bims-tumhet 2021-10-10 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2021‒10‒10
ten papers selected by
Sergio Marchini
Humanitas Research

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer.
BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer.
PARP inhibitor resistance in ovarian cancer: Underlying mechanisms and therapeutic approaches targeting the ATR/CHK1 pathway.
Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer.
Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition.
Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors.
Immune checkpoint CD155 promoter methylation profiling reveals cancer-associated behaviors within breast neoplasia.
Targeting ARID1A mutations in cancer.
The spatial context of tumor-infiltrating immune cells associates with improved ovarian cancer survival.
Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients.

Target Oncol. 2021 Oct 08.

Olaparib: A Review as First-Line Maintenance Therapy in Advanced Ovarian Cancer.

Julia Paik.

Olaparib (Lynparza®) is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor approved for first-line maintenance treatment in adults with advanced ovarian cancer who are in complete or partial response to first-line, platinum-based chemotherapy. Originally approved as monotherapy, olaparib is also approved to be administered in combination with bevacizumab in patients whose cancer is associated with homologous recombination deficiency (HRD), defined by either a BRCA1/2 mutation and/or genomic instability. In phase III trials, olaparib monotherapy significantly improved progression-free survival (PFS) relative to placebo (SOLO-1), as did olaparib plus bevacizumab relative to placebo plus bevacizumab (PAOLA-1), in patients with advanced ovarian cancer who had responded to platinum-based chemotherapy. In PAOLA-1, improvements in PFS with olaparib plus bevacizumab were not seen in patients with HRD-negative tumours relative to placebo plus bevacizumab. Both olaparib monotherapy and olaparib in combination with bevacizumab had generally manageable tolerability profiles. Olaparib, alone or in combination with bevacizumab, is a useful option for the first-line maintenance treatment of adults with HRD-positive, advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line, platinum-based chemotherapy.

DOI: https://doi.org/10.1007/s11523-021-00842-1
Mol Oncol. 2021 Oct 03.

BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer.

Maha Elazezy, Katharina Prieske, Lan Kluwe, Leticia Oliveira-Ferrer, Sven Peine, Volkmar Müller, Linn Woelber, Barbara Schmalfeldt, Klaus Pantel, Simon A Joosse.

  Methylation of the BRCA1 promoter is an epigenetic gene expression regulator and is frequently observed in ovarian cancer; however, conversion of methylation status is thought to drive disease recurrence. Therefore, longitudinal monitoring of methylation status by liquid biopsy in cell-free DNA (cfDNA) may be a predictive marker. In total, 135 plasma samples were collected from 69 ovarian cancer patients before and during systemic treatment. Our liquid biopsy assay could detect down to a single molecule of methylated DNA in a high background of normal DNA (0.03%) with perfect specificity in control samples. We found that 60% of the cancer patients exhibited BRCA1 promoter hypermethylation at one point, although 24% lost hypermethylation during treatment. Multivariate survival analyses indicate that relapses are independent events and that hypermethylation and methylation conversion are independently correlated to longer relapse-free survival. We present a highly sensitive and specific methylation-specific quantitative-PCR-based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcome.

Keywords:   BRCA1 ; MS-qPCR; ctDNA; liquid biopsy

DOI:  https://doi.org/10.1002/1878-0261.13108
Biochim Biophys Acta Rev Cancer. 2021 Oct 04. pii: S0304-419X(21)00131-1. [Epub ahead of print] 188633

PARP inhibitor resistance in ovarian cancer: Underlying mechanisms and therapeutic approaches targeting the ATR/CHK1 pathway.

Łukasz Biegała, Arkadiusz Gajek, Agnieszka Marczak, Aneta Rogalska.

  Ovarian cancer (OC) constitutes the most common cause of gynecologic cancer-related death in women worldwide. Despite consistent developments in treatment strategies for OC, the management of advanced-stage disease remains a significant challenge. Recent improvements in targeted treatments based on poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have provided invaluable benefits to patients with OC. Unfortunately, numerous patients do not respond to PARPi due to intrinsic resistance or acquisition of resistance. Here, we discuss mechanisms of resistance to PARPi that have specifically emerged in OC including increased drug efflux, restoration of HR repair, re-establishment of replication fork stability, reduced PARP1 trapping, abnormalities in PARP signaling, and less common pathways associated with alternative DNA sensing and repair pathways. Elucidation of the precise mechanisms is essential for the development of novel strategies to re-sensitize OC cells to PARPi agents. Additionally, novel potential concepts for preventing and combating resistance to PARPi under development and relevant clinical reports on treatment strategies have been reviewed, with emphasis on the exploitation of the ATR/CHK1 kinase pathway in sensitization to PARPi to overcome resistance-induced vulnerability in ovarian cancer.

Keywords:  ATR; CHK1; Ovarian cancer; PARP inhibitor; Resistance; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2021.188633
J Ovarian Res. 2021 Oct 06. 14(1): 129

Identification and clinical significance of somatic oncogenic mutations in epithelial ovarian cancer.

Takafumi Watanabe, Hideaki Nanamiya, Yuta Endo, Manabu Kojima, Shinji Nomura, Shigenori Furukawa, Shu Soeda, Hirosumi Tamura, Masae Ryufuku, Daisuke Tanaka, Takao Isogai, Jun-Ichi Imai, Shinya Watanabe, Keiya Fujimori.

  OBJECTIVE: Epithelial ovarian cancer (EOC) is a heterogeneous disease with diverse clinicopathological features and behaviors, and its heterogeneity may be concerned with the accumulation of multiple somatic oncogenic mutations. The major goals of this study are to systematically perform the comprehensive mutational profiling in EOC patients, and investigate the associations between somatic mutations and clinicopathological characteristics.METHODS: A total of 80 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery, and genomic DNAs were extracted from fresh-frozen tissues. We investigated mutational status in hot spot regions of 50 cancer-related genes by targeted next-generation sequencing using an Ion AmpliSeq Cancer Hotspot Panel v2 Kit.
RESULTS: Validated mutations were detected in 66 of the 80 tumors (82.5%). The five most frequently mutated genes were TP53 (43.8%), PIK3CA (27.5%), KRAS (23.8%), PTEN (10%) and CTNNB1 (10%). PTEN and CTNNB1 mutations were associated with younger age. PIK3CA1, KRAS and CTNNB1 mutations were observed in early-stage, whereas TP53 mutations were more common in advanced stage. Significant associations were observed between TP53 mutation and serous carcinoma, and between KRAS mutation and mucinous carcinoma. Both PIK3CA mutation and CTNNB1 mutation were also significantly associated with endometrioid and clear cell carcinoma. The patients with PIK3CA and KRAS mutations were significantly associated with favorable progression free survival (PFS). In particular, PIK3CA mutations had more significant associations with favorable PFS than PIK3CA wild-type in the endometrioid subtype (P = 0.012). Patients with mutations only in TP53 were significantly associated with worse PFS.
CONCLUSION: EOCs were heterogeneous at the genomic level and harbored somatic oncogenic mutations. Our molecular profiling may have the potential for becoming a novel stratification within histological subtypes of EOC. Further studies are needed to define molecular classification for improved clinical outcomes and treatment of EOC patients in future.

Keywords:  Epithelial ovarian cancer; Molecular profiling; Prognostic biomarker; Somatic oncogenic mutations

DOI:  https://doi.org/10.1186/s13048-021-00876-z
Front Oncol. 2021 ;11 733700

Targeting DNA Homologous Repair Proficiency With Concomitant Topoisomerase II and c-Abl Inhibition.

Arafat Siddiqui, Manuela Tumiati, Alia Joko, Jouko Sandholm, Pia Roering, Sofia Aakko, Reetta Vainionpää, Katja Kaipio, Kaisa Huhtinen, Liisa Kauppi, Johanna Tuomela, Sakari Hietanen.

  Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which, if not repaired, are detrimental to the cell. This repair process requires high-fidelity functional homologous recombination (HR) or error-prone non-homologous end joining (NHEJ). If either of these pathways is defective, a compensatory pathway may rescue the cells and induce treatment resistance. Consistently, HR proficiency, either inherent or acquired during the course of the disease, enables tumor cells competent to repair the DNA damage, which is a major problem for chemotherapy in general. In this context, c-Abl is a protein tyrosine kinase that is involved in DNA damage-induced stress. We used a low-dose topoisomerase II inhibitor mitoxantrone to induce DNA damage which caused a transient cell cycle delay but allowed eventual passage through this checkpoint in most cells. We show that the percentage of HR and NHEJ efficient HeLa cells decreased more than 50% by combining c-Abl inhibitor imatinib with mitoxantrone. This inhibition of DNA repair caused more than 87% of cells in G2/M arrest and a significant increase in apoptosis. To validate the effect of the combination treatment, we tested it on commercial and patient-derived cell lines in high-grade serous ovarian cancer (HGSOC), where chemotherapy resistance correlates with HR proficiency and is a major clinical problem. Results obtained with HR-proficient and deficient HGSOC cell lines show a 50-85% increase of sensitivity by the combination treatment. Our data raise the possibility of successful targeting of treatment-resistant HR-proficient cancers.

Keywords:  DNA repair; c-Abl; cell cycle arrest; imatinib; mitoxantrone

DOI:  https://doi.org/10.3389/fonc.2021.733700
BMC Cancer. 2021 Oct 09. 21(1): 1089

Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors.

Maria Moksnes Bjaanæs, Gro Nilsen, Ann Rita Halvorsen, Hege G Russnes, Steinar Solberg, Lars Jørgensen, Odd Terje Brustugun, Ole Christian Lingjærde, Åslaug Helland.

  BACKGROUND: Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes.METHODS: Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, and regional copy number aberration were subsequently obtained and analyzed jointly with the gene expression data.
RESULTS: The NSCLC tumors tissue displayed overall complex DNA copy number profiles with numerous recurrent aberrations. Despite histological differences, tissue samples from squamous cell carcinomas and adenocarcinomas had remarkably similar copy number patterns. The TP53-mutated lung adenocarcinomas displayed a highly aberrant genome, with significantly altered copy number profiles including gains, losses and focal complex events. The EGFR-mutant lung adenocarcinomas had specific arm-wise aberrations particularly at chromosome7p and 9q. A large number of genes displayed correlation between copy number and expression level, and the PI(3)K-mTOR pathway was highly enriched for such genes.
CONCLUSIONS: The genomic architecture in NSCLC tumors is complex, and particularly TP53-mutated lung adenocarcinomas displayed highly aberrant copy number profiles. We suggest to always include TP53-mutation status when studying copy number aberrations in NSCLC tumors. Copy number may further impact gene expression and alter cellular signaling pathways.

Keywords:  Copy number; Lung cancer; NSCLC; mTOR; p53

DOI:  https://doi.org/10.1186/s12885-021-08811-7
Cancer Immunol Immunother. 2021 Oct 04.

Immune checkpoint CD155 promoter methylation profiling reveals cancer-associated behaviors within breast neoplasia.

Hana Triki, Ken Declerck, Slim Charfi, Wala Ben Kridis, Kais Chaabane, Sawssan Ben Halima, Tahya Sellami, Ahmed Rebai, Wim Vanden Berghe, Boutheina Cherif.

  BACKGROUND: CD155 immune checkpoint has recently emerged as a compelling immunotherapeutic target. Epigenetic DNA methylation changes are recognized as key molecular mechanisms in cancer development. Hence, the identification of methylation markers that are sensitive and specific for breast cancer may improve early detection and predict prognosis. We speculate that CD155 promoter methylation can be a valuable epigenetic biomarker, based upon strong indications for its immunoregulatory functions.METHODS: Methylation analyses were conducted on 14 CpGs sites in the CD155 promoter region by bisulfite pyrosequencing. To elucidate the related gene expression changes, a transcriptional study using RT-qPCR was performed. Statistical analyses were performed to evaluate correlations of CD155 methylation profiles with mRNA expression together with clinical-pathological features, prognosis and immune infiltrate.
RESULTS: CD155 promoter methylation profile was significantly associated with SBR grade, tumor size, molecular subgroups, HER2 and hormonal receptors expression status. Low CD155 methylation rates correlated with better prognosis in univariate cox proportional hazard analysis and appeared as an independent survival predictor in cox-regression multivariate analysis. Further, methylation changes at CD155 specific CpG sites were consistent with CD155 membranous mRNA isoform expression status. Statistical analyses also showed a significant association with immune Natural Killer cell infiltrate when looking at the CpG7, CpG8, CpG9 and CpG11 sites.
CONCLUSION: Altogether, our results contribute to a better understanding of the impact of CD155 immune checkpoint modality expression in breast tumors, revealing for the first time that specific CpG sites from CD155 promoter may be a potential biomarker in breast cancer monitoring.

Keywords:  Breast cancer; CD155; DNA methylation; Immune checkpoint; mRNA expression

DOI:  https://doi.org/10.1007/s00262-021-03064-6
Cancer Treat Rev. 2021 Sep 06. pii: S0305-7372(21)00135-3. [Epub ahead of print]100 102287

Targeting ARID1A mutations in cancer.

Jaren Mullen, Shumei Kato, Jason K Sicklick, Razelle Kurzrock.

  Genes encoding SWI/SNF chromatin remodeling complex subunits are collectively mutated in approximately 20% of human cancers. ARID1A is a SWI/SNF subunit gene whose protein product binds DNA. ARID1A gene alterations result in loss of function. It is the most commonly mutated member of the SWI/SNF complex, being aberrant in ∼6% of cancers overall, including ovarian clear cell cancers (∼45% of patients) and uterine endometrioid cancers (∼37%). ARID1A has a crucial role in regulating gene expression that drives oncogenesis or tumor suppression. In particular, ARID1A participates in control of the PI3K/AKT/mTOR pathway, immune responsiveness to cancer, EZH2 methyltransferase activity, steroid receptor modulation, DNA damage checkpoints, and regulation of p53 targets and KRAS signaling. A variety of compounds may be of benefit in ARID1A-altered cancers: immune checkpoint blockade, and inhibitors of mTOR, EZH2, histone deacetylases, ATR and/or PARP. ARID1A alterations may also mediate resistance to platinum chemotherapy and estrogen receptor degraders/modulators.

Keywords:  ARID1A; Chromatin remodeling; SWI/SNF

DOI:  https://doi.org/10.1016/j.ctrv.2021.102287
Mol Cancer Res. 2021 Oct 06. pii: molcanres.0411.2021. [Epub ahead of print]

The spatial context of tumor-infiltrating immune cells associates with improved ovarian cancer survival.

Benjamin Steinhart, Kimberly R Jordan, Jaidev Bapat, Miriam D Post, Lindsay W Brubaker, Benjamin G Bitler, Julia Wrobel.

Ovarian cancer is the deadliest gynecological malignancy. Multi-omics techniques have provided a platform for improved predictive modeling of therapy response and patient outcomes. While high-grade serous carcinoma (HGSOC) tumors are immunogenic and numerous studies have defined positive correlation to immune cell infiltration, immunotherapies in clinical trials have exhibited low efficacy rates. There is a significant need to better comprehend the role and composition of immune cells in mediating ovarian cancer therapeutic response and progression. We performed multiplex immunohistochemistry with an HGSOC tissue microarray (n=127) to characterize the immune cell composition within tumors. After analyzing the composition and spatial context of T cells (CD4/CD8), macrophages (CD68), and B cells (CD19) within the tumor, we found that increased B cell and CD4 T cell presence correlated with overall survival. More importantly, we observed that the proximity between tumor-associated macrophages and B cells or CD4 T cells significantly correlated with overall survival. Implications: The results highlight the anti-tumor role of B cells and CD4 T cells, and that the spatial interactions between immune cell types are a novel predictor of therapeutic response and patient outcomes.

DOI: https://doi.org/10.1158/1541-7786.MCR-21-0411
Front Pharmacol. 2021 ;12 711813

Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients.

Dominique Berton, Anne Floquet, Willy Lescaut, Gabriel Baron, Marie-Christine Kaminsky, Philippe Toussaint, Rémy Largillier, Aude-Marie Savoye, Jérôme Alexandre, Catherine Delbaldo, Emmanuelle Malaurie, Hugues Barletta, Claire Bosacki, Claire Garnier-Tixidre, Philippe Follana, Hortense Laharie-Mineur, Charles Briac Levache, Bruno Valenza, Agnès Dechartres, Delphine Mollon-Grange, Frédéric Selle.

  Introduction: Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB-IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting. Patients and Methods: Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease. Results: Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0-28, interquartile range 6.9-14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4-19.1) months. The 3-year overall survival rate was 62% (95% CI, 58-67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin. Discussion: Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule. Clinical Trial Registration:ClinicalTrials.gov, Identifier NCT01832415.

Keywords:  bevacizumab; monitoring; ovarian cancer; progression-free survival; routine clinical practice

DOI:  https://doi.org/10.3389/fphar.2021.711813