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

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?

SUBMITTER: Saha A

PROVIDER: S-EPMC6588400 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Saha Ashirbani A Harowicz Michael R MR Cain Elizabeth Hope EH Hall Allison H AH Hwang Eun-Sil Shelley ES Marks Jeffrey R JR Marcom Paul Kelly PK Mazurowski Maciej A MA

Breast cancer research and treatment 20180710 1

<h4>Purpose</h4>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).<h4>Methods</h4>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-tum ...[more]

PMID: 29992418

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Project description:ImportancePatients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood.ObjectiveTo compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype.Design, setting, and participantsSecondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018.InterventionsPatients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy.Main outcomes and measuresDistant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics.ResultsIn the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59).Conclusions and relevancePatients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.

Project description:Purpose To characterize intratumoral spatial heterogeneity at perfusion magnetic resonance (MR) imaging and investigate intratumoral heterogeneity as a predictor of recurrence-free survival (RFS) in breast cancer. Materials and Methods In this retrospective study, a discovery cohort (n = 60) and a multicenter validation cohort (n = 186) were analyzed. Each tumor was divided into multiple spatially segregated, phenotypically consistent subregions on the basis of perfusion MR imaging parameters. The authors first defined a multiregional spatial interaction (MSI) matrix and then, based on this matrix, calculated 22 image features. A network strategy was used to integrate all image features and classify patients into different risk groups. The prognostic value of imaging-based stratification was evaluated in relation to clinical-pathologic factors with multivariable Cox regression. Results Three intratumoral subregions with high, intermediate, and low MR perfusion were identified and showed high consistency between the two cohorts. Patients in both cohorts were stratified according to network analysis of multiregional image features regarding RFS (log-rank test, P = .002 for both). Aggressive tumors were associated with a larger volume of the poorly perfused subregion as well as interaction between poorly and moderately perfused subregions and surrounding parenchyma. At multivariable analysis, the proposed MSI-based marker was independently associated with RFS (hazard ratio: 3.42; 95% confidence interval: 1.55, 7.57; P = .002) adjusting for age, estrogen receptor (ER) status, progesterone receptor status, human epidermal growth factor receptor type 2 (HER2) status, tumor volume, and pathologic complete response (pCR). Furthermore, imaging helped stratify patients for RFS within the ER-positive and HER2-positive subgroups (log-rank test, P = .007 and .004) and among patients without pCR after neoadjuvant chemotherapy (log-rank test, P = .003). Conclusion Breast cancer consists of multiple spatially distinct subregions. Imaging heterogeneity is an independent prognostic factor beyond traditional risk predictors.

Project description:Introduction: The I-SPY 1 TRIAL was designed to evaluate complete pathologic response and tumor volume change, measured by magnetic resonance imaging (MRI), stratified by molecular subtypes and link response to 3-year recurrence free survival (RFS).Methods: Eligible patients had T =3 cm and received neoadjuvant chemotherapy with AC plus optional taxane. Serial MRI, biopsy, and blood draws were conducted over the course of treatment, and a database of multiple molecular profiles was assembled.Results: A total of 221 patients were eligible for analysis: median tumor size was 6.0 cm and median age was 49 years. The I-SPY 1 TRIAL patients had tumors with aggressive biology: 45% were estrogen receptor (ER) negative, 31% Her2+; and 91% high risk by the Netherlands Cancer Institute (NKI) 70-gene profile. After a median of 3.9 years, RFS was 77%. HR/HER2 status improved predictability of RFS with the greatest difference between HR+/HER2- and triple-negative disease (hazard ratio 0.39). Wound healing signature activation, p53 mutation, and Risk of Relapse (ROR) score were highly correlated and also significantly improved the accuracy of RFS predictions when added to stage. The rate of pathologic complete response (pCR) varied considerably from a low of 0-2% (NKI low risk, luminal A) to a high of 43-61% (17q Amplified, HER2 enriched, HR-/HER2+). Both pCR and the more refined residual cancer burden (RCB) were significant predictors of RFS for all patients and even more predictive when analyzed within biomarker subsets. Good risk (NKI low, ROR-S low risk, Wound Healing quiescent, p53 wild type) signatures were associated with significantly higher 3-year RFS than poor risk expression signatures (ROR-S high risk, Wound Healing Activated, p53 mutation, NKI high risk).Conclusion: Importantly, in this set of biologically poor prognosis tumors, pCR predicts for better outcome, especially when analyzed within breast cancer subsets. Keywords: reference x sample reference x sample

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

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

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