| 1. |
- Boman, Caroline, et al.
(author)
-
Discordance of PD-L1 status between primary and metastatic breast cancer : A systematic review and meta-analysis
- 2021
-
In: Cancer Treatment Reviews. - : Elsevier. - 0305-7372 .- 1532-1967. ; 99
-
Research review (peer-reviewed)abstract
- INTRODUCTION: Programmed cell death ligand 1 (PD-L1) expression is predictive for benefit from immunotherapy in several human malignancies including triple negative breast cancer. Lower positivity rates but a larger relative benefit from atezolizumab has been implied when PD-L1 status is assessed at metastatic sites. We aimed to study the discordance of PD-L1 expression between primary tumor and metastasis in breast cancer due to its potential clinical utility.METHODS: Cochrane Library, Embase, Medline and Web of science were searched for studies reporting on PD-L1 expression in primary and metastatic breast cancer, followed by data extraction. Outcomes included pooled PD-L1 positivity rates in tumor cells, immune cells or both in primary tumor and metastasis, PD-L1 discordance between matched primary tumors and metastasis and direction of discordance.RESULTS: Of 2552 identified entries following de-duplication, 20 studies fulfilled the predefined inclusion criteria. Pooled PD-L1 positivity rate was higher in primary tumors compared to metastasis when assessed in immune cells (51.2% vs 37.1% p < 0.001) and tumor/immune cells (30.1% vs 14.6% p < 0.001), but not in tumor cells (18.7% vs 17.8% p = 0.65). PD-L1 positivity was lowest when assessed in bone metastases (12%) and highest in lymph nodes (60%). Discordance between primary tumors and metastasis was bidirectional, with higher pooled discordance rates when PD-L1 expression was assessed in immune compared to tumor cells (39.5% vs 13.6%, p < 0.001).CONCLUSION: The observed considerable discordance between PD-L1 status in primary and metastatic breast cancer emphasizes the importance of appropriate tissue sampling when selecting patients for immunotherapy.
|
|
| 2. |
- Digkas, Evangelos, et al.
(author)
-
Incidence and risk factors of hypothyroidism after treatment for early breast cancer : a population-based cohort study
- 2024
-
In: Breast Cancer Research and Treatment. - : Kluwer Academic Publishers. - 0167-6806 .- 1573-7217. ; 204:1, s. 79-87
-
Journal article (peer-reviewed)abstract
- PURPOSE: An increased incidence of hypothyroidism among breast cancer survivors has been observed in earlier studies. The impact of the postoperative treatment modalities and their potential interplay on hypothyroidism development needs to be studied.METHODS: We conducted a population- and registry-based study using the Breast Cancer Data Base Sweden (BCBaSe) including females diagnosed with breast cancer between 2006 and 2012. In total, 21,268 female patients diagnosed with early breast cancer between 2006 and 2012, with no previous prescription of thyroid hormones and no malignant diagnosis during the last ten years before breast cancer diagnosis, were included in the final analysis.RESULTS: During the follow-up (median follow-up time 7.9 years), 1212 patients (5.7%) developed hypothyroidism at a median time of 3.45 years from the index date. No association of the systemic oncological treatment in terms of either chemotherapy or endocrine therapy and hypothyroidism development could be identified. A higher risk (HR 1.68;95% CI 1.42-1.99) of hypothyroidism identified among patients treated with radiation treatment of the regional lymph nodes whereas no increased risk in patients treated only with radiation therapy to the breast/chest wall was found (HR 1.01; 95% CI 0.86-1.19). The risk of hypothyroidism in the cohort treated with radiotherapy of the regional lymph nodes was present irrespective of the use of adjuvant chemotherapy treatment.CONCLUSIONS: Based on the results of our study, the implementation of hypothyroidism surveillance among the breast cancer survivors treated with radiotherapy of the regional lymph nodes can be considered as reasonable in the follow-up program.
|
|
| 3. |
- Foukakis, Theodoros, et al.
(author)
-
Immune gene expression and response to chemotherapy in advanced breast cancer
- 2018
-
In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 118:4, s. 480-488
-
Journal article (peer-reviewed)abstract
- Background:Transcriptomic profiles have shown promise as predictors of response to neoadjuvant chemotherapy in breast cancer (BC). This study aimed to explore their predictive value in the advanced BC (ABC) setting.Methods:In a Phase 3 trial of first-line chemotherapy in ABC, a fine needle aspiration biopsy (FNAB) was obtained at baseline. Intrinsic molecular subtypes and gene modules related to immune response, proliferation, oestrogen receptor (ER) signalling and recurring genetic alterations were analysed for association with objective response to chemotherapy. Gene-set enrichment analysis (GSEA) of responders vs non-responders was performed independently. Lymphocytes were enumerated in FNAB smears and the absolute abundance of immune cell types was calculated using the Microenvironment Cell Populations counter method.Results:Gene expression data were available for 109 patients. Objective response to chemotherapy was statistically significantly associated with an immune module score (odds ratio (OR)=1.62; 95% confidence interval (CI), 1.03-2.64; P=0.04). Subgroup analysis showed that this association was restricted to patients with ER-positive or luminal tumours (OR=3.54; 95%, 1.43-10.86; P=0.012 and P for interaction=0.04). Gene-set enrichment analysis confirmed that in these subgroups, immune-related gene sets were enriched in responders.Conclusions:Immune-related transcriptional signatures may predict response to chemotherapy in ER-positive and luminal ABC.
|
|
| 4. |
- Matikas, Alexios, et al.
(author)
-
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
-
In: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 7:9
-
Journal article (peer-reviewed)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.
|
|
| 5. |
- Matikas, Alexios, et al.
(author)
-
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
-
In: Breast Cancer Research and Treatment. - : SPRINGER. - 0167-6806 .- 1573-7217. ; 168:2, s. 349-355
-
Journal article (peer-reviewed)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.
|
|
| 6. |
- Matikas, Alexios, et al.
(author)
-
PD-1 protein and gene expression as prognostic factors in early breast cancer
- 2020
-
In: ESMO Open. - : BMJ Publishing Group Ltd. - 2059-7029. ; 5:6
-
Journal article (peer-reviewed)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.
|
|
| 7. |
- Matikas, Alexios, et al.
(author)
-
Prognostic implications of PD-L1 expression in breast cancer : systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data
- 2019
-
In: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 25:18, s. 5717-5726
-
Research review (peer-reviewed)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.
|
|
| 8. |
- Matikas, Alexios, et al.
(author)
-
Prognostic implications of PD-L1 expression in breast cancer at the protein and mRNA levels
- 2019
-
In: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 37:15
-
Journal article (other academic/artistic)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.
|
|
| 9. |
- Matikas, Alexios, et al.
(author)
-
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
-
In: Clinical Cancer Research. - : American Association For Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 29:3, s. 532-540
-
Journal article (peer-reviewed)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.
|
|
| 10. |
- Matikas, Alexios, et al.
(author)
-
Tailored dose-dense versus standard adjuvant chemotherapy for high-risk early breast cancer : end-of-study results of the randomized PANTHER trial
- 2024
-
In: Journal of Clinical Oncology. - 0732-183X .- 1527-7755.
-
Journal article (peer-reviewed)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.
|
|
