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- Kornalijnslijper-Altena, Renske, et al.
(författare)
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PREDIX II HER2 : Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC)
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:15 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy.Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007.
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| 2. |
- Zerdes, Ioannis, et al.
(författare)
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PD-1 protein and gene expression in early breast cancer : Prognostic implications
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:15 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We have previously shown the prognostic value of PD-L1 protein and gene expression in early breast cancer (BC), however, the prognostic role of PD-1 expression remains unclear.Methods: The prognostic value of PD-1 in early BC was investigated using three different approaches: i) evaluation of PD-1 at the protein (IHC, immunohistochemistry in tissue microarrays) and mRNA levels in a retrospective patient cohort of 586 patients treated for early BC in Stockholm, Sweden between 1997-2005, ii) systematic review and trial-level meta-analysis of studies published in Medline, Embase, Cochrane Library and Web of Science Core Collection libraries on the prognostic value of PD-1 IHC expression, and iii) pooled analysis of transcriptomic data from 39 publicly available datasets for the prognostic capacity of PD-1 gene expression. Univariate and multivariable Cox regression models were used.Results: In the retrospective study cohort, PD-1 protein was significantly associated with biologically high-risk characteristics. PD-1 protein, but not gene expression, was correlated with improved overall survival (OS) (adjusted HR = 0.73, 95% CI 0.55 – 0.96, p = 0.023 and adjusted HR = 0.88, 95% CI 0.68 – 1.13, p = 0.307, respectively). In the trial-level meta-analysis, 4736 entries were initially identified and 15 studies, including our original cohort, fulfilled the predefined eligibility criteria. PD-1 IHC expression was not prognostic in unselected patients. However, a significant correlation to improved disease-free survival was seen within the triple-negative subtype (pooled multivariate HR = 0.57, 95% CI 0.29 – 0.90, p = 0.02). In the pooled gene expression analysis, PD-1 gene expression was associated with improved OS in the entire population (adjusted HR = 0.89, 95% CI 0.80 – 0.99, p = 0.025) and in basal-like (adjusted HR = 0.77, 95% CI 0.63 – 0.95, p = 0.014) tumors.Conclusions: PD-1 expression at the RNA and protein levels represent promising prognostic factors, especially in the triple-negative and basal-like subtypes. Standardization and further validation are needed prior to clinical implementation.
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| 3. |
- Zerdes, Ioannis, et al.
(författare)
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Tumor-infiltrating lymphocytes (TILs) dynamics in breast cancer patients receiving neoadjuvant therapy : A systematic review and meta-analysis
- 2022
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 40:16
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Increased baseline tumor-infiltrating lymphocytes (TILs) are associated with improved pathological complete response rates and better prognosis in HER2+ and triple negative breast cancer (TNBC) patients receiving neoadjuvant therapy (NAT). However, the role of TILs dynamics/change (DTILs) at the neoadjuvant setting remains unclear, thus a meta-analysis of the published studies was carried out.Methods: Medline, Embase, Cochrane Library and Web of Science Core Collection were searched for studies reporting on TILs expression in paired invasive breast cancer patient tissue samples before and after NAT. Data were extracted by two investigators (Y.Z., E.T.) and discordances were resolved by a third (I.Z.). Outcomes included pooled TILs rates pre- & post-treatment (also per subtype), pooled rates of DTILs and direction of change after NAT as well as correlation of DTILs with survival outcomes. Heterogeneity was assessed using the I2 statistic.Results: Of 1569 identified entries, 22 studies fulfilled the criteria and provided adequate data for the outcomes of interest. Overall, a significantly decreased level of TILs was observed after NAT in paired samples (pooled OR = 1.60, 95% CI: 1.12-2.30, p = 0.01; TILs as categorical variable). Regarding pooled rates of DTILs, a change was observed after NAT, irrespective of BC subtype. Among the different subtypes, the effect of NAT on TILs was most prominent in HER2+ disease with a direction towards decreased TILs to be more common (pooled DTILs rates: 14.4% increased vs 46.2%, decreased). In TNBC, bi-directional TIL kinetics were noted (pooled DTILs rates: 41.6% increased vs 37.1% decreased). An increase in DTILs in TNBC was associated with better disease-free/relapse-free survival in univariate analysis (HR = 0.59, 95% CI: 0.37–0.95, p = 0.03). Substantial between-study heterogeneity was observed in most analyses.Conclusions: The first to our knowledge meta-analysis on TILs dynamics during NAT in BC informs about differences in matched pre- and post-treatment patient samples and the prognostic implications of DTILs in TNBC. The potential clinical utility of the longitudinal assessment of immune response during neoadjuvant therapy warrants further investigation in prospective trials.
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