bims-ovdlit 2022-07-24 papers

Issue of 2022–07–24
five papers selected by
Lara Paracchini, Humanitas Research

Histopathology. 2022 Jul 20.

Serous tubal intraepithelial carcinoma: What Do We Really Know at this Point?

Serous tubal intraepithelial carcinoma (STIC) is the earliest morphologically recognizable step in the development of invasive high-grade serous carcinoma of the fallopian tube. Lesions occurring prior to STIC within the carcinogenic sequence for the pathogenesis of invasive high-grade serous carcinoma include the p53 signature and secretory cell outgrowth (SCOUT). Variable histologic criteria have been used for diagnosing STIC, but a combination of morphology and immunohistochemistry for p53/Ki-67 improves interobserver agreement. Half of all carcinomas identified in risk-reducing salpingo-oophorectomy specimens are in the form of STIC; however, STIC also may be incidentally found on occasion in specimens from women at low or average risk of ovarian/tubal/peritoneal carcinoma. TP53 mutation is the earliest known DNA sequence alteration in STIC and almost all invasive high-grade serous carcinomas of the ovary and peritoneum. Data on the clinical behavior of STIC are limited. While the short-term follow-up in the prior literature suggests a low risk of malignant progression, a more recent meta-analysis indicates a 10-year risk of 28%. STIC probably should be best regarded as a lesion with uncertain malignant potential at present, and future molecular analysis will help classify those with higher risk of dissemination. This review article provides an update on the current knowledge of STIC and related issues.

Keywords: SCOUT; STIC; p53 signature; serous tubal intraepithelial carcinoma

DOI: https://doi.org/10.1111/his.14722

Int J Gynecol Cancer. 2022 Jul 22. pii: ijgc-2022-003543. [Epub ahead of print]

Management of oligometastatic ovarian cancer recurrence during PARP inhibitor maintenance.

Eleonora Palluzzi, Claudia Marchetti, Serena Cappuccio, Giacomo Avesani, Gabriella Macchia, Maria Antonietta Gambacorta, Fabrizio Cocciolillo, Giovanni Scambia, Anna Fagotti.

OBJECTIVE: The benefit of surgery and maintenance treatment with PARP inhibitors (PARPi) has been clearly demonstrated in ovarian cancer. Also, the efficacy and safety of stereotactic body radiotherapy has been shown in patients with metastatic, persistent, and recurrent disease. The aim of this study is to evaluate the management of oligometastatic progression during PARPi maintenance treatment.
METHODS: This is an observational, retrospective, single-arm study conducted from June 2017 to December 2020 in patients with recurrent ovarian cancer with oligometastatic progression under PARPi maintenance treatment and receiving surgery or stereotactic body radiotherapy for such recurrence. PARPi treatment was continued until further progression of the disease. The primary objective of the study was the median prolongation of the treatment-free interval-p (without platinum) after local treatment.
RESULTS: A total of 186 patients with ovarian cancer were treated with PARPi at recurrence. Of these, 30 (16%) developed oligometastatic progression. The median age was 49.5 years (range 35-73). Olaparib, niraparib and rucaparib were administered to 33%, 60%, and 7% of patients, respectively. The median prolongation of the treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy was 6 and 10 months, respectively (p=0.53). The median treatment-free interval-p of patients treated with surgery or stereotactic body radiotherapy at the time of oligometastatic progression was 32 and 29 months, respectively (p=0.44). At the time of this publication, 50% of patients are still on treatment with PARPi following progression.
CONCLUSIONS: Patients with recurrent ovarian cancer who have oligometastic progression during PARPi maintenance may continue to benefit from PARPi if combined with local treatment.

Keywords: BRCA1 protein; cytoreduction surgical procedures; ovarian neoplasms; radiotherapy

DOI: https://doi.org/10.1136/ijgc-2022-003543

ESMO Open. 2022 Jul 15. pii: S2059-7029(22)00168-5. [Epub ahead of print]7(4): 100540

Comparison of actionable events detected in cancer genomes by whole-genome sequencing, in silico whole-exome and mutation panels.

BACKGROUND: Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the value of clinical whole-exome sequencing (WES) and whole-genome sequencing (WGS) for cancer care is less defined, specifically as the majority of variants found using these technologies are of uncertain significance.
PATIENTS AND METHODS: We used the Cancer Genome Interpreter and WGS in 726 tumours spanning 10 cancer types to identify drug repurposing opportunities. We compare the ability of WGS to detect actionable variants, tumour mutation burden (TMB) and microsatellite instability (MSI) by using in silico down-sampled data to mimic WES, a comprehensive sequencing panel and a hotspot mutation panel.
RESULTS: We reveal drug repurposing opportunities as numerous biomarkers are shared across many solid tumour types. Comprehensive panels identify the majority of approved actionable mutations, with WGS detecting more candidate actionable mutations for biomarkers currently in clinical trials. Moreover, estimated values for TMB and MSI vary when calculated from WGS, WES and panel data, and are dependent on whether all mutations or only non-synonymous mutations were used. Our results suggest that TMB and MSI thresholds should not only be tumour-dependent, but also be sequencing platform-dependent.
CONCLUSIONS: There is a large opportunity to repurpose cancer drugs, and these data suggest that comprehensive sequencing is an invaluable source of information to guide clinical decisions by facilitating precision medicine and may provide a wealth of information for future studies. Furthermore, the sequencing and analysis approach used to estimate TMB may have clinical implications if a hard threshold is used to indicate which patients may respond to immunotherapy.

Keywords: actionable mutations; cancer genomics; clinical genomics; microsatellite instability; precision oncology; tumour mutation burden (TMB); whole-genome sequencing

DOI: https://doi.org/10.1016/j.esmoop.2022.100540

Nature. 2022 Jul 20.

Whole-genome sequencing of the UK Biobank.

Keywords: Genomics; Health care; Medical research

DOI: https://doi.org/10.1038/d41586-022-01984-6

Nat Rev Genet. 2022 Jul 20.

The emerging landscape of spatial profiling technologies.

Jeffrey R Moffitt, Emma Lundberg, Holger Heyn.

Improved scale, multiplexing and resolution are establishing spatial nucleic acid and protein profiling methods as a major pillar for cellular atlas building of complex samples, from tissues to full organisms. Emerging methods yield omics measurements at resolutions covering the nano- to microscale, enabling the charting of cellular heterogeneity, complex tissue architectures and dynamic changes during development and disease. We present an overview of the developing landscape of in situ spatial genome, transcriptome and proteome technologies, exemplify their impact on cell biology and translational research, and discuss current challenges for their community-wide adoption. Among many transformative applications, we envision that spatial methods will map entire organs and enable next-generation pathology.

DOI: https://doi.org/10.1038/s41576-022-00515-3