Affiliations of authors: P. L. Porter, Program in Cancer Biology, Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, and Department of Pathology, University of Washington, Seattle; A. Y. El-Bastawissi, N. Khalid (Cancer Prevention Research Program, Division of Public Health Sciences), M. G. Lin, E. A. Watney, L. Cousens (Program in Cancer Biology), Division of Human Biology, Fred Hutchinson Cancer Research Center; M. T. Mandelson, Department of Epidemiology, University of Washington, and Center for Health Studies, Group Health Cooperative, Seattle; D. White, Department of Radiology, Group Health Cooperative; S. Taplin, Department of Family Medicine, University of Washington, and Center for Health Studies, Group Health Cooperative, Seattle; E. White, Cancer Prevention Research Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, and Department of Epidemiology, University of Washington.
Correspondence to: Peggy L. Porter, M.D., Fred Hutchinson Cancer Research Center, Cancer Biology, C1-015, 1100 Fairview Ave., N., Seattle, WA 98109 (e-mail: pporter{at}fhcrc.org).
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ABSTRACT |
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INTRODUCTION |
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Because it is difficult to separate the tumors that are masked from those that arise in the interval between screening because of rapid growth, these two categories of interval-detected cancers are often combined and assumed to be true interval cancers (12). Several investigators (1,12) have separated these "true" interval-arising cancers from those missed at screening because of technical errori.e., those that could be identified on the mammogram in retrospect. In reports of series in which such a distinction was made, true interval-arising cancers constituted 65%-75% of the cancers diagnosed in the interval between screening examinations (1,12-15). The subset of true interval cancers appears to comprise tumors that are more rapidly growing (12,13); in some studies (1,12,13,16), associations between interval cancers and measures of tumor aggressiveness, such as nodal metastasis and high histologic grade, have been reported.
The purpose of this study was to identify tumor and patient characteristics associated with increased risk of interval-detected cancer among screened women with breast cancer or, equivalently, characteristics associated with reduced likelihood of screen detection (reduced sensitivity of mammography). We compared the clinical presentation, histology, kinetics, and expression of tumor-related proteins in a study by the use of a case-control design of 150 interval- and 279 screen-detected cancers within the defined population of women participating in a screening program of a large health maintenance organization. Our data represent the largest comprehensive evaluation of the tumor characteristics of breast cancers not detected by mammography in a screened population of women.
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METHODS |
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Subjects were selected from women enrolled in the Group Health Cooperative of Puget Sound (GHC), a health maintenance organization serving 400 000 members in western Washington state. Beginning in 1986, all female members 50 years of age or older and high-risk women aged 40-49 years [those with risk factors including early onset of menarche, nulliparity by age 30 years, family history of breast cancer, or atypical hyperplasia on a previous breast biopsy (17)] were invited to participate in a formal Breast Cancer Screening Program (BCSP). Program enrollment begins by completing a BCSP Risk Factor Questionnaire and includes regular reminders to women who are due for screening. Screening occurs through centers where women receive a two-view mammogram and clinical breast examination. Approximately 85% of the women complete the questionnaire and enroll in the program; there was no appreciable change in the rate of participation over the study period. During the study period, women were sent reminders to come in for screening every 1-3 years on the basis of their breast cancer risk factors. Information from the risk factor questionnaire, results, and recommendations of all BCSP examinations and associated pathologic findings are stored in a centralized and linked database (18,19). Physicians also order screening mammograms in the course of usual care or to evaluate a symptomatic woman. These examinations occur through the radiology departments but outside the screening program.
Interval-detected cancer case subjects and comparison subjects whose breast cancer was screen detected (defined as control subjects for the purposes of this study) were drawn from women enrolled in the BCSP who had at least one screening mammogram during the period from January 1, 1988, through December 31, 1993, and who were diagnosed with a first primary invasive breast cancer within 24 months of their last screening mammogram and before their next screening mammogram. Subjects with breast cancer were identified by linking the BCSP database with the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER)1 cancer registry. Sixty-six percent of the interval-detected cancers were discovered by the patient, and 25% were detected by clinical breast examination. The study was restricted to women who did not have a history of breast cancer prior to their index mammogram and who were enrolled continuously at the GHC for at least 24 months following the index mammogram or who had died of any cause during that 24-month period. Women undergoing a biopsy gave signed consent to use their tissue for research purposes; all study procedures were approved by the human subjects review committee of the GHC.
Classification of Interval- Versus Screen-Detected Cancers
Classification of women's breast cancers into interval-detected (case subjects) versus screen-detected (control subjects) was based on the interpretation of the last BCSP mammogram before the diagnosis of breast cancer (the index mammogram). Evaluations were made after assessment of additional views, if any. For the purposes of this study, we used the BCSP database and information from medical record abstraction of all interval-detected cancer case subjects and screen-detected cancer control subjects diagnosed after 3 months from the index mammogram to reclassify the mammogram according to the Breast Imaging Reporting and Data System (BI-RADSTM) of the American College of Radiology (20). Cancers were classified as interval detected (cancer cases) if they occurred after a "negative" (BI-RADSTM code 1) or a "benign" (BI-RADSTM code 2) assessment on the index mammogram. Women who were given a recommendation for a 12-month follow-up (even though their normal follow-up interval was 2 or 3 years) were also considered as "negative" because this is a routine follow-up interval in many settings. We also counted any interpretation as "negative" if abnormalities noted by the radiologist were in the opposite breast from that where the cancer was detected.
Women's cancers were classified as screen detected if they occurred after a "positive" mammogram (BI-RADSTM code 5 = "highly suggestive of malignancy"), if they had a recommendation for surgical evaluation (BI-RADSTM code 4 = "suspicious for malignancy"), or if they had a recommendation for a 6-month follow-up (BI-RADSTM code 3 = "probably benign, short-interval follow-up suggested").
Sample Selection and Sample Size
A total of 578 women with invasive breast cancer met the eligibility requirements. One woman was dropped from the study at her request, and another was excluded because she was symptomatic at the time of the screening visit. Of the remaining 576 subjects, 162 were classified as interval-detected cancer case subjects and 414 were classified as screen-detected control subjects, using the above definitions. To conduct this study, we selected all interval-detected cancers and an approximate 2 to 1 random sample of screen-detected control subjects stratified by year of mammogram. Paraffin-embedded breast tumor tissue samples collected prior to any adjuvant treatment were available for 150 (93%) of the 162 case subjects and for 279 (97%) of the 287 selected control subjects.
Second Mammographic Assessment
We further classified the interval-detected cancers by whether or not they were detected by a second radiologist's review. An expert radiologist (D. White), blinded to the cancer status of each film, read a mixed group of mammograms: all available interval-detected cancers in the study plus mammograms from 50 randomly selected screen-detected cancers and 50 randomly selected age-stratified, cancer-free control subjects. Any additional views or ultrasound images obtained at the original assessment were available, but all marks on the films were removed. Films were interpreted by use of the five-category BI-RADSTM criteria. When a tumor was detected, the location of the lesion was indicated on the form. Of the 150 women with interval-detected cancer, films of eight could not be obtained. Of the 142 women reviewed, 44 (31%) received a positive interpretation (BI-RADSTM code 3, 4, or 5) and the affected breast was correctly identified. Those women with a negative assessment (BI-RADSTM code 1 or 2) (n = 98) from both the initial and second radiologists were termed "true interval cancers."
Laboratory Measures
Paraffin-embedded primary breast tumor tissue samples were microscopically examined for tumor characteristics and diagnosis and evaluated by immunohistochemistry for expression of selected proteins. For women with bilateral tumors diagnosed synchronously, the laboratory measures from the largest tumor were used in the analyses.
Clinical and Histologic Evaluation
Pathology data were obtained from data collected by the SEER Program and by pathology report abstraction and examination of hematoxylin-eosin-stained slides made from the tissue blocks. Information concerning tumor size, tumor location in the breast, status of surgical margins, distribution (focal versus multifocal), the number of lymph nodes examined, and the number of lymph nodes positive for tumor was abstracted from the pathology report. Tumor size was also obtained from the SEER data to minimize missing values. Data on tumor size, lymph node involvement, and metastasis of tumor were used to generate American Joint Committee on Cancer (AJCC) staging (21). Histologic diagnosis, using the World Health Organization classification of malignant breast tumors, and assignment of a histologic grade, according to the Bloom and Richardson grading scheme for invasive ductal carcinoma (22), were done by one pathologist (P. L. Porter), who was blinded to the case-control status of the material. Individual scores for differentiation, nuclear grade, and mitotic index were assessed from histology slide review along with the presence of lymphatic or vascular invasion, levels of tumor necrosis, stromal and lymphocyte response, and percentage of in situ components.
Immunohistochemical Studies
Immunoperoxidase assays for estrogen receptor (ER), progesterone receptor (PR), p53 tumor suppressor gene protein, Ki-67 proliferation-related antigen, c-erbB-2 oncogene protein, apoptosis (programmed cell death) regulatory protein bcl-2, and cell cycle regulatory proteins cyclin E and p27 were performed on sections from a single tumor block from women with interval- and screen-detected breast cancers. All scoring and interpretations of immunohistochemical results were made by the study pathologists (P. L. Porter and M. G. Lin), who had no knowledge of the interval cancer status or other clinical variables. In some instances, tumor tissue was depleted before the completion of all antibody tests, resulting in slightly different numbers of tumors tested for each antibody. Nine of the tissue samples (2%) from study participants were unsuitable for immunohistochemistry either because of an insufficient amount of tumor for analysis or because of loss of overall reactivity in the tumor block, demonstrated by poor immunoreactivity with antibodies to common antigens (e.g., cytokeratins and endothelial cell markers).
Antibodies used for the study have been extensively tested in this and other laboratories. They included monoclonal antiestrogen receptor clone ER1D5 (Immunotech, Westbrook, ME), monoclonal antiprogesterone receptor (clone1A6; Novacastra, Burlingame, CA), anti-Ki-67 clone MIB-1 (Immunotech), anti-p53 clone 1801 (Oncogene Science, Uniondale, NY), rabbit polyclonal anti-c-erbB-2 (Dako, Carpenteria, CA), hamster monoclonal anti-bcl-2 (Hockenbery Laboratory, Fred Hutchinson Cancer Research Center, Seattle, WA) (23), affinity purified polyclonal anticyclin E (Roberts Laboratory, Fred Hutchinson Cancer Research Center), and monoclonal anti-p27 clone DCS-72.F6 (Neomarkers Inc., Fremont, CA). Positive control tissue for all antibodies was tested along with the tumor tissue. Normal human tonsil was used as a positive control for p27, Ki-67, and bcl-2; formalin-fixed and paraffin-embedded pellets of rat fibroblast cells that had been engineered to overexpress cyclin E were used as positive controls for cyclin E; normal breast samples served as a control for ER and PR; and previously tested c-erbB-2- and p53-positive tumor samples served as a control for c-erbB-2 and p53. Immunostaining was done by use of previously reported immunoperoxidase procedures and modifications of the standard technique for antigen retrieval when required (26-28).
Antibodies were scored by use of a subjective interpretation of staining intensity and/or the
percentage of tumor cells that were positive. Categories of intensity and/or the percentage of
positive cells were collapsed into positive/high or negative/low categories according to the assay.
For ER and PR, any nuclear staining above negative was considered to be positive. The
percentage of Ki-67-positive tumor cells, averaged over four high-power fields, was converted to
the lowest quartile (5.7%) versus that above (i.e., upper three quartiles). Nuclear
staining of more than 10% tumor cells for p53 was considered to be positive. A
membranous staining pattern was considered to be positive for c-erbB-2. The negative and
low-intensity bcl-2 stains were grouped together as "low," while intermediate or
high staining was categorized as "high." Immunostaining for cyclin E and p27 was
given a value from 1 (negative) to 7 (highest intensity); low intensity included all values of 1-4,
and high intensity included values from 5 to 7 (29).
Statistical Methods
We used unconditional logistic regression to analyze the association of tumor characteristics
with risk of interval- versus screen-detected cancers, after adjustment for covariates. We present
odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of interval cancer among
women diagnosed with breast cancer within 24 months of a screening mammogram. (It should be
noted that, by definition, the inverse of each of these ORs is the OR for the sensitivity of
mammography, i.e., the odds of screen detection versus detection in the interval after a negative
screen among women with breast cancer.) Age at screening and tumor size confounded the
associations presented, and these were adjusted for in all models by use of 10-year age groups and
five categories of tumor size. For ordered categorical-independent variables, we tested the
statistical significance of the presence of a linear trend (P for trend) by treating the factor
as a single variable taking on the values 1,2, . . . n equal to the category number; this is
the logistic analog of the Mantel-Haenszel trend test. All P values were two-sided and
are based on Z scores, except those noted to be based on Fisher's exact test; P<.05 was considered to be statistically significant. Effect modification by age was assessed by
the statistical significance of an interaction term between age group (<50 years versus 50
years) and the tumor characteristic (expressed as a trend variable).
Analyses were also performed by use of different definitions of interval- versus screen-detected cancers: 1) the definition as described above, 2) the definition as described above except with a 12-month rather than a 24-month interval for follow-up, 3) the definition as described above except that those classified as BI-RADSTM code 3 (probably benign, short-term follow-up) were considered to be interval-detected case subjects rather than screen-detected case subjects, 4) all control subjects and only interval case subjects who had negative mammograms on the expert rereading ("true interval cancers"), and 5) only case and control subjects who presented with carcinoma other than lobular or mucinous.
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RESULTS |
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The comparison of multiple tumor characteristics related to tumor
growth and tumor aggressiveness, adjusted for age at screening
mammogram and tumor size, in all interval- and screen-detected cancers
is shown in Table 2. As shown, histologic type is a
predictor of screen detection: Tubular carcinoma was more likely to
be detected by mammography (P = .002), whereas mucinous or
lobular histology was more likely to be detected in the interval
between screening (P = .015 and .093, respectively). Women
with tumors of high histologic grade (P = .020), high nuclear
grade (P = .035), and high proliferative rate as measured
by both mitotic cell count (P = .002) and Ki-67 (P =
.003) were more likely to have interval-detected than screen-detected
cancers. ER- and PR-negative cancers were also more likely to be
detected in the screening interval, although the association with PR
negativity was not statistically significant in the analysis of
all of the interval-detected cancers. Ductal carcinomas composed of
a high percentage (>50%) of in situ disease were more
often detected by mammography screening than in the interval between
screening. p53 tumor suppressor protein and c-erbB-2 oncogene product,
two markers that in many studies are associated with poor prognosis,
were not associated with interval-detected cancers. In addition, there
were no differences in the expression of bcl-2 apoptosis-inhibitory
protein or cell-cycle regulatory proteins cyclin E and p27,
tumor location, distribution of tumor (multifocal versus unifocal),
lymphovascular invasion, level of tumor necrosis, or presence of
lymphocyte or stromal response (data not shown).
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To interpret more precisely the association of tumor characteristics
with screening mammographic or interval detection, we applied alternate
definitions for "case" and "control" or excluded tumors from
some analyses. As shown in Table 4, this included 1)
the exclusion of case subjects originally designated as
interval-detected cancers that were given a positive interpretation
(BI-RADSTM code 3, 4, or 5) on second assessment of the index
mammogram (probable false negatives), 2) the exclusion of tumors with
the histologic diagnoses that were associated with failure of
mammographic detectioni.e., mucinous and lobular types, and 3) the
exclusion of both false negatives and mammographically indistinct
subtypes (considered the most representative of tumors that truly
develop in the interval between screening or "true interval"
cancers). Overall, restriction of the analysis to true interval cancers
resulted in increased ORs for the association of high histologic grade
(OR = 2.1 [95% CI = 1.2-4.0] for all subjects and OR =
3.0 [95%
CI = 1.4-6.2] after exclusion of positive rereads and mucinous and
lobular histology) and increased proliferation measured by mitotic
count (OR = 2.9 [95% CI = 1.5-5.7] for all subjects and OR
= 4.4
[95% CI = 2.1-9.6] after exclusion of positive rereads and mucinous
and lobular histology) with interval-detected cancers. A high Ki-67
proliferation index also appeared to be more predictive of
interval-surfacing cancers than of true interval cancers but not when
just the false negatives were excluded. Tumor stage and size appeared
to be less predictive of interval cancers when the analysis was
restricted to the true interval cancers.
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DISCUSSION |
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Tumor growth patterns associated with histologic presentation are known to affect the efficacy of mammography; lobular cancer spreads diffusely and is less likely than ductal carcinoma to evoke a stromal response (5,14,31). Similarly, mucinous carcinoma exhibits a minimal stromal response and is composed of radiologically indistinct mucin. On the other hand, tubular cancers are discrete lesions composed of well-differentiated tubules of ductal epithelium surrounded by sometimes very dense collagenous stroma that are more readily visualized on mammography (12). Our finding that a high percentage of in situ component in the invasive tumor was associated with screening could conceivably result from multifocal distribution. Alternatively, this finding may suggest a greater likelihood of mammographic detection because of some factor such as calcification in in situ tumors, although it most likely reflects the limitationsi.e., low probabilityof detecting predominantly in situ tumors on clinical examination.
The established profile of aggressive breast tumors includes metastasis to regional lymph nodes, high histologic grade, loss of ERs and PRs, high proliferative rate, overexpression of c-erbB-2 oncogene, and, in some series, expression of p53 tumor suppressor protein (32,33). The tumor characteristic most frequently studied and equated with aggressive tumor behavior in interval-detected cancers is proliferative rate. More than 30% of interval-detected cancers in this study exhibited high mitotic rate versus 10% of screen-detected cancers, and 85% of the interval-detected tumors had a Ki-67 proliferation index in the highest three quartiles compared with 69% of the screen-detected cancers.
Although a high proliferative rate (as measured by flow cytometrically determined S-phase fraction or mitotic rate) has been identified by other investigators as a feature of interval-detected cancers (12,13,16,31), it is difficult to interpret the meaning of a high proliferative rate with respect to the overall aggressive nature of interval tumors, given the lead time to diagnosis, the variable proliferative rate of the tumor, and the measurement of proliferative rate at a single point in time (34). Our findings that additional tumor characteristics commonly associated with aggressive clinical behavior in breast cancer (high histologic grade, high nuclear grade, and loss of steroid receptors) were also associated with interval-detected cancers (especially when the analysis was restricted to those most likely to have truly developed in the screening interval) lend support to the hypothesis that interval cancers are biologically more aggressive than their screen-detected counterparts. The findings of other studies (13,31) that abnormal DNA content (aneuploidy) is associated with interval cancers lend further strength to the hypothesis.
One of the major features of aggressive breast cancermetastasis to regional lymph nodesis found by others to be associated with interval-surfacing cancers (13,31). In an unadjusted analysis, we also found a statistically significant association between lymph node-positive disease and interval cancer (data not shown). However, when we took into account the longer time to diagnosis of interval cancers by adjusting for tumor size (using tumor size as a surrogate for longer time to diagnosis), interval cancers were no more likely than screen-detected cancers to be lymph node positive. This finding held true using all definitions of case and control subjects and either 12 or 24 months for the definition of interval between screenings and suggests that the association between interval-surfacing tumors and lymph node-positive breast cancers stems primarily from increased time to diagnosis, even when false-negative case subjects are excluded from the analysis. Since tumor size is a function of both time and tumor growth rate, controlling for tumor size controls somewhat for both. Nonetheless, tumor growth rate as measured by the Ki-67 proliferation index and by mitotic count was still statistically significant after controlling for tumor size.
As has been reported in most studies (13-15,35,36) of interval-detected cancers, we found that interval cancers were more likely to occur in young women. Overall, women under age 50 years were about three times more likely to have a cancer that was not detected at their most recent screening mammogram than women over age 70 years. Even more striking, when we limited the analysis to those tumors most likely to have truly arisen in the interval, women under age 50 years were 10 times more likely to have interval cancer by this definition.
The increased risk of interval-detected cancers in young women has been attributed to the higher overall growth rate and aggressive nature of tumors occurring in young women; however, few studies (11,37,38) have directly compared tumor characteristics of interval- and screen-detected cancers between younger and older women. We found that high proliferation was associated with increased ORs in all age groups but with an especially high likelihood of interval cancer in young women. The association of aggressive features, such as high-grade histology and lack of steroid receptors, with interval cancer risk also appeared stronger in the group of young women. In addition to features associated with interval cancer risk, we found tumor characteristics, including percent in situ components and stromal response, which seemed to predict screen detection in young women. It is not clear why these tumor characteristics appeared to be more associated with screen detection in younger women, but it is possible that they are characteristics that enhance the detection of tumors in breasts that exhibit high radiographic density compared with those of lower radiographic density. Evaluation of mammographic density in this group of women is under way, and this may help explain the possible differences between mode of detection and tumor characteristics in young versus older women.
In summary, we have identified and characterized cancers diagnosed in the interval after screening within a defined population of women who are enrolled in a high-quality mammography screening program. The assessment of multiple markers of aggressive tumor behavior in these groups of interval- and screen-detected cancers provided a more comprehensive representation of true interval cancers than has previously been reported. We have shown that, even if observer accuracy could become optimal, there remains a subset of the most rapidly growing and highest grade tumors that will arise in the interval after screening. However, by understanding how tumor characteristics influence the sensitivity of mammography, we may be able to better understand why the sensitivity for mammography is lower for certain groups, such as younger women (39) and women on hormone replacement therapy (40). Such understanding could help inform the choice of optimal intervals between breast cancer screening examinations and improve screening technologies for specific groups of women.
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NOTES |
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Supported by Public Health Service grants U01CA63731 (to S. Taplin) and K07CA71869 (to M. T. Mandelson) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
We thank Mary Sunderland, Katy Gunville, and Kelly Wirtala for retrieval, management, and processing of the tissue specimen resource; Stephanie Stafford for the development of the laboratory database system; and Cynthia Sisk and Stephanie Hauge for the management of the mammography review. We also thank the clinicians, pathologists, and patients at the Group Health Cooperative whose expertise and participation were essential for this study.
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Manuscript received May 14, 1999; revised September 29, 1999; accepted October 1, 1999.
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