We found the method of detection to be an important prognostic factor for breast cancer survival, even after adjusting for tumor characteristics.
Because lead time manifests itself as an earlier stage of disease, fixing the stage of disease reduces the magnitude of lead-time bias. Such an adjustment, however, has little or no effect on length bias. Cancers found via screening include a higher proportion of slowly growing tumors, some of which might never be found by other means; this observation represents an extreme form of length bias known as overdiagnosis bias. Some studies indicate that the disease prognosis may be predestined at the time of diagnosis, independent of the tumoral characteristics at diagnosis [13, 14]. The other biological characteristics are potentially critical factors that determine the aggressiveness of a tumor and, thus, could be used to further quantify the length bias. The established profile of aggressive breast tumors includes metastasis to regional lymph nodes, loss of ERs and PRs, high proliferative rate and overexpression of c-erbB-2 oncogene [15, 16]. However, apoptosis has a strong association with proliferation, and in previous studies, apoptosis in primary breast carcinomas was independently associated with shorter survival [17, 18]. However, bcl-2 expression was statistically associated with a better clinical outcome and with a number of favorable prognostic features [19–21]. Our results indicate that screen-detected breast carcinomas are significantly associated with several features indicative of low malignant potential, as has been described in other studies [9, 22, 23].
The generally favorable outcomes of women with cancerous tumors detected by mammography screening compared with women whose tumors were found by other means might be explained not only by the smaller tumor size detected by screening but by the more favorable biological features of these tumors. In our series, cancerous tumors detected by screening were more often HER2/neu negative. In addition, bcl-2 and estrogen and progesterone receptors were found to be positive at a significantly higher rate in screen-detected tumors than in symptomatic tumors. Similar findings were reported by Crosier et al.  and Dawson et al. . However, these features do not fully explain the generally better outcomes of women with cancerous tumors detected by mammography screening because the mode of detection was an independent prognostic variable in the multivariate analyses.
In the present study, breast carcinoma recurrence rates were significantly lower among screened patients compared with unscreened patients after adjusting for tumor size. Two previous studies [25, 26] have also reported significant differences in 5-year recurrence rates between screened and unscreened women. In addition, our conclusions support those of other studies [5, 9] in showing that the method of detection is an independent prognostic factor. As in the study by Joensuu et al. , we adjusted the outcome for tumor size, the number of axillary lymph nodes involved, tumor grade and hormone receptor content, as well as for prognostic factors, such as Her-2 status and Ki67. Even after adjusting for all of these factors that might be expected to reflect the aggressiveness of tumor growth (and, hence, length bias due to screening), we found that diagnosis by a method other than mammographic screening was a statistically significant independent predictor of short disease-free survival. These results would appear to confirm those of previous studies that have suggested that screen detection is an independent prognostic factor for both disease-specific survival [7–9] and distant recurrence . Our results also show that in tumors < 2 cm, the disease-specific survival of symptomatic cancer is shorter than that in the screen-detected group. In fact, Joensuu et al.  observed that in women aged 50–69 years with node-negative tumors, the 10-year distant disease-free survival rate was better in the screen-detected cohort than in the symptomatically presenting group (93% vs. 87% for tumors ≤1 cm). This survival benefit is most likely due to differences in tumor biology between screen-detected and symptomatic cancers.
Interestingly, this study clearly shows that incident cancers are biologically different from prevalent ones. No previous studies have measured the expression of biological markers of prognosis in incident cancers. Incident cancers appeared to have worse prognosis than that of prevalent cancers based on the expression of biological marker. Additional tumor characteristics commonly associated with aggressive clinical behavior in breast cancer, such as positivity for Ki67 and HER2/neu, were associated with incident-detected cancers, which supports the hypothesis that incident cancers are biologically more aggressive than their prevalent screen-detected counterparts. Clearly, however, the size of breast cancers increases with time, as prevalent cancers were larger than incident cancers. The poorer outcomes for incident cancers may be associated with their biologic differences and more rapid tumor growth. In fact, these incident carcinomas were found after a “normal” mammogram, which suggests a faster growth rate for these tumors. It is known that indices of rapid growth are associated with breast cancer aggressiveness and poorer prognosis [27, 28].
It is possible that cancers diagnosed at the first screening round are subject to overdiagnosis and length bias; thus, first-round screening may have a lesser effect on breast cancer mortality. We also considered incident cancers separately from cancers found in the symptomatic group. Nevertheless, we found similar survival distributions for incident cancers and cancers detected in the symptomatic group.
In a previous work , a short, in-hospital, diagnostic delay for breast carcinomas was associated with advanced disease state and poor survival. In this series of patients, we report a short treatment delay for incident tumors. This delay most likely indicates that doctors give priority to patients with a previous negative mammogram.