bims-ovdlit 2021-08-22 papers

Front Oncol. 2021 ;11 697952

Beyond BRCA Status: Clinical Biomarkers May Predict Therapeutic Effects of Olaparib in Platinum-Sensitive Ovarian Cancer Recurrence.

Kazuho Nakanishi, Takashi Yamada, Gen Ishikawa, Shunji Suzuki.

The purpose of this study was to investigate the predictors of the effect of olaparib on platinum-sensitive recurrent ovarian cancer with unknown germline BRCA mutations. We retrospectively examined 20 patients with platinum-sensitive ovarian cancer who were treated at the Nippon Medical School Chiba Hokusoh Hospital, Japan, from 2018 to 2020. We found that the median progression-free survival was 11.4 months (95% Confidence interval (CI): 3.8-Not Available (NA)) in the group with NLPN score [recurrent neutrophil-lymphocyte ratio (rNLR) × number of previous regimens] >7.51, and median progression-free survival was not reached in the group with NLPN score <7.51 (95% CI: 21.8-NA) (p = 0.0185). There was a clear correlation between the degree of dose reduction of olaparib and recurrence (p = 0.00249). Our results show that NLPN scores lower than 7.51 are associated with a favorable outcome of olaparib treatment for platinum-sensitive recurrent ovarian cancer. In cases with a high rNLR, it may be necessary to start olaparib treatment as early as possible to obtain low NLPN scores. Our results imply that the effectiveness of olaparib can be determined after recurrence and before platinum treatment begins. As newer drugs for ovarian cancer are developed, the measurement of biomarker levels at the start of treatment for recurrent ovarian cancer, as shown in our study, may provide strong support for cancer treatment protocols.

Keywords: BRCA mutations; neutrophil-lymphocyte ratio; olaparib; ovarian cancer; systemic inflammation index

DOI: https://doi.org/10.3389/fonc.2021.697952

Gynecol Oncol. 2021 Aug 11. pii: S0090-8258(21)00647-8. [Epub ahead of print]

PARP inhibitor maintenance for primary ovarian cancer - A missed opportunity for precision medicine.

Stephanie L Wethington, Andrea E Wahner-Hendrickson, Elizabeth M Swisher, Scott H Kaufmann, Beth Y Karlan, Amanda Nickles Fader, Sean C Dowdy.

DOI: https://doi.org/10.1016/j.ygyno.2021.08.002

Nat Commun. 2021 Aug 20. 12(1): 5060

Detection and characterization of lung cancer using cell-free DNA fragmentomes.

Non-invasive approaches for cell-free DNA (cfDNA) assessment provide an opportunity for cancer detection and intervention. Here, we use a machine learning model for detecting tumor-derived cfDNA through genome-wide analyses of cfDNA fragmentation in a prospective study of 365 individuals at risk for lung cancer. We validate the cancer detection model using an independent cohort of 385 non-cancer individuals and 46 lung cancer patients. Combining fragmentation features, clinical risk factors, and CEA levels, followed by CT imaging, detected 94% of patients with cancer across stages and subtypes, including 91% of stage I/II and 96% of stage III/IV, at 80% specificity. Genome-wide fragmentation profiles across ~13,000 ASCL1 transcription factor binding sites distinguished individuals with small cell lung cancer from those with non-small cell lung cancer with high accuracy (AUC = 0.98). A higher fragmentation score represented an independent prognostic indicator of survival. This approach provides a facile avenue for non-invasive detection of lung cancer.

DOI: https://doi.org/10.1038/s41467-021-24994-w

Nat Commun. 2021 08 18. 12(1): 5016

RNF168-mediated localization of BARD1 recruits the BRCA1-PALB2 complex to DNA damage.

John J Krais, Yifan Wang, Pooja Patel, Jayati Basu, Andrea J Bernhardy, Neil Johnson.

DNA damage prompts a diverse range of alterations to the chromatin landscape. The RNF168 E3 ubiquitin ligase catalyzes the mono-ubiquitination of histone H2A at lysine (K)13/15 (mUb-H2A), forming a binding module for DNA repair proteins. BRCA1 promotes homologous recombination (HR), in part, through its interaction with PALB2, and the formation of a larger BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex. The mechanism by which BRCA1-P is recruited to chromatin surrounding DNA breaks is unclear. In this study, we reveal that an RNF168-governed signaling pathway is responsible for localizing the BRCA1-P complex to DNA damage. Using mice harboring a Brca1CC (coiled coil) mutation that blocks the Brca1-Palb2 interaction, we uncovered an epistatic relationship between Rnf168- and Brca1CC alleles, which disrupted development, and reduced the efficiency of Palb2-Rad51 localization. Mechanistically, we show that RNF168-generated mUb-H2A recruits BARD1 through a BRCT domain ubiquitin-dependent recruitment motif (BUDR). Subsequently, BARD1-BRCA1 accumulate PALB2-RAD51 at DNA breaks via the CC domain-mediated BRCA1-PALB2 interaction. Together, these findings establish a series of molecular interactions that connect the DNA damage signaling and HR repair machinery.

DOI: https://doi.org/10.1038/s41467-021-25346-4