Early Changes in [18F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.

We investigated the potential use of [18F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. Methods. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [18F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUVmax) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. Results. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUVmax (ΔSUVmax). For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (r = 0.69, p = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (-30% ± 10% and -20% ± 20%, respectively) and ΔSUVmax (-39% ± 36% and -42% ± 8%, respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and ΔSUVmax decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (r = 0.48, p = 0.028), but the correlation could be improved when combination with everolimus (r = 0.59, p = 0.023) or trastuzumab (r = 0.69, p = 0.015) was excluded. Conclusion. Reduction in [18F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [18F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [18F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.

18F-FDG and 18F-FLT Uptake Profiles for Breast Cancer Cell Lines Treated with Targeted PI3K/Akt/mTOR Therapies.

Background: To evaluate 18F-fluoro-2-deoxy-glucose (18F-FDG) and 18F-fluorothymidine (18F-FLT) as early-response biomarkers for phosphoinositide-3-kinase/Akt/mammalian-target-of-rapamycin (PI3K/Akt/mTOR) inhibition in breast cancer (BC) models. Materials and Methods: Two human epidermal growth factor receptor 2 (HER2)-positive (trastuzumab-sensitive SKBR3; trastuzumab-resistant JIMT1) and one triple-negative BC cell line (MDA-MB-231, trastuzumab, and everolimus resistant) were treated with trastuzumab (HER2 antagonist), PIK90 (PI3K inhibitor), or everolimus (mTOR inhibitor). Radiotracer uptake was measured before, 24, and 72 h after drug exposure and correlated with changes in cell number, glucose transporter 1 (GLUT1), cell cycle phase, and downstream signaling activation. Results: In responsive cells, cell number correlated with 18F-FLT at 24 h and 18F-FDG at 72 h of drug exposure, except in JIMT1 treated with everolimus, where both radiotracers failed to detect response owing to a temporary increase in tracer uptake. This flare can be caused by reflex activation of Akt combined with a hyperactive insulin-like growth factor I receptor (IGF-1R) signaling, resulting in increased trafficking of GLUTs to the cell membrane (18F-FDG) and enhanced DNA repair (18F-FLT). In resistant cells, no major changes were observed, although a nonsignificant flair for both tracers was observed in JIMT1 treated with trastuzumab. Conclusion: 18F-FLT positron emission tomography (PET) detects response to PI3K-targeting therapy earlier than 18F-FDG PET in BC cells. However, therapy response can be underestimated after trastuzumab and everolimus owing to negative feedback loop and crosstalk between pathways.

The predictive value of sentinel node biopsy in early breast cancer after neo-adjuvant chemotherapy: A prospective study.

OBJECTIVE: A sentinel Node (SN) has replaced axillary lymph node dissection (ALND) in patients with clinically node negative axilla (cN0). SN after Neo-adjuvant chemotherapy (NACT) is feasible but not accurate in clinically node positive (cN1-3) patients. The goal of this study is to determine the negative predictive value (NPV) of SN in cN0 breast cancer after NACT. A secondary endpoint is to determine if ALND can be avoided after NACT regardless of the pre-treatment clinical staging of the axilla, in case of a normalization of the 18F-fluoro-2-deoxy-glucose positron emission tomography scan (PET-CT scan). DESIGN: A single institution prospective study regarding the negative predictive value of the SN in breast cancer after NACT was conducted in the Multidisciplinary Breast Clinic of the Antwerp University Hospital from 29/03/2010 until 01/12/2015 (Study number: B30020108368). Inclusion criteria for study participation were: breast cancer, age above 18 years, female, tumor stages T2-T4 N0-3 or T1N1-N3. All patients were staged by a mammography, ultrasound of the axilla, MRI of the breast, PET-CT scan and bone scintigraphy. They received NACT consisting of 12 cycles of paclitaxel or 4 cycles of docetaxel followed by dose dense doxorubicin or epirubicin/cyclofosfamide or vice versa as a standard initial treatment. After 6 weeks, a PET-CT scan was performed for early tumour response evaluation. At the day of operation, a 99mTC-labelled nanocolloid was used to identify the SN. During the surgery the SN were removed separately together with a complete ALND. RESULTS: A total of 150 patients were enrolled in our study of which 129 were eligible for analysis. 53 patients had a positive SN of which 32 have a positive axillary lymph nodes (ALN), positive predictive value (PPV) was 60%; 76 patients had a negative SN of which 6 had a positive ALN (NPV 92%). The sensitivity is 84% and the specificity 76% with a false omission rate (FOR) of 8%. In total 45 patients ALN were clinical negative and no suspect lymph nodes were seen on ultrasound, MRI and PET-CT scan) and 45 patients had negative a SN, with no ALN and 2 patients had a positive SN of which 1 patients had axillary involvement (NPV 100%). The FOR of cN1: 5%, cN2: 37%, cN3 33%. A total of 22 patients out of 84 patients (26%) of which 15/49 cN1 (30%), 6/23 (26%) cN2, 1/12 (8%) have after 6 weeks of chemotherapy and normalization on PET-CT scan. A total of 17 patients had a negative SN and ALN. The FOR was in this group was 0%. CONCLUSION: A SNB should become the standard after NACT if case of a cN0. If after NACT the PET CT has normalized, no ALND should be performed if the SN is negative.

Innovative molecular targeted agents in hepatocellular carcinoma: new gladiators on the arena.

Treatment of advanced hepatocellular carcinoma remains a challenge, with discouraging results in terms of survival. Following the approval of the multikinase inhibitor sorafenib, a large number of molecular targeted agents have been tested, but many have failed to demonstrate significant efficacy in clinical trials. However, the deeper knowledge in HCC pathogenesis achieved through the years has enabled us to explore new targetable pathways as well as biomarkers that could lead to treatment personalization. In this review, we provide a comprehensive update of the most recent data regarding new drugs under investigation ‒ some like regorafenib, very close to its approval ‒ and new possible targets for future treatments.

Neoadjuvant systemic therapy in breast cancer: Challenges and uncertainties.

The management of locally advanced breast cancer (LABC) remains a major clinical issue, despite progress achieved in diagnosis and therapy. Preoperative or neoadjuvant therapy has gained interest since breast cancer has been regarded as a systemic disease. Comparing adjuvant versus neoadjuvant treatment, the neoadjuvant approach offers the advantage of downstaging the disease and testing the efficacy of therapy administered to patients. A large number of clinical trials have attempted to define the optimal neoadjuvant treatment, but little attention has been paid to the sequence of chemotherapy. Moreover, the integration of antibodies against Human Epidermal Receptor-2 (HER-2) and other biological therapies that may improve the long-term control of breast cancer patients, have a special clinical interest. In this review, we will discuss these topics attempting to answer the questions why, when and which regimen to use for patients with LABC. Especially, the introduction of the platina derivatives in neoadjuvant trials with their exceptional high pathological complete response rates are challenging to rethink the optimal treatment options in early and locally advanced breast cancer.

Efficacy Screening of Gloriosa Superba Extracts in a Murine Pancreatic Cancer Model Using (18)F-FDG PET/CT for Monitoring Treatment Response.

PURPOSE: In vivo efficacy of two herbal extracts of Gloriosa superba L. (Colchicaceae) was investigated in a murine pancreatic tumor model by tumor volume measurements and Positron Emission Tomography (PET) imaging using 2-deoxy-2-[(18)F]fluoro-d-glucose ((18)F-FDG). MATERIALS AND METHODS: A crude extract of G. superba (GS) seeds rich in colchicine and a colchicine-poor extract (GS2B) containing mostly colchicoside as a putative prodrug were prepared. PANC02-bearing C57BL/6 mice were treated with either placebo, gemcitabine, or one of the extracts (three different doses) for 10 days. Tumor volume measurements were performed daily during treatment and additionally (18)F-FDG Positron emission tomography/computed tomography was acquired at baseline and after 7 days of treatment. Ki-67 and cleaved caspase-3 immunostaining was performed on the resected tumors. RESULTS: After 7 days of treatment, a dose-dependent tumor growth inhibition of both extracts was observed with the highest in vivo response at the highest dose of GS and GS2B and gemcitabine. A positive significant correlation was found between Ki-67 scores and relative tumor volumes (RTV), and a negative significant correlation between caspase-3 staining scores and RTV. A decrease in (18)F-FDG uptake was clearly observed in all treatment groups. CONCLUSIONS: The therapeutic efficacy of the two different herbal extracts was demonstrated in an in vivo pancreatic tumor model. (18)F-FDG PET was able to detect an early response as overall lower (18)F-FDG uptake was measured in the treated groups.

The effect of smoking cessation on quality of life after lung cancer surgery.

OBJECTIVE: This study aimed to evaluate the effect of smoking status on quality of life (QoL) after non-small-cell lung cancer surgery with the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire-C30 and LC13. METHODS: QoL was prospectively recorded in 70 consecutive patients undergoing lobectomy or pneumonectomy. Questionnaires were administered preoperatively and 1, 3, 6 and 12 months postoperatively (MPO). RESULTS: Of all patients analysed, nine (13%) were non-smokers, 20 (29%) former smokers, six (8%) recent quitters and 35 (50%) current smokers. All four groups had comparable patients' characteristics and preoperative QoL scores, with exception of non-smokers who had significantly lower physical functioning, role functioning, cognitive functioning and a higher thoracic pain burden. In non-smokers, all QoL scores returned to baseline 3 months after surgery. Former smokers complained of a significant 3-month decrease in physical functioning (3 MPO, p = 0.01) and a 12-month decrease in role functioning (12 MPO, p = 0.01). Former smokers complained of a significant increase in dyspnoea (6 MPO, p = 0.001) during the first 6 months after surgery. Recent quitters had a longer impairment in physical functioning (6 MPO, p = 0.01) and a 3-month burden of dyspnoea (3 MPO, p=0.02). In current smokers, no return to baseline in physical (12 MPO, p = 0.01), role (12 MPO, p = 0.01) and social functioning (12 MPO, p = 0.02) and a persistent increase in dyspnoea (12 MPO, p = 0.04) were reported. Current smokers also complained of increased thoracic pain (12 MPO, p = 0.02). Except non-smokers, all patients complained of fatigue the first 3 months after surgery. CONCLUSIONS: Smoking cessation is beneficial at any time point to lung cancer surgery and current smoking at the time of surgery is associated with a poor postoperative QoL.