Konstantin J. Dedes

PTEN Deficiency in Endometrioid Endometrial Adenocarcinomas Predicts Sensitivity to PARP Inhibitors

Endometrioid endometrial cancer cell lines harboring PTEN loss of function have impaired homologous recombination response to DNA double-strand breaks and show an exquisite sensitivity to PARP inhibition. Putting PARP Inhibitors on the Map Targeted drug therapies that interfere with specific oncoproteins in certain cancers like lung cancer and chronic myeloid leukemia have shown great promise, but designing targeted therapies for tumors that have lost a tumor suppressor protein has proved challenging. Building on the idea of targeting a complementary gene or pathway in tumors with an inactive tumor suppressor protein, Dedes and colleagues set out to tackle endometrial cancer. This cancer is the fourth most common malignancy in women and is very difficult to treat particularly in the later stages of the disease. The authors demonstrate that endometrial cancer cell lines that lack the tumor suppressor protein PTEN show defects in the repair of DNA damage and are consequently very sensitive to drugs that block poly(ADP) ribose polymerase (PARP), an enzyme critical for DNA repair. Given that such PARP inhibitors are currently in late-stage clinical trials for treating breast and ovarian cancer, this study opens the door to using PARP inhibitors for treating endometrial cancer. First the authors demonstrated that the majority of endometrial cancer cell lines that they analyzed indeed had lost the PTEN tumor suppressor protein. PTEN both regulates a major growth signaling pathway in cells (the PI3K-AKT-mTOR pathway) and has recently been shown to be important for maintaining genomic stability. Dedes and co-workers then showed that loss of PTEN rendered endometrial cancer cells unable to repair DNA double-strand breaks induced by ionizing radiation. Other types of tumors that cannot repair DNA damage, such as breast and ovarian cancer cells carrying mutations in the BRCA1 and BRCA2 genes, are acutely sensitive to PARP inhibitors. Dedes et al. reasoned that endometrial cancer cells lacking PTEN may also be sensitive to these drugs. This is exactly what they found when they treated their endometrial cancer cell lines with the potent PARP inhibitor, KU0058948. To demonstrate that it was loss of PTEN that rendered the cancer cells highly sensitive to the drug, they re-expressed PTEN in endometrial cancer cell lines lacking this tumor suppressor protein and demonstrated that these cancer cell lines were now able to repair DNA damage and thus were resistant to treatment with the PARP inhibitor. Given that 80% of endometrial cancers lack PTEN, treatment with PARP inhibitors may be an effective way to treat this disease. PTEN (phosphatase and tensin homolog) loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is involved in the maintenance of genomic stability. Loss of PTEN function causes defects in repair of DNA double-strand breaks by homologous recombination and, therefore, sensitizes cells to inhibition of the poly(adenosine diphosphate ribose) polymerase (PARP). Here, we determined the PTEN status of eight endometrioid endometrial carcinoma cell lines and correlated it with in vitro sensitivity to the PARP inhibitor KU0058948. PTEN-deficient cells showed a significantly greater sensitivity to KU0058948 than the two endometrioid endometrial carcinoma cell lines with wild-type PTEN. The cell lines lacking PTEN expression were unable to elicit a homologous recombination damage response as assayed by RAD51 focus function (a marker of competent homologous recombination DNA repair) upon irradiation and treatment with PARP inhibitors. PTEN silencing in PTEN wild-type Hec-1b cells resulted in reduced RAD51 foci formation after DNA damage and increased sensitivity to PARP inhibition. PTEN reexpression in PTEN-null cell lines resulted in enhanced RAD51 foci formation and in relative resistance to KU0058948. Given that up to 80% of endometrioid endometrial cancers lack PTEN expression, our results suggest that PARP inhibitors may be therapeutically useful for a subset of endometrioid endometrial cancers.

Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: An economic evaluation

The addition of bevacizumab to weekly paclitaxel as primary chemotherapy for HER-2 negative metastatic breast cancer (MBC) prolongs progression-free survival without a substantial increase of toxicity. A Markov cohort simulation was used to follow the clinical course of typical patients with MBC. Information on response rates and major adverse effects was derived, and transition probabilities were estimated, based on the results of the E2100 clinical trial. Direct costs were assessed from the perspective of the Swiss health system. The addition of bevacizumab to weekly paclitaxel is estimated to cost an additional 40,369euro and to yield a gain of 0.22 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of 189,427euro/QALY gained. Probabilistic sensitivity analysis showed that the willingness-to-pay threshold of 60,000euro was never reached. The addition of bevacizumab to paclitaxel in MBC patients is expensive given the clinical benefit in terms of QALYs gained.

Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast

Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade‐ and oestrogen receptor (ER)‐matched invasive carcinomas of no special type (IC‐NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray‐based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC‐NSTs, and recurrent mutations affecting mitogen‐activated protein kinase family genes and NBPF10. RNA‐sequencing analysis identified 17 high‐confidence fusion genes, eight of which were validated and two of which were in‐frame. No recurrent fusions were identified in an independent series of MPCs and IC‐NSTs. Forced expression of in‐frame fusion genes (SLC2A1–FAF1 and BCAS4–AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out‐of‐frame rearrangements was found in one MPC and in 13% of HER2‐positive breast cancers, identified through a re‐analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild‐type CDK12 in a CDK12‐null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.

ARID1A Mutations and PI3K/AKT Pathway Alterations in Endometriosis and Endometriosis-Associated Ovarian Carcinomas

Endometriosis is a common gynecological disease affecting 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear cell carcinomas (OCCC) and the endometrioid ovarian carcinomas (EnOC), have been molecularly and epidemiologically linked to endometriosis. Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) have been found to occur in high frequency in OCCC and EnOC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWI/SNF chromatin remodeling complex and considered as a bona fide tumor suppressor. ARID1A mutations frequently co-occur with mutations, leading to an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, such as mutations in PIK3CA encoding the catalytic subunit, p110α, of PI3K. In combination with recent functional observations, these findings strongly suggest cooperating mechanisms between the two pathways. The occurrence of ARID1A mutations and alterations in the PI3K/AKT pathway in endometriosis and endometriosis-associated ovarian carcinomas, as well as the possible functional and clinical implications are discussed in this review.

Loss of ARID1A /BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating Human SWI/SNF complexes, which have an important role in the control of cell proliferation and tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas, and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. Here, we examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n=136) served as a control. Epithelial BAF250a expression was assessable in 90/104 (87%) and stromal BAF250a expression in 95/104 (91%) of the endometriosis, and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n=3/20, 15%) and one deep-infiltrating endometriosis sample (n=1/22, 5%), but in none of the peritoneal endometriosis (n=0/16) and eutopic endometrium samples (n=0/30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (P<0.0005), as well as peritoneal (P=0.003) and deep-infiltrating endometriosis (P=0.02). Our data demonstrates that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriomas. In addition, we report that a partial loss of BAF250a expression is occurring in the form of cell clusters indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be of importance in the determination of individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be further studied.

Management and Costs of Treating Lung Cancer Patients in a University Hospital

AbstractBackground: New diagnostic tools and emerging medications have significantly changed the existing medical treatment options for lung cancer over the last 5 years. However, the increase in healthcare costs in all developed societies has put the more economical treatments on centre stage. Objective: To examine the patterns and costs of lung cancer management at a Swiss University hospital at which there is a focus on interdisciplinary treatment. Patients and methods: All patients encountered during 1998 at the University Hospital of Zurich (USZ) with any diagnosis of lung cancer were selected for this retrospective study. Medical and sociodemographic data were collected by medical chart review for a period beginning with the first contact and ending with the last follow-up examination up to 30 months afterwards. Costs were calculated by assessing all resources used by each patient, multiplied by a uniform average cost factor. Results are in euros at 1999 prices. Results: The sample included 118 patients (72% male) with a mean age of 64.2 years (SD 9.8, range 34–85 years) and a mean smoking history of 45 pack-years (SD 31.8, range 0–13 pack-years). Eighty-nine percent of all patients showed histology of non-small cell lung cancer (NSCLC), whereas 11% showed small cell lung cancer (SCLC). Of the NSCLC patients, 27% were classified as stage I, 14% as stage II, 19% as stage IIIA, 11% as stage IIIB and 26% as stage IV disease. The overall survival rate after 1 year was 55% and after 2 years was 29%. Gender and health insurance status were not associated with overall survival. The median length of hospitalisation during the first year of treatment was 14 days (range 0–112 days). For the entire patient sample, the mean cost per patient was €19 408 (median €14 691, range €1821–80 020), 71% of which was due to the hospitalisation costs. The mean cost per NSCLC patient was €19 212 (median €14 511, range €1821–80 020) and for SCLC patients it was €20 992 (median €15 367, range €5282–51 840). Conclusion: This is the first study attempting to estimate the hospital cost of treatment for lung cancer patients in Switzerland and central Europe. The major part of the total cost was due to hospitalisation costs. Patients with advanced stages of lung cancer show the highest cost, mainly due to the costs of chemotherapy. We found that the distribution of total cost is asymmetric: a small number of patients with an excessively long hospital stay cause very high costs.

Cost-effectiveness analysis of adding a quadrivalent HPV vaccine to the cervical cancer screening programme in Switzerland

ABSTRACT Objective: Based on positive safety and efficacy data, a quadrivalent Human PapillomaVirus (HPV) vaccine has been approved in Switzerland to prevent HPV types 6, 11, 16 and 18 infections. The objective of this study was to explore the cost-effectiveness of an HPV vaccination in Switzerland. Design and methods: A Markov model of the natural history of HPV infection was adapted to the Swiss context and followed a hypothetical cohort of 41 200 girls aged 11 years over their lifetime. Main epidemiological and economic parameters were extracted from the literature. Two strategies were compared: conventional cytological screening only and HPV vaccination followed by conventional cytological screening. A coverage rate of 80% was used and the vaccine was assumed to provide a lifelong protection. Analyses were performed from the direct health care cost perspective including only direct medical costs. Results: Compared to screening only, adding a quadrivalent HPV vaccine could prevent over lifetime 62% of cervical cancers and related deaths, 19% of Cervical Intraepithelial Neoplasia (CIN 1), 43% of CIN 2, 45% of CIN 3 and 66% of genital warts per cohort. Incremental cost-effectiveness ratios (ICER) were estimated to be CHF 45 008 per Life Year Gained (LYG) and CHF 26 005 per Quality Adjusted Life Year (QALY) gained. Sensitivity analyses demonstrated that the ICER was robust to all parameters, but was most sensitive to the need for a booster and discount rates. Conclusions: Compared to commonly accepted standard thresholds in Europe and other vaccination strategies implemented in Switzerland, adding a quadrivalent HPV vaccine alongside the current cervical cancer screening programme is likely to be cost-effective in Switzerland.

A cost-effectiveness analysis of nivolumab versus docetaxel for advanced nonsquamous NSCLC including PD-L1 testing

Introduction Nivolumab (NIV) was recently approved in several countries for patients with pretreated advanced NSCLC. NIV is not cost‐effective compared with docetaxel (DOC) for the treatment of squamous NSCLC. However, its cost‐effectiveness for nonsquamous NSCLC and the consequences of programmed death ligand 1 (PD‐L1) testing are unknown. Methods This literature‐based health economic study used CheckMate‐057 trial data to model the incremental cost‐effectiveness ratio (ICER) of NIV versus DOC in the Swiss health care setting. The effect of PD‐L1 positivity for patient selection was assessed. Results In the base case model, NIV (mean cost CHF66,208; mean effect 0.69 quality‐adjusted life‐years [QALYs]) compared with DOC (mean cost CHF37,618; mean effect 0.53 QALYs) resulted in an ICER of CHF177,478/QALY gained. Treating only patients with PD‐L1–positive tumors (threshold ≥10%) with NIV compared with treating all patients with DOC produced a base case ICER of CHF124,891/QALY gained. Reduced drug price, dose, or treatment duration decreased the ICER partly below a willingness‐to‐pay threshold of CHF100,000/QALY. Health state utilities strongly influenced cost‐effectiveness. Conclusions Compared with DOC, NIV is not cost‐effective for the treatment of nonsquamous NSCLC at current prices in the Swiss health care setting. Price reduction or PD‐L1 testing and selection of patients for NIV on the basis of test positivity improves cost‐effectiveness compared with DOC.

Acquired vorinostat resistance shows partial cross-resistance to 'second-generation' HDAC inhibitors and correlates with loss of histone acetylation and apoptosis but not with altered HDAC and HAT activities.

Histone deacetylase (HDAC) inhibitors such as vorinostat (suberoylanilide hydroxamic acid), valproic acid, romidepsin (FK-228), and LBH589 comprise a relatively new class of potent anticancer agents. This study provides evidence for the potential of vorinostat to cause acquisition of multidrug resistance protein-independent resistance in HCT116 colon tumor cells. This acquired resistance is moderate (two-fold to three-fold), is nonreversible, and correlates with the loss of responses typically seen with HDAC inhibitors, that is the loss of acetylation of the histones H2A, H2B, H3, and H4, the loss of the G2/M checkpoint activation, and the loss of caspase 3-dependent and caspase 7-dependent apoptosis. This acquired resistance also associates with cross-resistance to the hydroxamate-class (LBH589 and JNJ26481585) and to the aliphatic acid-class (valproic acid) HDAC inhibitors but not to the benzamide-class (MGCD0103) and the cyclic peptide-class (romidepsin) HDAC inhibitors. The acquired HDAC inhibitor resistance described hereis not a result of altered HDAC and histone acetyltransferase activities and differs from that previously reported for romidepsin.

Effect of MRE11 Loss on PARP-Inhibitor Sensitivity in Endometrial Cancer In Vitro

Aim of the study To evaluate the frequency of MRE11/RAD50/NBS1 (MRN)-complex loss of protein expression in endometrial cancers (EC) and to determine whether loss of MRE11 renders the cancer cells sensitive to Poly(ADP-ribose) polymerase (PARP)-inhibitory treatment. Methods MRN expression was examined in 521 samples of endometrial carcinomas and in 10 cancer cell lines. A putative mutation hotspot in the form of an intronic poly(T) allele in MRE11 was sequenced in selected cases (n = 26). Sensitivity to the PARP-inhibitor, BMN673 was tested in colony formation assays before and after MRE11 silencing using siRNA. Homologous recombination (HR) DNA repair was evaluated by RAD51-foci formation assay upon irradiation and drug treatment. Results Loss of MRE11 protein was found in 30.7% of EC tumours and significantly associated with loss of RAD50, NBS1 and mismatch repair protein expression. One endometrial cell line showed a markedly reduced MRE11 expression due to a homozygous poly(T) mutation of MRE11, thereby exhibiting an increased sensitivity to BMN673. MRE11 depletion sensitizes MRE11 expressing EC cell lines to the treatment with BMN673. The increased sensitivity to PARP-inhibition correlates with reduced RAD51 foci formation upon ionizing radiation in MRE11-depleted cells. Conclusion Loss of the MRE11 protein predicts sensitivity to PARP-inhibitor sensitivity in vitro, defining it as an additional synthetic lethal gene with PARP. The high incidence of MRE11 loss in ECs can be potentially exploited for PARP-inhibitor therapy. Furthermore, MRE11 protein expression using immunohistochemistry could be investigated as a predictive biomarker for PARP-inhibitor treatment.