Audit of performance of needle core biopsy diagnoses of screen detected breast lesions

Breast needle core biopsy (NCB) is now a standard diagnostic procedure in the triple assessment of screen detected breast lesions. Therefore, it is important to provide robust and up-to-date data on the performance of NCB in the screening setting. However, previous studies of NCB have suffered from either limitation in the number of assessed cases or included a mix of symptomatic and screen detected breast lesions. In this study, we have evaluated the performance of a large series of uniformly assessed NCBs of screen detected lesions (20001 cases) over a period of 10 years (1997-2007). Our results showed a gradual increase in the number of NCBs and an improvement of their performance over the period of the study; absolute sensitivity increased from 84.9% to 96.4% and complete sensitivity increased from 90.9% to 99.7%. There was also a gradual reduction in the number of surgical interventions after benign (B2) and negative (B1) NCB diagnoses. Our study provides data showing variance from the suggested thresholds for the measures of performance of NCB in the United Kingdom which could be used to provide updated evidence-based thresholds for assessment of performance of NCB diagnosis use in the assessment of breast cancer screen detected lesions in the UK and elsewhere.     

Outcome of radiotherapy after breast conserving surgery in screen detected breast cancers

The treatment outcomes were reviewed for all the patients at this institute who underwent breast irradiation after breast conserving surgery in 1991. Of a total of 643 patients treated, 194 (30%) had presented with tumours detected by screening mammography. The breast was irradiated with a tangential pair of fields, giving a dose of 40 Gy in 15 fractions over 3 weeks in 97% of these patients. A boost was not used. With a median follow-up of 4.7 years, there was better cancer related survival in patients with screen detected cancers compared with those that were non-screen detected (94% versus 84% at 5 years; P = 0.002). The breast recurrence rate at 5 years was 1% for screen detected cancers compared with 6% for those that were non-screen detected (P = 0.01). Factors additional to screen detected status that were found to be significant for cancer survival were pathological stage (P = 0.03) and histological grade (P = 0.01). In a Cox multivariate analysis, only two factors were significant for breast recurrence: screen detected status (P = 0.023) and histological grade (P = 0.016). This study suggests that breast irradiation with 40 Gy given over 3 weeks after breast conserving surgery for screen detected breast cancer gives a high level of local control out to 5 years.     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

A comparative study of risk factors and prognostic features between symptomatic and screen detected breast cancer

Aims

To compare prognostic factors in screen detected breast cancer (SDBC) and symptomatically presenting breast cancer (SBC).

Methods

Data were examined on 100 SDBC and 100 SBC. Multiple clinical patient factors were assessed including histopathological features. Using the Gail model each patient's risk of developing breast cancer was calculated and these data were examined for differences between groups.

Results

There was no difference in the mean age of patient presentation or in the risk of breast cancer development between groups (2.2% vs. 2.2%, SDBC vs. SBC, actuarial risk of cancer at 5 years). SDBC patients had a significantly lower grade (1.95 vs. 2.44, SDBC vs. SBC, P < 0.05), a smaller size of tumour (15.4 mm vs. 29.3 mm, SDBC vs. SBC, P < 0.05) and a higher rate of oestrogen (94% vs. 81%, P < 0.05) and progesterone (75% vs. 52%, P < 0.05) receptor positivity. When compared using the Nottingham Prognostic Index, SDBC was associated with a better prognosis (r = −0.444, P < 0.001).

Conclusions

Though both groups have similar demographics and risk, SDBC patients appear to have more favourable prognostic features. This has implications for the application of systemic therapy in breast cancer and supports the observation that SDBC is a more indolent form of disease.     

BCL-1 participates in the 11q13 amplification found in breast cancer

In an attempt to probe the significance of HST and INT-2 gene amplification in human breast carcinomas, we have surveyed the amplification status of five molecular markers located on the long arm of chromosome 11 (BCL-1, HST, INT-2 & SEA on 11q13, and ETS-1 on 11q23) in a population of 297 mammary tumors. ETS-1 was rarely amplified and always independently from the other proto-oncogenes. Concerning band q13: (i) 50 tumors (approximately 17%) were co-amplified for BCL-1, HST & INT-2; (ii) in 3 cases, amplification extended to the SEA gene; (iii) in 6 carcinomas, BCL-1 was the only amplified marker. The fact that we never observed amplification of HST & INT-2 independently of BCL-1, which in turn can be amplified solely, suggests the presence, between HST/INT-2 and BCL-1, of a genetic element which could be important in the development of a subset of mammary tumors.     

High rates of loss of heterozygosity on chromosome 19p13 in human breast cancer

We have recently discovered that the nuclear matrix protein SAFB is an oestrogen receptor corepressor. Since it has become clear that many steroid receptor cofactors play important roles in breast tumorigenesis, we investigated whether SAFB could also be involved in breast cancer. To address this question, the gene locus was examined for structural alterations in breast cancer tissue. Laser capture microdissection was used for isolating DNA from paired primary breast tumour and normal tissue specimens, and the loss of heterozygosity (LOH) at chromosome 19p13.2-3 was determined by use of microsatellite markers. LOH was detected at the marker D19S216, which colocalizes with the SAFB locus, in specimens from 29 (78.4%) of 37 informative patients. The peak LOH rate occurred at D19S216 near the SAFB locus, with LOH frequencies ranging from 21.6% to 47.2% at other markers. The finding of a very high LOH rate at the marker D19S216 strongly indicates the presence of a breast tumour-suppressor gene locus. While preliminary findings of mutations in SAFB suggest that this indeed may be a promising candidate, other potential candidate genes are located at this locus.     

Cyclin D1, EMS1 and 11q13 amplification in breast cancer

Chromosome locus 11q13 is frequently amplified in a number of human cancers including carcinoma of the breast where up to 15% carry this chromosomal abnormality. Originally 11q13 amplification was thought to involve a single amplicon spanning many megabases, but more recent data have identified four core regions within 11q13 that can be amplified independently or together in different combinations. Although the region harbors several genes with known or suspected oncogenic potential, the complex structure of the amplicons and the fact that 11q13 is gene-rich have made definitive identification of specific genes that contribute to the genesis and progression of breast cancer a difficult and continuing process. To date CCND1, encoding the cell cycle regulatory gene cyclin D1, and EMS1, encoding the filamentous actin binding protein and c-Src substrate cortactin, are the favored candidates responsible for the emergence of two of the four amplification cores.     

Loss of chromosome 11 and 11 P/Q imbalances in bladder cancer detected by fluorescence in situ hybridization

To identify chromosomal imbalances in non-diploid transitional-cell carcinoma (TCC) of the bladder we performed double-target in situ hybridization (FISH), using the centromeric probe for chromosome 11 together with 2 cosmid probes located on the 11p and 11q arm in the proximity of the telomere. The FISH protocol was optimized to ensure a highly efficient and reproducible detectability of all 3 targets. As a consequence, it was possible to calculate ratios between the number of spots obtained with cosmid and centromere probes. Furthermore, the number of chromosomes 11 present was compared with the DNA index and the chromosome ploidy as obtained with other chromosome centromere probes. In this study we found that: (i) in 54 diploid TCCs a monosomy for chromosome 11 was detected in only one case; (ii) chromosome 11 was completely lost in 9 of 16 non-diploid TCCs; (iii) in 8 of these 16 non-diploid tumors an imbalance was observed between the 11p and 11q arm, in 4 of these cases a complete loss of chromosome 11 being observed in addition; (iv) the copy number counted for 11q was always identical to the 11 centromere number, except in one case, indicating a loss of 11p in the cases with imbalances. In total, 13 of 16 non-diploid TCCs (81%) showed either a loss of a complete chromosome 11, of (part of) the 11p arm, or both. Therefore we concluded that during tetra- or aneuploidization in TCCs, (part of) chromosome 11 is lost. In addition, our results indicate that under-representation of chromosome 11p occurs in the majority of the tumor cells, supporting the idea that loss of these sequences is an important step in the development of TCC. © 1996 Wiley-Liss, Inc.     

Completion axillary dissection can safely be omitted in screen detected breast cancer patients with micrometastases. A decade's experience from a single institution

Background

The need for completion axillary lymph node dissection (ALND) in breast cancer patients with micrometastases in the sentinel nodes (SNs) is controversial. The aim of this retrospective observational study is to determine if the method of detection of early breast cancer is predictive for additional positive nodes in patients with micrometastases in the SNs.

Methods

Between 2001 and 2011 a total of 1993 women with primary unilateral breast cancer had surgery at Skåne University Hospital, Lund. Of 1993 patients, 1458 had an SN biopsy and nearly all patients with micro- and macrometastases had ALND.

Results

Micrometastases defined as >0.2 mm/>200 cells and ≤2.0 mm were found in 62 of 757 screen-detected patients and in 81 of 701 patients with symptomatic breast cancer. Only 3 of the screen-detected patients with micrometastases, all with tumour size >15 mm (range 18–39 mm), had metastases in the completion ALND whereas this was found in 18 of the symptomatic patients with micrometastases (p = 0.01), (tumour size, range 10–30 mm). Logistic regression analysis adjusted for method of detection, tumour size and histological grade showed 5 times higher odds for further metastases in ALND in patients with symptomatic presentation vs. screen-detected breast cancer.

Conclusion

Despite the small number of patients with micrometastases in this large cohort of breast cancer patients, these results support the contention that completion ALND can safely be omitted in screen-detected breast cancer patients with micrometastases in the SNs.     

Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer

We have analysed DNA from 183 primary breast cancers for amplification or rearrangement of a number of cellular proto-oncogenes, focusing primarily on a cluster of markers on the long arm of chromosome 11. Two of these oncogenes, INT2 and HST1, both of which encode members of the fibroblast growth factor family, are implicated in the generation of virally induced mammary tumours in mice. Here we confirm earlier reports that the q13 region of chromosome 11, in which these genes are tandemly linked, is modestly amplified in approximately 15% of primary human breast cancers. This amplification is confined, with one exception, to cases in which the oestrogen receptor (ER) levels are in excess of 20 fmol/mg protein (P = 0.001). However, DNA amplification does not usually result in detectable expression of either the INT2 or HST1 gene. The data imply that some other gene in the vicinity must contribute to the development of a subset of ER-positive tumours and that assessing the amplification of this region of DNA may be of value in defining a separate category of ER-positive tumour.     

A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors.

Interval breast cancer reduce the effectiveness of mammography screening programs. We studied 95 interval cancers, diagnosed during 1996 to 2001 as part of the population-based Norwegian Breast Cancer Screening Program. These cases were matched on size (+/-2.0 mm) to 95 screen-detected breast cancers, and the tumors were compared by immunohistochemical methods using tissue microarrays. Patients with interval cancers were more likely to be younger [odds ratio (OR), 4.7; P = 0.0001], to have dense breasts (OR, 3.4; P = 0.004), and to have estrogen receptor-negative tumors (OR, 2.6, P = 0.01), and p53 expression was more frequent (OR, 4.0; P = 0.001). Notably, interval cancers were more likely to have a basal epithelial phenotype, in that expression of cytokeratin 5/6 (OR, 2.3; P = 0.04) and P-cadherin (OR, 2.5; P = 0.04) was more frequent in interval cases than in size-matched, screen-detected tumors. In a logistic regression model, p53 expression, age, and breast density were independent predictors of interval cancers. Our data suggest that breast cancers with a basal epithelial phenotype are more likely than nonbasal breast cancers to present between regular mammograms.     

Prostate cancer mortality in screen and clinically detected prostate cancer: Estimating the screening benefit

BackgroundTo estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening.MethodsBetween 1997 and 1999, a total of 11,970 men, aged 55–74 years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55–74 years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006.ResultsMedian age in both groups was 63 years at study entry (p = 0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1 ng/ml. In NI, 3962 men (3.0%, p < 0.001) were diagnosed with Pca with median baseline PSA of 18.0 ng/ml (p < 0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35–0.63; p < 0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5 years: 0.63 (95% CI, 0.45–0.88; p = 0.008); absolute mortality reduction was 1.8 deaths per 1000 men.ConclusionsA relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5 years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended.