What Rapid Autopsies Reveal About Metastatic Breast Cancer Biology

Therapeutic decision-making in metastatic breast cancer, which remains incurable, often relies on the molecular profile of the primary tumor. Yet tumor biology often evolves under treatment pressure, so primary tumor biomarkers may no longer reflect the disease driving progression at a later stage.

In addition, access to metastatic tissue is limited; since opportunities for surgical sampling are uncommon, metastatic sites may be difficult to safely biopsy, and small tissue volumes are unable to capture intrapatient heterogeneity.

But research autopsies, also referred to as rapid autopsies or post-mortem tissue donation programs, help address this gap. Performed shortly after death, they enable systematic, high-volume sampling across organs while preserving tissue integrity for histopathologic and molecular analysis.

Leveraging rapid autopsies, a study published in Laboratory Investigation examined disease burden and biomarker heterogeneity in metastatic breast cancer.

A Panoramic View of Metastatic Burden

Investigators analyzed tissue from 662 unique breast cancer metastases across 20 patients enrolled in the UZ/KU Leuven Program for post-mortem Tissue Donation to Enhance Research (UPTIDER). Tissue procurement followed individualized donation plans informed by imaging and clinical data. Even so, about one-third of sampled lesions hadn’t been anticipated pre-autopsy, underscoring how actual disease extent can be underestimated despite imaging.

Liver, bone, pleura, and nonaxillary lymph nodes emerged as the most commonly involved sites, and certain patterns emerged by histology. For instance, invasive lobular carcinoma showed diffuse, infiltrative growth across organs such as stomach, pericardium, skeletal muscle, and visceral fat, often without gross abnormalities apparent. Leptomeningeal disease, on the other hand, had a different presentation.

Despite aggressive clinical courses, overall metastatic burden was relatively modest. Tumor cells preferentially occupied the arachnoid and perivascular spaces, with limited parenchymal invasion, suggesting that disease impact may relate more to anatomical disruption than tumor volume.

Hormone Receptor Instability at End-Stage Disease

The most clinically provocative findings relate to biomarker heterogeneity. Among patients with ER+ primary tumors, half harbored at least one ER– metastasis at autopsy, and even more had ER-low lesions. For PR, all patients with PR+ primaries had at least one PR– metastatic lesion.

Beyond categorical loss, receptor expression varied widely in frequency and intensity across metastases within the same patient. Median intrapatient interquartile ranges approached 20% for both ER and PR. Compared with untreated primary tumors, metastatic lesions showed significantly lower median ER and PR expression, supporting the gradual receptor erosion rather than abrupt conversion.

These findings exceed discordance rates reported in biopsy-based series and likely reflect both deeper sampling and cumulative treatment exposure. They highlight how reliance on a single metastatic biopsy, or on the primary tumor alone, may underestimate endocrine resistance in advanced disease.

Proliferation and HER2 Heterogeneity

KI67 expression showed marked variability between metastases, with highly proliferative regions coexisting with nearly quiescent tumor areas within the same lesion. Although median KI67 levels didn’t differ significantly between primary tumors and metastases, this local heterogeneity raises questions about small biopsy samples when proliferation informs prognosis or trial eligibility.

The HER2 analysis revealed frequent coexistence of HER2-low, HER2-ultralow, and HER2-undetected lesions within individual patients—even within the same organ.

It’s important to note, however, that the study is limited by the small cohort size with heterogenous treatment histories and its focus on end-stage disease. But nonetheless, the depth and breadth of sampling provide insights that cannot be replicated with ante-mortem biopsies alone.

What Rapid Autopsies Add That Clinical Sampling Cannot

This rapid autopsy series suggests that characterization of disease burden in metastatic breast cancer is often limited despite data from imaging, clinical presentation, the primary tumor, or a single metastatic biopsy. The extent of biomarker heterogeneity and occult disease observed here reinforces the need for repeated reassessment of tumor biology over the disease course and for therapeutic strategies that account for intrapatient diversity.

More broadly, these findings highlight the unique translational insights made possible by extensive post-mortem tissue studies and underscore how rapid autopsy programs allow patients with end-stage disease to continue contributing meaningfully to scientific discovery, even when direct therapeutic benefit is no longer attainable.

Reference:
Zels G, Pabba A, De Schepper M, et al. Histopathological insights into metastatic breast cancer gained from rapid autopsies. Lab Invest. 2025;105(10):104202. doi:10.1016/j.labinv.2025.104202