bims-ovdlit 2023-05-28 papers

Issue of 2023–05–28
seven papers selected by
Lara Paracchini, Humanitas Research

Ann Oncol. 2023 May 19. pii: S0923-7534(23)00686-5. [Epub ahead of print]

Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial.

PAOLA-1/ENGOT-ov25 investigators

BACKGROUND: In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.
PATIENTS AND METHODS: Patients were randomized 2:1 to olaparib (300 mg bid; up to 24 months) plus bevacizumab (15 mg/kg q3w; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.
RESULTS: After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the ITT (hazard ratio [HR]=0.92, 95% CI 0.76-1.12; P=0.4118). Subsequent poly(ADP-ribose) polymerase (PARP) inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR=0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR=0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.
CONCLUSIONS: Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving PARP inhibitors post-progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.

Keywords: advanced ovarian cancer; bevacizumab; olaparib; overall survival

DOI: https://doi.org/10.1016/j.annonc.2023.05.005

Cell Rep Med. 2023 May 16. pii: S2666-3791(23)00169-6. [Epub ahead of print] 101055

Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Paula Cunnea, Edward W Curry, Elizabeth L Christie, Katherine Nixon, Chun Hei Kwok, Ahwan Pandey, Ratri Wulandari, Kerstin Thol, Jennifer Ploski, Cristina Morera-Albert, Stephen McQuaid, Jingky Lozano-Kuehne, James J Clark, Jonathan Krell, Euan A Stronach, Iain A McNeish, David D L Bowtell, Christina Fotopoulou.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.

Keywords: Cyclin E1; HRD; cytoreductive surgery; high-grade serous ovarian cancer; homologous recombination deficiency score; spatial and temporal heterogeneity; tumor evolution

DOI: https://doi.org/10.1016/j.xcrm.2023.101055

Int J Cancer. 2023 May 25.

Characterization of ovarian cancer survival by histotype and stage: A nationwide study in Norway.

Renée Turzanski Fortner, Cassia B Trewin-Nybråten, Torbjørn Paulsen, Hilde Langseth.

Contemporary population-based data on ovarian cancer survival using current subtype classifications and by surgical status are sparse. We evaluated 1-, 3-, 5- and 7-year relative (and overall) survival, and excess hazards in patients with borderline tumors or invasive epithelial ovarian cancer diagnosed 2012 to 2021 in a nationwide registry-based cohort in Norway. Outcomes were evaluated by histotype, FIGO stage, cytoreduction surgery and residual disease. Overall survival was evaluated for non-epithelial ovarian cancer. Survival of women with borderline ovarian tumors was excellent (≥98.0% 7-year relative survival). Across all evaluated invasive epithelial ovarian cancer histotypes, 7-year relative survival for cases diagnosed with stages I or II disease was ≥78.3% (stage II high-grade serous). Survival for ovarian cancers diagnosed at stage ≥III differed substantially by histotype and time since diagnosis (eg, stage III, 5-year relative survival from 27.7% [carcinosarcomas] to 76.2% [endometrioid]). Overall survival for non-epithelial cases was good (91.8% 5-year overall survival). Women diagnosed with stage III or IV invasive epithelial ovarian cancer and with residual disease following cytoreduction surgery had substantially better survival than women not operated. These findings were robust to restriction to women with high reported functional status scores. Patterns for overall survival were similar to those for relative survival. We observed relatively good survival with early stage at diagnosis even for the high grade serous histotype. Survival for patients diagnosed at stage ≥III invasive epithelial ovarian cancer was poor for all but endometrioid disease. There remains an urgent need for strategies for risk reduction and earlier detection, together with effective targeted treatments.

Keywords: cytoreduction surgery; histotype; ovarian cancer; stage; survival

DOI: https://doi.org/10.1002/ijc.34576

Diagnostics (Basel). 2023 May 09. pii: 1665. [Epub ahead of print]13(10):

Evaluating Pre-Analytical Variables for Saliva Cell-Free DNA Liquid Biopsy.

Blake Salfer, Daisy Havo, Skyllar Kuppinger, David T W Wong, Feng Li, Liying Zhang.

Liquid biopsy utilizing cell-free DNA (cfDNA) has become an emergent field of study for cancer screening and monitoring. While blood-based liquid biopsy has been investigated extensively, there are advantages to using other body fluids. Using saliva is noninvasive, repeatable, and it may be enriched with cfDNA from certain cancer types. However, the lack of standardization in the pre-analytical phase of saliva-based testing is a concern. In this study, we evaluated pre-analytical variables that impact cfDNA stability in saliva specimens. Using saliva from healthy individuals, we tested different collection devices and preservatives and their effects on saliva cfDNA recovery and stability. Novosanis's UAS preservative helped stabilize cfDNA at room temperature for up to one week. Our study provides useful information for further improvements in saliva collection devices and preservatives.

Keywords: biomarkers; body fluids; cell-free nucleic acids; circulating tumor DNA; neoplasms; pre-analytical phase

DOI: https://doi.org/10.3390/diagnostics13101665

Biology (Basel). 2023 Apr 28. pii: 671. [Epub ahead of print]12(5):

Chromosomal Instability in Genome Evolution: From Cancer to Macroevolution.

Valentine Comaills, Maikel Castellano-Pozo.

The integrity of the genome is crucial for the survival of all living organisms. However, genomes need to adapt to survive certain pressures, and for this purpose use several mechanisms to diversify. Chromosomal instability (CIN) is one of the main mechanisms leading to the creation of genomic heterogeneity by altering the number of chromosomes and changing their structures. In this review, we will discuss the different chromosomal patterns and changes observed in speciation, in evolutional biology as well as during tumor progression. By nature, the human genome shows an induction of diversity during gametogenesis but as well during tumorigenesis that can conclude in drastic changes such as the whole genome doubling to more discrete changes as the complex chromosomal rearrangement chromothripsis. More importantly, changes observed during speciation are strikingly similar to the genomic evolution observed during tumor progression and resistance to therapy. The different origins of CIN will be treated as the importance of double-strand breaks (DSBs) or the consequences of micronuclei. We will also explain the mechanisms behind the controlled DSBs, and recombination of homologous chromosomes observed during meiosis, to explain how errors lead to similar patterns observed during tumorigenesis. Then, we will also list several diseases associated with CIN, resulting in fertility issues, miscarriage, rare genetic diseases, and cancer. Understanding better chromosomal instability as a whole is primordial for the understanding of mechanisms leading to tumor progression.

Keywords: cancer; chromosomal instability; genome evolution; meiosis; micronuclei; speciation; structural variant

DOI: https://doi.org/10.3390/biology12050671