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. 2018 Nov;172(1):123-132.
doi: 10.1007/s10549-018-4879-7. Epub 2018 Jul 10.

Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival

Ashirbani Saha  1   2 , Michael R Harowicz  3 , Elizabeth Hope Cain  3 , Allison H Hall  4 , Eun-Sil Shelley Hwang  5 , Jeffrey R Marks  6 , Paul Kelly Marcom  7 , Maciej A Mazurowski  3   8   9
Affiliations

Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival

Ashirbani Saha et al. Breast Cancer Res Treat. 2018 Nov.

Abstract

Purpose: The purpose of the study was to define quantitative measures of intra-tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS).

Methods: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease.

Results: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size.

Conclusions: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.

Keywords: Breast cancer; Distant recurrence-free survival; Immunohistochemistry; Intra-tumor heterogeneity; Receptor status; Survival analysis.

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Conflict of interest statement

Conflicts of Interest

The authors have no conflicts of interest to disclose

Figures

Figure 1:
Figure 1:
Flow Diagram for selection of patient population.
Figure 2:
Figure 2:
The lower triangular portion of the figure contains pie charts of the Pearson’s correlation coefficient between any pair of measures after binarizing them. Completely filled pie chart indicates a correlation of 1 (when blue) or −1 (when orange). Partially filled pie charts, the direction of fill indicates the sign (positive for clockwise and negative for correlation) of correlation and the proportion indicates the values. Additionally, colors of the pie chart are bluish for high positive correlation and orangish for low correlation (positive or negative).
Figure 3:
Figure 3:
Hazard ratios with confidence intervals for 31 measures of heterogeneity for the entire available population and subsets of patients that received specific therapies (detailed definitions of these measures are available in Supplementary Material eTable 1)
Figure 4:
Figure 4:
Hazard Ratio for the entire available population and subsets of patients that received specific therapies using maximum difference of binarized ER Percentage Staining between samples as the measure of heterogeneity.
See this image and copyright information in PMC

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