Jacques De Grève

Tumor regressions observed in patients with metastatic melanoma treated with an antigenic peptide encoded by gene MAGE-3 and presented by HLA-A1.

Thirty‐nine tumor‐bearing patients with metastatic melanoma were treated with 3 subcutaneous injections of the MAGE‐3.A1 peptide at monthly intervals. No significant toxicity was observed. Of the 25 patients who received the complete treatment, 7 displayed significant tumor regressions. All but one of these regressions involved cutaneous metastases. Three regressions were complete and 2 of these led to a disease‐free state, which persisted for more than 2 years after the beginning of treatment. No evidence for a cytolytic T lymphocyte (CTL) response was found in the blood of the 4 patients who were analyzed, including 2 who displayed complete tumor regression. Our results suggest that injection of the MAGE‐3.A1 peptide induced tumor regression in a significant number of the patients, even though no massive CTL response was produced. Int. J. Cancer 80:219–230, 1999.

Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval

PURPOSE Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. PATIENTS AND METHODS Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. RESULTS Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). CONCLUSION Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

miR-146a Inhibits Cell Growth, Cell Migration and Induces Apoptosis in Non-Small Cell Lung Cancer Cells

Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-κB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC.

Performance of Two Geriatric Screening Tools in Older Patients With Cancer

PURPOSE To compare the diagnostic characteristics of two geriatric screening tools (G8 and Flemish version of the Triage Risk Screening Tool [fTRST]) to identify patients with a geriatric risk profile and to evaluate their prognostic value for functional decline and overall survival (OS). PATIENTS AND METHODS Patients ≥ 70 years old with a malignant tumor were included if a new cancer event occurred requiring treatment decision. Geriatric screening with G8 and fTRST (cutoff ≥ 1 [fTRST (1)] and ≥ 2 [fTRST (2)] evaluated) was performed in all patients, as well as a geriatric assessment (GA) evaluating social situation, functionality (activities of daily living [ADL] + instrumental activities of daily living [IADL]), cognition, depression, and nutrition. Functionality was re-evaluated 2 to 3 months after cancer treatment decision, and death rate was followed. Functional decline and OS were evaluated in relation to normal versus abnormal score on both screening tools. RESULTS Nine hundred thirty-seven patients were included (October 2009 to July 2011). G8 and fTRST (1) showed high sensitivity (86.5% to 91.3%) and moderate negative predictive value (61.3% to 63.4%) to detect patients with a geriatric risk profile. G8 and fTRST (1) were strongly prognostic for functional decline on ADL and IADL, and G8, fTRST (1), and fTRST (2) were prognostic for OS (all P < .001). G8 had the strongest prognostic value for OS (hazard ratio for G8 normal v abnormal, 0.38; 95% CI, 0.27 to 0.52). CONCLUSION Both geriatric screening tools, G8 and fTRST, are simple and useful instruments in older patients with cancer for identifying patients with a geriatric risk profile and have a strong prognostic value for functional decline and OS.

Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)]. Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma

Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. Methods: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with 68Ga via a NOTA derivative. Administered activities were 53–174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OLINDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. Results: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. Conclusion: 68Ga-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase II trial.

Genomic activation of the EGFR and HER2-neu genes in a significant proportion of invasive epithelial ovarian cancers

BackgroundThe status of the EGFR and HER2-neu genes has not been fully defined in ovarian cancer. An integrated analysis of both genes could help define the proportion of patients that would potentially benefit from targeted therapies.MethodsWe determined the tumour mutation status of the entire tyrosine kinase (TK) domain of the EGFR and HER2-neu genes in a cohort of 52 patients with invasive epithelial ovarian cancer as well as the gene copy number and protein expression of both genes in 31 of these patients by DGGE and direct sequecing, immunohistochemistry and Fluorescent in Situ Hybridisation (FISH).ResultsThe EGFR was expressed in 59% of the cases, with a 2+/3+ staining intensity in 38%. HER2-neu expression was found in 35%, with a 2/3+ staining in 18%. No mutations were found in exons 18–24 of the TK domains of EGFR and HER2-neu. High polysomy of the EGFR gene was observed in 13% of the invasive epthelial cancers and amplification of the HER2-neu gene was found in 10% and correlated with a high expression level by immunohistochemistry.Mutations within the tyrosine kinase domain were not found in the entire TK domain of both genes, but have been found in very rare cases by others.ConclusionGenomic alteration of the HER2-neu and EGFR genes is frequent (25%) in ovarian cancer. EGFR/HER2-neu targeted therapies should be investigated prospectively and specifically in that subset of patients.

Cancer predisposing missense and protein truncating BARD1 mutations in non‐BRCA1 or BRCA2 breast cancer families

Fifteen years ago BRCA1 and BRCA2 were reported as high penetrant breast cancer predisposing genes. However, mutations in these genes are found in only a fraction of high risk families. BARD1 is a candidate breast cancer gene, but only a limited number of missense mutations with rather unclear pathogenic consequences have been reported.We screened 196 high risk breast cancer families for the occurrence of BARD1 variants. All genetic variants were analyzed using clinical information as well as IN SILICO predictive tools, including protein modeling. We found three candidate pathogenic mutations in seven families including a first case of a protein truncating mutation (p.Glu652fs) removing the entire second BRCT domain of BARD1. In conclusion, we provide evidence for an increased breast cancer risk associated to specific BARD1 germline mutations. However, these BARD1 mutations occur in a minority of hereditary breast cancer families. ©2010 Wiley‐Liss, Inc.

Deconvolution-based Dynamic Contrast-enhanced MR Imaging of Breast Tumors: Correlation of Tumor Blood Flow with Human Epidermal Growth Factor Receptor 2 Status and Clinicopathologic Findings—Preliminary Results

PURPOSE To prospectively determine whether breast carcinomas possess characteristic values of tumor blood flow (TBF) that correlate with pathologic and molecular prognostic markers. MATERIALS AND METHODS The institutional ethics committee approved this study. After informed consent was obtained, 57 women (age range, 31-80 years) with histologically proved breast cancer underwent routine magnetic resonance (MR) mammography, which included a whole-breast dynamic contrast material-enhanced (DCE) sequence. A second contrast material bolus was injected during dynamic single-section turbo field-echo imaging of the section where the lesion was maximally enhanced. The relative signal intensity changes were deconvolved in a pixelwise fashion to yield the TBF. Formalin-fixed paraffin-embedded tumor specimens on slides were evaluated for histologic size and grade, as well as for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) protein. In patients with a HER2 protein score of 2+ or 3+, HER2 gene status was assessed. For all prognostic parameters, the Mann-Whitney U test was used to compare median TBF in the HER2-positive group with that in the HER2-negative group. RESULTS Significantly higher TBF was observed in tumors larger than 2 cm in diameter and in PR-negative and HER2 gene-amplified tumors (P < .05). In the HER2-positive and HER2-negative groups, ER-positive PR-positive tumors had a lower median TBF than did ER-negative PR-negative tumors, and the difference was significant in the HER2-positive group (P < .05). CONCLUSION Pixelwise deconvolution analysis of DCE MR data in patients with breast cancer can provide preoperative information regarding TBF. These results also support the hypothesis that there is increased TBF in HER2-positive tumors.

The influence of clinical assessment (including age) and geriatric assessment on treatment decisions in older patients with cancer

OBJECTIVES The aim of this prospective study in older patients with cancer was to evaluate how clinical assessment (including age) determines the physicians treatment decisions, and how geriatric assessment (GA) further influences these decisions. PATIENTS AND METHODS Patients aged ≥70years old with cancer were included if a new therapy was considered. All patients underwent a GA and results were communicated to the treating physician. After the final treatment decision, a predefined questionnaire was completed by the physician. RESULTS In total, 937 patients with median age of 76years old were included. A total of 902 (96.3%) questionnaires were completed by the treating physicians. In 381/902 patients (42.2%) clinical assessment led to a different treatment decision compared to younger patients without co-morbidities. This difference was most prominent for chemotherapy/targeted therapy decisions. In 505/902 cases (56%) the treating physician consulted GA results before the final treatment decision. In these patients, the treatment decision was influenced by clinical assessment in 44.2%. In 31/505 patients (6.1%) the GA further influenced treatment, mostly concerning chemotherapy/targeted therapy. In eight patients GA influenced the physician to choose a more aggressive chemotherapy. CONCLUSIONS Physicians use different treatment regimens in older versus younger patients, based on clinical assessment, including age. GA results further influence treatment decisions in a minority of patients and may trigger the use of less aggressive as well as more aggressive treatments. GA information is not always utilized by oncologists, indicating the need for better education and sensitization.