Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) ...are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabine-resistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect
and in mice xenografted with the gemcitabine-sensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.
Ewing sarcoma (EWS) is a common pediatric solid tumor with high metastatic potential. Due to toxic effects of treatments on reproductive functions, the cryopreservation of ovarian tissue (OT) or ...testicular tissue (TT) is recommended to preserve fertility. However, the risk of reintroducing residual metastatic tumor cells should be evaluated before fertility restoration. Our goal was to validate a sensitive and specific approach for EWS minimal residual disease (MRD) detection in frozen germinal tissues. Thawed OT (
= 12) and TT (
= 14) were contaminated with tumor RD-ES cells (10, 100, and 1000 cells) and EWS-FLI1 tumor-specific transcript was quantified with RT-qPCR. All contaminated samples were found to be positive, with a strong correlation between RD-ES cell numbers and EWS-FLI1 levels in OT (
= 0.93) and TT (
= 0.96) (
< 0.001). No transcript was detected in uncontaminated control samples. The invasive potential of Ewing cells was evaluated using co-culture techniques. After co-culturing, tumor cells were detected in OT/TT with histology, FISH, and RT-qPCR. In addition, four OT and four TT samples from children with metastatic EWS were tested, and no MRD was found using RT-qPCR and histology. We demonstrated the high sensitivity and specificity of RT-qPCR to detect EWS MRD in OT/TT samples. Clinical trial: NCT02400970.
Purpose
Pathological complete response to the neoadjuvant therapy (NAT) for triple negative breast cancer (TNBC) is predictive of prolonged patient survival. Methods for early evaluation of NAT ...efficiency are still needed, in order to rapidly adjust the therapeutic strategy in case of initial non-response. One option for this is molecular imaging of apoptosis induced by chemotherapy. Therefore, we investigated the capacity of
18
FML-10 PET imaging, an apoptosis radiotracer, to detect tumor cell apoptosis and early predict the therapeutic response of human TNBC.
Results
Initially, the induction of apoptosis by different therapies was quantified. We confirmed, in vitro, that paclitaxel or epirubicin, the fundamental cytotoxic drugs for breast cancer, induce apoptosis in TNBC cell lines. Exposure of TNBC models MDA-MB-231 and MDA-MB-468 to these drugs induced a significant increase (
p
< 0.01) of the apoptotic hallmarks: DNA fragmentation, membrane phospholipid scrambling, and PARP activation. Secondarily, apoptotic fraction was compared to the intracellular accumulation of the radiotracer.
18
FML-10 accumulated in the apoptotic cells after 72 h of treatment by paclitaxel in vitro; this accumulation positively correlated with the apoptotic fraction. In vivo,
18
FML-10 was rapidly cleared from the nontarget organs and mainly eliminated by the kidneys. Comparison of the in vivo
18
FFDG,
18
FFMISO, and
18
FML-10 uptakes revealed that the tumor accumulation of
18
FML-10 was directly related to the tumor hypoxia level. Finally, after the in vivo treatment of TNBC murine xenografts by paclitaxel, apoptosis was well induced, as demonstrated by the cleaved caspase-3 levels; however, no significant increase of
18
FML-10 accumulation in the tumors was observed, either on day 3 or day 6 after the end of the treatment.
Conclusions
These results highlighted that PET imaging using
18
FML-10 allows the visualization of apoptotic cells in TNBC models. Nevertheless, the increase of the chemotherapy-induced apoptotic response when using paclitaxel could not be assessed using this radiotracer in our mouse model.
AXL receptor tyrosine kinase (RTK) is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently ...required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated antihuman AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting growth arrest-specific factor 6 (GAS6) binding, induced downexpression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy.
Ki67 assessment in breast cancer: an update Penault-Llorca, Frederique; Radosevic-Robin, Nina
Pathology,
February 2017, 2017-Feb, 2017-02-00, 20170201, 2017-02, Volume:
49, Issue:
2
Journal Article
Peer reviewed
Although immunohistochemical detection of the Ki67 antigen has been used for many years to assess cancer proliferation, this marker is still not recommended for routine use in clinical management of ...breast cancer. The major reason for this situation is a lack of a standardised procedure for Ki67 assessment as well as persistence of several issues of debate with regards to the Ki67 assay interpretation and the marker’s clinical utility. Nowadays Ki67 assessment is principally used for estimation of prognosis and guiding the decision on adjuvant treatment choice, as well as for prediction of response to neoadjuvant treatment in ER+/HER2– breast cancer. In ER–/HER2+ and ER–/HER2– tumours, high post-neoadjuvant Ki67 index is associated with unfavourable prognosis.
We review here the elements impacting analytical validity of the Ki67 immunohistochemical assay, the evidence of its clinical utility and the current recommendations for its use in breast cancer management.
Nowadays, the decision of which adjuvant treatment should be given to patients with residual breast cancer after neoadjuvant therapy is based on the initial, pretreatment breast cancer molecular ...subtype and on the estimated residual tumour burden after neoadjuvant therapy. Substantial biological differences exist, however, between treatment-naive breast cancer and the residual tissue that remains after neoadjuvant therapy. In addition, the evaluation of relapse risk in patients is subject to a lack of uniformity in pathological qualification and quantification of remnant breast cancer following neoadjuvant treatment. In this Review, we present the recent recommendations for standardized evaluation of response to neoadjuvant therapy in patients with breast cancer, followed by a comprehensive overview of the pathobiological features of the residual disease after neoadjuvant therapy, which could serve as prognostic biomarkers or guide the choice of targeted adjuvant approaches. These biomarker candidates are at different stages of development, but some already have demonstrated superior prognostic value compared with biomarkers derived from pretreatment breast-cancer characteristics. The evidence presented herein indicates that further research on the biology of breast cancer that persists after neoadjuvant therapy is necessary to improve the management of this disease.
The clinical success of trastuzumab in breast cancer taught us that appropriate tumor evaluation is mandatory for the correct identification of patients eligible for targeted therapies. Although HER2 ...protein expression by immunohistochemistry (IHC) and gene amplification by fluorescence in situ hybridization (FISH) assays are routinely used to select patients to receive trastuzumab, both assays only partially predict response to the drug. In the case of epidermal growth factor receptor (EGFR), the link between the presence of the receptor or its amplification and response to anti-EGFR therapies could not be demonstrated. Even less is known for HER3 and HER4, mainly due to lack of robust and validated assays detecting these proteins. It is becoming evident that, besides FISH and IHC, we need better assays to quantify HER receptors and categorize the patients for individualized treatments. Here, we present the current available methodologies to measure HER family receptors and discuss the clinical implications of target quantification.
Breast cancer (BC) is the most common cancer and among the leading causes of cancer death in women. It is a heterogeneous group of tumours with numerous morphological and molecular subtypes, making ...predictions of disease evolution and patient outcomes difficult. Therefore, biomarkers are needed to help clinicians choose the best treatment for each patient. For the last years, studies have increasingly focused on biomarkers obtainable by liquid biopsy. Circulating proteins (from serum or plasma) can be used for inexpensive and minimally invasive determination of disease risk, early diagnosis, treatment adjusting, prognostication and disease progression monitoring. We provide here a review of the main published studies on serum proteins in breast cancer and elaborate on the potential of circulating proteins to be predictive and/or prognostic biomarkers in breast cancer.
Purpose
Radiation therapy (RT) for triple-negative breast cancer (TNBC) treatment is currently delivered in the adjuvant setting and is under investigation as a booster of neoadjuvant treatments. ...However, TNBC radioresistance remains an obstacle, so new biomarkers are needed to select patients for any integration of RT in the TNBC therapy sequence. MicroRNAs (miRs) are important regulators of gene expression, involved in cancer response to ionizing radiation (IR) and assessable by tumor tissue or liquid biopsy. This systematic review aimed to evaluate the relationships between miRs and response to radiation in TNBC, as well as their potential predictive and prognostic values.
Methods
A thorough review of studies related to miRs and RT in TNBC was performed on PubMed, EMBASE, and Web of Science. We searched for original English articles that involved dysregulation of miRs in response to IR on TNBC-related preclinical and clinical studies. After a rigorous selection, 44 studies were chosen for further analysis.
Results
Thirty-five miRs were identified to be TNBC related, out of which 21 were downregulated, 13 upregulated, and 2 had a double-side expression in this cancer. Expression modulation of many of these miRs is radiosensitizing, among which miR-7, -27a, -34a, -122, and let-7 are most studied, still only in experimental models. The miRs reported as most influencing/reflecting TNBC response to IR are miR-7, -27a, -155, -205, -211, and -221, whereas miR-21, -33a, -139-5p, and -210 are associated with TNBC patient outcome after RT.
Conclusion
miRs are emerging biomarkers and radiosensitizers in TNBC, worth further investigation. Dynamic assessment of circulating miRs could improve monitoring and TNBC RT efficacy, which are of particular interest in the neoadjuvant and the high-risk patients’ settings.
The established role of morphological evaluation of tumour-infiltrating lymphocytes (TILs) with immune checkpoint inhibitors (ICIs) in non–small cell lung cancer (NSCLC) is unknown. We aimed to ...determine TIL association with the outcome for ICIs and for chemotherapy in advanced NSCLC.
This is a multicenter retrospective study of a nivolumab cohort of 221 patients treated between November 2012 and February 2017 and a chemotherapy cohort of 189 patients treated between June 2009 and October 2016. Patients with available tissue for stromal TIL evaluation were analysed. The presence of a high TIL count (high-TIL) was defined as ≥10% density. The primary end-point was overall survival (OS).
Among the nivolumab cohort, 64% were male, with median age of 63 years, 82.3% were smokers, 77% had performance status ≤1 and 63% had adenocarcinoma histology. High-TIL was observed in 22% patients and associated with OS (hazard ratio HR 0.48; 95% confidence interval 95% CI: 0.28–0.81) and progression-free survival PFS (HR = 0.40; 95% CI: 0.25–0.64). Median PFS was 13.0 months (95% CI: 5.0–not reached) with high-TIL versus 2.2 months (95% CI: 1.7–3.0) with the presence of a low TIL count (low-TIL). Median OS for high-TIL was not reached (95% CI: 12.2–not reached) versus 8.4 months (95% CI: 5.0–11.6) in the low-TIL group. High-TIL was associated with the overall response rate (ORR) and disease control rate (DCR) (both, P < .0001). Among the chemotherapy cohort, 69% were male, 89% were smokers, 86% had performance status ≤1 and 90% had adenocarcinoma histology. High-TIL was seen in 37%. Median PFS and OS were 5.7 months (95% CI: 4.9–6.7) and 11.7 months (95% CI: 9.3–13.0), respectively, with no association with TILs.
High-TIL was associated with favourable outcomes in a real-world immunotherapy cohort of patients with NSCLC, but not with chemotherapy, suggesting that TILs may be useful in selecting patients for immunotherapy.
•High–tumour infiltrating lymphocyte (TIL) density was associated with immunotherapy benefit in non–small cell lung cancer (NSCLC) patients.•No correlation with outcome was observed in chemotherapy-treated patients with NSCLC.•TILs may be useful in selecting patients for immunotherapy.
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