Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain
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Date
2014
Authors
Domingo, Laia
Salas, Dolores
Zubizarreta, Raquel
Baré, Marisa
Sarriugarte, Garbiñe
Barata, Teresa
Ibáñez, Josefa
Blanch, Jordi
Puig-Vives, Montserrat
Fernández, Ana Belén
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Abstract
Introduction: Interval cancers are tumors arising after a negative screening episode and before the next screening
invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors
based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe
tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer
categories.
Methods: We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from
2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers
were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224),
minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was
conflated into: <25%; 25 to 50%; 50 to 75%; >75%. Tumor-related information was obtained from cancer registries
and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER
+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype
and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and
95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided.
Results: Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True
interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96),
OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)).
However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly
fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001).
False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast
density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were
biologically close to true interval cancers but showed no association with breast density.
Conclusions: Our findings revealed that both the distribution of tumor phenotype and breast density play specific and
independent roles in each category of interval cancer. Further research is needed to understand the biological basis of
the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers.
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Breast Cancer Research, 2014, vol. 16, núm. 3, p. 1-11