Breast Cancer Risk From Sonographic Glandular Tissue Component (or International GTC Study)

Study Overview
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Brief Summary
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An international multicenter study to prospectively validate the association between sonographic GTC and subsequent breast cancer risk in women with dense breasts.

Detailed Description
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Women with similarly dense breasts on mammography may have different subsequent risks of developing breast cancer due to varying degrees of lobular involution. Breast ultrasound (US) can assess the relative amount of glandular tissue component (GTC) to the fibrous stroma in dense breast parenchyma and can reflect the degree of lobular involution. In women with dense breasts on mammography, an association between high levels of sonographic GTC, defined as the percent of glandular tissue within fibroglandular tissue, and an increased risk of breast cancer was demonstrated in a retrospective single-center study of 8483 Korean women. The purpose of this international multicenter study is to prospectively validate whether sonographic GTC is associated with subsequent breast cancer risk and whether it can provide additional information beyond established risk factors (age, race/ethnicity, breast density, family history, or benign breast disease). In this study, investigators from Asia and Europe will enroll 16164 women with dense breasts (BI-RADS density categories C and D on mammography) undergoing screening breast US using either an automated or handheld device. GTC will be assessed qualitatively as minimal, mild, moderate, or marked at the time of US interpretation and will be dichotomized into low (minimal or mild) versus high (moderate or marked). The primary outcome is a pathologic diagnosis of breast cancer, including invasive cancer and ductal carcinoma in situ (DCIS). Women are observed from 3 months after date of GTC assessment to breast cancer diagnosis or censoring as a result of death or end date of complete cancer capture. Covariate information will be obtained from self-report at the time of breast US examination and includes age, race/ethnicity, menopausal status, first-degree family history of breast cancer, and history of breast biopsy. The 5-year cumulative incidence of breast cancer by level of sonographic GTC will be compared based on marginal standardization with the predicted risk summed to a weighted risk according to the observed covariate distribution in the study population. The association of sonographic GTC with breast cancer risk will be estimated by using the Fine-Gray subdistribution hazards model to account for the competing risk of death. In addition, investigators will compare the discriminatory accuracy of the breast cancer surveillance consortium (BCSC) 5-year risk score and the BCSC model integrated with sonographic GTC.

Official Title
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Association of Sonographic Glandular Tissue Component With Breast Cancer Risk Among Women With Dense Breasts: A Prospective, Multinational Validation Study

Conditions
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Breast Cancer, Screening

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria be ≥ 40 and <70 years old at time of US No history of previous breast cancer including DCIS have dense breasts (BI-RADS category C and D on mammography performed within 12 months of breast US) and negative/benign BI-RADS assessment categories on mammography (BI-RADS 1, 2) undergoing screening breast US using either automated or handheld device Exclusion Criteria history of bilateral prophylactic mastectomy history of bilateral foreign body injection history of bilateral breast implants history of bilateral breast reduction surgery or surgical excision currently pregnant or breast feeding in the preceding 6 months Known distant metastasis from other primary cancer

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incident breast cancer within 3 months to 7 years after the assessment of sonographic GTC | The 5-year cumulative incidence of breast cancer and hazard ratio by level of sonographic GTC using standardized risk | from 3 months to 7 years after the GTC assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation of sonographic GTC with risk according to tumor type | Correlation of sonographic GTC with risk according to tumor type (DCIS vs. invasive cancer) | from 3 months to 7 years after the GTC assessment | 
| Correlation of sonographic GTC with breast cancer according to the breast US device | Correlation of sonographic GTC with breast cancer according to the breast US device (hand-held vs. automated) | from 3 months to 7 years after the GTC assessment | 
| The expected-to-observed (E/O) number of cancer diagnoses and concordance index (discriminatory accuracy) | The expected-to-observed (E/O) number of cancer diagnoses and concordance index (discriminatory accuracy) for the BCSC model (5-year risk score) and BCSC model integrated with sonographic GTC | from 3 months to 7 years after the GTC assessment | 
| Breast US diagnostic performance according to sonographic GTC | Sensitivity, specificity, positive predictive value | from the examination till 1 year after the GTC assessment |