| 11. |
- Karakatsanis, Andreas, et al.
(författare)
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Axillary Staging in the Setting of a Preoperative Diagnosis of Ductal Cancer In Situ (DCIS) : Results of an International Expert Panel and a Critical Guideline Performance Using Frequentist and Bayesian Analysis
- 2020
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Ingår i: Annals of Surgical Oncology. - : Springer. - 1068-9265 .- 1534-4681. ; 27:Suppl. 2, s. S337-S338
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Objective: Sentinel lymph node biopsy (SLNB) is not routine in DCIS. Guidelines suggest SLNB when there is high risk for underlying invasion (large size, high grade, symptomatic lesion) or for detection failure (e.g., after mastectomy). However, guidelines and current practice patterns are inconsistent. Moreover, whilst SLNB is thought to be feasible and accurate after wide local excision (WLE), there is less consensus to support its use after oncoplastic breast-conserving surgery (OPBCS), which can reduce the need for mastectomy (Mx) and is gradually adopted as standard of care. The study aim was to assess if guidelines or individualized assessment result in optimal selection of patients for upfront SLNB.Methods: A panel of 28 international experts (20 surgeons, 8 oncologists, Europe 20, USA 5, Asia/Australia 3) was formed, all blind to the identity of the others. They reviewed anonymized patient cases from the SentiNot study (n=184, m. age 60 years, DCIS m. size 4 cm, Grade 2/3= 36%/64%, mass lesions 13,4%, underlying invasion 24.5%) and answer if they would consider upfront SLNB and why. Consensus and majority were set to >75 and >50%. At the same time, 6 independent raters (4 surgeons, 2 oncologists) reviewed guidelines and assessed the same patient cases per each guideline. Accuracy in relation to underlying invasion was assessed by Receiver Operating Characteristic (ROC) curves and Area Under the Curve (AUC) was reported. Agreement was investigated by kappa statistics and decision-making patterns by logistic multivariate regression and cluster analysis. To allow for flexibility and adaptation to current knowledge, both a frequentist and a Bayesian approach were undertaken. Priors were adjusted after a literature review regarding the factors that are commonly thought to be associated with higher risk for underlying invasion.Results: A total of 44,896 decisions were retrieved and analysed. The panel reached consensus/majority for upfront SLNB in 41.3/61.4%, whereas individual rates ranged from 11 to 100%. Agreement among panelists was low (kappa=0.37). In multivariate regression analysis for the entire panel, type of surgery was the most common determinant, (simple WLE=less, OPBCS=more and Mx=constant for SLNB), followed by symptomatic diagnosis and DCIS size. Most (26) members had a clear decision-making pattern regarding SLND, based mainly on DCIS size and type of surgery. Individual decision-making performed modestly in identifying patients with underlying invasion (AUC range 0,47-0,59), resulting mainly in overtreatment in 44-77% of patients. The panel performed similarly by majority (AUC 0,5) and by consensus (AUC 0,55) but “undertreated” 60-75% of patients with invasion, failing to identify them as "high-risk." After the recognition of different decision-making patterns, panelists were divided in subgroups with similar decision-making pattern. Analysis identified subgroups with difference in SLNB rate but not with better AUC. The disagreement among panelists in the same subgroups was significant, not only regarding which patients should undergo SLNB, but also on what factors that recommendation was based on. Eight guidelines with relevant recommendations were identified [USA (ASCO/NCCN), Europe (ESMO), Sweden, Denmark, UK, Netherlands and Italy, retrieval date May 2019]. Agreement among raters for each guideline separately varied (kappa: 0.23-0.9). Interpretation as to whether SLNB should be performed ranged widely (40-90%) and with varying concordance (32-88%). No guideline demonstrated accuracy (AUC range 0.45-0.55). Overtreatment risk was high (50-90%), whereas 10-50% of patients with invasion were not identified as “high- risk.” Agreement across guidelines was low (kappa=0.24), meaning that different patients had similar risk to be treated inaccurately, regardless of which guideline was examined.Conclusions: Individualized decision-making and guideline interpretation may be highly subjective and with low accuracy in terms of prediction of invasive disease, resulting in almost random risk for over- or undertreatment of the axilla in patients with DCIS. This suggests that current views and guidelines should be challenged. More accurate preoperative workup and novel techniques to allow for delayed SLNB may be of value in this setting.
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| 12. |
- Lee, Jia-Jing, et al.
(författare)
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Array-CGH identifies cyclin D1 and UBCH10 amplicons in anaplastic thyroid carcinoma.
- 2008
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Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 15:3, s. 801-815
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic thyroid cancer (ATC) is a rare but highly aggressive disease with largely unexplained etiology and molecular pathogenesis. In this study, we analyzed genome-wide copy number changes, BRAF (V-raf sarcoma viral oncogene homolog B1) mutations, and p16 and cyclin D1 expressions in a panel of ATC primary tumors. Three ATCs harbored the common BRAF mutation V600E. Using array-comparative genomic hybridisation (array-CGH), several distinct recurrent copy number alterations were revealed including gains in 16p11.2, 20q11.2, and 20q13.12. Subsequent fluorescence in situ hybridization revealed recurrent locus gain of UBCH10 in 20q13.12 and Cyclin D1 (CCND1) in 11q13. The detection of a homozygous loss encompassing the CDKN2A locus in 9p21.3 motivated the examination of p16 protein expression, which was undetectable in 24/27 ATCs (89%). Based on the frequent gain in 11q13 (41%; n=11), the role of CCND1 was further investigated. Expression of cyclin D1 protein was observed at varying levels in 18/27 ATCs (67%). The effect of CCND1 on thyroid cell proliferation was assessed in vitro in ATC cells by means of siRNA and in thyroid cells after CCND1 transfection. In summary, the recurrent chromosomal copy number changes and molecular alterations identified in this study may provide an insight into the pathogenesis and development of ATC.
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| 13. |
- Lee, Jia-Jing, et al.
(författare)
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Molecular cytogenetic profiles of novel and established human anaplastic thyroid carcinoma models
- 2007
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Ingår i: Thyroid. - : Mary Ann Liebert Inc. - 1050-7256 .- 1557-9077. ; 17:4, s. 289-301
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Tidskriftsartikel (refereegranskat)abstract
- In this study we present two novel anaplastic thyroid carcinoma (ATC) lines (HTh 104 and HTh 112) and further characterize six frequently used ATC lines (HTh 7, HTh 74, HTh 83, C 643, KAT-4, and SW 1736). Three of the lines carried a heterozygous BRAF mutation V600E, which is in line with reports of BRAF mutations in primary ATC and papillary thyroid cancer. Several nonrandom breakpoints were identified by spectral karyotyping (SKY) and G-banding in these lines including the novel 1p36 and 17q24-25 as well as 3p21-22 and 15q26 that are also implicated in well-differentiated thyroid cancers. Comparative genomic hybridization showed frequent gain of 20q, including the UBCH10 gene in 20q13.12, which was further confirmed by array-comparative genomic hybridization and fluorescence in situ hybridization analyses. Our results concur with previous studies in both primary tumors and cell lines, indicating that gain of chromosome 20 is important in the pathogenesis of ATC and/or progression of differentiated thyroid cancers to ATC.
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| 14. |
- Matikas, Alexios, et al.
(författare)
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Dynamic evaluation of the immune infiltrate and immune function genes as predictive markers for neoadjuvant chemotherapy in hormone receptor positive, HER2 negative breast cancer
- 2018
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression (GE) signatures and Tumor Infiltrating Lymphocytes (TIL) enumeration are predictive for response to neoadjuvant chemotherapy in HR- and in HER2+ breast cancer, but data are conflicting in HR+/HER2- disease. This study aimed to explore their predictive value in this subset, measured both at baseline and after short exposure to chemotherapy. Specifically, the PROMIX phase 2 trial enrolled patients with locally advanced HER2- BC to receive six cycles of epirubicin and docetaxel, plus bevacizumab during cycles 3-6. Patients underwent tumor biopsies at baseline and after cycle 2 for GE profiling and enumeration of TIL, FOXP3+ T-cells and CD163+ macrophages. An immune related gene module and the quantification of the immune infiltrate were analyzed for association with pathologic complete response (pCR), decrease in tumor size and disease-free survival (DFS). Of the 150 patients enrolled in PROMIX, 113 were HR+/HER2-. Baseline GE and immune cell enumeration data were available from 71 patients, while data after 2 cycles of chemotherapy were available from 41. At baseline, only GE was statistically significantly associated with higher pCR rates (OR 2.29, 95% CI 1.05 - 5.38, p = 0.037) and decrease in tumor size (r = 0.25, p = 0.047). In contrast, longitudinal data indicate that both GE (r = 0.54, p<0.001) and TIL abundance (p = 0.009) are stronger predictors for the reduction of tumor size, while low FOXP3+ was statistically significantly associated with an improved DFS (p = 0.027). In conclusion, GE analysis, TIL and FOXP3+ enumeration after short-term exposure to chemotherapy carry important predictive information in HR+/HER2- breast cancer at the neoadjuvant setting.
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| 15. |
- Matikas, Alexios, et al.
(författare)
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Long-term safety and survival outcomes from the Scandinavian Breast Group 2004-1 randomized phase II trial of tailored dose-dense adjuvant chemotherapy for early breast cancer
- 2018
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Ingår i: Breast Cancer Research and Treatment. - : SPRINGER. - 0167-6806 .- 1573-7217. ; 168:2, s. 349-355
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Tidskriftsartikel (refereegranskat)abstract
- Although adjuvant polychemotherapy improves outcomes for early breast cancer, the significant variability in terms of pharmacokinetics results in differences in efficacy and both short and long-term toxicities. Retrospective studies support the use of dose tailoring according to the hematologic nadirs. The SBG 2004-1 trial was a randomized feasibility phase II study which assessed tailored dose-dense epirubicin and cyclophosphamide (EC) followed by docetaxel (T) (group A), the same regimen with fixed doses (group B) and the TAC regimen (group C). Women aged 18-65 years, ECOG PS 0-1 with at least one positive axillary lymph node were randomized 1:1:1. The primary endpoint of the study was the safety and feasibility of the treatment. Toxicity was graded according to CTC-AE version 3.0. The design and short-term toxicity have been previously published. Here, we report safety and efficacy data after 10 years of follow-up. A total of 124 patients were included in the study. After a median follow-up of 10.3 years, the probability for 10-year survival was 78.5, 75.1, and 63.4% and for relapse free survival 64.1, 71.0, and 59.5% for groups A, B, and C, respectively. There were no cases of clinically diagnosed cardiotoxicity or hematologic malignancies. No patient was lost to follow-up. In this randomized phase II trial, tailored dose adjuvant chemotherapy was feasible, without an increased risk for long-term adverse events after a median follow-up of 10 years.
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| 16. |
- Matikas, Alexios, et al.
(författare)
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PD-1 protein and gene expression as prognostic factors in early breast cancer
- 2020
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Ingår i: ESMO Open. - : BMJ Publishing Group Ltd. - 2059-7029. ; 5:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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.
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| 17. |
- Matikas, Alexios, et al.
(författare)
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Prognostic implications of PD-L1 expression in breast cancer : systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data
- 2019
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Ingår i: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 25:18, s. 5717-5726
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Forskningsöversikt (refereegranskat)abstract
- PURPOSE: 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 4184 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%, pheterogeneity<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), pinteraction 0.005.CONCLUSION: 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 BC. Discrepant prognostic information might be related to PD-L1 gene expression in the stroma.
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| 18. |
- Matikas, Alexios, et al.
(författare)
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Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels
- 2019
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Conflicting data have been reported on the prognostic value of PD-L1 expression per immunohistochemistry (IHC) in breast cancer (BC). There is a paucity of data on the role of PD-L1 gene expression (GE).Methods: 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 positivity in tumor cells, immune cells or both, per subtype and per antibody used; and the prognostic value of PD-L1 positivity for DFS and OS. Heterogeneity was assessed using the Q and I2 statistics. A pooled GE analysis of 39 publicly available transcriptomic datasets was also performed.Results: Of the initial 4184 entries, 38 retrospective studies fulfilled the inclusion criteria. The overall pooled PD-L1 positivity rate in tumor cells was 24%, 33% in immune cells and 25% in both; highest positivity was reported with Dako 28-8 clone. PD-L1 IHC expression in tumor cells was prognostic for shorter DFS (HR = 1.36, 95% CI 1.02 – 1.83, p < 0.04) and OS (HR = 1.66; 95% CI 1.09 – 2.50, p = 0.02); there was significant heterogeneity. PD-L1 IHC expression in immune cells was associated with better DFS (HR = 0.61; 95% CI 0.51 – 0.73, p < 0.001) and OS (HR = 0.53, 95% CI 0.39 – 0.73, p < 0.001) in TNBC. In addition, higher PD-L1 GE predicted better survival in multivariate analysis in the entire population (HR = 0.70, 95% CI 0.60 – 0.82, p < 0.001 for DFS and HR = 0.84, 95% CI 0.75 – 0.93, p = 0.001 for OS) and in basal-like tumors (HR = 0.55, 95% CI 0.38 – 0.80, p = 0.001 for DFS and HR = 0.63, 95% CI 0.50 – 0.79, p < 0.001 for OS), pinteraction 0.124 for DFS and 0.005 for OS.Conclusions: The largest to our knowledge meta-analysis on IHC PD-L1 expression in BC informs on PD-L1 positivity rates and its prognostic value. Standardization is needed prior to routine implementation. PD-L1 GE is a promising prognostic factor, especially in basal-like BC.
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| 19. |
- Matikas, Alexios, et al.
(författare)
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Survival Outcomes, Digital TILs, and On-treatment PET/CT During Neoadjuvant Therapy for HER2-positive Breast Cancer : Results from the Randomized PREDIX HER2 Trial
- 2023
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Ingår i: Clinical Cancer Research. - : American Association For Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 29:3, s. 532-540
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:PREDIX HER2 is a randomized Phase II trial that compared neoadjuvant docetaxel, trastuzumab, and pertuzumab (THP) with trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Rates of pathologic complete response (pCR) did not differ between the two groups. Here, we present the survival outcomes from PREDIX HER2 and investigate metabolic response and tumor-infiltrating lymphocytes (TIL) as prognostic factors.Patients and Methods:In total, 202 patients with HER2-positive breast cancer were enrolled and 197 patients received six cycles of either THP or T-DM1. Secondary endpoints included event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS). Assessment with PET/CT was performed at baseline, after two and six treatment cycles. TILs were assessed manually at baseline biopsies, while image-based evaluation of TILs [digital TILs (DTIL)] was performed in digitized full-face sections.Results:After a median follow-up of 5.21 years, there was no difference between the two treatment groups in terms of EFS [HR = 1.26; 95% confidence interval (CI), 0.54–2.91], RFS (HR = 0.69; 95% CI, 0.24–1.93), or OS (HR = 0.52; 95% CI, 0.09–2.82). Higher SUVmax at cycle 2 (C2) predicted lower pCR (ORadj = 0.65; 95% CI, 0.48–0.87; P = 0.005) and worse EFS (HRadj = 1.27; 95% CI, 1.12–1.41; P < 0.001). Baseline TILs and DTILs provided additional prognostic information to clinical parameters and C2 SUVmax.Conclusions:Long-term outcomes following neoadjuvant T-DM1 were similar to neoadjuvant THP. SUVmax after two cycles of neoadjuvant therapy for HER2-positive breast cancer may be an independent predictor of both short- and long-term outcomes. Combined assessment with TILs may facilitate early selection of poor responders for alternative treatment strategies.
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| 20. |
- Matikas, Alexios, et al.
(författare)
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Tailored dose-dense versus standard adjuvant chemotherapy for high-risk early breast cancer : end-of-study results of the randomized PANTHER trial
- 2024
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755.
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Tidskriftsartikel (refereegranskat)abstract
- Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.
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