Danish Breast Cancer Group Research Articles

Oncoplastic breast surgery does not delay the onset of adjuvant chemotherapy: a population-based study

Background: Only a few studies of limited size have examined whether oncoplastic breast surgery delays the onset of adjuvant chemotherapy as compared to conventional breast surgery. We investigated whether oncoplastic breast surgery causes a delay in the onset of adjuvant chemotherapy in comparison to lumpectomy and mastectomy.Material and methods: The study is a population-based cohort study. Within the nationwide registry of the Danish Breast Cancer Group (DBCG), we identified 1798 patients who received adjuvant chemotherapy following mastectomy, lumpectomy or oncoplastic breast surgery for early and unilateral invasive breast cancer. Women treated with neoadjuvant chemotherapy were excluded.Results: We found no significant difference between the three groups (mastectomy, lumpectomy, oncoplastic breast surgery) in the time from biopsy to surgery (mean time 17.9, 17.0 and 18.3 days, respectively), the time from surgery to onset of adjuvant chemotherapy, nor total time from biopsy to the onset of adjuvant chemotherapy (mean time 52.7, 51.9 and 53.2 days, respectively).Conclusions: Our study shows that oncoplastic breast surgery does not delay the onset of adjuvant chemotherapy in comparison with mastectomy and lumpectomy. Accordingly, patients should not be excluded from treatment with oncoplastic breast surgery due to concerns of delay in adjuvant chemotherapy.

Failure pattern and survival after breast conserving therapy. Long-term results of the Danish Breast Cancer Group (DBCG) 89 TM cohort

Based on the results from the DBCG 82 trial, breast conserving therapy (BCT) has been implemented as standard in Denmark since 1989, and today constitutes more than 70% of the primary treatment. Our aim was to evaluate the implementation of BCT as a routine procedure in patients treated according to the DBCG 89 program and compare recurrence pattern and survival both overall and when separated in age groups, with the results from the randomized DBCG 82 TM trial. Material and methods: A total of 1847 patients treated between 1989 and 1999 were included in a retrospective population-based cohort study. Data from the DBCG database were completed via search through the Danish Pathology Data Bank and medical records. Results: Median follow-up time was 17 years. At 20 years the cumulative incidences of local recurrence (LR) and disease-specific mortality (DSM) were 15.3% and 25.8%, respectively. Twenty-year overall survival (OS) and recurrence-free survival were 63.7% and 43.1%, respectively. Subdivided by age groups cumulative incidences at 20 years were LR: 18.9%, 10.5% and 12.4%, and DSM: 28.9%, 18.9% and 28.4% in young (≤45 years), middle-aged (46–55 years) and older (≥56 years) women, respectively. In an adjusted analysis age maintained a significant and independent effect on both LR and DSM. Conclusion: The DBCG 82 TM program was successfully implemented. The women treated with BCT in the DBCG 89 program displayed equal failure pattern and improved survival in comparison with women from the DBCG 82 TM protocol. Occurrence of first failure and mortality varied with age; demonstrated by increased risk of LR, DM and DSM in the young patients and increased risk of DM and DSM in the older patients, compared to the middle-aged patients.

New and chronic use of hypnotics after diagnosis with early breast cancer. A retrospective cohort study

Background. To determine use and investigate factors associated with use of hypnotics the first year after a diagnosis with breast cancer.Material and methods. A retrospective registry based cohort study linking clinical data from the Danish Breast Cancer Group with the National Prescription Drug Database and other health and administrative registries. We included 26 082 women diagnosed with early breast cancer as first time primary cancer during 1996–2006. Use of hypnotics was measured as redeemed prescriptions in the first year after diagnosis of early breast cancer. Prior use of hypnotics was defined as one or more prescriptions of hypnotics 13 months to 1 month before diagnosis, and chronic use was defined as four or more prescriptions. Hazard ratios (HRs) for clinical variables, treatment-related factors and sociodemographic factors were calculated.Results. Among women with no prior history of hypnotic use, 17% became new users with 4% on a chronic level. Among prior users, 82% continued their use with one or more prescriptions of hypnotics and 15% increased their use to a chronic level. Significantly increased hazard ratios for use of hypnotics were seen with increasing age [age 50–59 years: HR 1.43 (95% CI 1.31–1.57), age 60–69: HR 1.57 (95% CI 1.44–1.71)], increasing number of tumor positive lymph nodes [1–3 lymph nodes: HR 1.12 (95% CI 1.05–1.09), 4–9 lymph nodes: HR 1.11 (95% CI 1.02–1.29)], chemotherapy [HR 1.25 (95% CI 1.12–1.39)], somatic comorbidity [HR 1.31 (95% CI 1.21–1.42)] and use of antidepressants the year before breast cancer diagnosis [HR 1.97 (95% CI 1.85–2.10)].Conclusion. This study detected a group of patients at great risk for initiating and increasing use of hypnotics and preventive and prophylactic mechanism should be investigated and initiated when this group of patients is seen in the clinical setting.

Tunnelled lateral fasciocutaneous thoracodorsal flap with a skin island in breast reconstruction in oncoplastic breast surgery

The technique and results of a tunnelled lateral fasciocutaneous flap with a skin island is described in immediate partial breast reconstruction in a subpopulation in oncoplastic breast surgery. Fifteen patients were operated on from January 2008 to January 2011. The subpopulation consisted of patients with small or medium-sized breasts. All patients had invasive ductal carcinomas, located in the lateral or central parts of the breast, of which the lumpectomy in three cases included the nipple areola complex. Eleven patients had axillary lymph node dissection because of positive sentinel node biopsy. In four patients a re-resection was performed due to insufficient primary resection margins. No primary or secondary mastectomies were performed. One haematoma at the site of reconstruction was registered as the only postoperative complication. No patient developed wound infection, delayed wound healing, seroma, or any flap complications. All patients had adjuvant chemotherapy and radiation therapy according to the guidelines of The Danish Breast Cancer Group. The patients were seen at follow-up visits at 14 days, 3, 12, and 24 months. No recurrences were seen during the observation time except for one patient, who had recurrence with dissemination of the disease and died 19 months postoperatively.

Quality Assurance of an Organised Screening Programme for Breast Cancer in Denmark 1991-2008.

Abstract Background: The capital city of Copenhagen, Denmark, has had an organised programme for screening with mammography since 1991. All women resident within the area of uptake and aged 50-69, representing around 45000 women, are invited biennially, unless they actively have asked not to be invited. We have evaluated the programme with regard to the European guidelines for quality assurance in breast cancer screening and diagnosis, to assess performance and impact.Methods: The target population was identified through the national population register, identifying all women meeting the inclusion criteria in terms of age and place of residence, migration and death. The mammography programme supplied data on all invited women, participation and screening test results. Oncological data was retrieved from the National Cancer Register and the Danish Breast Cancer Group. Data was linked using the Danish unique personal identity number.Results: In the first invitation round (1991-1992) the invasive cancer detection rate was 10/1000 and was by the 8th invitation round (2006-2007) 8/1000. The in situ detection rate has been 1/1000 throughout the period. The programme sensitivity is approximately 70%. The detection rate of small tumours (≤ 10mm) was, on average, 39% over the first 4 invitation rounds and 62% by the 8th invitation round. The benign to malign ratio changed from 1:1.6 to 1:11.4, from the first to the 8th invitation round. Recall rates at initial screen dropped from 7% to 4% in the period, and for subsequent screens from 4% to 2%. The false positive rate was 5.5% in the first invitation round and had by the 8th invitation round dropped to 1.3%, with a cumulative risk of 15% over 8 rounds. In the 8th invitation round, there was 82% coverage, a participation rate of 61% and a long term adherence of 50%.Conclusions: The results for the majority of indicators were well within the recommended levels. There had been a significant improvement in the benign to malign ratio, despite that the false positive rate at assessment had decreased. The detection of small tumours had also improved significantly. Participation rates were, however, lower than recommended. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4005.

How much can improved molecular and pathologic discriminants change local therapy?

How much can improved molecular and pathologic discriminants change local therapy?

Evaluation of and quality assurance in HER2 analysis in breast carcinomas from patients registered in Danish Breast Cancer Group (DBCG) in the period of 2002–2006. A nationwide study including correlation between HER-2 status and other prognostic variables

Introduction. In Denmark, analysis for HER2 is situated in the pathology laboratories dealing with breast pathology. The analysis was introduced during the late 1990's, and was gradually intensified in the following years up to now. The present study deals with the experience with the analysis during the last 5 years, from 2002 – 2006. Patients and methods. All patients, registered in DBCG (Danish Breast Cancer Group) and with a HER2-test were included. The analysis followed international recommendations, with an initial immunohistochemical (IHC) analysis with a semiquantitative grading of the reaction in four grades, 0 and 1+, defined as HER2-negative, 2+, equivocal and 3+, HER2-positive. In the 2+ group, a FISH-test was applied to identify the presence of gene amplification, defined as a ratio ≥2. We investigated the number of analyses performed, the number of positive cases and the relation between the result of IHC and the result of FISH. Furthermore we looked at the relation to other prognostic factors. Results. The number of analyses gradually increased during the years of investigation, from 30% of patients in 2002 to 71% in 2006. The increase was seen in all laboratories resulting in all laboratories but one having a substantial number of analyses. Sixty-two percent of all cases were HER2-negative, 18% were equivocal and 21% positive in the IHC-analysis. Of the 2+, equivocal cases, 23% had gene-amplification. Thus, 23% of patients were defined as HER2-positive and eligible for treatment with trastuzumab. There was a significant correlation to other prognostic factors. The results are in accordance with what is found elsewhere. The quality of the test is further assured by all laboratories participating in external quality assurance schemes.

Who should not receive adjuvant chemotherapy? International databases.

The optimal selection of patients for adjuvant therapy, avoiding overtreatment and undertreatment, of disease is a significant challenge in the management of early breast cancers. Population-based cohorts in Denmark and in two Swedish health care regions were investigated to identify patients with breast cancer who have a sufficiently low risk of recurrence without adjuvant therapy. Published data on different calcification patterns were also included from the randomized Swedish mammography two-county study. The Danish Breast Cancer Group's population-based registry revealed that patients with lymph node-negative and estrogen receptor- or progesterone receptor-positive cancers of histological grade I that were less than 20 mm in size had a 5-year survival rate similar to age-matched groups without breast cancer. Data from the Stockholm Breast Cancer Group identified a similar risk group (no information on cancer grade) with an approximate 10% risk of dying from breast cancer after 10 years without any adjuvant therapy. In women older than 50 years, approximately 20% died of other causes. Mammographically and lymph node-negative-detected cancers that are less than 15 mm in size generally have an excellent survival outcome, excluding patients with casting calcifications. Patients who have lymph node-negative breast cancers that are less than 20 mm in size, combined with estrogen receptor positivity, can be identified as a low-risk group. The vast majority of these patients are unlikely to benefit from the addition of conventional chemotherapy, but some of them may. The dilemma is that we cannot identify these patients prospectively because of the lack of relevant predictive factors for chemotherapy.

Adjuvant Tamoxifen Therapy for Early Stage Breast Cancer and Second Primary Malignancies

Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers. Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer. The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8-9 years. All P values were calculated from two-tailed tests of statistical significance. In the Stockholm Trial, there was a statistically significant (P = .008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P < .001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9-8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1-3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9-11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients. The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans. The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials.

Oestrogen-induced pro-cathepsin D in breast cancer: from biology to clinical applications

SynopsisIn addition to secreted growth factors, acting as autocrine or paracrine mitogens, breast cancer cells secrete other proteins whose function and significance in mammary carcinogenesis may be important. Among them, proteases are particularly interesting since it has been suggested that they play a role in metastatic process, and since at least two of them, the tissue type plasminogen activator and pro-cathepsin D, the precursor of a lysosomal protease, are induced by oestrogens and secreted in excess in some mammary cancer cells.In oestrogen-receptor-positive human breast cancer cell lines (MCF7, ZR75–1), oestrogens stimulate cell proliferation and specifically increase the secretion into the culture medium of a 52,000-dalton (52-kDa) glycoprotein identified as the secreted precursor of a cathepsin D bearing mannose-6-phosphate signals, which is routed to lysosomesviamannose-6-phosphate-IGF-II receptors. We have determined the structure of this procathepsin D by sequencing its complete cDNA sequence, its chromosomal localisation and its transcriptional regulation by oestrogens and other mitogens. In breast cancer cells, pro-cathepsin D production and secretion is much higher and its processing is altered compared to normal mammary epithelial cells in culture.In vitro, pro-cathepsin D acts as an autocrine mitogen on breast cancer cells and can be activated at acidic pH to degrade extracellular matrix, suggesting a role in mediating the effect of oestrogens on tumour growth and invasion. Retrospective clinical studies indicate a significant correlation between high 52-kDa cathepsin D concentrations in the cytosol of primary breast cancer and poor prognosis (Danish Breast Cancer Group, S. Thorpe, Copenhagen). We propose that among the proteases secreted by cancer cells, 52-kDa cathepsin D is important both as a tissue marker in breast cancer and as a potential factor involved in carcinogenesis.

The Danish Breast Cancer Group (DBCG) biochemical tumor marker program.

One hundred and thirty-three high-risk breast cancer patients entered the DBCG (Danish Breast Cancer Cooperative Group) tumor marker program between May 1978 and June 1980. Eleven were excluded from the DBCG protocol and 23 left the program prematurely. The remaining patients were seen at the clinical laboratory once a month during the first year and every third month during the second and third year following mastectomy. Blood and urine specimens were collected and plasma, serum and urine specimens stored at -80 degrees C. The purposes of the program were 1) to collect a biological material which may later be used to assess the usefulness of biochemical markers for the prediction of recurrence and 2) to develop statistical time series models suitable for this assessment. Such a model is presented and its application for the assessment of the usefulness of 14 common tumor markers reviewed. Only P-CEA proved to be of any value but its usefulness was marginal.