bims-ovdlit 2021-12-26 papers

Issue of 2021–12–26
six papers selected by
Lara Paracchini, Humanitas Research

Diagnostics (Basel). 2021 Nov 23. pii: 2171. [Epub ahead of print]11(12):

Can Circulating Tumor DNA Support a Successful Screening Test for Early Cancer Detection? The Grail Paradigm.

Oscar D Pons-Belda, Amaia Fernandez-Uriarte, Eleftherios P Diamandis.

Circulating tumor DNA (ctDNA) is a new pan-cancer tumor marker with important applications for patient prognosis, monitoring progression, and assessing the success of the therapeutic response. Another important goal is an early cancer diagnosis. There is currently a debate if ctDNA can be used for early cancer detection due to the small tumor burden and low mutant allele fraction (MAF). We compare our previous calculations on the size of detectable cancers by ctDNA analysis with the latest experimental data from Grail's clinical trial. Current ctDNA-based diagnostic methods could predictably detect tumors of sizes greater than 10-15 mm in diameter. When tumors are of this size or smaller, their MAF is about 0.01% (one tumor DNA molecule admixed with 10,000 normal DNA molecules). The use of 10 mL of blood (4 mL of plasma) will likely contain less than a complete cancer genome, thus rendering the diagnosis of cancer impossible. Grail's new data confirm the low sensitivity for early cancer detection (<30% for Stage I-II tumors, <20% for Stage I tumors), but specificity was high at 99.5%. According to these latest data, the sensitivity of the Grail test is less than 20% in Stage I disease, casting doubt if this test could become a viable pan-cancer clinical screening tool.

Keywords: cancer screening; circulating tumor DNA; clonal hematopoiesis; early cancer detection; liquid biopsy; molecular analysis; positive predictive value

DOI: https://doi.org/10.3390/diagnostics11122171

Eur J Cancer. 2021 Dec 15. pii: S0959-8049(21)01214-4. [Epub ahead of print]161 55-63

Validation of MiROvaR, a microRNA-based predictor of early relapse in early stage epithelial ovarian cancer as a new strategy to optimise patients' prognostic assessment.

Antonino Ditto, Loris De Cecco, Biagio Paolini, Paola Alberti, Fabio Martinelli, Umberto Leone Roberti Maggiore, Giorgio Bogani, Paolo Chiodini, Sandro Pignata, Antonella Tomassetti, Francesco Raspagliesi, Delia Mezzanzanica, Marina Bagnoli.

AIM: Early-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting.
METHODS: We retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis.
RESULTS: MiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan-Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82-16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53-0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04-6.8, p = 0.041; AUC:0.68, 95%CI:0.52-0.82).
CONCLUSIONS: We validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

Keywords: Early-stage ovarian cancer; Prognosis; microRNA signature

DOI: https://doi.org/10.1016/j.ejca.2021.11.003

Gynecol Oncol. 2021 Dec 21. pii: S0090-8258(21)01673-5. [Epub ahead of print]

Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.

OBJECTIVES: Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status.
METHODS: Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status.
RESULTS: Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher-risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates).
CONCLUSIONS: In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRD-positive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone.

Keywords: (max 6): Olaparib; Bevacizumab; Clinical risk; Newly diagnosed; Ovarian cancer

DOI: https://doi.org/10.1016/j.ygyno.2021.12.016

Cancers (Basel). 2021 Dec 11. pii: 6231. [Epub ahead of print]13(24):

Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment.

Racheal Louise Johnson, Michele Cummings, Amudha Thangavelu, Georgios Theophilou, Diederick de Jong, Nicolas Michel Orsi.

A lack of explicit early clinical signs and effective screening measures mean that ovarian cancer (OC) often presents as advanced, incurable disease. While conventional treatment combines maximal cytoreductive surgery and platinum-based chemotherapy, patients frequently develop chemoresistance and disease recurrence. The clinical application of immune checkpoint blockade (ICB) aims to restore anti-cancer T-cell function in the tumour microenvironment (TME). Disappointingly, even though tumour infiltrating lymphocytes are associated with superior survival in OC, ICB has offered limited therapeutic benefits. Herein, we discuss specific TME features that prevent ICB from reaching its full potential, focussing in particular on the challenges created by immune, genomic and metabolic alterations. We explore both recent and current therapeutic strategies aiming to overcome these hurdles, including the synergistic effect of combination treatments with immune-based strategies and review the status quo of current clinical trials aiming to maximise the success of immunotherapy in OC.

Keywords: adaptive; genomic; immunotherapy; innate; metabolism; ovarian cancer; resistance; tumour microenvironment

DOI: https://doi.org/10.3390/cancers13246231

J Clin Med. 2021 Dec 17. pii: 5919. [Epub ahead of print]10(24):

Ovarian Cancer: Latest Advances and Prospects.

Ludivine Dion, Vincent Lavoué.

The landscape of ovarian cancer therapeutics is experiencing an increase in new opportunities [...].

DOI: https://doi.org/10.3390/jcm10245919

J Clin Med. 2021 Dec 17. pii: 5927. [Epub ahead of print]10(24):

The Uncertain Benefit of Adjuvant Chemotherapy in Advanced Low-Grade Serous Ovarian Cancer and the Pivotal Role of Surgical Cytoreduction.

Racheal Louise Johnson, Alexandros Laios, David Jackson, David Nugent, Nicolas Michel Orsi, Georgios Theophilou, Amudha Thangavelu, Diederick de Jong.

In our center, adjuvant chemotherapy is routinely offered in high-grade serous ovarian cancer (HGSOC) patients but less commonly as a standard treatment in low-grade serous ovarian cancer (LGSOC) patients. This study evaluates the efficacy of this paradigm by analysing survival outcomes and by comparing the influence of different clinical and surgical characteristics between women with advanced LGSOC (n = 37) and advanced HGSOC (n = 300). Multivariate analysis was used to identify independent prognostic features for survival in LGSOC and HGSOC. Adjuvant chemotherapy was given in 99.7% of HGSOC patients versus in 27% of LGSOC (p < 0.0001). The LGSOC patients had greater surgical complexity scores (p < 0.0001), more frequent postoperative ICU/HDU admissions (p = 0.0002), and higher peri-/post-operative morbidity (p < 0.0001) compared to the HGSOC patients. The 5-year OS and progression-free survival (PFS) was 30% and 13% for HGSOC versus 57% and 21.6% for LGSOC, p = 0.016 and p = 0.044, respectively. Surgical complexity (HR 5.3, 95%CI 1.2-22.8, p = 0.024) and complete cytoreduction (HR 62.4, 95% CI 6.8-567.9, p < 0.001) were independent prognostic features for OS in LGSOC. This study demonstrates no clear significant survival advantage of chemotherapy in LGSOC. It highlights the substantial survival benefit of dynamic multi-visceral surgery to achieve complete cytoreduction as the primary treatment for LGSOC patients.

Keywords: cytoreduction; high-grade serous ovarian cancer (HGSOC); low-grade serous ovarian cancer (LGSOC); surgical complexity; survival

DOI: https://doi.org/10.3390/jcm10245927