TP53 and ovarian cancer

Ovarian cancer represents the fourth most frequent type of cancer among females and is the leading cause of death from gynecological cancer in the western world. This review describes gene alterations in ovarian cancer. Specific emphasis is placed on genetic alterations and the prevalence of TP53 (p53) gene alterations in the distinct biological ovarian tumors (benign, borderline, and malignant) and histological subtypes (serous, mucinous, endometrioid, clear cell), as well as in BRCA1-associated hereditary ovarian cancer. Although multi-modality treatment regimens, including cytoreductive surgery and cisplatin- containing combination chemotherapy, have usefully prolonged survival, the overall cure rate of the disease has not changed dramatically. Ovarian cancer is difficult to eradicate completely by surgery and many patients have only a partial response to postoperative chemotherapy and/or many will develop chemotherapy resistance. All these important factors contribute to the poor prognosis of ovarian cancer patients. In this review, the putative prognostic or predictive value of TP53 in ovarian cancer is addressed

PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients

Introduction: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) α-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERα-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERα-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins.Methods: Primary tumors from 563 ERα-positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction.Results: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found.Conclusion: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERα- positive, postmenopausal, early breast cancer patients

Ovarian cancer cell line panel (OCCP): Clinical importance of in vitro morphological subtypes

Epithelial ovarian cancer is a highly heterogeneous disease and remains the most lethal gynaecological malignancy in the Western world. Therapeutic approaches need to account for inter-patient and intra-tumoural heterogeneity and detailed characterization of in vitro models representing the different histological a

Sensitivity to systemic therapy for metastatic breast cancer in CHEK2 1100delC mutation carriers

Purpose: The role of CHEK2 in DNA repair by homologous recombination suggests that CHEK2-associated breast cancer (BC) patients might be more sensitive to chemotherapy inducing double-strand DNA breaks, but results hereon are lacking. We compared the sensitivity to first-line chemotherapy and endocrine therapy between CHEK2 1100delC and non-CHEK2 metastatic breast cancer (MBC) patients. Methods: Sixty-two CHEK2 1100delC MBC patients were selected from three cohorts genotyped for CHEK2 1100delC (one non-BRCA1/2 cohort and two sporadic cohorts). Controls were 62 non-CHEK2 MBC patients, matched for age at and year of primary BC diagnosis, and year of metastatic disease. Objective response rate (complete and partial response) to, and progression-free survival (PFS) and overall survival (OS) after start of first-line chemotherapy and endocrine therapy were compared between CHEK2 and non-CHEK2 patients. Results: Median age at BC diagnosis was 46 and 51 years at MBC diagnosis. First-line chemotherapy consisted of anthracycline-based chemotherapy (n = 73), taxanes (n = 16), CMF(-like) chemotherapy (n = 33) and taxane/anthracycline regimens (n = 2). CHEK2 and non-CHEK2 patients had a comparable objective response rate (44 vs. 52 %). Also, PFS and OS after start of chemotherapy were comparable between both patient groups (hazard ratio 0.91; 95 % confidence interval 0.63–1.30 and 1.03; 95 % CI 0.71–1.49, respectively). Thirty-six CHEK2 and 32 non-CHEK2 patients received first-line endocrine therapy (mainly tamoxifen) for MBC. No significant differences were observed in objective response rate to, and PFS and OS after start of endocrine therapy. Conclusion: No differ

Precision medicine in cancer: Challenges and recommendations from an EU-funded cervical cancer biobanking study

Background:Cervical cancer (CC) remains a leading cause of gynaecological cancer-related mortality worldwide. CC pathogenesis is triggered when human papillomavirus (HPV) inserts into the genome, resulting in tumour suppressor gene inactivation and oncogene activation. Collecting tumour and blood samples is critical for identifying these genetic alterations.Methods:BIO-RAIDs is the first prospective molecular profiling clinical study to include a substantial biobanking effort that used uniform high-quality standards and control of samples. In this European Union (EU)-funded study, we identified the challenges that were impeding the effective implementation of such a systematic and comprehensive biobanking effort.Results:The challenges included a lack of uniform international legal and ethical standards, complexities in clinical and molecular data management, and difficulties in determining the best technical platforms and data analysis techniques. Some difficulties were encountered by all investigators, while others affected only certain institutions, regions, or countries.Conclusions:The results of the BIO-RAIDs programme highlight the need to facilitate and standardise regulatory procedures, and we feel that there is also a need for international working groups that make recommendations to regulatory bodies, governmental funding agencies, and academic institutions to achieve a proficient biobanking programme throughout EU countries. This represents the first step in precision medicine

TP53 Mutations in Serum Circulating Cell-Free Tumor DNA As Longitudinal Biomarker for High-Grade Serous Ovarian Cancer

The aim of this study was to determine an optimal workflow to detect TP53 mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether TP53 mutations are suitable as biomarker for disease. TP53 was investigated in tissue and archived serum from 20 HGSOC patients by a next-generation sequencing (NGS) workflow alone or combined with digital PCR (dPCR). AmpliSeq™-focused NGS panels and customized dPCR assays were used for tissue DNA and longitudinal cfDNAs, and Oncomine NGS panel with molecular barcoding was used for baseline cfDNAs. TP53 missense mutations were observed in 17 tissue specimens and in baseline cfDNA for 4/8 patients by AmpliSeq, 6/9 patients by Oncomine, and 4/6 patients by dPCR. Mutations in cfDNA were detected in 4/6 patients with residual disease and 3/4 patients with disease progression within six months, compared to 5/11 patients with no residual disease and 6/13 patients with progression after six months. Finally, mutations were detected at progression in 5/6 patients, but not during chemotherapy. NGS with molecular barcoding and dPCR were most optimal workflows to detect TP53 mutations in baseline and longitudinal serum cfDNA, respectively. TP53 mutations were undetectable in cfDNA during treatment but re-appeared at disease progression, illustrating its promise as a biomarker for disease monitoring

Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versu