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Three commercial brands of Swedish snus (SWS), an experimental SWS, and the 2S3 reference moist snuff were each tested in four in vitro toxicology assays. These assays were: Salmonella reverse mutation, mouse lymphoma, in vitro micronucleus, and cytotoxicity. Water extractions of each of the 5 products were tested using several different concentrations; the experimental SWS was also extracted using dimethyl sulfoxide (DMSO). Extraction procedures were verified by nicotine determinations. Results for SWS in the mutagenicity assays were broadly negative: there were occasional positive responses, but these were effectively at the highest concentration only (concentrations well above those suggested by regulatory guidelines), and were often associated with cytotoxicity. The 2S3 reference was unequivocally positive in one of the three conditions of the micronucleus assay (MNA), at the highest concentration only. Positive controls produced the expected responses in each assay. The SWS data are contrasted with data reported for combusted tobacco in the form of cigarettes, where strongly positive responses have been routinely reported for mutagenicity and cytotoxicity. These negative findings in a laboratory setting concur with the large amount of epidemiological data from Sweden, data showing that SWS are associated with considerably lower carcinogenic potential when compared with cigarettes.

Background: Epidemiological studies suggest that smokeless tobacco in the form of Swedish snus has been used by many smokers in Scandinavia to quit smoking, but the efficacy of snus has so far not been evaluated in controlled clinical trials., Methods: We conducted a randomized, double-blind, placebo-controlled, clinical trial aimed at assessing the efficacy of snus to help adult cigarette smokers in Serbia to substantially reduce, and, eventually, completely stop smoking. The study enrolled 319 healthy smokers aged 20-65 years at two occupational health centers in Belgrade, Serbia. Most of them (81%) expressed an interest to quit rather than just reduce their smoking. Study products were used ad libitum throughout the 48-week study period. The main study objective during the first 24 weeks was smoking reduction. The primary end-point was defined as a biologically verified reduction of ≥ 50% in the average number of smoked cigarettes per day during week 21-24 compared to baseline. During week 25-48 participants were actively instructed to stop smoking completely. Outcome measures of biologically verified, complete smoking cessation included 1-week point prevalence rates at clinical visits after 12, 24, 36, and 48 weeks, as well as 4-, 12- and 24-week continued cessation rates at the week 36 and 48 visits., Results: At the week 24 visit, the proportion of participants who achieved the protocol definition of a ≥ 50% smoking reduction was similar in the two treatment groups. However, the proportion that reported more extreme reductions (≥ 75%) was statistically significantly higher in the snus group than in the placebo group (p < 0.01). The results for biologically verified complete cessation suggested that participants in the snus group were more likely to quit smoking completely than the controls; the odds ratio (snus versus placebo) for the protocol estimates of cessation varied between 1.9 to 3.4, but these ratios were of borderline significance with p-values ranging from 0.04-0.10. Snus was well tolerated and only 2/158 (1.3%) participants in the snus group discontinued treatment due to an adverse event (in both cases unrelated to snus)., Conclusions: Swedish snus could promote smoking cessation among smokers in Serbia, that is, in a cultural setting without traditional use of oral, smokeless tobacco., Trial Registration: www.clinicaltrials.gov, identifier: NCT00601042.

Some smokeless tobacco products, such as Swedish snus, are today considered to be associated with substantially fewer health hazards than cigarettes. This risk differential has contributed to the scientific debate about the possibilities of harm reduction within the tobacco area. Although current manufacturing methods for snus build on those that were introduced more than a century ago, the low levels of unwanted substances in modern Swedish snus are largely due to improvements in production techniques and selection of raw materials in combination with several programs for quality assurance and quality control. These measures have been successively introduced during the past 30-40 years. In the late 1990s they formed the basis for a voluntary quality standard for Swedish snus named GothiaTek®. In recent years the standard has been accepted by the members of the trade organization European Smokeless Tobacco Council (ESTOC) so it has now evolved into an industrial standard for all smokeless tobacco products in Europe.The initial impetus for the mentioned changes of the production was quality problems related to microbial activity and formation of ammonia and nitrite in the finished products. Other contributing factors were that snus came under the jurisdiction of the Swedish Food Act in 1971, and concerns that emerged in the 1960s and 1970s about health effects of tobacco, and the significance of agrochemical residues and other potential toxicants in food stuffs.This paper summarizes the historical development of the manufacture of Swedish snus, describes the chemical composition of modern snus, and gives the background and rationale for the GothiaTek® standard, including the selection of constituents for which the standard sets limits. The paper also discusses the potential future of this voluntary standard in relation to current discussions about tobacco harm reduction and regulatory science in tobacco control.

Unlabelled: The adverse health effects of cigarette smoking are well established including the increased risk of various types of cancer. In this study, the direct effects of ethanol, pure nicotine, cigarette smoke extract and Swedish type smokeless tobacco (Snus) extract on normal cells were investigated., Materials and Methods: Primary normal adult human endothelial cells and fibroblasts at early passage were used. Upon exposure to pure nicotine, cigarette smoke extract, Snus extract and ethanol, these cells were assessed for DNA synthesis, gene expression profile and cellular morphology., Results: Normal human fibroblasts and endothelial cells have unique gene expression profiles. The effects of treatment with ethanol and nicotine from different sources was more prominent in endothelial cells than fibroblasts. The combination of alterated gene expressions and strongly inhibited DNA synthesis was only detected in cells exposed to smoke extract. In the presence and absence of ethanol, pure nicotine and Snus extract induced abnormalities in the cytoplasm without any significant degree of cell death. With similar doses of nicotine and ethanol, the additional components in smoke extract had a dominant effect. The smoke extract induced vast cellular abnormalities and massive cell death., Conclusion: Cigarette smoke induced massive cell death and various abnormalities at cellular and molecular levels in surviving endothelial cells and fibroblasts. The combination of genomic alterations and the chronic inflammatory microenvironment induced from massive cell death, will potentially promote tumourigenesis and various diseases in cigarette smokers.

Objective: The aims of this study were to generate new knowledge about factors predicting return to work (RTW) among women treated for early-stage breast cancer, and about changes in life satisfaction, and coping, and to examine the association between these concepts and RTW., Methods and Participants: A cohort of 102 women aged 18-64 were assessed six weeks, six months, and ten months after surgery using data from questionnaires and medical files., Results: Factors independently predicting no RTW at six months were: chemotherapy, > 30 days of sick leave during the previous 12 months, low satisfaction with activities of daily living, and not having been born in Sweden. No RTW at ten months was predicted by irradiation to breast/chest wall and regional nodes, and low satisfaction with vocational situation. Global life satisfaction was higher among the working women, both six months after surgery and ten months after surgery. The working women used more positive coping resources as compared to the sick-listed women, particularly sick-listed women treated with chemotherapy., Conclusion: Factors associated with RTW appear to include not only treatment-related factors such as chemotherapy and irradiation, but also psychosocial factors such as life satisfaction and coping resources. With increased understanding of the complex factors related to RTW after a breast cancer diagnosis, it will be possible to identify and support survivors who are at risk of being marginalized from the labor market.

Unlabelled: Long-term survival of head and neck squamous cell carcinoma (HNSCC) patients has not improved significantly during the last 20 years and recurrent disease is frequently observed. In this study, the potential presence of pre-malignant cells or rare malignant cells at the time of diagnosis in HNSCC was investigated., Patients and Methods: Fifty-nine biopsies obtained from 41 HNSCC patients were analysed. Eighteen of these biopsies were normal mucosal tissue, located at least 5 cm from the tumour margin. DNA content and DNA methylation of p16, DAPK and RASSF1A was examined., Results: Thirty-nine out of 41 (95%) tumour biopsies showed p16 methylation and 21 (51%) of them displayed aneuploidy. Of 18 distant normal mucosal biopsies, 6 (33%) of these showed evidence of aneuploidy and 15(83%) of them showed methylated p16 genes. Among paired samples, the highest frequencies of DNA methylation were found in tumours with aneuploidy. Regardless of DNA content, methylation at DAPK, RASSF1A or p16 were found in the corresponding distant mucosal biopsies., Conclusion: The cells with abnormal DNA content or DNA methylation in mucosal tissue were not detected clinically or by pathological macroscopic and microscopic examination. Thus, distant mucosal tissue DNA content and DNA methylation analyses in combination with histopathology will provide a better prognostic base for the evaluation and treatment of HNSCC patients.

The purpose of this qualitative study was to identify factors contributing to a successful return to the labour market after treatment for breast cancer from the women's own perspective. The study is based on 16 narratives - open-ended, in-depth interviews - about women's experiences and thoughts from the period after breast cancer surgery when they focused on their return to work. The women were recruited from participants of a multicentre trial, which allowed comparisons across a range of adjuvant therapies. The narratives of women who worked full time at a cut-off point of 1 year after surgery are analysed separately from the narratives of women still sick-listed at that point of time. The findings show that while all the women strove to belong to the labour market, the study also reveals changes in women's perceptions of the value of employment. The quality of social support received from employers and coworkers differed between women who returned to work and those still sick-listed 1 year after breast cancer treatment. A need to design interventions focusing on the work arena of women treated for breast cancer is pointed out.

cDNA microarray is an established technique. However, difficulties such as handling tissue samples under RNase-free conditions, the heterogeneous tumor composition, i.e. non-malignant versus malignant cells and different pathologic types of malignant cells, and lack of appropriate reference may limit the potentially benefit of this method in clinical use. In this study, we examined how standardization of gene expression to total mg RNA or mg tissue and tumor heterogeneity affect the final results. We found that the gene expression of human breast tumors was approximately 9 times higher in malignant tissue as compared to the non-malignant tissue when expressed per total mg RNA, but approximately 40 times higher when expressed per mg tissue. Genes that were expected to act as housekeeping genes (PUC18, RPL and beta-actin) varied between different parts of the tumor and also between non-malignant and malignant tissues, excluding them as reference genes. We also found that the gene expression differed in various parts of the breast tumor, probably due to a mixture of different types of cells, i.e. non-malignant and malignant cells. To find out if the variations in the gene expression were due to cell heterogeneity we used microdissection to collect malignant cells separately. We found that the gene expression was markedly different in the isolated malignant cells as compared to the gene expression of the bulk tumor tissue. Thus, to be able to evaluate results from cDNA array gene expression experiments it is, to our opinion, necessary to work with pure tumor cell populations, until solid information is available on the impact of stromal component. Housekeeping genes should be handling with care and mg tissue may be preferred instead of microg RNA for standardization.

Taste and smell changes (TSCs) are known side effects of chemotherapy, but smell changes (SCs) in the absence of taste changes are understudied. This study aims to explore SCs occurring without taste changes during chemotherapy, to better understand the characteristics of such changes, and how these experiences affect patients in their daily lives. Data derives from a qualitative interview study and a cross-sectional survey of 518 patients, with all patients receiving out-patient cancer chemotherapy in Sweden. Case studies of three patients with SCs and the 8% of survey participants with SCs only are in focus. All 43 participants with exclusively SCs reported increased sensitivity to one or several odors, with no participants reporting decreased sensitivity. Those reporting SCs significantly more often reported weight gain than those reporting TSCs, with oral problems and appetite loss significantly less common in the SC group. There were no differences in reported nausea between SC and TSC groups, but nausea was more common in the SC group than in those without TSCs. The case study reports were linked to and discussed in relation to possible explanatory models for increased olfactory sensitivity. SCs increase during chemotherapy, were often unpredictable and led to emotional consequences. The participants all reported heightened sensitivity to one or several odors which could not fully be explained by the potential explanatory models of anticipatory nausea and vomiting, pseudohallucinations, or increased chemical sensitivity.

Background: The most common female cancer in Western countries is breast cancer and women diagnosed with this disease are often under 65 years old. With increasing prevalence of survivors it is important to shed light on problems facing these women after diagnosis and treatment. The aim of this study was to assess factors predicting return to work (RTW) in women with early-stage breast cancer., Material and Methods: A cohort of 102 women aged 18-64 with early-stage breast cancer who had undergone curative primary surgery with or without systemic adjuvant therapy were followed for 10 months using data from questionnaires and medical files., Results: Ten months after primary surgery, 59% of the women had returned to work while 41% were sick-listed part-time or full-time. After adjusting for age, health status, life satisfaction, vocational situation, and irradiation to the breast/chest wall and regional nodes, a multivariate logistic regression revealed the following factors as being negatively associated with RTW: a high-demand job (OR=0.1, 95% CI 0.0-0.8), axillary node dissection (OR=0.1, 95% CI 0.0-0.6), and treatment with chemotherapy (OR=0.1, 95% CI 0.0-0.7)., Discussion: Treatment factors and high demands at work play an important role in RTW for women with early-stage breast cancer.

Background: Metastatic cancer from an unknown primary tumour (CUP) is a common and heterogeneous clinical entity. In Sweden like in many other countries, the continuum of care for such patients remains to be established., Material and Methods: Data on CUP cases reported to the Swedish Cancer Registry during 1960 through 2007 was used to assess time trends for incidence, survival, and histological tumour type., Results: There was an upward trend for the age-adjusted incidence until the late 1990s. This roughly paralleled the increase for all reported cancers during the same period. The increase of CUP mainly concerned patients aged above 50 years, and tumours classified as adenocarcinomas. The relative survival at 12 months after a diagnosis of CUP was estimated at 20%. However, after 12 months the relative survival levelled of and the 5-year estimate was 10-15% which suggests that a small proportion of CUP cases may be cured. Relative survival was highly dependent on age with substantially better outcome for young patients, particularly those aged below 30 years. We observed no time trend for survival., Discussion: Cases diagnosed as CUP includes patients with metastatic spread from a wide variety of tumours although certain tumour types probably are overrepresented, for example, cancers in sites that are difficult to examine clinically. Incidence trends probably represent the sum of trends for these cancers as well as diagnostic trends. The decreased incidence observed during the last decade might thus be explained in terms of a combination of improved diagnostic methods to detect primary tumours and decreasing incidence for e.g. pancreatic cancer and lung cancer among males. There is a need of evidence-based programs that define the continuum of care for CUP patients. Such a program is currently being developed through collaboration between all health care regions in Sweden.

Background: Both adjuvant therapy and mammography screening can decrease breast cancer mortality and there is a need of knowing to what extent those two modalities are used in the population. Screening coverage is well documented but there is a scarcity of population-based data on use of systemic adjuvant treatment., Aim: To describe the introduction, and trends in the use of adjuvant systemic therapy for breast cancer in two of six public health regions in Sweden., Material & Methods: Population-based data on use of adjuvant therapy were available from databases with documented high quality and high coverage data for Stockholm (1976-2005) and North Sweden (1980-2003, and 2005)., Results: The use of systemic treatment was infrequent before the late 1980s in both regions, but increased during the 1990s. In 2005, the proportion of operable breast cancer patients treated with adjuvant endocrine therapy in the ages 40-59 was around 60 to 80%. The proportion adjuvant chemotherapy was less than 15% for the ages 70-74. For the north region the use of endocrine therapy increased successively over time, with an exception for age group 40-49 were a more rapidly increase occurred in the late 1990s. In Stockholm the increment was higher and more rapidly. There was no clear difference in chemotherapy use between the regions, and the use increased from the mid 1980s in age group 40-49, and in the early 1990s for women aged 50-59. In age group's 60-69 and 70-74 the use was relatively infrequent., Conclusions: Trends in, and levels of the use of adjuvant systemic therapy for breast cancer varied over time in the two study regions, particularly for endocrine therapy. We consider that the differences between the regions mainly reflect different interpretations of new scientific evidence. We stress the importance of a good documentation of all new treatment protocols.

Many cancer patients continue to smoke past diagnosis and treatment, even though smoking in some cases may cause more side effects and increase the risk of treatment failure. We developed and evaluated a nurse-led smoking cessation programme on 50 patients with head and neck (H&N) cancer undergoing radiotherapy (RT) with 1-year follow-up. To evaluate the effectiveness of the programme (proportion of smoke-free patients), smoking status was tested by measuring carbon monoxide in expired air. Thirty-seven patients (74%) were tested smoke-free weekly during the RT period. At the 1-year follow-up visit, 28 patients (68%) were tested smoke-free. The results indicated that even H&N cancer patients with a heavy smoking history and multiple abuses could quit smoking with systematic support but a more sophisticated evaluation including larger study populations and control groups are needed.

Purpose: Recent studies on the pattern of gene expression in estrogen receptor positive and negative tumours have revealed profound differences according to receptor status. However, it remains unclear if these differences reflect phenotypic traits in addition to sensitivity to endocrine therapy. This paper describes the long-term pattern of disease recurrence among ca. 2,600 pre- and post-menopausal patients with primary breast cancer according to estrogen receptor status., Material and Methods: The study was based on patients with an operable, invasive breast cancer entered in one of three controlled clinical trials conducted by the Stockholm Breast Cancer Group. We selected those 2,562 patients who had been randomly allocated between adjuvant tamoxifen and no adjuvant systemic therapy. These patients had a known estrogen receptor status., Result: Tamoxifen reduced locoregional (8.8% vs. 12.4%, hazard ratio (HR), 0.66; 95% CI, 0.52-0.83; P = 0.001, distant recurrences (17.2% vs. 20.2%, HR, 0.81; CI, 0.68-0.97; P = 0.018, as well as breast cancer death (18.7% vs. 23.7%, HR, 0.78; CI, 0.67-0.92; P = 0.002). Among patients not allocated to tamoxifen there was no significant differences in term of neither locoregional (12.4% vs. 12.4%, HR, 1; CI, 0.72-1.41; P = 0.98), nor distant metastases (18.5% vs. 20.7%, HR, 1.11;CI, 0.85-1.45; P = 0.46) according to ER status. The pattern of metastases was not different in ER positive comparison with ER negative., Conclusion: The results showed that the mentioned substantial differences in terms of gene expression appeared mainly to be related to endocrine sensitivity and not to metastatic potential. However, a slight advantage during the first five years for the ER positive versus ER negative patients in terms of cumulative incidence of events, suggested that ER negativity in some cases is correlated with an increased tumour growth rate.

Background: Prediction of distant metastases is of paramount importance in the knowledge and management of breast cancer patients. The objective of this study was to assess conventional prognostic factors in a large database of patients with early breast cancer, including those with small tumors diagnosed through regional screening, to determine the risk of distant dissemination., Methods: The study included 4,797 patients of the Stockholm database who did not receive systemic adjuvant treatments. The main endpoint was metastasis free-interval. Individual risks of distant metastasis were estimated using the regression coefficients of the significant prognostic factors in Cox multivariate analyses. For each level of metastatic risk the pattern of failure was analyzed by a model assuming competing risks., Results: The three independent significant prognostic factors were histologic tumor size, number of involved axillary lymph nodes and progesterone receptor level. However, the latter factor added limited additional information of borderline clinical significance. Thus, subsequent estimations were done with a prognostic score taking into account only the former two most performant factors in the whole population. The risk of distant metastasis of observed values of tumor size categories fitted with published results of a series containing significantly larger tumors. A large variation of tumor size predicts 10-year distant metastasis risk ranging from below 10% up to 90%. Tumors of 10 mm or less had a 10-year metastatic risk of less than 10%., Conclusions: The results of this study are consistent with a linear effect of tumor size, within the range of data, on 10-year distant dissemination probabilities. Further refinement on prognostic value is needed for tumors of 15 mm or less.

Few studies explore patients' experiences of smell and taste changes during cytotoxic chemotherapy. Issues, such as how such changes impact daily life, their consequences, and how patients respond to chemotherapy-induced chemosensory changes, have not previously been systematically addressed. The aim of this study was to examine these questions by exploring experiences of chemotherapy-induced chemosensory changes. In this qualitative longitudinal study, semistructured interviews were conducted with 14 women and 7 men with a variety of cancer diagnoses, who were known to have smell and taste changes. The participants were chosen for heterogeneity in regard to factors that might impact on experiences of chemotherapy. Participants were followed monthly until chemosensory changes ceased. There was great individual variation in patterns, intensity and impact of smell and/or taste changes, with changes reported to have ceased in all participants within 3.5 months after treatment ended. While not all participants found reported changes "bothersome," those who did reported predominantly emotional and social consequences. Smell and taste changes were said to be influenced by, or to influence, other symptoms, for example, appetite loss, early satiation, nausea, and oral problems. Although participants said they lacked ways to manage chemosensory changes, coping strategies described included frequent oral hygiene, searching for tolerable food, relying on smell and taste memory, and acceptance of changes. Although chemosensory changes resolved in all participants within several months after completed chemotherapy, the reported variation in experiences of taste and smell changes makes these side effects especially challenging to assess and alleviate.

Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer., Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors., Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction., Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.

Purpose: To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients., Methods and Materials: The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy., Results: Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p = 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098-0.72, p = 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy., Conclusions: Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer.

Relatively few studies have addressed problems regarding return to work after primary treatment for early-stage breast cancer. The purpose of this study was to investigate whether socio-economic and treatment-related factors were associated with problems of returning to work among pre-menopausal women included in a randomized trial of adjuvant endocrine therapy. The duration of all endocrine treatments in the trial was two years. At 24 months after randomization 35 of the 222 recurrence-free patients (16%) had not returned to work. The use of adjuvant endocrine therapy was associated with a twofold increase in the odds ratio of not having returned to work, although the confidence interval of this ratio was wide and included unity. Tumour stage was negatively associated with work status, possibly because of its association with adjuvant chemotherapy and radiotherapy to the regional nodes. Age and investigated social factors (educational level, matrimonial status and presence of under-age children) were not significantly associated with return to work. Determining the significance of other social factors such as vocational motivation, level of income and vocational rehabilitation merits further research.

The Stockholm Breast Cancer Study Group conducted a randomized trial during 1976 through 1990 comparing adjuvant tamoxifen versus control. A total of 2,738 postmenopausal women with invasive, early stage disease were randomised between tamoxifen for 2 or 5 years, or no adjuvant endocrine therapy. Among high-risk patients the treatment was given against a background of either postoperative, locoregional radiation or CMF-type chemotherapy. The median follow up was 18 years (range 11-25 years). There was a statistically significant (p =0.001) interaction between ER status and tamoxifen with no treatment benefit among receptor negatives. PgR-status had little additional predictive value. Among ER-positive patients tamoxifen reduced locoregional recurrences by 48%, contralateral breast cancers by 54%, distant metastases by 28%, and all events by 24% (p <0.001). On the other hand, there was a substantial increase of endometrial cancer associated with tamoxifen. There was no effect of tamoxifen on intercurrent mortality whereas breast cancer deaths were reduced by 31% (p <0.001) and overall mortality by 15% (p =0.01). Tamoxifen produced long-term benefits among estrogen receptor positive patients in terms of breast cancer-related events, but also an increased incidence of endometrial cancer. Despite long-term follow-up we observed no benefit with tamoxifen in terms of cardiovascular mortality.

Background: The prognostic value of the concentration of serum thymidine kinase 1 (S-TK1) with regard to recurrence in low risk breast cancer patients, 3 months after surgery was evaluated., Patients and Methods: The concentration of S-TK1 in serum was determined in 120 breast cancer patients at the time of surgery and in 67 patients 3 months after surgery, by anti-TK1 chicken IgY antibody, using a dot-blot immuno-assay. The S-TK1 concentration was compared with the serological activity of thymidine kinase (STK) and of carbohydrate antigen (CA 15-3)., Results: A statistically significant trend (unadjusted) was found for recurrence (distant or loco-regional) in patients with a higher S-TK1 concentration, as compared with patients with a lower S-TK1 concentration. A multivariate analysis gave the same results. The hazard rate ratio for developing distant and/or loco-regional recurrence in patients with a higher S-TK1 concentration was about six to seven times higher than in patients with a lower S-TK1 concentration., Conclusion: Our results indicate that the S-TK1 concentration is higher in patients developing distant and/or loco-regional recurrence 3 months post-surgery.

A program to ensure an equivalent standard of care for all patients with breast cancer was initiated in the Stockholm area in the mid 1970s. As part of an evaluation of this program, social gradients in clinical stage at presentation and survival were analyzed among patients diagnosed during 1977 through 1997. The patients (n = 15,021) were selected from a database covering about 88% of all diagnosed breast cancer cases in the region. Putative associations were analyzed between clinical stage, survival and different socioeconomic indicators (level of education, income and occupation). There were significant social differences (p < 0.01) in distribution of clinical stage as well as in total and stage-specific survival. High income, more skilled work and a high level of education were all associated with clinically less advanced tumors and hence better survival. However, stage-specific survival differences were mostly generated by differences in nonbreast cancer mortality. The results indicate social inequalities regarding awareness of the disease and/or access to early detection. Social gradients in nonbreast cancer mortality were also found to influence observed survival. In contrast, we observed no significant social differences in stage-specific breast cancer mortality.

COX-2 is upregulated in many breast tumors, and one of the products of COX-2 is PGE2 that is suggested to upregulate aromatase through cAMP signaling in breast cancer. Although aromatase can increase the estrogen levels in tumors, 17beta-hydroxysteroid dehydrogenase (17HSD) activity is finally needed for the estrone/estradiol regulation. The aim of this study was to investigate if the protein expression of enzymes involved in estrogen synthesis shows covariation with the expression of COX-2. We also wanted to correlate these results with prognosis. We analyzed the expression of COX-2, aromatase, 17HSD1 and 17HSD2 with immunohistochemistry using tissue microarrays composed of 356 primary breast tumors. In the present study COX-2 was correlated to aromatase (P<0.00001), 17HSD1 (P=0.0073), and 17HSD2 (P<0.00001). Patients with ER positive tumors expressing low amounts of 17HSD2 had decreased breast cancer survival (P=0.013). Elevated expression of COX-2 and aromatase was more frequent among larger tumors (P=0.017 and P=0.013). COX-2 expression correlates with the levels of the examined steroid converting enzymes and may contribute to increased estrogen levels in the tumor. In breast cancer cells, the regulatory function of 17HSD2 could be lost, and in the present study patients with low or non-detectable levels of 17HSD2 had worse prognosis than had breast cancer patients with higher levels of the enzyme.

P21WAF1/Cip1 (p21) translocates to the cytoplasm inducing cell cycle progression and survival upon Akt/PKB activation. We studied whether heregulin beta1 (HRGbeta1), that activates the PI3K/Akt and MAPK pathways, also misallocates p21. We also explored whether HRGbeta1 interferes with the effects of tamoxifen. The clinical material studied helped us to clarify whether p21 was associated with phosphorylated Akt, recurrence-free survival and response to tamoxifen. MCF-7 cells treated with HRGbeta1 -/+ E2 were analyzed by flow cytometry to observe how the different compounds affected tamoxifen-induced cell cycle arrest and apoptosis. Total cell lysate and nuclear and cytoplasmic fractions were used to detect p21, phospho-Akt and other proteins by Western blotting. Immunofluorescence was used to visualize p21+ cells upon HRGbeta1 and E2 stimulation. The localization of p21 in breast cancer was studied by immunohistochemistry in frozen tumor sections from 280 patients. In MCF-7 we found that HRGbeta1 counteracted the inhibition of p21 expression by tamoxifen and caused p21 cytoplasmic accumulation. HRGbeta1 partially counteracted the cytostatic effect of tamoxifen but abrogated its cytotoxic effect. The clinical material revealed that nuclear p21 (P=0.022) and cytoplasmic p21 (P=0.00001) were associated with phospho-Akt. Based on p21 cell location, we identified 3 subgroups of ER+ patients: the p21N+/C- group for whom tamoxifen was needed otherwise the survival was poor (P=0.0082), the p21N+/C+ or p21N-/C- group, that responded to tamoxifen (P=0.034), and the p21C+/N- group, that might not benefit from this treatment (P=0.7). In conclusion, HRGbeta1 inhibits tamoxifen-induced apoptosis, contributes to p21 cytoplasmic expression while the cellular localization of p21 interacts with the benefit from tamoxifen treatment.

Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress., Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen., Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12-0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088)., Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

Background: The aim of the present study was to define the proportion of different levels of family history in a cohort of consecutive breast cancer patients from the Stockholm region, and to assess whether familial breast cancer has phenotypic traits different from those of sporadic patients., Methods: All incident breast cancer patients in a 19-month period were eligible for the study and 70% (489/696) participated. The family history and clinical parameters were obtained from questionnaires and medical records., Results: In total 35% had a family history. Age at onset was 58.9 years in the familial group vs. 60.7 years in the sporadic patients (P = 0.14) and 8% of the familial patients had bilateral breast cancer compared to 4% in the sporadic group (P = 0.08). There were 31% node positive tumors in the sporadic group vs. 22% in the cases with family history (P = 0.04). Hormonal background, treatment and prognosis (median follow-up 4.7 years) were not related to family history., Conclusion: In addition to high-risk familial breast and breast-ovarian cancer, constituting about 10% of all breast cancer cases, another 25% of the breast cancer cases have a family history, a group hypothetically valuable for association studies on low-risk genes. In contrast to previous reports, we did not observe a relationship between family history and phenotypic traits. A possible explanation for this can be different study design. The considerable heterogeneity in familial breast cancer means that different criteria for familiality can influence the result. Furthermore, our study was prospective and population based and included paternal inheritance.

Heterogeneous gene expression in tumours and the degradation of RNA when sampling under non-RNAse-free conditions may limit the potential benefit of cDNA array studies. This study examines changes in the integrity of RNA by means of RNA gel electrophoresis at various post-operative intervals on canine mammary tumours (n=10) and malignant lymphoma (n=1). The tumours were cut into pieces (3-5 mm diameter, approximately 50 mg) and kept in tubes without RNAse-free buffer at room temperature. No special precautions were taken to avoid the influences of Rnase; rather, normal surgical procedures were used. We found that total RNA of the mammary tumours started to degrade within 30 min of the operation, and the rate of degradation increased up to 4 h, which was the last time point included in this study. RNA in the lymphoma tumours degraded more rapidly, and was completely degraded at 30 min post-operation. The degradation of mRNA in the mammary tumours, as studied by human cDNA arrays, was heterogeneous, i.e. some mRNA degraded completely, some only partially. This indicates that the mRNA degradation rate varied depending on the type of mRNA. However, since we found that gene expression differs depending on the part of the mammary tumour examined, one cannot exclude that the variation in the mRNA degradation rate may simply reflect heterogeneous gene expression within the tumour. We conclude that RNA integrity is unaffected immediately after sampling under non-RNAse-free conditions; however, the tumour sample should be preserved under RNAse-free conditions within 15 min to avoid RNA degradation. This is a much shorter time interval than previously reported in other similar studies; however, these studies generally treated normal tissue, under which 3-5 h non-RNAse-free conditions have been found not to affect RNA quality.

From January 1, 1983, through December 31, 1992, a total of 4610 patients entered a randomized trial that compared mortality among patients receiving 2 years of adjuvant tamoxifen therapy with that in patients receiving 5 years of adjuvant tamoxifen therapy, 4175 of whom were recurrence free after 2 years of tamoxifen therapy. Among the 2046 patients randomly assigned to the 5-year group all-cause mortality, breast cancer-specific mortality, and the incidence of contralateral breast cancer were reduced, compared with those among 2129 patients randomized in the 2-year group, but the incidence of endometrial cancer was increased. In addition, mortality from coronary heart disease was statistically significantly reduced in the 5-year group, compared with that in the 2-year group (hazard ratio = 0.67, 95% confidence interval = 0.47 to 0.94; P = .022 [two-sided Wald test]). Ten years after surgery, 2.1% of the patients in the 5-year group and 3.5% of those in the 2-year group had died from coronary heart disease. No statistically significant increases in mortality from other heart diseases, cerebrovascular diseases, or other vascular diseases were observed.

Cyclin D1 plays an important role in the regulation of the G1 phase in the cell cycle. In mammary epithelial cells the expression of cyclin D1 is regulated through the oestrogen receptor and via ErbB2 signalling. Here we investigated the prognostic significance of cyclin D1 among 230 breast cancer patients randomised for tamoxifen, CMF chemotherapy and radiotherapy. The importance of combined cyclin D1 and ErbB2 overexpression was also analysed. Immunohistochemical analysis of the cyclin D1 expression resulted in 69 (29.8%) weakly positive, 107 (46.5%) moderately positive and 54 (23.7%) strongly positive cases. The prognostic importance of ErbB2 was significantly greater for patients whose tumours overexpressed cyclin D1 than for other patients (p = 0.026). In the former group, ErbB2 overexpression was strongly associated with increased risk of recurrence (RR = 4.7; 95% CI, 2.1-10.4) and breast cancer death (RR = 5.4; 95% CI, 2.3-12.6). This result is in accordance with experimental studies demonstrating a link between cyclin D1 and ErbB2 in oncogenesis. Among oestrogen receptor positive patients, those with moderate cyclin D1 expression significantly did benefit from tamoxifen treatment (RR = 0.42; 95% CI, 0.21-0.82) whereas those with weak or strong expression did not. Therefore cyclin D1 might be a predictive marker for tamoxifen resistance.

In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer--Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.

The cDNA array technique is an efficient approach for studying the expression of a large number of genes in a single experiment. The cDNA array analysis indicates the relative level of corresponding gene expression from a specimen and a reference. Our investigation was performed to address the significance of reference RNA on the outcome of the cancer-related gene expression profile obtained from cDNA array analysis. Human head and neck squamous cell carcinoma (HNSCC) biopsies and 5 sources of RNA reference were used for this purpose. In these biopsies, each individual patient expressed a unique set of genes both in normal and tumour tissue. It is important to note that 5 striking patterns of tumour-related gene expression were obtained according to the 5 references used. Significant differences in 60%, 16%, 15% and 15% of the genes expressed were shown when autologous normal matched tissue biopsy references were compared to pooled cell lines, allogenic normal mixed cell types, tumours or allogenic normal matched cell type references, respectively. Thus, theoretically and our study suggested that patient autologous normal cells matching with the tumour type should be the most suitable reference in cDNA array for the identification of individual tumour gene profiles with clinical purpose.

For many years, tamoxifen has been the 'gold standard' amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs), such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but the use of oestrogens is limited by their toxicity profile. Consequently, there is a need for new endocrine treatment options for breast cancer, particularly for use in disease that is resistant to tamoxifen or AIs. Fulvestrant ('Faslodex') is a new type of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine therapies for advanced breast cancer.

Background: Total mesorectal excision (TME) and use of adjuvant radiotherapy are major advances in the treatment of rectal cancer that have emerged in the past 20 years. The aim of this study was to evaluate the effects of an initiative to teach the TME technique on outcomes at 5 years after surgery., Methods: TME-based surgery was introduced in Stockholm in 1994. The study population comprised all 447 patients who underwent abdominal operations for rectal cancer in Stockholm County during 1995 and 1996. Outcomes were compared with those in the Stockholm I (790 patients) and Stockholm II (542 patients) radiotherapy trials., Results: The permanent stoma rate was reduced from 60.3 and 55.3 per cent in the Stockholm I and II trials respectively to 26.5 per cent in the TME project (P < 0.001). Five-year local recurrence rates decreased from 21.9 and 19.1 per cent to 8.2 per cent respectively (P < 0.001). Five-year cancer-specific survival rates increased from 66.0 and 65.7 per cent in the Stockholm trials to 77.3 per cent in the TME project (hazard ratio 0.62 (95 per cent confidence interval 0.49 to 0.80); P < 0.001)., Conclusion: A surgical teaching programme had a major impact on rectal cancer outcome.

Several recent epidemiologic studies on occupational magnetic field exposure have suggested an association with female breast cancer. The purpose of this study was to test this hypothesis by using the extensive Swedish population registers in combination with improved exposure assessment. The study base consisted of all women between 1976 and 1999 gainfully employed in Stockholm or Gotland County in Sweden. A total of 20,400 cases of breast cancer were identified from the cancer registry, and 116,227 controls were selected randomly from the study base. Information was available on estrogen receptor status, occupation, socioeconomic status, and age. Parity was available for a subset. The exposure was assessed by linkage to a newly developed job-exposure matrix based on personal magnetic field measurements on women. All risk estimates were close to unity regardless of exposure cutpoint or choice of exposure parameter. The overall odds ratio for women exposed to 0.30 microT or more was 1.01 (95% confidence interval: 0.93, 1.10). The size of the study allowed for estimates with good precision also in subgroups where previous studies have suggested increased risk, but the findings do not support the hypothesis that magnetic fields influence the risk of female breast cancer.

The third generation aromatase inhibitors anastrozole, exemestane, and letrozole have been compared with tamoxifen and other endocrine therapies in several studies in early and advanced breast cancer. These studies are reviewed in this report. Based on the available evidence, the panel recommends that adjuvant treatment with tamoxifen for 5 years should no longer be considered as the sole standard but that a third-generation aromatase inhibitor should be used either alone or in a sequence with tamoxifen in the adjuvant treatment of postmenopausal women with hormone-receptor-positive breast cancer. Third generation aromatase inhibitors may be considered as the first line therapy of hormone-receptor-positive advanced breast cancer in postmenopausal women, and they may also be used for preoperative therapy of breast cancer.

Background: Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy., Methods: The patients were genotyped using PCR followed by cleavage with restriction enzymes., Results: Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11-0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21-1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19-0.74, P = 0.0041)., Conclusion: The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

Purpose: Radiation therapy for head-and-neck cancer requires a reliable immobilization for an accurate and consistent treatment setup. This prospective, randomized study was done to compare two types of Posicast thermoplastic face masks, in terms of reproducibility, patient comfort, tolerability, and skin damage., Methods and Materials: The patients were randomly assigned to use a head mask (HM) or a head-and-shoulder mask (HSM). Three-dimensional treatment planning was followed by fractionated external-beam radiation therapy. Reproducibility was assessed by comparing port films with simulator films twice during treatment and by comparing actual treatment table positions weekly. Patient tolerability and comfort were studied weekly. The radiation-induced skin damage was assessed every week according to the World Health Organization toxicity scale., Results: A total of 260 patients were included, and 241 (93%) were evaluated. There were no statistically significant differences between the groups (HM or HSM) in terms of reproducibility. Patients using HSM experienced significantly more claustrophobia (p = 0.023). Patients allocated to HSM receiving > or = 60 Gy were found to have more skin reactions., Conclusions: The smaller HM reduced feelings of claustrophobia, as well as skin reactions, for patients receiving > or = 60 Gy. The smaller mask did not compromise the reproducibility of the setup.

Purpose: To examine the effects on bone mineral density of 2 years of treatment with a luteinizing hormone-releasing hormone (LHRH) agonist alone or in combination with tamoxifen or tamoxifen alone in premenopausal breast cancer., Patients and Methods: We recruited 89 women from two centers in Stockholm participating in a randomized multicenter trial of three different endocrine approaches in the adjuvant setting (Zoladex in Premenopausal Patients Trial). The women were assigned to receive the LHRH agonist goserelin with or without tamoxifen, tamoxifen alone, or no endocrine therapy. The treatment was given for 2 years. We measured total-body bone density before start of treatment and at 12, 24, and 36 months., Results: After 2 years of treatment, there was a significant loss of bone mineral density (mean change, -5%; P <.001) in the women receiving goserelin alone. The combined goserelin and tamoxifen treatment, as well as tamoxifen alone, resulted in a lesser but statistically significant decline in bone mineral density (mean change, -1.4%; P =.02; and -1.5%; P <.001). One year after cessation of treatment, the goserelin group alone showed a partial recovery from bone loss (mean change, 1.5%; P =.02)., Conclusion: Two years of ovarian ablation from goserelin treatment caused a significant reduction in bone mineral density but there was a partial recovery from the bone loss 1 year after cessation of treatment. The addition of tamoxifen seems to partially counteract the demineralizing effects of goserelin.

Background: Information on whether surgery has been 'curative' is essential for prediction of prognosis and for selection of patients for adjuvant treatment. The aim of this study was to analyse the prognostic value of surgeons' and pathologists' assessments of tumour clearance in patients with primary rectal cancer who underwent resection., Methods: A total of 1550 patients were studied prospectively. Data were collected from reports made by surgeons and pathologists on whether tumour clearance had been 'complete', 'uncertain' or 'incomplete'. The predictive value in relation to outcome after at least 5 years of follow-up was assessed., Results: In patients assessed as having a complete surgical clearance, tumour recurrence developed in 33.3 per cent. For patients with an uncertain or incomplete clearance the recurrence rate was 59.5 and 61 per cent respectively (P < 0.001). The relative risk of recurrence was twice as high when the surgeon and pathologist disagreed than when they both agreed on the complete clearance. Survival in patients with a complete, uncertain or incomplete surgical clearance was 55.3, 23.0 and 10 per cent respectively (P = 0.050)., Conclusion: Assessments of tumour clearance were of strong prognostic value in relation to outcome. When the surgeon or pathologist was uncertain, or there was disagreement about the completeness of clearance, the risk of recurrence was similar to that among patients in whom an incomplete resection had been performed., (Copyright 2004 British Journal of Surgery Society Ltd.)

Background: To reduce the risk of seroma after modified radical mastectomy in breast cancer patients, the use of suction axillary drainage is a standard procedure. The optimal time to remove the drain is not established. Whether the removal or preservation of the pectoral fascia influences the risk of seroma formation or loco-regional recurrence rate remains unclear., Method: The trial included 247 patients with breast cancer who underwent modified radical mastectomy in five Swedish hospitals 1993-1997. The median follow-up time was 6 years. One hundred and twenty-two and 125 patients, respectively, were randomised between removal versus preservation of the pectoral fascia. Of these 247 patients a total of 198 patients were also randomised to have the drain removed 24 h postoperatively or to keep the drain in until discharge had decreased to less than 40 ml/24 h., Results: Early removal of the axillary drain was associated with significantly more seromas and a shorter average postoperative hospital stay. There were no differences between the two groups regarding the rate of wound infections and/or hematoma formation. Removal or preservation of the pectoral fascia did not influence the formation of seroma or the amount of peroperative bleeding. A trend towards an increased risk for chest wall recurrence was observed in patients with preserved pectoral fascia (16/125 compared with 8/122; hazard ratio=2.0, 95% confidence interval=0.9-4.7)., Conclusion: Early removal of axillary drain shortened the duration of hospital stay without any increase in wound complications. However, it yielded a significantly higher incidence of seroma. Seroma formation and the chest wall recurrence rate was not significantly influenced by the preservation of the pectoral fascia or not.

Endocrine therapy remains a cornerstone of systemic therapy for breast cancer even though it was first introduced more than a century ago. In the past three decades a large number of randomized trials involving several tens of thousands of patients have been performed to determine the role of endocrine therapy in the adjuvant setting. The results of these studies indicate that hormonal therapy should be considered the standard adjuvant systemic treatment for the majority of patients with invasive breast cancer irrespective of age, menopausal status or tumour stage. This chapter aims to describe the "state of the art" relative to the use of adjuvant endocrine therapy with special focus on a number of salient issues, including: (i) the role of ovarian ablation and luteinising hormone releasing hormone (LHRH) analogues among pre-menopausal patients; (ii) optimal duration of tamoxifen; (iii) adjuvant therapy with third-generation, selective aromatase inhibitors; (iv) predictive biomarkers; (v) side-effects; (vi) combination endocrine therapy; (vii) future development of endocrine therapy.

The molecular mechanism(s) behind the development of endocrine resistance in breast cancer remains controversial. Here, we compare the capability of oestrogen receptor (ER)-negative cells (MDA-231) versus ER-positive tamoxifen-sensitive cells (MCF-7) to handle DNA repair, transmit signals from damaged DNA, initiate cell death via apoptosis, and then to control transmitted signals from the cell cycle and to synthesize growth factors and receptors. Genes related to these events were studied by cDNA micro-array. Normal human breast cells (H2F) and human lymphoblastoid tumour cells (CEM) were used as controls. Of the 18 genes investigated, 10 genes showed differences in their expression between the cell types. The ER-negative cells showed higher expressions of BRCA1, BRCA2, cdc2, cyclin B1, cyclin D1, cyclin E, IGFBP-3, TGF-alpha, TGF beta 2 and a lower expression of TGF beta R1. No differences in the expressions of bax, bcl-2, p53, p21 and GADD45 were found between the two cell lines. We found that the ER-negative cells were characterized by: (1) a stimulated expression of growth factors and cell cycle regulation compounds, (2) improved DNA repair capacity, but (3) no change in DNA damage signals and apoptotic pathways. Improved DNA repair capacity of ER-negative cells would have a growth advantage over ER-positive tumours when receiving antitumour therapy., (Copyright 2004 S. Karger AG, Basel)

p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. no endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083 0.62), whereas no benefit from radiotherapy was found for patients showing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.

Aim: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer., Methods: A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d., Results: We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression., Conclusion: The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.

Purpose: To compare the effect of adjuvant endocrine therapies with and without chemotherapy on physical symptoms, anxiety, and depressive symptoms in premenopausal women with breast cancer in a randomized clinical trial (the Zoladex in Premenopausal Patients trial)., Patients and Methods: The patients were randomly assigned to goserelin, goserelin plus tamoxifen, tamoxifen alone, or no endocrine therapy. The duration of the endocrine treatment was 2 years. The groups were observed for 3 years after primary treatment (ie, during 2 years of active treatment as well as 1 year after cessation of the adjuvant endocrine therapy). All patients with node-positive disease received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), which was given concurrently with the endocrine treatment., Results: Patients treated with CMF typically reported higher levels of physical symptoms than did patients who did not receive CMF. It was only among patients who did not receive chemotherapy that the endocrine treatment had differential effects. Goserelin was most burdensome and resulted in similar symptom levels as those of CMF, whereas the side effects of tamoxifen alone were milder. After cessation of the endocrine treatment, the side effects diminished in patients who had not received CMF, whereas patients treated with CMF reported ongoing problems at the 3-year follow-up. In contrast, anxiety and depressive symptoms were not significantly affected by endocrine treatment or chemotherapy during the 3 years of assessment., Conclusion: Goserelin and tamoxifen resulted in menopausal symptoms, but these symptoms were reversible. However, women treated with CMF experienced physical symptoms throughout the whole study period.

Aim: Uncontrolled local disease (ULD) following breast conservation constitutes a clinical problem with a major impact on quality of life. The current study analysed the outcome following treatment of ipsilateral breast tumour recurrence (IBTR) and the risk for ULD with the aim to identify risk factors for ULD., Methods: In a cohort of 5502 patients treated for invasive breast cancer Stage I-II with breast-conserving surgery 1976-1998 in Stockholm, 307 patients with subsequent IBTR were identified. The majority (n = 219) had received postoperative radiotherapy. Twenty-six per cent of the patients received adjuvant tamoxifen, for 2 or 5 years, and 9% received adjuvant polychemotherapy. Median follow-up time was 11(2-23) years. 50/307 patients developed ULD, defined as the appearance of clinically manifest invasive adenocarcinoma in the remaining breast or on the ipsilateral chest wall which could not be eradicated within 3 months of detection. Multivariate linear logistic regression was used in the statistical analysis to identify prognostic factors for ULD., Results: Five years following the diagnosis of IBTR the cumulative incidence of ULD was 13%. Five independent risk factors for ULD were identified; non-surgical treatment of IBTR, disseminated disease concurrent with IBTR, axillary lymph node metastases (at primary breast conservation), time < 3 years between breast conservation and IBTR, no adjuvant endocrine therapy. Eighty-eight per cent of the patients were treated with salvage mastectomy (n = 207) or re-excision (n = 62). The cumulative incidence at 5 years of ULD following salvage mastectomy and salvage re-excision were 10% and 16% respectively compared to 32% among patients treated non-surgically. Following IBTR, the 5-year overall survival among patients with local control was 78% in contrast to 21% among patients with ULD., Conclusion: Uncontrolled local disease is an infrequent but important outcome following breast-conserving surgery. Primary postoperative radiotherapy reduces the risk for IBTR and is therefore recommended as part of the primary treatment to avoid both IBTR and ULD. In addition to radiotherapy, adjuvant therapy reduces the risk for IBTR and thereby the risk for subsequent ULD. Patients with IBTR, independent of concurrent distant metastases, should when feasible be recommended for salvage surgery as it provides superior local control compared to salvage systemic therapy alone., (Copyright 2002 Elsevier Science Ltd.)