Abstract P5-06-16: Histomorphometric measure of disorder of collagen fiber orientation is associated with risk of recurrence in ER+ breast cancers in ECOG-ACRIN E2197 and TCGA-BRCA
Authors: Li Haojia , Bera Kaustav , Gilmore Hannah , Davidson Nancy E , Goldstein Lori J , Madabhushi Anant 
Published: March 2020

Background: Recent research has shown that collagen fiber arrangement in the tumor microenvironment plays a key role determining breast cancer prognosis. In this work, we present a new quantitative histomorphometric approach to identify and evaluate whether Collagen Fiber Orientation Disorder from Tumor-associated Stroma (CFOD-TS) on digitized H&E slides are associated with disease free survival (DFS) in estrogen receptor positive (ER+) breast cancer patients.

Method: 234 and 171 ER+ invasive breast cancer patient’s slides were acquired and digitized from E2197 (training set) and TCGA-BRCA (test set) respectively. Collagen fibers were first segmented out on the digitized H&E slides by a combination of Derivative of Gaussian filters. The CFOD-TS features were then extracted from tumor patches in the whole slide image. A multiple linear regression model (MLR) was then trained in conjunction with the CFOD-TS features distinguishing patients likely to recur from not (&gt;15 year follow-up period) to predict DFS for the non-censored patients.

Result: The CFOD-TS discriminated patients (p=0.01) with and without recurrence and was significantly associated with DFS on ECOG 2197. The univariate and multivariate analysis on the training set were summarized in table 1 and table 2. CFOD-TS was also independently prognostic on patients in the TCGA for stratifying patients into low- and high-risk groups with p=0.009 via a log rank test and a hazard ratio (HR) of 3.09 (95% CI =1.33~7.18, p=0.0088). HR between the two risk groups was 7.11 (n=104, 95% CI =1.53~32.94, p=0.01) for stage I / II tumors and 3.03 (n=39, 95% CI =0.79-8.67, p=0.11) for stage III / IV cancers. In a multivariate setting, CFOD-TS (HR -3.7) was more significant than T-stage (HR-2.88) in stratifying risk. (Table2)

Table 1: Univariate DFS analysis on the training setP-valueHR(95% CI)Case numberCFDO-TS derived risk groups0.00272.04 (1.28 – 3.26)234low / intermediate Oncotype DX (ODx) vs High ODx0.940.96(0.36 – 2.56)68low ODx vs intermediate / High ODx0.00323.49 (1.52 – 8.01)68grade0.300.82 (0.56 – 1.19)209

Table 2: Multivariate DFS analysis on the training set (n=68) and test set (n = 171)VariableP-valueHR(95% CI)ECOG 2197low ODx vs intermediate / High ODx0.00144.00 (1.71 – 9.34)CFDO-TS derived risk groups: Low vs high-risk0.0192.53 (1.17 – 5.47)TCGAT-stage: T1/T2 vs T3/T40.032.88 (1.10 -7.50)N-stage: N0 vs N1/N2/N30.411.47 (0.59 - 3.70)CFOD-TS derived risk groups: Low vs high-risk0.0033.70 (1.57 - 8.67)

Conclusion: Over-expression of CFOD-TS was found to be independently associated with lower likelihood of recurrence and could potentially serve as a prognostic marker of outcome for ER+ breast cancer.

Citation Format: Haojia Li, Kaustav Bera, Hannah Gilmore, Nancy E Davidson, Lori J Goldstein, Anant Madabhushi. Histomorphometric measure of disorder of collagen fiber orientation is associated with risk of recurrence in ER+ breast cancers in ECOG-ACRIN E2197 and TCGA-BRCA [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-16.