In summary, we compared the clinical outcomes of patients whose tumors were detected by screening examinations with those whose tumors were detected symptomatically. After adjusting for the known prognostic factors and major treatments received, we found the tumor detection method to be an independent predictor of disease recurrence. Specifically, patients with symptom-detected breast tumors had a greater risk of recurrence and death (RR for RFS =1.34, 95% CI = 1.09 to 1.66, P = 0.006; RR for BCSS = 1.31, 95% CI = 0.93 to 1.84, P = 0.117) than patients with screen-detected tumors.
The only tumor characteristic significantly associated with method of detection was Ki67, when including all four biomarkers in the regression model (the last column in ). Our observation that screen-detected tumors tended to have lower Ki67 expression and ER-positive status is consistent with earlier observations that screening examinations preferentially identify cancers with these prognostic features (18
). Because of missing Ki67 and HER2/neu score in the data, we performed exploratory analyses to examine the missing patterns of Ki67 expression and HER2/neu score by patient age, race, and other tumor characteristics. The results indicated that the subgroup of patients who had Ki67 information was sufficiently representative of the general cohort of patients with breast cancer at M. D. Anderson, because the missing Ki67 data were evenly distributed among each of the above factors. The analysis results using Ki67 data should be representative enough in Tables -. In contrast, the missing pattern of HER2/neu IHC score was dependent on the year of diagnosis. Patients diagnosed between 1997 and 1998 were less likely to have HER2/neu data, as expected.
Similar to the findings in many other studies (21
), we found that African American women had an elevated risk of death from breast cancer (RR = 1.87; 95% CI = 1.36 to 2.58) compared to women of other races, after adjusting for method of detection, tumor characteristics and treatments. While it is critical to promote targeting education and screening services to minority populations, a parallel effort is to better understand biologic difference in tumors among different ethnic groups to improve disease prognosis among minorities.
Our results are also consistent with conclusions from randomized screening trials, including a study of the Health Insurance Plan [HIP] and the Canadian National Breast Screening Studies [CNBSS] (7
), and an observational study based on the Finnish Cancer Registry (8
). In the former study, patients in the control groups had an increased risk of breast-cancer–specific death (RR = 1.36; 95% CI = 1.10 to 1.68) than patients in the screening groups, after accounting for tumor size, lymph node status, and disease stage. In the latter study, patients in the non-screened group had 1.90 times greater risk of distant recurrence (RR = 1.90; 95% CI = 1.15 to 3.11) and 2.11 times greater risk of breast-cancer–specific death (RR = 2.11; 95% CI = 1.16 to 3.85) after controlling for the number of positive lymph nodes, tumor size, PR status, histological grade, HER2/neu amplification, and patient age. The differences separating the current study from the earlier studies with similar conclusions include the following: 1. this study uses the largest sample size from one of the largest multidisciplinary breast cancer centers in the U.S.; 2. this study focuses on recently diagnosed patients (from 1997-2005) who have received adjuvant chemotherapy and hormonal therapies in the modern era; and 3. patient information in this study includes biomarker data such as Ki67 expression and HER2/neu IHC score that has become available only recently.
There are several limitations of our study. First, it is observational. Unlike randomized controlled screening trials, women who chose to have screening examinations may have very different characteristics from those who did not. However, despite the possibility of such a bias, our conclusions from this observational study are consistent with those of our earlier study of the HIP and CNBSS randomized trials (7
). Second, conclusions from this study were based on the data from a single hospital, which may be subject to some selection bias. Compared with the Surveillance, Epidemiology, and End Results [SEER] data collected from 17 geographic areas of the United States for women aged 40 years and older and diagnosed with primary invasive breast cancer between 1997 and 2003, we found that more patients represented in the breast cancer database at M. D. Anderson tended to have later-stage breast cancer (16.7% stage III/IV tumors compared to 10.4% stage III/IV tumors from SEER), and to be of a racial/ethnic minority (9.9% African American and 15.1% Hispanic and other minority women, compared to 8.3% African American and 7.2% other minority women from SEER). Patients represented in the database at M. D. Anderson were also younger than those from the SEER database: 36.4% compared to 18.4% of patients, respectively, were younger than 50 years. Finally, the information on breast density at diagnosis is not available in our database.
Part of the observed residual survival benefit associated with tumor screening may not be completely due to screening itself but is partially due to lead-time bias and length bias. As indicated in our results, women diagnosed by screening examinations often had better tumor characteristics at diagnosis than those otherwise diagnosed, which explained the lead-time bias. The amount of time by which the diagnosis is advanced as a result of early detection by screening is the lead-time. Length-bias is revealed from the fact that tumors detected by screening examination may have biologic profiles (e.g., slower growing or less aggressive) that are different from tumors otherwise diagnosed (7
). The finding that patients with screen-detected tumors still have better prognosis than those with symptomatically detected tumors after adjusting for tumor characteristics such as ER/PR status, Ki67 expression and HER2/neu score in the models indicates that the improved prognosis of screen-detected patients is due to some combination of length bias and actual screening benefit. But it is impossible to separate length-bias and the actual screening benefit.
Breast tumors are heterogeneous. It is still impossible now to obtain a complete profile to describe the heterogeneity of the tumors. Including method of detection in the model better enables predicting patients' prognoses. Method of detection is not a prognostic factor in the conventional sense (such as tumor size and nodal status), but it gives important information and partially adjusts for length bias.
This study suggests that the information of the detection method should be routinely collected in the breast cancer database to help clinical trialists and health care providers improve prognosis prediction for patients with breast cancer.