Impact of mammographic screening on the detection of good and poor prognosis breast cancers

Abstract

We sought to compare the molecular signature of node negative cancers from two cohorts 15 years apart, to determine if there is molecular evidence of increase in low and ultralow risk cancers over time. We studied the impact of age, time period of diagnosis, and mammographic screening on biology of tumors where The Netherlands Cancer Institute 70-gene prognosis signature was generated as part of 2 validation series, one retrospective (1984-1992), Cohort 1, and one prospective (2004-2006), Cohort 2. A total of 866 patients were analyzed. Regardless of time period of diagnosis, the proportion of T1, grade 1, hormone receptor positive (HR) tumors, and good prognosis by 70-gene signature significantly increases as age increases (P < 0.01). In women aged 49-60, the time period of diagnosis significantly affects the proportion of cancers that were NKI 70-gene low risk: 40.6% (67/165) compared with 58% (119/205) for Cohorts 1 and 2, respectively. This is in contrast to the absence of a significant change for women under age 40, where 25% (17/68) and 30% (17/56) were low risk in Cohorts 1 and 2, respectively. In women aged 49-60, using an ultralow risk threshold of the 70-gene signature, 10% of tumors in Cohort 1 were ultralow risk compared with 30% for women with screen-detected cancers in Cohort 2. Older age and method of detection (screening) are associated with a higher likelihood of a biologically low risk tumor. In women over age 50, biologically low risk tumors are frequent and tools that classify risk may minimize overtreatment.

Fig. 1

Identification of an ultralow risk subset. An additional 70-gene signature index score was designated as ultra-low (threshold at index score = 0.6). Expression array heat map showing the 70-gene profile for the original 78 patients. Every row represents a patient and every column one of the 70 genes. The standard threshold for good prognosis tumors is represented by the thick red dashed line and the threshold for the ultralow risk designation is the thin blue dashed line. Adjacent to the array on the right is the Cosine correlation coefficient to the average good prognosis profile and represents the index score. The column on the far right shows the outcome for each patient either black (absence of distant metastasis) or white (presence of metastasis). Adapted from van't Veer, Nature [7]

Fig. 2

Mammographic screening results in an increase in the proportion of good prognosis cancers in Cohort 2, among women invited for population-wide screening. a Percentages of good versus poor prognosis cancers as a fraction of all cancers from Cohorts 1 and 2, respectively, are shown for patients under 40 years. There is no difference in the proportion of good prognosis cancers between Cohorts 1 and 2. Women in this age range did not undergo mammographic screening in either Cohort. b The percentages of good versus poor prognosis cancers as a fraction of all cancers in Cohort 1 and Cohort 2, respectively, are shown for patients aged 49–60 years. This age group was invited to participate in mammographic screening in Cohort 2, but not in Cohort 1. The third column shows the percentages of good versus poor cancers in the subset of Cohort 2 whose cancers were screen-detected. The P value refers the proportion of the low risk cancers as compared with Cohort 1

Fig. 3

Patients from Cohort 2 have tumors with a much higher proportion of low and ultralow risk biology. a Distribution of 70-gene prognosis index scores in women aged 49–60 years in the Cohort 1 (top panel), Cohort 2 (second panel), and the subsets of women from Cohort 2 with non-screen-detected (third panel) and screen-detected (fourth panel) cancers by frequency percent. An index score greater than 0.4 (solid line) corresponds to tumors with a good prognosis (low risk), and an index >0.6 (dashed line) corresponds to ultralow risk. b Distribution of 70-gene signature risk groups as a percentage of total cancers in Cohort 1 versus screen-detected cancers from Cohort 2 in patients aged 49–60 years. The ultralow risk group is defined as index score >0.6, low risk (non-ultralow) is index score between 0.4 and 0.6, and high risk is index score <0.4. In the screen-detected group, 64% are low risk, approximately half of which are ultralow risk