5P - Clinicopathologic features and genomic profiling of occult breast cancer

Background

Axillary lymph node metastases from adenocarcinoma or poorly differentiated carcinoma of unknown primary (CUPAx) is a rare disease in women. This subgroup shares similar biological characteristics with stage II-III breast cancer and is named occult breast cancer (OBC). This study intended to examine the clinicopathological features of OBC and compared OBC genetically with axillary lymph node metastases from breast cancer (BCAx), investigating differences in their biological behavior.

Methods

We conducted the clinical and prognostic analysis of 58 OBC patients in West China Hospital spanning from 2009 to 2021. Gemonic profiling of 12 OBC patients and 16 BCAx patients was conducted by the FoundationOne CDx (F1CDx) platform, including 324 genes along with genomic features such as TMB and MSI. Moreover, we also compared the gene mutation spectrum and relevant pathways between the two groups and both TCGA and COSMIC databases.

Results

The majority of the 58 OBC patients were HR-/HER2- subtype. OBC patients had a higher expression of breast origin-related immunohistochemical markers, such as GATA3, GCDFP15, and CK5/6. Most patients received mastectomy combined radiotherapy (50Gy/25f). OBC had a favorable overall prognosis. Radiotherapy was the independent prognostic factor in multivariate analysis (HR=0.04, 95%CI=0.00-0.85, P=0.0390). In 28 samples and 401 TCGA-BRCA patients, IRS2 only mutated in OBC (33.33%) but amplified in BCAx (11.11%) and TCGA-BRCA (1.5%). Pathway analysis revealed that BCAx had more NOTCH pathway mutations than OBC, where NOTCH3 and GATA3 was highly amplified in OBC (16.67% vs. 0%) and BCAx (16.67% vs. 0%) respectively. GATA6 only had novel mutations in BCAx (31.25%) according to the COSMIC database. Enrichment analysis showed that OBC enriched more in mammary development and PML bodies than BCAx, but less in the positive regulation of kinase activity.

Conclusions

More active treatment methods could improve the prognosis of OBC. The differential mutation genes of OBC and BCAx might be associated with their respective biological behaviors like invasiveness and prognosis. The differences in NOTCH pathway and enrichment analysis might cause the occult lesions in the OBC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (ZYJC18022 and ZYJC21017).

Disclosure

All authors have declared no conflicts of interest.