Antoni S, Sasco AJ, dos Santos Silva I, McCormack VIs mammographic density differentially associated with breast cancer according to receptor status? A meta-analysis. Breast Cancer Res Treat 137: 337-347

International Agency for Research on Cancer, 150 cours Albert Thomas, 69008, Lyon, France.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 12/2012; 137(2). DOI: 10.1007/s10549-012-2362-4
Source: PubMed


Mammographic density (MD) is a strong marker of breast cancer risk, but it is debated whether the association holds, and is of a similar magnitude, for different subtypes of breast cancer defined by receptor status or gene expression profiles. A literature search conducted in June 2012 was used to identify all studies that had investigated the association of MD with subtype-specific breast cancer, independent of age. 7 cohort/case-control and 12 case-only studies were included, comprising a total of >24,000 breast cancer cases. Random effects meta-analysis models were used to combine relative risks (RR) of MD with subtype-specific breast cancer for case-control studies, and in case-only studies to combine relative risk ratios (RRR) of receptor positive versus negative breast tumors. In case-control/cohort studies, relative to women in the lowest density category, women in the highest density category had 3.1-fold (95 % confidence interval [CI] 2.2, 4.2) and 3.2-fold (1.7, 5.9) increased risk of estrogen receptor positive (ER+) and ER- breast cancer, respectively. In case-only analyses, RRRs of breast tumors being ER+ versus ER- were 1.13 (95 % CI 0.89, 1.42) for medium versus minimal MD. MD remained associated with screen-detected ER+ tumors, despite the expectation of this association to be attenuated due to masking bias and overdiagnoses of ER+ tumors. In eight contributing studies, the association of MD did not differ by HER2 status. This combined evidence strengthens the importance of MD as a strong marker of overall and of subtype-specific risk, and confirms its value in overall breast cancer risk assessment and monitoring for both research and clinical purposes.

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    • "Like other studies [37], we found no difference in associations by PR status; however, one recent case-only study found that tumors diagnosed in women with denser breasts were more likely to be PR-positive compared with tumors in women with more fatty breasts [18]. Our findings of MD positively associated with both HER2-negative and HER2-positive tumors within age groups are consistent with prior studies [11,15,19,20], including a meta-analysis of studies that did not show MD differentially associated by tumors defined by HER2 across all ages combined [19]. The significant interaction between MD, HER2 status, and age that we observed may have been influenced by small numbers of HER2-positive tumors in older age groups and/or due to chance. "
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    ABSTRACT: Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models. Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (<55, 55--64, and >=65 years). MD was positively associated with risk of invasive tumors across all ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55--64 and >=65 years (Page-interaction = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P's < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55--64 and >=65 years (Page-interaction = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group. MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.
    Breast cancer research: BCR 11/2013; 15(6):R104. DOI:10.1186/bcr3570 · 5.49 Impact Factor
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    • "Of the thirteen studies with cases only, all but two [34,35] concluded that there were no significant differences in mammographic density by hormone receptor status [36-46]. A recent meta-analysis on the topic also concluded that mammographic density is similarly strongly associated with both ER+ and ER- tumors [47]. "
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    ABSTRACT: Mammographic density is a strong risk factor for breast cancer overall, but few studies have examined the association between mammographic density and specific subtypes of breast cancer, especially aggressive Basal-like breast cancers. Because Basal-like breast cancers are less frequently screen-detected, it is important to understand how mammographic density relates to risk of Basal-like breast cancer. We estimated associations between mammographic density and breast cancer risk according to breast cancer subtype. Cases and controls were participants in the Carolina Breast Cancer Study (CBCS) who also had mammograms recorded in the Carolina Mammography Registry (CMR). A total of 491 cases had mammograms within five years prior to and one year after diagnosis and 528 controls had screening or diagnostic mammograms close to the dates of selection into CBCS. Mammographic density was reported to the CMR using Breast Imaging Reporting and Data System categories. The expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 1 and 2 (HER1 and HER2), and cytokeratin 5/6 (CK5/6) were assessed by immunohistochemistry and dichotomized as positive or negative, with ER+ and/or PR+, and HER2- tumors classified as Luminal A and ER-, PR-, HER2-, HER1+ and/or CK5/6+ tumors classified as Basal-like breast cancer. Triple negative tumors were defined as negative for ER, PR and HER2. Of the 491 cases 175 were missing information on subtypes; the remaining cases included 181 Luminal A, 17 Luminal B, 48 Basal-like, 29 ER-/PR-/HER2+, and 41 unclassified subtypes. Odds ratios comparing each subtype to all controls and case-case odds ratios comparing mammographic density distributions in Basal-like to Luminal A breast cancers were estimated using logistic regression. Mammographic density was associated with increased risk of both Luminal A and Basal-like breast cancers, although estimates were imprecise. The magnitude of the odds ratio associated with mammographic density was not substantially different between Basal-like and Luminal A cancers in case--control analyses and case-case analyses [case-case OR = 1.08 (95% confidence interval: 0.30, 3.84)]. These results suggest that risk estimates associated with mammographic density are not distinct for separate breast cancer subtypes (Basal-like/Triple negative vs. Luminal A breast cancers). Studies with a larger number of Basal-like breast cancers are needed to confirm our findings.
    Breast cancer research: BCR 09/2013; 15(5):R76. DOI:10.1186/bcr3470 · 5.49 Impact Factor
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    • "Lastly, MD may be associated with tumor characteristics or tumor subtype. Results are highly inconsistent, although most of these studies show no association [4-9]. Previous studies directly addressing the relationship between PD and survival show conflicting results [10-13], but the most recent and largest study [10] failed to detect an association between pre-diagnostic MD and survival. "
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    ABSTRACT: It is debated whether mammographic density gives rise to more aggressive cancers. We therefore aimed to study the influence of mammographic density on prognosis. This is a case-only study within a population-based case-control study. Cases were all postmenopausal women in Sweden with incident breast cancer, diagnosed 1993-1995, and aged 50-74 years. Women with pre-diagnostic/diagnostic mammograms were included (n=1774). Mammographic density of the unaffected breast was assessed using a computer-assisted thresholding technique. The Cox proportional hazards model was used to study recurrence and survival with and without stratification on surgical procedure (breast-conserving surgery vs. mastectomy). Percentage density (PD) was associated with both local and locoregional recurrence even after adjustment for established prognosticators; hazards ratio (HR) 1.92, p=0.039, for local recurrence and HR 1.67, p=0.033, for locoregional recurrence for women with PD>=25% compared to PD<25%. Stratification on surgical procedure showed that the associations were also present in mastectomized women. PD was neither associated with distant recurrence nor survival. High mammographic density is an independent risk factor of local and locoregional recurrence but is neither associated with distant metastasis nor survival. The relationships with local and locoregional recurrences were also present in women treated with mastectomy, indicating that they are not merely explained by density masking residual disease in women treated with breast-conserving surgery. Rather there appears to be a true association. Thus, mammographic density should possibly influence adjuvant therapy decisions in the future.
    Breast cancer research: BCR 07/2013; 15(4):R56. DOI:10.1186/bcr3450 · 5.49 Impact Factor
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