1. Characterizing Disparate Breast Cancer Phenotypes in Hispanic Women:
A Foundation for Assigning Oligorecurrence vs. Polymetastasis
Kyle D. Goble§, Jacob Smith§, Nima Pouladi§, and Yves A. Lussier§
§ Department of Medicine, Bio5 Institute, The University of Arizona, Tucson, AZ, USA
Carcinoma of the breast in females is recognized as exhibiting significant phenotypic variation from
patient to patient due in part to the large number of discrete characteristics expressed by the primary
tumor. This is problematic when treatment modalities are not applicable to all patients with such
varied disease expression.
Oligometastasis (OM), an intermediary state of cancer metastasis defined by limited or isolated
metastatic sites (fewer than 5 to distant organs), further complicates breast cancer treatment; less
invasive and more focused treatments have been shown to be effective in OM treatment. Thus, the
clinician must be able to accurately diagnosis OM vs. polymetastasis (PM). Oligorecurrence (OR) is
defined as a controlled primary tumor exhibiting OM1.
This phenotypic variability combined with probable differential states of response to certain disease
states necessitates the advent of precision medicine.
This study involved a characterization of breast cancer phenotypes in a population of Hispanic women
in order to begin the process of assigning OM/OR vs. PM states as part of a larger ongoing study that
will seek to elucidate biomolecular markers specific to Hispanic women with oligometastatic breast
cancer. This will contribute to the field of precision medicine and will allow for customizable treatment
plans.
This research was supported by The University of Arizona, The Graduate College, and the Western Alliance to
Expand Student Opportunities (WAESO) “Senior Alliance” Louis Stokes Alliance for Minority Participation
(LSAMP) National Science Foundation (NSF) Grant No. HRD-1101728.
I. The majority of patients displayed ER or PR positive or Her2/neu receptor negative phenotypes.
Twenty patients displayed triple negative breast cancer (TNBC).
II. A significant proportion (91%) of Hispanic women in this cohort expressed intermediate to high
histological grades (mean overall histological score=6.89±1.48).
III. Unfavorable prognostic factors were correlated with other unfavorable prognostic factors.
Table IIIa: Significance tests between Ki67 expression and hormone receptor phenotypes or
histological grade
Table IIIa: Significance tests between Ki67 expression and hormone receptor phenotypes or
histological grade
Breast cancer displays wide variation in phenotypes even among a relatively
homogenous patients of the same ethnicity.
Estrogen receptor and progesterone receptor phenotypes occur together in
similar patterns. In this study, ER and PR followed the same trends in several
aspects; namely, they were both expressed as positive in the majority of
patients and both positive states were strongly correlated with higher Ki67
expression. Other poor prognostic factors were not correlated in this study.
The majority of cancers represented by this group of records were
intermediate to high grade (poorly differentiated) and thus had relatively
unfavorable prognoses.
This data characterization provides the foundation and framework for a future
study in identifying the hypothesized molecular markers (mRNA, miRNA, and
DNA) for oligometastatic breast cancer in Hispanic women in a translational
precision medicine study. The data collection tool and the process will be
continued to identify samples for these studies.
The University of Arizona | UROC-Minority Health Disparities
References:
1. Ralph R. Weichselbaum and Samuel Hellman. Oligometastases Revisited. Nat. Rev. Clin. Oncol. 8:378-382 (2011).
2. Paul A. Harris, Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel Gonzalez, Jose G. Conde. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow
process for providing translational research informatics support. J. Biomed. Inform. 42(2):377-81 (2009).
3. William F. Anderson, Ismail Jatoi, and Susan S. Devesa. Distinct breast cancer incidence and prognostic patterns in the NCI’s SEER program: suggesting a possible link between etiology and
outcome. Breast Cancer Res. Treat. 90:127-137 (2005).
Introduction
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Medicine - Bioinformatics - Biology
Y. LUSSIER GROUP
Methods
Acknowledgments
Results
ConclusionsDetermination of
relevant
phenotypic
variables
• Relevant and available phenotype variables contained within surgical pathology
reports:
• Specimen laterality
• Location of carcinoma
• Type of carcinoma
• Uni- vs. multifocality
• Primary tumor size*
Development of
data collection
tool
• Used RedCap web application to build online survey2
• Crated multivariable form to collect one record per surgical pathology report
Data collection
and comparison
• Double data entry performed for quality control
• Performed manual record-by-record comparison to solve discrepancies between
double records
• Reviewer merged records from both collectors into a set of 137 records
Analysis
• Statistical analyses performed using R software v. 3.2.0
• Hormone receptor +/- proportions calculated and expressed as percentages
• Histological grade (I,II,III) broken down based on overall score from 3 to 9
• Hormone receptor phenotypes and histological grade were compared to Ki67
expression and tumor size using two-tailed Wilcoxon significance tests
• Presence of correlation between tumor size and Ki67 expression was
determined using Spearman’s method
• Tissue involvement
• Histological grade*
• Estrogen receptor (ER) status*
• Progesterone receptor (PR) status*
• Her2/neu receptor status
• Ki-67 expression
• No. of involved lymph nodes*
• pT stage
• pN stage
• pM stage
*Important prognostic factors where tumor size >2.0cm, high histological grade, ER- status, PR- status, and
positive axillary lymph nodes are correlated with relatively unfavorable prognosis/high risk of relapse and/or
death3.
Fig. 1: Example of
RedCap form used
to input data.
Grade I
9
• Score 3: 0
• Score 4: 3
• Score 5: 3
Grade II
55
• Score 6: 16
• Score 7: 9
Grade III
34
• Score 8: 6
• Score 9: 10
98
Fig. Ia: 72.8% of patients displayed
ER positive phenotype.
Fig. Ib: 60.8% of patients displayed
PR positive phenotype.
Fig. Ic: 86.9% of patients displayed
Her2/neu negative phenotype.
Reports
containing
histological
grade
Decreasingcelldifferentiation
Figure II: Of 98 reports that reported histological grade, 9 reported a low Grade I tumor, 55 reported an
intermediate Grade II tumor, and 34 reported a high Grade III tumor. The majority of tumors were Grade II and
Grade III (91%). The average overall score reported was 6.89.
Results, continued
Fig. IIIc: Scatter plot of primary tumor size plotted against the percentage of cells that are Ki67
positive as stated in pathology reports. Spearman’s test performed to compute correlation
coefficient and significance. Correlation coefficient = 0.13, p-value = 0.06. This indicates no
significant correlation between tumor size and Ki67 expression. Ki67 status determined to be a
semi-continuous variable due to “stacking” of values at seemingly discrete Ki67 values.
ER PR Her2/neu receptor Hist. Grade
+ - + - + - I II/III
Median Ki67 (mm)
[IQR]
0.10
[.20]
0.80
[.30]
0.10
[.20]
0.70
[0.59]
0.40
[0.25]
0.18
[0.50]
0.10
[0.14]
0.23
[0.50]
P-value 1.34x10-10**
1.82x10-7**
0.11 0.11
Table IIIa shows median values of Ki67 expression for two possible outcomes of each hormone receptor/histological grade variable.
Both ER-/PR- phenotypes were associated with higher Ki67 expression and were shown to be significant.
Table IIIb shows median values of primary tumor size for two possible outcomes of each hormone receptor/histological grade variable.
No significant associations were demonstrated.
ER PR Her2/neu receptor Hist. Grade
+ - + - + - I II/III
Median size (mm)
[IQR]
15
[22.25]
11
[32]
12
[19]
14.50
[27.25]
17.50
[18.75]
11
[22]
11
[10]
13
[23]
P-value 0.56 0.18 0.27 0.61