Utility of gross tumor palpability or tumor size as a measure of drug efficacy for cancer prevention Alexander Koh, Anjana Bhardwaj , Matthew D. Embury, Raniv D. Rojo, Isabelle Bedrosian Department of Breast Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX Correspondence: abhardwaj@mdanderson.org; ibedrosian@mdanderson.org
Models and strategies
Introduction
Drug efficacy studies show significant discord between the two systems of measuring tumor development. Histological grading is a better measure of tumor development and drug efficacy
Spontaneous mouse model of TNBC
Invasive cancer
Atypical hyperplasia
• The options to prevent breast cancer development are limited. Only endocrine agents have proven efficacy of reducing the risk of ER+ breast cancer by about 50%. • No agents are available to reduce the risk of non-ER+ breast cancers • Multiple other agents, such as lapatinib, rexinoid, and arzoxifene have shown preventative efficacy in preclinical studies, but not for clinical studies. • Potential reasons for this discrepancy include inherent differences between preclinical models and human subjects, as well as the inconsistent endpoints chosen for assessment of efficacy in preclinical studies • Preclinical efficacy studies typically use tumor size as endpoints, as measured by gross examination of the mammary lesions • Another measure of tumor development which is commonly used in patients but not so much in preclinical cancer prevention studies is histological grading • The concordance between the histologic and gross diagnosis of tumor has not been well described
SV40 C3TAg
DCIS
Necropsy: Collected 4 mammary glands/ mouse
22 weeks
A
8 weeks
12 weeks
Birth
100
Drug efficacy as measured by two
% Tumor free per gland
Discord: 35 glands misidentified
Grade: 0-3 Grade: 4 Grade: 5 Histological Grading System
Gross measurements, Histological grading
75
different methods. (A) shows this relationship for each mammary gland, and (B) shows this for each mice.
Benign
Cancer
50
< 3mm (Non tumor)
25
Gross Palpability
> 3mm (Tumor)
0
Gross Assessment (n=53/81)
Histologic Grade (n=18/81)
Drug Treatments / Vehicle Treatment period: 6 weeks-22 weeks
B
100
% Tumor free per mouse
Results
75
There is high concordance between tumor palpability and a higher histological grading for palpable tumors, but poor concordance in nonpalpable glands
Discord: 8 mice misidentified
50
A
0 20 40 60 80 100 0 20 40 60 80 100
Tumor incidence measured by two different methods. (A) shows this relationship for each mammary gland sample, and (B) shows this for each mice.
N=108 mammary glands
25
Objective
0
Gross Assessment (n=10/28)
Histologic Grade (n=2/28)
The objective of this study was to assess the concordance between histological grading and gross tumor assessment in determining the presence or absence of cancer in preclinical models.
Conclusion Due to the lack of consistency between the two differing methods of identifying tumor development, the use of tumor palpability as the sole endpoint measure in chemoprevention studies should be reconsidered. 2. Concordance is poor ( < 40 %) between the two assessment methods for non- palpable glands, with many of these glands harboring tumors histologically 3. Response to drug treatment is overestimated when using gross assessment of the mammary gland as the study endpoint Summary 1. Concordance is high ( >90 %) between the two assessment methods for palpable tumors
Grades 0-3 (n = 2) Grades 4-5 (n = 34) Grades 4-5 (n = 47) Glands with palpable tumor (n = 36) Glands without non-palpable tumor (n = 72) Grades 0-3 (n = 25)
Hypothesis
B
N=38 mice
We hypothesized that concordance between gross palpability or histological grading, for measuring tumor development and drug efficacy, will be poor in non-palpable tumors.
Grades 0-3 (n = 1) Grades 4-5 (n = 24) Grades 0-3 (n = 2) Grades 4-5 (n = 11) Mice with palpable tumor (n = 25) Mice without palpable tumor (n = 13)
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