Cytometric characterization and clinical course of breast cancer diagnosed in a population-based screening program

A randomized controlled trial evaluating mammographic screening was started in two Swedish counties in 1977. In one of these, Osterg?tland county, the authors performed static cytofluorometry on 161 cancers detected at the second and third screening rounds, 50 interval cancers, and 219 cancers appearing in the nonscreened control group during the same time period. The median follow-up time was 42 months. No difference in mean S-phase was found between screening and control group cancers, but interval cancers, appearing between two screenings, had increased mean S-phase levels (P = 0.01) compared to both of the other groups. A high S-phase fraction was associated with distant recurrence in both node-negative and node-positive tumors. Aneuploid tumors were more often found in the control group (67%) and among interval cancers (72%) than among screening detected cancers (55%, P = 0.02). In Cox's multivariate analysis, including all patients, the lymph node status, tumor size, estrogen receptor content, and S-phase all contributed independent prognostic information about the clinical course. DNA ploidy predicted the outcome in simple but not in multivariate Cox's analysis. When analyzing screening-detected cancers separately, only the S-phase significantly predicted distant recurrence in multivariate analysis. In tumors with local recurrence, a high S-phase implicated an increased, although not statistically significant, risk for distant recurrence. Survival with metastatic disease was significantly influenced by the S-phase level (P = 0.002). The authors conclude that S-phase fraction provides valuable kinetic information related to the clinical outcome for all stages of the disease and serves as a prognostic factor in screened populations, which have tumors predominantly in early stages.     

Identification of women at increased risk for breast cancer in a population-based screening program.

A multivariate model to assess breast cancer risk was developed by Gail et al. (M. H. Gail, L. A. Brinton, D. B. Byar, D. K. Corle, S. B. Green, C. Schairer, and J. J. Mulvihill, J. Natl. Cancer Inst., 81: 1879-1886, 1989) based on data analysis of the Breast Cancer Detection and Demonstration Project. We evaluated the model's usefulness for assigning women to risk groups for counseling and follow-up by applying it to the 1987 Texas Breast Screening Project data. We identified 3165 women with one or more first-degree relatives affected with breast cancer. The mean risk score for the group was 3.3 (range, 2.7-11.8), indicating a greater than 3-fold elevated risk. The mean risk score for the remaining 27,439 women without affected first-degree relatives was 1.5 (range, 1.24-3.2). Risk perception was found to be a motivator for participation. Women with a risk score greater than 5 perceived themselves to be at high risk for breast cancer. The perception of risk was related to the type of affected first-degree relatives: 80.0% of the women with three affected first-degree relatives and 71.5% of women whose mother and sister were both affected with breast cancer perceived themselves to be at high risk. The Gail model is potentially useful in the clinical setting because women at high risk for breast cancer can be entered into etiological studies, enrolled in primary prevention trials, or referred to programs seeking to improve compliance with screening mammography. The Gail model needs validation, but it is useful for estimating the risk of breast cancer in large populations.     

Mammography screening interval and the frequency of interval cancers in a population-based screening.

In a population-based mammography screening, 129,731 examinations were carried out among 36,000 women aged 40-74 in the city of Turku, Finland, in the period 1987-94. Women older than 50 were screened at 2-year intervals, and those younger than 50 at either 1-year or 3-year intervals, depending on their year of birth. Screen-detected breast cancers numbered 385 and, during the same time period, 154 women were diagnosed with breast cancer outside screening in the same age group in the same city, and 100 interval cancers were detected. Two hundred and fifty (67%) of the screen-detected cancers were of post-surgical stage I compared with 45 (45%) of the interval cancers and 52 (34%) of the cancers found outside screening (P<0.0001). However, among women aged 40-49 the frequency of stage I cancers did not differ significantly among screen-detected cancers, interval cancers and cancers found outside screening (50%, 42% and 44% respectively; P=0.73). Invasive interval cancers were more frequent among women aged 40-49 if screening was done at either 1-year (27%) or 3-year intervals (39%) than in older women screened at 2-year intervals (18%; P=0.08 and P=0.0009 respectively). Even if adjusted for the primary tumour size, screen-detected cancers had smaller S-phase fractions than interval cancers or control cancers (P=0.01), but no difference in the S-phase fraction size was found between cancers of women younger than 50 and those older than this (P=0.13). We conclude that more interval cancers were found among women younger than 50 than among those older than 50 and that this could not be explained by the rate of cancer cell proliferation.     

Age-specific interval breast cancers in Japan: estimation of the proper sensitivity of screening using a population-based cancer registry

The age-specific sensitivity of a screening program was investigated using a population-based cancer registry as a source of false-negative cancer cases. A population-based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population-based cancer registry to estimate the number of false-negative cases of screening program. Among 112 071 women screened by mammography combined with CBE, the number of detected cancers, false-negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false-negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population-based cancer registry was much lower than that in women 50-59 and 60-69 years of age (40-49: 18, 71.4%, 50-59: 19, 85.8%, 60-69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population-based cancer registry for detecting false-negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age.     

Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain

Introduction

Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories.

Methods

We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was conflated into: <25%; 25 to 50%; 50 to 75%; >75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided.

Results

Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001). False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were biologically close to true interval cancers but showed no association with breast density.

Conclusions

Our findings revealed that both the distribution of tumor phenotype and breast density play specific and independent roles in each category of interval cancer. Further research is needed to understand the biological basis of the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers.     

Complementary approaches to assessing risk factors for interval breast cancer

Objective

To examine risk factors for interval breast cancer among women screened in a population-based mammography program.

Methods

Risk for interval cancer was assessed in terms of both the incidence per 10,000 negative screens and the proportion of all breast cancers diagnosed among screened women. Interval (N = 557) and screen-detected cancers (N = 1,545) were identified among 208,667 women receiving mammography in Colorado (1994?C2001). Logistic regression was used to assess independent effects of multiple factors.

Results

Overall risk of interval cancer was 29.5/10,000 women screened. Incidence was higher in women >50 years (OR: 2.28, 1.86?C2.80), with family history (OR: 2.23, 1.85?C2.70), with dense breasts (OR: 3.84, 2.76?C5.35), and using hormones (OR: 1.54, 1.20?C1.97). Hispanics had lower incidence than Whites (OR: 0.52, 0.34?C0.81). Interval cancers represented 26% of all cancers diagnosed. This proportion was higher in women <50 (OR: 1.41, 1.09?C1.82) and in women with dense breasts (OR: 2.95, 1.94?C4.48).

Conclusions

Incidence of interval cancer increases with age, breast density, hormone use, and family history. Attempts to reduce occurrence of these cancers through more sensitive and/or intensive screening should focus on these subgroups. The disproportionate number of interval cancers associated with young age and dense breasts suggests these cancers result from both rapid growth and difficulties in detection.     

Differences in risk factors for breast cancer molecular subtypes in a population-based study.

Analysis of gene expression data suggests that breast cancers are divisible into molecular subtypes which have distinct clinical features. This study evaluates whether pathologic features and etiologic associations differ among molecular subtypes. We evaluated 804 women with invasive breast cancers and 2,502 controls participating in a Polish Breast Cancer Study. Immunohistochemical stains for estrogen receptor alpha, progesterone receptor, human epidermal growth factor receptors (HER2 and HER1), and cytokeratin 5 were used to classify cases into five molecular subtypes: luminal A, luminal B, HER2-expresing, basal-like, and unclassified. Relative risks were estimated using adjusted odds ratios and 95% confidence intervals. We observed that compared with the predominant luminal A tumors (69%), other subtypes were associated with unfavorable clinical features at diagnosis, especially HER2-expressing (8%) and basal-like (12%) tumors. Increasing body mass index significantly reduced the risk of luminal A tumors among premenopausal women (odds ratios, 0.71; 95% confidence intervals, 0.57-0.88 per five-unit increase), whereas it did not reduce risk for basal-like tumors (1.18; 0.86-1.64; P(heterogeneity) = 0.003). On the other hand, reduced risk associated with increasing age at menarche was stronger for basal-like (0.78; 0.68-0.89 per 2-year increase) than luminal A tumors (0.90; 0.95-1.08; P(heterogeneity) = 0.0009). Although family history increased risk for all subtypes (except for unclassified tumors), the magnitude of the relative risk was highest for basal-like tumors. Results from this study have shown that breast cancer risk factors may vary by molecular subtypes identified in expression studies, suggesting etiologic, in addition to clinical, heterogeneity of breast cancer.     

Radiological surveillance of interval breast cancers in screening programmes

Interval breast cancers-those diagnosed after a negative mammographic screen and before the next scheduled screen-are an important indicator of the potential effectiveness of population screening for breast cancer. Although the incidence of interval cancers is usually monitored, radiological surveillance is not undertaken routinely in most screening programmes. Here, we describe radiological surveillance of interval breast cancers and discuss methodological difficulties in the radiological review process and in the categorisation of interval cancers as false-negative, true, or occult. Furthermore, we identify methods that affect whether an interval cancer is classified as a false-negative (missed) or a true interval cancer. For all radiological categories of interval cancers, we outline possible changes to screening programmes that might improve cancer detection. Standardised radiological surveillance of interval cancers might allow within-programme comparisons and has the potential to guide practice and improve quality.     

The value of risk factors in screening for breast cancer

The value of risk factors in selecting women for repeat screening for the detection of early breast cancer is considered. The screening methods used are a detailed history, clinical examination, thermography and mammography. The risk factors assessed are the effect of a personal and family history and thermography. There are 11 240 women in the series. The incidence of cancer in the no risk group is 24/5825 (0.4%), the group with one risk factor 127/3881 (3.3%) and in those with more than one factor 263/1534 (17.1%). It is suggested that the use of risk factors is sufficiently discriminating to select women for further screening over the next 10 years after an initial negative test.     

Sporadic breast, ovarian, or uterine cancers as risk factors for colorectal cancer

Sporadic colorectal, breast, endometrial, and ovarian cancers are common human malignancies. Not surprisingly, epidemiologic studies have identified multiple shared risk factors, including obesity, low exercise levels, and possibly hormonal (particularly estrogen) modulation. In addition, unlike hereditary nonpolyposis colorectal cancer syndrome, in which colorectal, endometrial, and ovarian cancers may occur because of a germline mutation in important mismatch repair genes, sporadic versions of these cancers may develop because of shared epigenetic alterations. These changes may be useful predictors of clinical outcome and response to disease-specific therapies.     

Stage-specific breast cancer incidence rates among participants and non-participants of a population-based mammographic screening program

The Norwegian Breast Cancer Screening Program was rolled out county by county over the course of a decade, from 1996 to 2005, and now encompasses all Norwegian women aged 50–69 years. We aim to compare DCIS and stage-specific invasive breast cancer incidence rates among participants, non-participants, and women not yet invited to the screening program over this entire implementation period. We estimate stage-specific breast tumor incidence rates for 640,347 women 50–69 years of age invited to the screening program between 1996 and 2007. We compare incidence rates and stage distribution among women diagnosed with breast cancer who were invited and participated, invited but not participated, and women not yet invited to the screening program using two-sided Chi-squared tests to determine statistical significance between groups. The incidence of ductal carcinoma in situ (DCIS) was 3.0 times higher and invasive breast cancer was 1.5 times higher for invited participants compared to invited non-participants (p < 0.001). While the incidence of Stage I cancer was two times higher among participants compared to non-participants (p < 0.001), the incidences of Stages III and IV cancer were two and three times lower, respectively, among participants compared to non-participants (p < 0.001 for both). No significant differences in stage-specific incidence or treatment utilization rates were observed between invited non-participants and not yet invited women, except for stage IV cancers, which were detected at a higher rate among women who were not yet invited (7.5 vs. 4.6 %, p = 0.001). Compared with women invited who did not participate, participants in the screening program are more likely to be diagnosed with DCIS and early stage invasive breast cancer and are less likely to be diagnosed with advanced stage breast cancer. More research is required to determine whether these differences in stage-specific incidences among invited participants and non-participants are associated with differences in mortality rates.     

Validation of a tool for identifying women at high risk for hereditary breast cancer in population-based screening

BACKGROUND: Recent scientific advances provide the opportunity to identify women in the general population at increased breast cancer risk and to offer effective early detection and disease prevention interventions. METHODS: A pedigree assessment tool (PAT) was designed to identify women in primary care settings who are at increased risk for hereditary breast cancer, including potential BRCA mutation carriers. The PAT is a simple point-scoring system based on family cancer history with points weighted to account for features associated with a higher probability that a BRCA mutation is present. The ability of the PAT and the Gail model to accurately identify potential BRCA mutation carriers in 3,906 women without a personal history of breast cancer presenting for a screening mammogram at a community hospital was tested. RESULTS: Eighty-six (2.2%) women had a family history indicative of a high probability (>10%) that a BRCA mutation was present within the family. The PAT performed better than the Gail model in correctly assigning women to the "high BRCA probability" cohort. The area under the receiver operating characteristic (ROC) curve for the PAT was 0.9625 compared with 0.389 and 0.5861 for the Gail model 5-year and lifetime risk estimates, respectively. At the optimal threshold score, the PAT performed with 100% sensitivity and 93% specificity. CONCLUSIONS: The PAT is a simple and accurate tool for identifying women at risk for the hereditary breast cancer syndromes that can be employed as part of a comprehensive breast cancer risk-screening strategy in the primary care setting.     

Breast cancer risk factors among screening program participants.

Data were obtained by mailed questionnaire from 405 breast cancer patients identified during the first 2 years of operation of the Breast Cancer detection Demonstration Project in the U.S. and from a sample of 1156 normal screenees (response rate = 88%) in an attempt to examine whetHer the usual risk indicators for breast cancer apply to individuals participating in screening programs. No substantial differences were found between the respondents and the nonrespondents for the variables on which information had been obtained at the time of the initial screening. Nearly all of t(e recognized risk factors were seen in this population. The relative risk (FF) of breast cancer was 3.9 among women whose mothers were also affected; this finding was statistically significant. Relative risk was increased for women reporting early menarche, late menopause, nulliparity, late age when 1st child was born, and excessive weight. The relative risk was not elevated in women with a prior breast biopsy but was excessive for those with more than 1 biopsy. No association with thyroid medications or menopausal hormones was found. Among women having undergone a natural menopause, a nonstatistically significant elevation in the relative risk was noted for long term oral contraceptive users; this excess relative risk was restricted to those using OCs in the presence of breast cancer risk indicators. The results indicate the need for further study of women with extended periods of OC use, particularly when accompanied by other known risk indicators.     

Developing a breast cancer screening program for Chinese-American women

The Chinese, like other minority groups, often underuse cancer screening services because of language, cultural, and economic barriers. Nonattendance reduces the probability that cancer will be detected in its earliest and often most curable form. To improve use of cancer screening services among Chinese-Americans, a community-based coalition organized a one-day demonstration cancer awareness and screening program--the Breast Cancer Screening Day for Chinese Women. More than 100 women, many of whom did not speak English, attended the program. Six abnormal mammograms required follow-up and one breast cancer was detected. The planning process used to develop this successful project is described as are suggestions to improve future screening programs for ethnic minorities.     

Prognostic factors for node-negative breast cancers: Results of a study program by the Japanese breast cancer society

Background  Prognostic factors for predicting the recurrence of node-negative breast cancers have been controversial. The present study was performed to elucidate practically useful prognostic factors using formalin-fixed paraffin sections. Methods  This was a case-controlled multi-institutional study that composed 40 patients with recurrent node-negative breast cancer and 80 patients with node-negative breast cancer but without recurrence after radical surgery. Tumors were smaller than 3 cm in diameter and were treated surgically between January 1, 1985 and December 31, 1990. The recurrent and non-recurrent cases were matched with regard to their age, adjuvant chemotherapy and the year in which surgery was performed. Fourteen immunohistochemical factors and 8 histological factors of the primary tumor were studied on formalin-fixed, paraffin-embedded sections by immunohistochemical and histochemical analyses. Results  According to univariate analysis, factors such as progesterone receptor (PgR), MIB-1, CD44_v6, CD44_v9 and platelet-derived endothelial cell growth factor (PDECGF) were significantly different between the recurrent and non-recurrent groups (p>0.1; Wilcoxon-Mann-Whitney analysis). Chisquared test showed significant differences in MIB-1, cdc2 and stromal plasminogen activator receptor (suPAR). Histologically, mitotic count was also significantly different between the two groups (p>0.005). Multivariate analysis revealed that positivity for cdc2 (p=0.01), high mitotic count (p=0.04) and negativity for CD44_v9 (p=0.02) were independent prognostic factors among variables selected by univariate analysis, and that positivity for MIB-1 (p=0.03) and cdc2 (p=0.01), and negativity for CD44_v9 (p=0.03) were independent prognostic factors among the immunohistochemical markers examined. Conclusion  Our results indicated that positivity for MIB-1 and cdc2, high mitotic count and negativity for CD44_v9 could serve as independent factors for predicting the recurrence of node-negative breast cancer.