• Endometrium

Chacon et al present the SENECA study,1 which examines the interplay between molecular subtype and sentinel lymph node (SLN) positivity in a retrospective cohort of over 2000 patients from 66 international centers.

Endometrial cancer is a heterogeneous disease with a highly variable phenotype. Research has shown that traditional risk factors, such as histology, depth of invasion, and regional lymph node metastases, impact patient prognosis.2 With the publication of The Cancer Genome Atlas (TCGA) and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) algorithm, we were introduced to a system of molecular subtyping, which is also prognostic, though there is limited evidence on how molecular subtype may impact surgical staging paradigms, including SLN biopsy. The SENECA study sought to explore this.

The authors reported an 83% rate of successful bilateral SLN mapping, validating center expertise. The reported rate of lymph node metastases (including isolated tumor cells) ranged from 6.3%, and 7.8% in patients with POLE and no specific molecular profile tumors, respectively, to 12.4%, and 12.5% in patients with mismatch repair-deficient or p53 abnormal tumors, respectively. POLE testing was conducted in just 57% of patients, representing a real-world experience.

Ultimately, as Dr Chacon and colleagues note, this is an important effort toward clinical implementation of molecular profiling. But what can clinicians derive from these data? There are several key themes—in particular, the relevance of SLN biopsy and how molecular subtyping could be leveraged to improve patient outcomes.

A large body of literature shows that SLN mapping is accurate and less morbid than total lymphadenectomy.3 There is enhanced detection of micrometastases, which guide treatment and prognostication, though the clinical relevance of isolated tumor cells is controversial. In the SENECA study, the SLN ‘positive’ rates of 6.3% and 7.8% in POLE and copy number-low tumors, respectively, reaffirms that universal SLN assessment is warranted, regardless of molecular subtype. In the future, patients with significant co-morbidities or without access to SLN mapping may be able to defer nodal assessment based on pre-operative pathologic and molecular features; however, there are no such studies yet to embolden this approach. It is of great interest to see a multivariable analysis that integrates traditional and molecular risk factors with SLN status. For example, SENECA authors observed a higher rate of myometrial invasion and lymphovascular space invasion in the mismatch repair-deficient and p53 abnormal groups. This is also reflected in the equivalent areas under the curve (0.74 and 0.73) between molecular subtyping and the molecular-agnostic European Society of Gynecological Oncology (ESGO) prognostic risk classification.

The PORTEC-3 investigators and other groups have examined the benefit of post-operative treatment by molecular subtype, and the ongoing PORTEC-4a study could provide insight into tailoring adjuvant treatment according to molecular subtype.4 We eagerly await SENECA’s oncologic outcomes data from this large cohort to add to the currently limited literature. We encourage any outcome studies to omit isolated tumor cell-positive SLNs, as current National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines recommend against consideration of isolated tumor cells as metastatic disease.

The SENECA study has raised the bar for research with its commitment to standardized data collection across global practice settings. It demonstrates that it is possible, and importantly, show us how it can be done.