Efficacy of olaparib in advanced cancers with germline or somatic mutations in BRCA1, BRCA2, CHEK2 and ATM, a Belgian Precision tumor-agnostic phase II study.

BACKGROUND: The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic next-generation sequencing in patients with advanced cancer and enhance access to molecularly guided treatment options. Academic tumor-agnostic basket phase II studies are part of this initiative. The current investigator-driven trial aimed to investigate the efficacy of olaparib in advanced cancers with a (likely) pathogenic mutation (germline or somatic) in a gene that plays a role in homologous recombination (HR). PATIENTS AND METHODS: This open-label, multi-cohort, phase II study examines the efficacy of olaparib in patients with an HR gene mutation in their tumor and disease progression on standard of care. Patients with a somatic or germline mutation in the same gene define a cohort. For each cohort, a Simon minimax two-stage design was used. If a response was observed in the first 13 patients, 14 additional patients were included. Here, we report the results on four completed cohorts: patients with a BRCA1, BRCA2, CHEK2 or ATM mutation. RESULTS: The overall objective response rate across different tumor types was 11% in the BRCA1-mutated (n = 27) and 21% in the BRCA2-mutated (n = 27) cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 germline-mutated colon cancer has an ongoing complete response with 19+ months on treatment. Median progression-free survival in responding patients was 14+ months (5-34+ months). The clinical benefit rate was 63% in the BRCA1-mutated and 46% in the BRCA2-mutated cohorts. No clinical activity was observed in the ATM (n = 13) and CHEK2 (n = 14) cohorts. CONCLUSION: Olaparib showed efficacy in different cancer types harboring somatic or germline mutations in the BRCA1/2 genes but not in ATM and CHEK2. Patients with any cancer type harboring BRCA1/2 mutations should have access to olaparib.

Estilos de humor, afrontamiento y soporte social en padres de niños con cáncer

Objetivo: Analizar el rol predictivo de las estrategias de afrontamiento y el soporte social percibido, sobre los estilos de humor en padres migrantes de niños con cáncer. Método: Se empleó un diseño cuantitativo transaccional-correlacional y un muestreo no probabilístico por conveniencia. Participaron 62 progenitores (11 hombres y 51 mujeres) entre los 20 y 61 años, quienes respondieron la Escala del Sentido del Humor (HSQ), el Cuestionario de Estimación del Afrontamiento (COPE) y el Medical Outcomes Study Social Support Survey (MOS-SSS). Resultados: Se establecieron modelos de regresión para el humor afiliativo (R²=0,19, p<0,001) y agresivo (R²=0,25, p<0,001), ambos considerados estilos de humor orientados a los demás. Respecto a los estilos orientados a uno mismo, para el humor de mejoramiento personal se desarrollaron dos modelos, el primero considera el soporte social global (R²=0,25, p< 0,001) y el segundo el soporte afectivo (R²=0,27, p< 0,001); y de la misma forma para el humor de descalificación personal, un modelo incluye el soporte social global (R²=0,28, p< 0,001) y el segundo el soporte instrumental (R²=0,27, p< 0,001). Conclusión: Las estrategias de afrontamiento y el soporte social en relación con los estilos de humor en contexto de enfermedad y migración demuestra la efectividad de ciertas estrategias y estilos considerados desadaptativos ante una situación altamente estresante.

Objective: To analyze the predictive role of coping strategies and social support over humor styles in parents who migrate along with children with cancer. Method: A transactional-correlational quantitative design and non-probabilistic convenience sampling were used. It involved 62 parents (11 men and 51 women) between 20 and 61 years. They answered the Humor Styles Questionnaire (HSQ), COPE Inventory (COPE) and the Medical Outcomes Study Social Support Survey (MOS-SSS). Results: Regression models were developed for affiliative (R²=0,19, p<0,001) and aggressive humor (R²=0,25, p<0,001), both considered humor styles towards others. For self-oriented humor styles, two models were built to predict self-enhancing humor. The first model considers global social support (R²=0,25, p<0,001), while the second model, affective support (R²=0,27, p<0,001). Likewise, the first model explaining self-defeating humor considers global social support (R²=0,28, p<0,001) and the second, instrumental support (R²=0,27, p<0,001). Discussion: Coping strategies and social support in relation to humor styles in the context of illness and migration demonstrate the effectiveness of certain strategies and styles considered maladaptive in face of a highly stressful situation.

Homologous recombination repair deficiency (HRD) testing in newly diagnosed advanced-stage epithelial ovarian cancer: A Belgian expert opinion.

Ovarian cancer (OC) has a poor prognosis as most patients present with non-specific symptoms and the disease is mostly diagnosed at advanced stages. Approximately 90% of cases are classified as epithelial OC (EOC), a category comprising histologically and molecularly distinct tumours. Identifying reliable biomarkers and employing personalised therapies in OC subgroups is crucial for battling the disease. EOCs are often characterised by homologous recombination repair deficiency (HRD), frequently caused by inactivation of the breast cancer susceptibility (BRCA) genes. These findings have led to the development of poly- (adenosine diphosphate [ADP])- ribose polymerase inhibitors (PARPi), which are synthetically lethal to HRD tumour cells. Both patients with HRD and non-HRD tumours can benefit from PARPi therapy in the recurrent setting. Moreover, recent phase III trials in patients with newly diagnosed advanced-stage OC have demonstrated greater clinical benefit from PARPi in treating HRD than non-HRD tumours. These findings offer new opportunities for the use of PARPi as maintenance therapy after first-line chemotherapy based on the presence of HRD. In the current article, we provide recommendations for HRD testing and treatment of patients with newly diagnosed advanced-stage EOC.

Treatment algorithm in patients with ovarian cancer.

Most ovarian cancer patients are diagnosed only at advanced stages when survival outcomes are worse, andwhen therapeutic decisions might prove challenging. The fundamental treatment for women with ovarian cancerincludes debulking surgery whenever possible and appropriate systemic therapy (chemotherapy, targeted andantiangiogenic agents). In the last few years, knowledge about histological and molecular characteristics of ovariancancer subtypes and stages has increased considerably. This has enabled the development and improvement ofseveral options for the diagnosis and treatment of ovarian cancer in a patient-tailored approach. Accordingly,therapeutic decisions are guided by the characteristics of the patient and the tumour, especially the molecularfeatures of the cancer subtype and disease stage. Particularly relevant are the advances in early genetic testing ofgermline and somatic mutations involved in DNA repair, and the clinical development of targeted agents. In orderto implement the best individual medical strategies, in this article, we present an algorithm of treatment options,including recently developed targeted agents, for primary and recurrent ovarian cancer patients in Belgium.

Extraskeletal osteosarcoma of the orbit: A clinicopathologic case report and review of literature.

Primary extraskeletal osteosarcoma (EOS) is an extremely rare malignancy. In this report, the clinical course of a 32-year-old man presenting with proptoses is described. Medical history included Hirschsprung disease (HD), horseshoe kidney, azoospermia, and vertebral anomalies. Imaging of the orbit showed an oval, well-defined heterogeneous mass adjacent to the lateral wall of the orbit. The patient underwent a lateral orbitotomy and complete excision of the mass. The mass was not attached to the bone. Histopathologic and immunohistochemical examination confirmed the diagnosis of an EOS. The patient received chemotherapy and radiotherapy and is free of the disease 3 years after the diagnosis. Genetic screening showed no mutations for both the RET proto-oncogene for HD and the p53 tumor suppressor gene for osteosarcoma.

Evaluation of the quality of the management of cancer of the corpus uteri--selection of relevant quality indicators and implementation in Belgium.

OBJECTIVE: Describe the methodology and selection of quality indicators (QI) to be implemented in the EFFECT (EFFectiveness of Endometrial Cancer Treatment) project. EFFECT aims to monitor the variability in Quality of Care (QoC) of uterine cancer in Belgium, to compare the effectiveness of different treatment strategies to improve the QoC and to check the internal validity of the QI to validate the impact of process indicators on outcome. METHODS: A QI list was retrieved from literature, recent guidelines and QI databases. The Belgian Healthcare Knowledge Center methodology was used for the selection process and involved an expert's panel rating the QI on 4 criteria. The resulting scores and further discussion resulted in a final QI list. An online EFFECT module was developed by the Belgian Cancer Registry including the list of variables required for measuring the QI. Three test phases were performed to evaluate the relevance, feasibility and understanding of the variables and to test the compatibility of the dataset. RESULTS: 138 QI were considered for further discussion and 82 QI were eligible for rating. Based on the rating scores and consensus among the expert's panel, 41 QI were considered measurable and relevant. Testing of the data collection enabled optimization of the content and the user-friendliness of the dataset and online module. CONCLUSIONS: This first Belgian initiative for monitoring the QoC of uterine cancer indicates that the previously used QI selection methodology is reproducible for uterine cancer. The QI list could be applied by other research groups for comparison.

Intensity-modulated arc therapy with cisplatin as neo-adjuvant treatment for primary irresectable cervical cancer. Toxicity, tumour response and outcome.

PURPOSE: The goal of this work was to evaluate the feasibility and outcome of intensity-modulated arc therapy ± cisplatin (IMAT ± C) followed by hysterectomy for locally advanced cervical cancer. PATIENTS AND METHODS: A total of 30 patients were included in the study. The primary tumour and PET-positive lymph node(s) received a simultaneous integrated boost. Four weeks after IMAT ± C treatment, response was evaluated. Resection consisted of hysterectomy with or without lymphadenectomy. Tumour response, acute and late radiation toxicity, postoperative morbidity and outcome were evaluated. RESULTS: All hysterectomy specimens were macroscopically tumour-free with negative resection margins; pathological complete response was 40%. In 2 patients, one resected lymph node was positive. There was no excess in postoperative morbidity. Apart from two grade 3 hematologic toxicities, no grade 3 or 4 acute radiation toxicity was observed. No grade 3, 1 grade 4 (4%) intestinal, and 4 grade 3 (14%) urinary late toxicities were observed. The 2-year local and regional control rates were 96% and 100%, respectively. The 2-year distant control rate was 92%. Actuarial 2-year progression free survival rate was 89%. Actuarial 1- and 2-year overall survival rates were 96% and 91%, while 3-year overall survival was 84%. CONCLUSION: Surgery after IMAT ± C is feasible with low postoperative morbidity and radiation toxicity. Local, regional, distant control and survival rates are promising.

PARP inhibitors in oncology: a new synthetic lethal approach to cancer therapy.

Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)-deficient tumour cells--including those with defects in BRCA1/2--are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a novel 'synthetic lethal' approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as first-line therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.

Cardiac toxicity of trastuzumab: experience at the Ghent Unversity Hospital, Belgium.

INTRODUCTION: Trastuzumab (TRAS) is a humanised monoclonal antibody that is targeted against the HER2 growth factor receptor. Over-expression of the receptor occurs in around 15-25% of women with early breast cancer (CA). Four major adjuvant trials compared trastuzumab treatment with observation after neoadjuvant or adjuvant chemotherapy in women with high risk HER2-positive breast cancer. Results of these trials showed that trastuzumab treatment given every 3 weeks for 1 year achieved a significant improvement of disease free survival and overall survival. However, cardiac toxicity occurred more in the trastuzumab arm than in the observation arm resulting in symptomatic congestive heart failure and a significant drop in left ventricular ejection function (LVEF). AIM OF THE STUDY: The purpose of this analysis is to evaluate cardiac toxicity of adjuvant trastuzumab treatment in 30 breast cancer patients. Study parameters were cardiac toxicity assessed by LV function, disease free survival and overall survival. MATERIALS AND METHODS: Based on the adjuvant trials and in expectation of the reimbursement of trastuzumab in the adjuvant setting, a convention was set up between the Belgian National Institute for Health and Disability Insurance and hospital centres specialized in the treatment of breast cancer. In this convention, trastuzumab was offered to patients diagnosed with invasive, non-metastatic breast cancer with an over-expression of HER2 proven by a positive FISH test. Metastatic lymph nodes or a tumour measuring more than 10 mm had to be present. At least 4 cycles of adjuvant or neoadjuvant chemotherapy had to be given to the patient. Radiotherapy could be administered. The time interval between chemotherapy or radiotherapy and treatment with trastuzumab could not be more than 6 months. LVEF determined by MUGA scan or by ultrasonography at the start of trastuzumab treatment had to be more than 55%. RESULTS: 30 breast cancer patients were treated with adjuvant trastuzumab in our hospital between June 2006 and July 2007. All patients met the inclusion criteria. Six patients stopped trastuzumab treatment because of cardiac toxicity. All these patients had received prior anthracycline neoadjuvant or adjuvant chemotherapy. Five of these patients were found to have a LVEF < 55%, one showing symptoms of congestive cardiomyopathy.The sixth patient was diagnosed with a newly developed tricuspid valve insufficiency grade 3. Follow-up data of 20 months since the start of trastuzumab treatment showed that 27 patients were disease-free. Two patients died because of progressive breast cancer disease. One patient was lost of follow-up. CONCLUSION: In this small group of breast cancer patients, treated with adjuvant trastuzumab, cardiac toxicity expressed as a decreased left ventricular function seems to have a higher incidence compared to the other adjuvant trials. Therefore, a close cardiac monitoring for several years should be recommended in patients treated with trastuzumab.

Osteosarcoma with extensive calcified pleural metastases at diagnosis.

We report the case of an 18 year old woman presenting with shortness of breath and pain in the left shoulder. Imaging of the lungs revealed pleural effusion and calcification of the left pleura. An osteosarcoma of the left humerus was the final diagnosis. A review of the literature reveals that calcified pleural metastatic disease in cases of osteosarcoma has been infrequently reported. Other causes of pleural calcification are briefly discussed.

Preceding sentinel node biopsy in early breast cancer: does it affect the number of axillary lymph nodes?

In the staging of early breast cancer a positive sentinel node biopsy is followed by axillary dissection in order to assess the number of metastasised lymph nodes. Immediate axillary dissection has been abandoned in our centre. If necessary, an axillary dissection takes place about two weeks later, but the post surgical inflammatory reaction might hinder dissection and decrease the number of removed lymph nodes. In a retrospective study, the total number of lymph nodes removed by sentinel node biopsy followed later by axillary dissection (n = 53) was compared with the total number of lymph nodes removed by axillary dissection without previous sentinel node biopsy in combination with breast conserving therapy (n = 113), or following breast conserving therapy (n = 15), or in combination with mastectomy (n = 65). A total number of 12 (median) lymph nodes were removed by sentinel node biopsy followed later by axillary dissection. Only in the mastectomy + axillary dissection group were less lymph nodes (median of 9) removed (P = 0.009). Multiple regression showed the total number of axillary lymph nodes to be correlated with age (R = -0.21; P = 0.002) and with the number of lymph nodes with metastasis (R = 0.31; P < 0.0001). Age distribution showed that the mastectomy + axillary dissection group had the oldest patient population. The number of removed axillary lymph nodes is not decreased by preceding sentinel node biopsy, but depends on other factors.

Analysis of Wnt/Beta catenin signalling in desmoid tumors.

Desmoid tumors are fibromatous lesions occurring both sporadically and in patients with familial adenomatous polyposis (FAP). Because of the association of these tumors with the hereditary colorectal cancer syndrome FAP we set out to define the molecular events driving desmoid tumorigenesis, hypothezising these might be identical to events driving colorectal tumorigenesis. We found that whereas FAP-associated desmoid tumors are caused by germline APC mutations followed by somatic inactivation of the wild-type APC allele, sporadic desmoids are usually characterized by oncogenic mutations in the b-catenin gene, both identical molecular alterations to those found in the vast majority of colorectal cancers. Next we set out to investigate the cellular pathways activated by these mutations, and identified activation of the Wnt signaling pathway in desmoid tumors. Wnt signaling modulates expression of developmental genes and cell fate via beta-catenin, and has been implicated in many cancer types. Currently we are investigating tissue-specific downstream effectors of the Wnt pathway that might be responsible for the behaviour of these invasive fibrous tumors. Our findings also point to a role for this pathway in the regulation of normal myofibroblast proliferation and suggest novel treatments in desmoid tumors and other fibrous proliferative disorders.

Invasion and MMP expression profile in desmoid tumours.

Desmoid tumours are locally invasive soft tissue tumours in which beta-catenin mediated TCF-dependent transcription is activated. The role of soluble factors secreted by the myofibroblastic desmoid tumour, which could stimulate tumour invasiveness, was investigated. Using collagen gel invasion assays, the presence of factors stimulating invasion in desmoid conditioned media (CM) could be established. Since matrix metalloproteinases (MMPs) have been implicated in the process of tumoral invasion, the expression levels of the MMP family members were evaluated. Quantitative reverse transcription-PCR was used to determine the expression levels of MMP1, MMP2, MMP3, MMP7, MMP11, MMP12, MMP13, MMP14 and the inhibitors TIMP1, TIMP2 and TIMP3. Besides overexpression of MMP7, a known TCF-dependent target gene, a striking upregulation of the expression levels of MMP1, MMP3, MMP11, MMP12 and MMP13 in desmoid tumours, compared to unaffected fibroblasts from the same patients, was found. Treating the CM of desmoids with a synthetic and a physiologic MMP inhibitor reduced the invasion-stimulating capacity of the desmoid CM by approximately 50%. These results suggest the involvement of soluble factors, released by the desmoid cells, in stimulating invasion and implicate the MMPs as facilitators of invasion.

Tcf-3 expression and beta-catenin mediated transcriptional activation in aggressive fibromatosis (desmoid tumour).

Aggressive fibromatosis harbours mutations resulting in beta-catenin protein stabilization. Primary cell cultures demonstrate constitutive tcf activation in aggressive fibromatosis. Expression and co-immunoprecipitation studies suggest that beta-catenin binds and activates tcf-3 in this tumour. This is the first demonstration of tcf-3 activation by beta-catenin stabilization in a human neoplastic process.

Postoperative spindle cell nodule of bladder.

We describe a new tumor of the bladder resembling sarcoma. The tumor typically develops after damage to the bladder wall, and the clinicopathologic features make it possible to recognize it as a benign lesion rather than the malignant lesions for which it can be mistaken.

Pain treatment in metastatic prostatic carcinoma by radiofrequency thermolesion on the pituitary gland. Preliminary report.

Radiofrequency thermolesion on the pituitary gland is a simple and safe procedure to reduce pain in metastatic prostatic carcinoma. The method is indicated in patients with multiple and bilateral painful areas due to bone metastases, which are resistant to hormonal therapy and Estracyt. A good pain relief is achieved in over 60% of patients. Only one infectious complication has been encountered in a series of 17 patients treated this way.