Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Refining patient selection for breast cancer immunotherapy: beyond PD-L1

International audienc

Abstract P2-09-29: Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes

Abstract Background: Epidermal growth factor receptor (EGFR) is expressed in ˜50% of triple negative breast cancer (TNBC) and has been proposed as a therapeutic target in this disease. However, trials testing EGFR blockade in TNBC failed to show significant clinical benefit. Probable reasons for such results were patient selection based on EGFR expression and the enrollment of heavily pretreated metastatic patients. Our team has conducted two neoadjuvant trials testing the activity of the anti-EGFR antibodies panitumumab (PTB) and cetuximab (CTX) combined with chemotherapy in locally advanced TNBC. Biomarkers predictive of pathological complete response (pCR) were the level of tumor cell EGFR protein expression and tumor-infiltrating lymphocytes' (TILs) profile (PMIDs 24827135, 26649807). The PTB-treated pts had a higher pCR rate (47%) than the CTX-treated pts (24%), but also a twice higher relapse rate, after 5 years of follow-up. Here we report results of genomic and TILs studies, performed in order to reveal possible determinants of recurrences in those trials. Methods: Tumor tissues sampled before and after neoadjuvant therapy (NAT) have been analyzed by next generation sequencing (NGS) using a targeted exome panel (MSK-IMPACT) of 410 cancer-related genes. Gene expression was evaluated by Affymetrix arrays. TIL density was assessed on pre-NAT samples according to Salgado et al, 2014 (PMID 25214542). The correlation between response, recurrences, genomic and TIL findings was analyzed in a case-by-case fashion. Results: Sixteen tumors that achieved pCR (PTB: 11, CTX: 5) and 23 non-pCR tumors (PTB: 11, CTX: 12) have been analyzed. For 14 non-pCR tumors (PTB: 6, CTX: 8) data have been obtained both from the pre-NAT and the post-NAT sample. Among those tumors, 6 recurred within 2 years after surgery (PTMB: 3, CTX: 3) and assays are on-going on several others that relapsed. Several genomic aberrations that potentially played a causative role in opposing to therapy were identified. We observed multiple mutations in the PI3K pathway in several non-pCR or relapsing pts. Interestingly, in a residual tumor (RT) of a non-pCR patient we found 3 different activating mutations in PIK3CA and one in PTEN. Another example of genomic selection induced by pharmacological pressure is the emergence of a HRAS G12S mutation in a RT after CTX. Additional novel findings include in-frame mutations and deletions in ARID1B and PARP1 amplification in non-pCR pts. Most of the tumors which recurred had ≤10% TILs (9/13) and only 4/13 had ≥30%. Among the tumors with a post-NAT RT but without recurrence, 17/33 had ≤10% TILs and 16/33 ≥30%. No particular link between TIL density and mutation pattern was observed. Conclusions: This is an example of a case-by-case approach where we captured the intrinsic inter-tumor heterogeneity, which is likely responsible for the different responses to EGFR-targeting in TNBC. Genes/pathways candidate of resistance to therapy are currently being validated. Citation Format: Radosevic-Robin N, Cocco E, Privat M, Abrial C, Penault-Llorca F, Scaltriti M. Potential recurrence markers of locally advanced triple negative breast cancer treated by combined neoadjuvant EGFR targeting and chemotherapy, revealed by genomic analyses and assessment of tumor-infiltrating lymphocytes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-29

Conception et validation préclinique de nanobodies radiomarqués dirigés contre HER3 dans le cancer du sein triple négatif

International audienc

Tumour-infiltrating lymphocytes in non-invasive breast cancer: A systematic review and meta-analysis

BACKGROUND: The role of tumour infiltrating lymphocytes (TILs) as a biomarker in non-invasive breast cancer is unclear. This meta-analysis assessed the prognostic impact of TIL levels in patients with non-invasive breast cancer. METHODS: Systematic literature search was performed to identify studies assessing local recurrence in patients with non-invasive breast cancer according to TIL levels (high vs. low). Subgroup analyses per local recurrence (invasive and non-invasive) were performed. Secondary objectives were the association between TIL levels and non-invasive breast cancer subtypes, age, grade and necrosis. Odds ratios (ORs) and 95% confidence intervals (CI) were extracted from each study and a pooled analysis was conducted with random-effect model. RESULTS: Seven studies (N = 3437) were included in the present meta-analysis. High-TILs were associated with a higher likelihood of local recurrence (invasive or non-invasive, N = 2941; OR 2.05; 95%CI, 1.03-4.08; p = 0.042), although with a lower likelihood of invasive local recurrence (N = 1722; OR 0.69; 95%CI, 0.49-0.99; p = 0.042). High-TIL levels were associated with triple-negative (OR 3.84; 95%CI, 2.23-6.61; p < 0.001) and HER2-positive (OR 6.27; 95%CI, 4.93-7.97; p < 0.001) subtypes, high grade (OR 5.15; 95%CI, 3.69-7.19; p < 0.001) and necrosis (OR 3.09; 95%CI, 2.33-4.10; p < 0.001). CONCLUSIONS: High-TIL levels were associated with more aggressive tumours, a higher likelihood of local recurrence (invasive or non-invasive) but a lower likelihood of invasive local recurrence in patients with non-invasive breast cancer

Recurrence biomarkers of triple negative breast cancer treated with neoadjuvant chemotherapy and anti-EGFR antibodies

To find metastatic recurrence biomarkers of triple-negative breast cancer (TNBC) treated by neoadjuvant chemotherapy and anti-EGFR antibodies (NAT), we evaluated tumor genomic, transcriptomic, and immune features, using MSK-IMPACT assay, gene arrays, Nanostring technology, and TIL assessment on H&amp;E. Six patients experienced a rapid fatal recurrence (RR) and other 6 had later non-fatal recurrences (LR). Before NAT, RR had low expression of 6 MHC class I and 13 MHC class II genes but were enriched in upregulated genes involved in the cell cycle-related pathways. Their TIL number before NAT in RR was very low (&lt;5%) and did not increase after treatment. In post-NAT residual tumors, RR cases showed high expression of SOX2 and CXCR4. Our results indicate that high expression of cell cycle genes, combined with cold immunological phenotype, may predict strong TNBC resistance to NAT and rapid progression after it. This biomarker combination is worth validation in larger studies