Abstract
Cancer risk prognosis could improve patient survival through early personalized treatment decisions. This is the first systematic analysis of the spatial and prognostic distribution of different pan cytokeratin immunostaining intensities in breast tumors. The prognostic model included 102 breast carcinoma patients, with distant metastasis occurrence as the endpoint. We segmented the full intensity range (0–255) of pan cytokeratin digitized immunostaining into seven discrete narrow grey level ranges: 0–130, 130–160, 160–180, 180–200, 200–220, 220–240, and 240–255. These images were subsequently examined by 33 major (GLCM), fractal and first-order statistics computational analysis features. Interestingly, while moderate intensities were strongly associated with metastasis outcome, high intensities of pan cytokeratin immunostaining provided no prognostic value even after an exhaustive computational analysis. The intense pan cytokeratin immunostaining was also relatively rare, suggesting the low differentiation state of epithelial cells. The observed variability in immunostaining intensities highlighted the intratumoral heterogeneity of the malignant cells and its association with a poor disease outcome. The prognostic importance of the moderate intensity range established by complex computational morphology analyses was supported by simple measurements of its immunostaining area which was associated with favorable disease outcome. This study reveals intratumoral heterogeneity of the pan cytokeratin immunostaining together with the prognostic evaluation and spatial distribution of its discrete intensities.
Highlights
As a primary breast tumor is not life-threatening, the outcome of breast cancer depends on metastasis occurrence, which is the main cause of death [1]
The major advantage of the used patient group was that treatments were only local in terms of surgery and radiation, without systemic hormonal or cytotoxic drugs which could interfere with metastasis occurrence
Single-cell heterogeneity has been previously investigated in breast cancer [30], but the current study shows for the first time that even broad pan cytokeratin immunostaining is a good measure for intratumoral heterogeneity
Summary
As a primary breast tumor is not life-threatening, the outcome of breast cancer depends on metastasis occurrence, which is the main cause of death [1]. Most breast cancer patients do not incur metastasis even without cytotoxic chemotherapy and are unnecessarily exposed to toxic side effects of chemotherapy treatment [2,3]. This issue could be resolved by the precision medicine, with less intense treatments for those at low risk and more intense ones for those at a reliably established high metastasis risk. Improvement of the breast cancer patient survival rate through such individualized adjustment of chemotherapy is still not possible only because the risk of metastasis occurrence cannot be reliably prognosticated. Even the most advanced gene signature tools deliver an accuracy of only 65% and an area under the ROC curve (AUC) of 0.69 [9]
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