
= 0.046) in the HER2+ subtype. Similarly, pre-NAT, low progesterone receptor expression (PR; 1-10%) was associated with higher RCB (
< 0.001) in TN tumours. Only clinical and pathological T-stage (cpT-stage) had prognostic capacity in HER2+ tumours, whereas pre-NAT cpT-stage and post-NAT TILs had this capacity for the prognosis of TN tumours. We conclude that ER and PR expression may help predict response to NAT in HER2 and TN BC and should be taken into account in residual tumours. Also, changes observed in the phenotype after NAT suggest the need to reevaluate biomarkers in surviving residual tumour cells.
Liquid biopsy has proven valuable in identifying individual genetic alterations; however, the ability of plasma ctDNA to capture complex tumor phenotypes with clinical value is unknown. To address ...this question, we have performed 0.5X shallow whole-genome sequencing in plasma from 459 patients with metastatic breast cancer, including 245 patients treated with endocrine therapy and a CDK4/6 inhibitor (ET + CDK4/6i) from 2 independent cohorts. We demonstrate that machine learning multi-gene signatures, obtained from ctDNA, identify complex biological features, including measures of tumor proliferation and estrogen receptor signaling, similar to what is accomplished using direct tumor tissue DNA or RNA profiling. More importantly, 4 DNA-based subtypes, and a ctDNA-based genomic signature tracking retinoblastoma loss-of-heterozygosity, are significantly associated with poor response and survival outcome following ET + CDK4/6i, independently of plasma tumor fraction. Our approach opens opportunities for the discovery of additional multi-feature genomic predictors coming from ctDNA in breast cancer and other cancer-types.
Presence of disseminated tumour cells (DTCs) in the bone marrow (BM) has been described as a surrogate of residual disease in patients with early breast cancer (EBC). PADDY (Pooled Analysis of DTC ...Detection in Early Breast Cancer) is a large international analysis of pooled data that aimed to assess the prognostic impact of DTCs in patients with EBC.
Individual patient data were collected from 11 centres. Patients with EBC and available follow-up data in whom BM sampling was performed at the time of primary diagnosis before receiving any anticancer treatment were eligible. DTCs were identified by antibody staining against epithelial cytokeratins. Multivariate Cox regression was used to compare the survival of DTC-positive versus DTC-negative patients.
In total, 10,307 patients were included. Of these, 2814 (27.3%) were DTC-positive. DTC detection was associated with higher tumour grade, larger tumour size, nodal positivity, oestrogen receptor and progesterone receptor negativity, and HER2 positivity (all p < 0.001). Multivariate analyses showed that DTC detection was an independent prognostic marker for overall survival, disease-free survival and distant disease-free survival with hazard ratios (HR) and 95% confidence intervals (CI) of 1.23 (95% CI: 1.06–1.43, p = 0.006), 1.30 (95% CI: 1.12–1.52, p < 0.001) and 1.30 (95% CI: 1.08–1.56, p = 0.006), respectively. There was no association between locoregional relapse-free survival and DTC detection (HR 1.21; 95% CI 0.68–2.16; p = 0.512).
DTCs in the BM represent an independent prognostic marker in patients with EBC. The heterogeneous metastasis-initiating potential of DTCs is consistent with the concept of cancer dormancy.
•Disseminated tumour cells (DTCs) from bone marrow are detectable in breast cancer.•Individual data from 11 centres were pooled, comprising a total of 10.307 patients.•DTCs were detected in 27.3% of the patients and associated with impaired survival.
Metastatic breast cancer (MBC) diagnosis in young women negatively impacts on quality of life (QoL) and daily activities, disrupting their life project and forcing them to face new psychosocial ...challenges. The recently published results on the improvement of the overall survival of pre- or perimenopausal women with hormone-receptor-positive, HER2-negative MBC treated with CDK4/6 inhibitors plus endocrine therapy, while preserving, and in some items improving their QoL, will change the landscape of the management of this patient population. Their extended survival and potential improvement in QoL will, therefore, modify their specific needs in terms of psychosocial support.
The complexity of the care of young women with MBC is described herein, based on an extensive literature review. Further research about the specific psychosocial requirements of these women and a new multidisciplinary holistic approach is paramount to properly address their concerns and preferences. The communication with and support of their partners, parents and children is an important factor affecting the QoL of these patients. Altogether, a multidisciplinary care, open communication and personalized support is required to address the psychosocial implications of the new prognostic expectations on these patients with the incorporation of new targeted therapies.
•Life project disruption in young women with metastatic breast cancer.•Scarce research and lack of specific QoL questionnaires.•Multidisciplinary holistic approach key to address concerns of young MBC patients.•New therapies extend survival and improve quality of life of MBC patients.•Psychosocial support needs to be adapted to these new prognostic expectations.
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