Neoduct dedifferentiation is associated with poorer breast cancer-specific survival

Imaging biomarkers combined with large format histopathology have been shown to indicate the apparent site of breast cancer origin in either the major lactiferous ducts or the acini of the terminal ductal lobular units. The imaging biomarker of fragmented casting type calcifications on the mammogram provides a reliable indicator of a complex malignant tumour arising within the major lactiferous ducts, proliferating as neoducts, and eventually forming discrete tumour foci. The high fatality rate of this breast cancer subtype prompted our study.

From our database of all breast cancer patients in two consecutive epochs, Jan 1st 1996-Dec 31st 2007 and Jan 1st 2008-June 30th 2022, in a single geographical healthcare district, we selected all women having prospectively documented fragmented casting type calcifications on the mammogram (ductal origin) (n = 161, n = 309 respectively) and stellate/circular tumours (apparent acinar origin) (n = 1,413, n = 2,444 respectively) from all women diagnosed with breast cancer in the first (n = 2359) and second (n = 3553) epochs. Breast cancer-specific survival was estimated by the life-table method, and the prognostic effect of the imaging biomarker was quantified as hazard ratios (95% CIs) from Cox regression in a 1:1 grade-matched cohort, adjusted for tumour size, nodal status and treatment. A refined assessment of cause of death was performed in all cases of breast cancer death from all available clinical, histopathologic and imaging data.

Women with the cancer subtype having casting type calcifications originating from the major lactiferous ducts had significantly poorer survival than women with grade matched cancers of apparent acinar origin (HR = 2.54, 95% CI 1.09-6.04). Comparison of the two consecutive epochs revealed a significant survival improvement in women with cancers of apparent acinar origin (HR = 1.90, 95% CI 1.56-2.32), whereas the long-term survival of cancers of ductal origin (HR = 0.88, 95% CI 0.56-1.38) did not improve during the second epoch (2008-2022). Breaches in the neoduct boundaries appear to release the cellular contents to the interstitial spaces, where they form mammographically detectable stellate and circular tumour masses, which co-exist with the neoducts in the primary tumours and in metastases to the lymph nodes and distant sites.

Our observations suggest that neoduct formation producing fragmented casting type calcifications on the mammogram is an invasive process, further exacerbated by the escape of the cellular contents from the neoducts to the surrounding extraductal space. We also propose that due to structural dedifferentiation the extraductal cells are no longer able to form neoducts but instead form tumour masses. The co-occurrence of neoduct-like structures and the extraductal cellular component, which is seen in both the primary and metastatic tumours, suggests a dependent relationship, the combination being responsible for the poor survival. The continuing poor outcome of these patients compared with the more recently improved outcome of patients with tumours of apparent acinar origin suggests a need to re-evaluate our current diagnostic and therapeutic strategies.