Background Mammographic density (MD) is a solid marker of breast cancer risk, but it is unclear whether tumours arise specifically within dense tissue. 1cm-squares that subsequently contained the tumour and 41.0% (31.5%-53.9%) for the whole-breast. The odds of a tumour arising in a 1cm-square were, respectively, 6.1 (95%CI: 1.9, 20.1), 16.6 (5.2, 53.2) and 25.5-fold (8.1, 80.3) higher for squares in the 2nd, 3rd and 4th quartiles of pre-diagnostic MD relative to those in the lowest quartile within that breast (Ptrend 0.001). The corresponding odds were 2.3 (1.3, 4.0), 3.9 (2.3, 6.4) and 4.6 (2.8, 7.6) if a 3cm-square grid was used. Conclusion Tumours arise SU 5416 inhibitor predominantly within the radiodense breast tissue. Impact Localised MD may be SOCS2 used as a predictor of subsequent tumour location within the breast. em 0.001 /em Open in a separate window MD=mammographic density aThe total number is less than 231 because tumour-squares for which no control squares of similar size (i.e. within 10%) could be identified were excluded (see Methods section). bOdds ratio (OR) and 95% confidence interval (CI) estimated using a conditional logistic regression model where the matching set SU 5416 inhibitor is a womans pre-diagnostic breast consisting of a square where the tumour will subsequently originate (tumour-square) and several tumour-free squares (control-squares) (see Methods section). The association between within-woman square-specific MD quartiles and subsequent tumour location was not modified by pre-diagnostic whole-breast MD (0%?, 20%?, 40%? and 60%+), time between pre-diagnostic film and cancer diagnosis ( 5 and 5 years), or the nature (exclusively non-invasive vs. invasive/non-invasive), grade (1/2 vs. 3) and size ( 20mm vs. 20mm) of the tumour (P for interaction: 012 in all for a 3cm grid; P028 in all for a 1cm grid). Using the extremely high dense threshold, ORs (95% CI) were 1, 12 (05-30), 17 (10-28) and 47 (35-63) for percent of extremely high density in the square being 25% (reference category), 25-49%, 50-199% and 200%, respectively. 36% of tumour-squares, but only 17% whole-breasts, had squares with 20% extremely high density. Discussion This study demonstrates that breast tumours arise predominantly within pre-diagnostic radiodense cells. The likelihood of a location subsequently developing right into a tumour improved as the quantity of radiodense cells in that region increased, highly suggesting that it’s particularly concentrations of radiodense fibroglandular cells that are in risk of going through malignant transformation. Strengths and restrictions Previous research (7-8) assessed whether tumours originated within the quadrant with the best pre-diagnostic MD. Applying this process to SU 5416 inhibitor your data yielded a fairly poor association (P=007) because 75% of our tumour-squares (no matter grid size) had an increased density compared to the highest density quadrant. The usage of a validated sign up technique (10) to accurately align serial digitised mammograms can be a major power of our research since it allowed the measurement of localised MD at a very much smaller sized level. The precision of the affine sign up is relatively lower for pictures with small density (10), nonetheless it can be unlikely that affected considerably our results because virtually all pre-diagnostic images had some density (5th percentile of pre-diagnostic whole-breast MD: 168%) and the magnitude of the association between square-specific MD and tumour location did not vary according to pre-diagnostic whole-breast MD level. Radiologists were unable to identify the tumour on the diagnostic films for 17% of cases, mainly because their breasts were dense. This, coupled with the fact that these cases had higher pre-diagnostic whole-breast MD than those included in the study (mean difference 78%, 95% CI 26%-130%), provides further indirect support to the hypothesis that tumours arise predominantly within pre-diagnostic dense tissue. As density, and its spatial distribution within the breast, change with age, it would be informative to assess images taken further back in time. The participants were mainly pre-menopausal.