bims-ovdlit 2023-01-01 papers

Issue of 2023–01–01
three papers selected by
Lara Paracchini, Humanitas Research

Cancer. 2022 Dec 26.

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study.

AOCS Group

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.
METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.
RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.
CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Keywords: CCNE1 amplification; cyclin E1 expression; high-grade serous carcinoma; ovarian cancer; prognosis

DOI: https://doi.org/10.1002/cncr.34582

Ther Adv Med Oncol. 2022 ;14 17588359221143975

Circulating tumor DNA in early-stage colon cancer: ready for prime time or needing refinement?

Joao Paulo Solar Vasconcelos, Melina Boutin, Jonathan M Loree.

Liquid biopsies are the detection of molecular information in fluids from patients with cancer. In colorectal cancer (CRC), the most promising liquid biopsy strategy is the use of circulating tumor DNA (ctDNA) from plasma. In early-stage CRC, the potential for ctDNA to impact care stems from the detection of minimal residual disease (MRD) to guide adjuvant therapy after curative intent treatment and in identifying recurrences during surveillance. As for any new diagnostic test, ctDNA assays must overcome pre-analytical and analytical challenges before clinical implementation. We will discuss important logistical and assay considerations that clinicians and patients should understand when assessing ctDNA assays. We will also delve into important concepts to aid in interpreting ctDNA results and potential incidental findings that may arise. Sequencing errors, germline variants, and clonal hematopoiesis of indeterminate potential (CHIP) must be addressed to properly interpret results. CHIP is also an important consideration that impacts patient prognosis through association with cardiovascular and hematologic diseases. With this background in place, we next review the best available evidence for the use of ctDNA in early-stage colon cancer. Observational cohorts have established MRD after surgery as a significant prognostic factor for recurrence in stage II and III colon cancer. It also has the ability to anticipate clinical recurrence before standard investigations when used in surveillance. The first and only interventional randomized trial to date evaluating ctDNA is DYNAMIC. The study demonstrated the noninferiority of a MRD detection-guided approach in selecting patients with stage II colon cancer for adjuvant treatment. Notwithstanding the important results, there are still important questions to be answered before ctDNA enters prime time in the clinic. However, future appears bright and ongoing trials will help clarify how to best use this technology in early-stage colon cancer.

Keywords: anti-EGFR; colorectal cancer; ctDNA; plasma; resistance; sequencing

DOI: https://doi.org/10.1177/17588359221143975

Cancer. 2022 Dec 26.

The risks of cancer in older women with BRCA pathogenic variants: How far have we come?

BACKGROUND: The purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant.
METHODS: Participants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow-up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow-up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan-Meier method.
RESULTS: There were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk-reducing mastectomy and bilateral salpingo-oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%.
CONCLUSION: Women with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

Keywords: BRCA1; BRCA2; breast neoplasm; fallopian tube neoplasm; ovarian neoplasm

DOI: https://doi.org/10.1002/cncr.34615