Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes.

Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases.

Gestational trophoblastic neoplasm: Patient outcomes and clinical pearls from a multidisciplinary referral center.

Objectives: To describe clinical outcomes and pearls for patients with gestational trophoblastic neoplasm (GTN).

Methods: Patients with GTN treated at a referral center from 1/2006 to 12/2022 were included. Clinical characteristics, World Health Organization risk score (low-risk 0-6, high-risk ≥7), and treatments/outcomes were evaluated using summary statistics, stratified by initial treatment at a referral center versus locally.

Association between genomic instability score and progression-free/overall survival in patients with newly diagnosed non-BRCA1/2 ovarian cancer.

Objective: We sought to describe the association between genomic instability score (GIS) and progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed, non-BRCA1/2 ovarian cancer.

Methods: Homologous recombinant deficiency (HRD) status was based on a cutoff of ≥42 GIS; patients <42 were categorized with homologous recombination proficiency (HRP). We collected type and duration of maintenance therapy, among other variables, and built a multivariate model with landmark analysis at 6 months from baseline and applied it for time-dependent variables.

Interferon response and epigenetic modulation by mutations drive ovarian tumor immunogenicity.

Cell-intrinsic mechanisms of immunogenicity in ovarian cancer (OC) are not well understood. Damaging mutations in the SWI/SNF chromatin remodeling complex, such as (BRG1), are associated with improved response to immune checkpoint blockade; however, the mechanism by which this occurs is unclear. We found that loss in OC models resulted in increased cancer cell-intrinsic immunogenicity, characterized by up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery.

A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor-Positive Advanced or Recurrent Endometrial Cancer.

Purpose: Inhibition of the cyclin D-cyclin dependent kinase (CDK)4/6-INK4-retinoblastoma pathway can overcome acquired or de novo treatment resistance to endocrine monotherapy. Responses to endocrine monotherapy in advanced endometrial cancer (EC) are suboptimal, perhaps due to genomic alterations that promote estrogen receptor (ER)-independent cyclin D1-CDK4/6 activation. We hypothesized that addition of abemaciclib, a CDK4/6 kinase inhibitor, to antiestrogen therapy with fulvestrant will be an effective therapeutic strategy in patients with advanced or recurrent EC.

Evolutionary pathways in early-stage, non-myoinvasive endometrioid endometrial cancers of no specific molecular profile.

Objective: To characterize the genomic landscape of FIGO 2009 stage IA, non-myometrial invasive endometrioid endometrial cancers (ECs) of no specific molecular profile (NSMP) and define the earliest driver genetic alterations and subsequent tumor evolution.

Methods: Early-stage (FIGO 2009 stage IA), non-myoinvasive endometrioid NSMP ECs subjected to clinical tumor-normal targeted sequencing between 2014 and 2022 were identified. ECs were dichotomized into low- and high-volume disease based on gross and histologic measurement using a cutoff of 1.

Lymph node metastases in endometrial carcinoma: A modern assessment in the era of sentinel lymph node mapping and molecular subtyping.

Objective: To examine the risk of sentinel lymph node (SLN) metastases in apparent uterine-confined endometrial cancer (EC) using molecular classification with clinicopathologic features and assess oncologic outcomes by molecular subtypes with micro- or macro-metastases in SLN.

Methods: Patients undergoing surgical staging for presumed uterine-confined EC of any histology, with successful bilateral SLN mapping were included. Primary tumors were assigned molecular subtypes using a published algorithm.

Concurrent POLE hotspot mutations and mismatch repair deficiency/microsatellite instability in endometrial cancer: A challenge in molecular classification.

Objective: Endometrial carcinoma (EC) has different molecular subtypes associated with varied prognosis. We sought to characterize the molecular features of ECs with POLE hotspot mutations and concurrent mismatch repair (MMR) deficiency/high microsatellite instability (MSI).

Methods: We identified POLE-mutated (POLEmut), MMR-deficient (MMRd)/MSI-high (MSI-H), or combined POLEmut/MMRd ECs subjected to clinical tumor-normal panel sequencing between 2014 and 2023.

Tracking clonal evolution of drug resistance in ovarian cancer patients by exploiting structural variants in cfDNA.

Drug resistance is the major cause of therapeutic failure in high-grade serous ovarian cancer (HGSOC). Yet, the mechanisms by which tumors evolve to drug resistant states remains largely unknown. To address this, we aimed to exploit clone-specific genomic structural variations by combining scaled single-cell whole genome sequencing with longitudinally collected cell-free DNA (cfDNA), enabling clonal tracking before, during and after treatment.

Factors associated with an inconclusive result from commercial homologous recombination deficiency testing in ovarian cancer.

Introduction: Homologous recombination deficiency (HRD) testing is used to determine the appropriateness of poly ADP-ribose polymerase inhibitors for patients with epithelial ovarian cancer and no germline/somatic BRCA1/2 alterations. Myriad MyChoice CDx reports a genomic instability score (GIS) to quantify the level of HRD, with a positive score defined as ≥42. The authors sought to define factors associated with obtaining an inconclusive HRD test result.

Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer.

Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity.

Spatial molecular profiling of mixed invasive ductal and lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity - e.

ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype.

Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC.

Basket study of oral progesterone antagonist onapristone extended release in progesterone receptor-positive recurrent granulosa cell, low-grade serous ovarian cancer, or endometrioid endometrial cancer.

Objective: To determine the safety and efficacy of the oral progesterone antagonist onapristone extended release (onapristone-XR) in patients with recurrent progesterone receptor (PR)-positive adult-type granulosa cell tumor (aGCT), low-grade serous ovarian cancer (LGSOC), or endometrioid endometrial cancer (EEC).

Methods: This single-institution phase II study included patients with PR-positive aGCT, LGSOC, or EEC who received ≥1 prior line of chemotherapy. Patients were enrolled from 5/2019-5/2020.

Circulating cell-free (cf)DNA analysis: Current technologies and applications in gynecologic cancer.

Cell-free DNA (cfDNA) analysis has several promising clinical applications in the management of cancer patients, with clinical validity established in different types of solid tumors (e.g., lung, breast, and colon cancer).

Spatial molecular profiling of mixed invasive ductal-lobular breast cancers reveals heterogeneity in intrinsic molecular subtypes, oncogenic signatures, and mutations.

Unlabelled: Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially-resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity (e.

RB1 Genetic Alterations in Estrogen Receptor-Positive Breast Carcinomas: Correlation With Neuroendocrine Differentiation.

Genetic alterations in the retinoblastoma susceptibility gene (RB1) are present in up to 40% of triple-negative breast cancers (BCs) and frequent in tumors with neuroendocrine differentiation, including small cell neuroendocrine carcinoma. Data on RB1 genetic alterations in estrogen receptor (ER)-positive BCs are scarce. In this study, we sought to define the morphologic, immunohistochemical, and genetic features of ER-positive BCs harboring somatic alterations in RB1, with emphasis on neuroendocrine differentiation.

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Background: Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.

Prognosis of isolated tumor cells and use of molecular classification in early stage endometrioid endometrial cancer.

Objective: We assessed the prognosis and molecular subtypes of early stage endometrioid endometrial cancer with isolated tumor cells within sentinel lymph nodes (SLNs) compared with node negative disease.

Methods: Patients diagnosed with stage IA, IB, or II endometrioid endometrial cancer and primary surgical management were identified from January 1, 2007 to December 31, 2019. All SLNs underwent ultrastaging according to the institutional protocol.

APOBEC3 mutagenesis drives therapy resistance in breast cancer.

Acquired genetic alterations commonly drive resistance to endocrine and targeted therapies in metastatic breast cancer , however the underlying processes engendering these diverse alterations are largely uncharacterized. To identify the mutational processes operant in breast cancer and their impact on clinical outcomes, we utilized a well-annotated cohort of 3,880 patient samples with paired tumor-normal sequencing data. The mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) enzymes were highly prevalent and enriched in post-treatment compared to treatment-naïve hormone receptor-positive (HR+) cancers.