bims-ovdlit 2021-03-21 papers

Issue of 2021–03–21
seven papers selected by
Lara Paracchini, Humanitas Research

Gynecol Oncol Rep. 2021 May;36 100729

Can TP53 variant negative be high-grade serous ovarian carcinoma? A case series.

Lawrence Kasherman, Swati Garg, Nairi Tchrakian, Blaise Clarke, Katherine Karakasis, Raymond H Kim, Tracy L Stockley, Neesha Dhani, Amit M Oza, Stephanie Lheureux.

•TP53 variant negative high-grade serous ovarian cancer is rare and can still show p53 abnormal immunohistochemistry.•Diagnostic and therapeutic considerations include pathologic, molecular and clinical domains.•Genetic reassessment through more comprehensive assays should be considered to ensure no missed rare or complex variants.•Presence of BRCA mutations can occur in TP53 variant high-grade serous ovarian cancer.

Keywords: Diagnosis; High grade serous ovarian cancer; Next generation sequencing; P53 immunohistochemistry; TP53 variant negative

DOI: https://doi.org/10.1016/j.gore.2021.100729

Clin Adv Hematol Oncol. 2021 Mar;19(3): 155-161

Circulating tumor DNA in early-stage breast cancer: new directions and potential clinical applications.

Sarah Croessmann, Ben Ho Park.

The use of circulating tumor DNA (ctDNA) in liquid biopsy as a biomarker is becoming the new paradigm for the screening and surveillance of breast and many other cancers. Liquid biopsies provide prognostic and predictive information without the limitations of tissue biopsies. Most early studies of the use of ctDNA focused on metastatic disease. However, recent advancements in ctDNA technologies have improved sensitivity and selectivity, allowing ctDNA to be detected in early-stage disease, including early-stage breast cancer. Despite a clear potential for utility, the implementation of ctDNA liquid biopsy in standard of care is significantly lacking. Researchers and clinicians are currently working to validate the clinical utility of ctDNA in diagnostics, prognostics, the surveillance of minimal residual disease, and the monitoring of therapeutic response. This review summarizes the current applications of ctDNA in early-stage breast cancer and discusses its potential uses in clinical practice.

Cancer. 2021 Mar 19.

Molecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: A meta-analysis.

Gynecologic Cancer Intergroup Meta-Analysis Committee

BACKGROUND: The authors performed a meta-analysis to better quantify the benefit of maintenance poly(ADP-ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum-sensitive, recurrent, high-grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild-type BRCA but homologous recombinant-deficient (HRD), homologous recombinant-proficient (HRP), and baseline clinical prognostic characteristics.
METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression-free survival were pooled across trials using the inverse variance weighted method.
RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23-0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17-0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12-0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild-type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31-0.56); and, in those who had wild-type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49-0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab.
CONCLUSIONS: In platinum-sensitive, recurrent, high-grade ovarian cancer, maintenance PARPi improves progression-free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy.

Keywords: BRCA mutation; homologous recombination deficiency; meta-analysis; platinum-sensitive recurrent ovarian cancer; poly(ADP-ribose) polymerase inhibitors

DOI: https://doi.org/10.1002/cncr.33517

Sci Rep. 2021 Mar 16. 11(1): 6068

Single-copy detection of somatic variants from solid and liquid biopsy.

Ana-Luisa Silva, Paulina Klaudyna Powalowska, Magdalena Stolarek, Eleanor Ruth Gray, Rebecca Natalie Palmer, Bram Herman, Cameron Alexander Frayling, Barnaby William Balmforth.

Accurate detection of somatic variants, against a background of wild-type molecules, is essential for clinical decision making in oncology. Existing approaches, such as allele-specific real-time PCR, are typically limited to a single target gene and lack sensitivity. Alternatively, next-generation sequencing methods suffer from slow turnaround time, high costs, and are complex to implement, typically limiting them to single-site use. Here, we report a method, which we term Allele-Specific PYrophosphorolysis Reaction (ASPYRE), for high sensitivity detection of panels of somatic variants. ASPYRE has a simple workflow and is compatible with standard molecular biology reagents and real-time PCR instruments. We show that ASPYRE has single molecule sensitivity and is tolerant of DNA extracted from plasma and formalin fixed paraffin embedded (FFPE) samples. We also demonstrate two multiplex panels, including one for detection of 47 EGFR variants. ASPYRE presents an effective and accessible method that simplifies highly sensitive and multiplexed detection of somatic variants.

DOI: https://doi.org/10.1038/s41598-021-85545-3

Front Oncol. 2021 ;11 601512

c-MYC and Epithelial Ovarian Cancer.

Jeyshka M Reyes-González, Pablo E Vivas-Mejía.

Ovarian cancer is the deadliest of gynecological malignancies with approximately 49% of women surviving 5 years after initial diagnosis. The standard of care for ovarian cancer consists of cytoreductive surgery followed by platinum-based combination chemotherapy. Unfortunately, despite initial response, platinum resistance remains a major clinical challenge. Therefore, the identification of effective biomarkers and therapeutic targets is crucial to guide therapy regimen, maximize clinical benefit, and improve patient outcome. Given the pivotal role of c-MYC deregulation in most tumor types, including ovarian cancer, assessment of c-MYC biological and clinical relevance is essential. Here, we briefly describe the frequency of c-MYC deregulation in ovarian cancer and the consequences of its targeting.

Keywords: MYC; biomarkers; ovarian cancer; targeted therapies; undruggable oncogenes

DOI: https://doi.org/10.3389/fonc.2021.601512

Cancer Res. 2021 Mar 16. pii: canres.2123.2020. [Epub ahead of print]

Single-cell RNA sequencing reveals the cellular origin and evolution of breast cancer in BRCA1 mutation carriers.

Li Hu, Liming Su, Hainan Cheng, Chunling Mo, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin, Jianguang Zhang, Yuntao Xie.

The cell of origin and the development of breast cancer are not fully elucidated in BRCA1 mutation carriers, especially for estrogen receptor (ER)-positive breast cancers. Here, we performed single-cell RNA sequencing on 82,122 cells isolated from the breast cancer tissues and adjacent or prophylactic normal breast tissues from four BRCA1 mutation carriers and three non-carriers. Whole-exome sequencing was performed on breast tumors from the four BRCA1 mutation carriers; for validation, bulk RNA sequencing was performed on adjacent normal breast tissues from eight additional BRCA1 mutation carriers and fourteen non-carriers. Correlation analyses suggested that breast cancers in BRCA1 mutation carriers might originate from luminal cells. The aberrant luminal progenitor cells with impaired differentiation were significantly increased in normal breast tissues in BRCA1 mutation carriers compared with non-carriers. These observations were further validated by the bulk RNA sequencing data from additional BRCA1 mutation carriers. These data suggest that the cell of origin of basal-like breast tumors (ERneg) in BRCA1 mutation carriers might be luminal progenitor cells. The expression of TP53 and BRCA1 was decreased in luminal progenitor cells from normal breast tissue in BRCA1 mutation carriers, which might trigger the basal/mesenchymal transition of luminal progenitors and might result in basal-like tumor development. Furthermore, ERhigh luminal tumors might originate from mature luminal cells. Our study provides in-depth evidence regarding the cells of origin of different breast cancer subtypes in BRCA1 mutation carriers.

DOI: https://doi.org/10.1158/0008-5472.CAN-20-2123

Target Oncol. 2021 Mar 18.

Liquid Biopsy for Prognosis and Treatment in Metastatic Colorectal Cancer: Circulating Tumor Cells vs Circulating Tumor DNA.

Giorgio Patelli, Caterina Vaghi, Federica Tosi, Gianluca Mauri, Alessio Amatu, Daniela Massihnia, Silvia Ghezzi, Erica Bonazzina, Katia Bencardino, Giulio Cerea, Salvatore Siena, Andrea Sartore-Bianchi.

Liquid biopsy recently gained widespread attention as a noninvasive alternative/complementary technique to tissue biopsy in patients with cancer. As technological advances have improved both feasibility and turnaround time, liquid biopsy has expanded tumor molecular analysis with acknowledgement of both spatial and temporal heterogeneity, overcoming many limitations of traditional tissue biopsy. Because of its diagnostic, prognostic, and predictive value, liquid biopsy has been extensively studied also in metastatic colorectal cancer. Indeed, as personalized medicine establishes its role in cancer treatment, genetic biomarkers unveiling the emergence of early resistance are needed. Among the wide variety of tumor analytes amenable to collection, circulating DNA and circulating tumor cells are the most adopted approaches, and both carry clinical relevance in colorectal cancer. However, few studies focused on comparing feasibility between these two approaches. In this review, we discuss the potential implications of liquid biopsy in metastatic colorectal cancer, assessing the advantages and drawbacks of circulating DNA and circulating tumor cells, and highlighting the most relevant trials for clinical practice.

DOI: https://doi.org/10.1007/s11523-021-00795-5