St Gallen 2019 guidelines understage the axilla in lobular breast cancer: a population-based study.

BACKGROUND: The St Gallen 2019 guidelines for primary therapy of early breast cancer recommend omission of completion axillary lymph node dissection (cALND), regardless of histological type, in patients with one or two sentinel lymph node (SLN) metastases. Concurrently, adjuvant chemotherapy is endorsed for luminal A-like disease with four or more axillary lymph node (ALN) metastases. The aim of this study was to estimate the proportion of patients with invasive lobular cancer (ILC) versus invasive ductal cancer of no special type (NST) with one or two SLN metastases for whom cALND would have led to a recommendation for adjuvant chemotherapy. METHODS: Patients with ILC and NST who had surgery between 2014 and 2017 were identified in the National Breast Cancer Register of Sweden. After exclusion of patients with incongruent or missing data, those who fulfilled the St Gallen 2019 criteria for cALND omission were included in the population-based study cohort. RESULTS: Some 1886 patients in total were included in the study, 329 with ILC and 1507 with NST. Patients with ILC had a higher metastatic nodal burden and were more likely to have a luminal A-like subtype than those with NST. The prevalence of at least four ALN metastases was higher in ILC (31.0 per cent) than NST (14.9 per cent), corresponding to an adjusted odds ratio of 2.26 (95 per cent c.i. 1.59 to 3.21). Luminal A-like breast cancers with four or more ALN metastases were over-represented in ILC compared with NST, 52 of 281 (18.5 per cent) versus 43 of 1299 (3.3 per cent) (P < 0.001). CONCLUSION: Patients with ILC more often have luminal A-like breast cancer with at least four nodal metastases. Omission of cALND in patients with luminal A-like invasive lobular cancer and one or two SLN metastases warrants future attention as there is a risk of nodal understaging and undertreatment in one-fifth of patients.

Nowadays patients who have breast cancer with one to two metastases in the first draining axillary lymph nodes are not recommended to undergo completion surgery of the axilla if they have breast-conserving surgery and will have adequate postoperative oncological treatment. Lobular breast cancer is the second most common type of breast cancer, and this study shows that patients with this type have an increased risk of having lymph node metastases remaining if completion surgery is omitted. The diagnosis of additional lymph node metastases is importance for guidance regarding adjuvant oncological therapy in lobular cancer with a hormonally sensitive low proliferative subtype.

Effects of adjuvant tamoxifen over three decades on breast cancer-free and distant recurrence-free interval among premenopausal women with oestrogen receptor-positive breast cancer randomised in the Swedish SBII:2pre trial.

AIMS: The primary aim was to compare 2 years of adjuvant tamoxifen versus no systemic treatment in premenopausal patients with oestrogen receptor (ER)-positive tumours, regarding breast cancer-free interval (BCFi) and distant recurrence-free interval (D-RFi), with 30 years of follow-up and for specified intervals. Moreover, we aimed to investigate the effects of adjuvant tamoxifen on the incidence of secondary malignancies and survival after distant recurrence. METHODS: Premenopausal patients with primary breast cancer were randomised to 2 years of tamoxifen (n = 277) or no systemic treatment (n = 287), irrespective of ER status. Information regarding events was collected by a review of medical records and from national registers. RESULTS: The median follow-up for all patients without events was 28 years, and only four of the patients alive had a follow-up of <20 years. With 30 years of follow-up, tamoxifen prolonged BCFi in the intention-to-treat population (hazard ratio [HR] = 0.76, 95% confidence interval (CI) 0.61-0.94, p = 0.011) compared with no treatment. In patients with ER-positive tumours (n = 362), tamoxifen prolonged BCFi (HR = 0.62, 95% CI 0.47-0.82, p = 0.001) and D-RFi (HR = 0.73, 95% CI 0.54-0.99, p = 0.043). The positive effect on BCFi was significant also for the interval >15-30 years (HR = 0.53, 95% CI 0.28-0.98, p = 0.042). For patients with ER-positive tumours who were diagnosed with distant recurrence (n = 165), survival after distant recurrence was shorter among tamoxifen-treated patients (median, 29 months versus 43 months). The incidence of contralateral breast cancer was 42% lower in the tamoxifen group (HR = 0.58, 95% CI 0.35-0.96, p = 0.035), whereas no differences were observed regarding other secondary malignancies. CONCLUSIONS: With three decades of follow-up, 2 years of adjuvant tamoxifen reduced the incidence of breast cancer-related events and distant recurrence, and the carryover effect seems to extend beyond 15 years. Moreover, adjuvant tamoxifen seems to be associated with shorter survival after diagnosis of distant recurrence.

Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98.

PURPOSE: To evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer. METHOD: AIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs). RESULTS: Forty-six percent of the tumors had a high AIB1 expression. In line with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80-100 vs. 1-79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival (univariable: hazard ratio 1.35, 95% confidence interval 1.12-1.63. Multivariable: hazard ratio 1.29, 95% confidence interval 1.06-1.58) and overall survival (univariable: hazard ratio 1.34, 95% confidence interval 1.07-1.68. Multivariable: hazard ratio 1.25, 95% confidence interval 0.99-1.60). HER2 did not seem to modify the prognostic effect of AIB1. No difference in treatment effect between tamoxifen and letrozole in relation to AIB1 was found. CONCLUSIONS: In a subset of the large international randomized trial BIG 1-98, we confirm AIB1 to be a strong prognostic factor in early breast cancer. Hence, although tumor AIB1 expression does not seem to be useful for the choice of tamoxifen versus an aromatase inhibitor in postmenopausal endocrine-responsive breast cancer, AIB1 is an interesting target for new anti-cancer therapies and further investigations of this biomarker is warranted.

St Gallen molecular subtypes in screening-detected and symptomatic breast cancer in a prospective cohort with long-term follow-up.

BACKGROUND: Diagnosis by screening mammography is considered an independent positive prognostic factor, although the data are not fully in agreement. The aim of the study was to explore whether the mode of detection (screening-detected versus symptomatic) adds prognostic information to the St Gallen molecular subtypes of primary breast cancer, in terms of 10-year cumulative breast cancer mortality (BCM). METHODS: A prospective cohort of patients with primary breast cancer, who had regularly been invited to screening mammography, were included. Tissue microarrays were constructed from primary tumours and lymph node metastases, and evaluated by two independent pathologists. Primary tumours and lymph node metastases were classified into St Gallen molecular subtypes. Cause of death was retrieved from the Central Statistics Office. RESULTS: A total of 434 patients with primary breast cancer were included in the study. Some 370 primary tumours and 111 lymph node metastases were classified into St Gallen molecular subtypes. The luminal A-like subtype was more common among the screening-detected primary tumours (P = 0·035) and corresponding lymph node metastases (P = 0·114) than among symptomatic cancers. Patients with screening-detected tumours had a lower BCM (P = 0·017), and for those diagnosed with luminal A-like tumours the 10-year cumulative BCM was 3 per cent. For patients with luminal A-like lymph node metastases, there was no BCM. In a stepwise multivariable analysis, the prognostic information yielded by screening detection was hampered by stage and tumour biology. CONCLUSION: The prognosis was excellent for patients within the screening programme who were diagnosed with a luminal A-like primary tumour and/or lymph node metastases. Stage, molecular pathology and mode of detection help to define patients at low risk of death from breast cancer.

Molecular subtype and tumor characteristics of breast cancer metastases as assessed by gene expression significantly influence patient post-relapse survival.

BACKGROUND: We and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients. PATIENTS AND METHODS: The translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and ß-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature. RESULTS: A significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and ß-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3-10.9] and HER2-enriched (HR 4.4; 95% CI 1.5-12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like. CONCLUSIONS: We show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information. CLINICALTRIALS.GOV: This is the translational part of the Swedish multicenter and randomized trial TEX, clinicaltrials.gov identifier nct01433614 (http://www.clinicaltrials.gov/ct2/show/nct01433614).

Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial.

The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTum™ assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre-treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p < 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26-2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTum™ predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven.

A prospective, multicenter validation study of a prognostic index composed of S-phase fraction, progesterone receptor status, and tumour size predicts survival in node-negative breast cancer patients: NNBC, the node-negative breast cancer trial.

BACKGROUND: In a retrospective study on node-negative breast cancer, a prognostic index consisting of a proliferation factor, S-phase fraction (SPF), progesterone receptor status (PR), and tumour size identified one-third of patients as high risk, with a sixfold increased risk of breast cancer death. This prospective multicenter cohort study was set up to validate the index. PATIENTS AND METHODS: In 576 T1-2N0 patients <60 years, prospective analyses of PR and SPF were carried out. High risk was defined as ≥2 of the following: size >20 mm, PR-negativity, and high SPF (in the absence of SPF, Bloom-Richardson grade 3). Median follow-up was 17.8 years. RESULTS: Thirty-one percent were high risk. In univariate analysis, the index was prognostic for breast cancer-specific survival after 5 years [hazard ratio (HR) = 4.7, 95% confidence interval (95% CI) 2.5-8.9], 10 years (HR = 2.2, 95% CI 1.5-3.3), and 15 years (HR = 1.7, 95% CI 1.2-2.5), and remained significant after adjustment for adjuvant medical treatment and age. In the 37% of patients with no risk factors, only one patient died of breast cancer the first 5 years. CONCLUSIONS: This prospective study validates a prognostic index consisting of a proliferation factor, PR-status, and tumour size. The index may be helpful for prognostic considerations and for selection of patients in need of adjuvant therapy.

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.

Comparison of the oestrogen and progesterone receptor status in primary breast carcinomas as evaluated by immunohistochemistry and immunocytochemistry: a consecutive series of 267 patients.

OBJECTIVE: The use of cytological specimens to evaluate tumour biomarkers in metastatic breast cancer lesions has attracted increased interest because of the considerable number of reports that have shown discordance between the primary tumour and metastatic lesion. Oestrogen receptor (ER) and progesterone receptor (PgR) assays are crucial for the management of patients with breast cancer, in both adjuvant and palliative settings. The aim of this study was to compare the ER and PgR immunocytochemical analysis of fine needle aspiration (FNA) samples with the immunohistochemistry (IHC) of surgical specimens and core biopsies from primary breast cancers. METHODS: The FNA specimens were prepared as cell blocks (n = 25) or ThinPreps (n = 258) for the immunocytochemistry (IC) ER and PgR analyses. Sixteen patients were excluded because of lack of follow-up (n = 1), neoadjuvant therapy (n = 3) or cell counts in their fine needle aspirates that were too low (n = 12). The results of IC on 25 cell blocks and 242 ThinPreps were compared with IHC on the corresponding core needle biopsies (n = 16) or excised tumours (n = 251). The ER and PgR status was defined as negative (when less than 10% of the nuclei were stained) or positive (when equal or more than 10% of the nuclei were stained). Kappa statistics were used to evaluate the concordance. RESULTS: The ER concordance was 98% with ThinPrep (κ = 0.93) and 92% with cell block (κ = 0.82). The corresponding values for PgR were 96% (κ = 0.91) and 96% (κ = 0.92). CONCLUSIONS: Our results confirm that, in cases in which biopsies or surgical specimens are not available, IC (with either cell block or ThinPrep techniques) is a reliable method for the determination of the ER and PgR status performed under strict conditions using primary breast carcinomas, and is therefore potentially useful in metastatic settings.

The role of AIB1 and PAX2 in primary breast cancer: validation of AIB1 as a negative prognostic factor.

Background The steroid-receptor coactivator amplified in breast cancer one (AIB1) is implicated to be a prognostic factor, although the results are not unanimous. Recently its effect was suggested to be modified by paired box 2 gene product (PAX2). Patients and methods Using immunohistochemistry (IHC) AIB1 and PAX2 were investigated in two cohorts of early breast cancer, including systemically untreated premenopausal lymph-node-negative women and pre- and postmenopausal women receiving tamoxifen. Results AIB1 scores were available for 490 patients and PAX2 scores were available for 463 patients. High AIB1 was a negative prognostic factor for distant disease-free survival (DDFS, P = 0.02) and overall survival (OS, P < 0.001) in systemically untreated women, while no prognostic effect was seen in the tamoxifen-treated cohort, indicating AIB1 to be a predictor of tamoxifen response. In systemically untreated patients, PAX2 was not a prognostic factor, nor did it modify the effect of AIB1. However, in ER-positive patients receiving tamoxifen, PAX2 appeared to be a positive prognostic factor in premenopausal patients, while a negative factor in postmenopausal. The interaction between the menopausal status and PAX2 was significant (P = 0.01). Conclusions In an independent cohort of low-risk premenopausal patients, we validate AIB1 as a negative prognostic factor, indicating AIB1 to be an interesting target for new anti-cancer therapies. The effect of PAX2 warrants further studies.

Comparison of residual oil cluster size distribution, morphology and saturation in oil-wet and water-wet sandstone.

We imaged an oil-wet sandstone at residual oil saturation (S(or)) conditions using X-ray micro-tomography with a nominal voxel size of (9 µm)(3) and monochromatic light from a synchrotron source. The sandstone was rendered oil-wet by ageing with a North Sea crude oil to represent a typical wettability encountered in hydrocarbon reservoirs. We measured a significantly lower S(or) for the oil-wet core (18.8%) than for an analogue water-wet core (35%). We analysed the residual oil cluster size distribution and find consistency with percolation theory that predicts a power-law cluster size distribution. We measure a power-law exponent τ=2.12 for the oil-wet core which is higher than τ for the water-wet system (τ=2.05), indicating fewer large clusters in the oil-wet case. The clusters are rough and sheet-like consistent with connectivity established through layers in the pore space and occupancy of the smaller pores; in contrast the clusters for water-wet media occupy the centres of the larger pores. These results imply less trapping of oil, but with a greater surface area for dissolution. In carbon storage applications, this suggests that in CO(2)-wet systems, capillary trapping is less significant, but that there is a large surface area for dissolution and reaction.

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial.

Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin(®)) and paclitaxel (Taxol(®)) alone (ET) or in combination with capecitabine (Xeloda(®), TEX). Starting doses for ET were epirubicin 75 mg/m(2) plus paclitaxel 175 mg/m(2), and for TEX epirubicin 75 mg/m(2), paclitaxel 155 mg/m(2), and capecitabine 825 mg/m(2) BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65-1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63-1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ(2) 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58-0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.

Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort.

A large proportion of women with lymph node negative breast cancer do not benefit from chemotherapy. Proliferation markers have been shown to recognize patients at high risk for recurrence. The Ki67 protein has recently been included in the St Gallen guidelines. The authors investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study, 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death were defined as controls. Inclusion criteria were tumor size

AIB1 is a predictive factor for tamoxifen response in premenopausal women.

BACKGROUND: Clinical trials implicate the estrogen receptor (ER) coactivator amplified in breast cancer 1 (AIB1) to be a prognostic and a treatment-predictive factor, although results are not unanimous. We have further investigated this using a controlled randomised trial of tamoxifen versus control. MATERIALS AND METHODS: A total of 564 premenopausal women were entered into a randomised study independent of ER status. Using a tissue microarray, AIB1 and ER were analysed by immunohistochemistry. RESULTS: AIB1 scores were obtained from 349 women. High AIB1 correlated to factors of worse prognosis (human epidermal growth factor receptor 2, Nottingham histological grade 3, and lymph node metastases) and to ER negativity. In the control arm, high AIB1 was a negative prognostic factor for recurrence-free survival (RFS) (P = 0.02). However, ER-positive patients with high AIB1 responded significantly to tamoxifen treatment (P = 0.002), increasing RFS to the same level as for systemically untreated patients with low AIB1. Although ER-positive patients with low AIB1 had a better RFS from the beginning, this was not further improved by tamoxifen (P = 0.8). CONCLUSIONS: In the control group, high AIB1 was a negative prognostic factor. However, ER-positive patients with high AIB1 responded significantly to tamoxifen. This implicates high AIB1 to be an independent predictive factor of improved response to tamoxifen and not, as has previously been discussed, a factor predicting tamoxifen resistance.

Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern.

AIMS: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. METHODS: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. RESULTS: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. CONCLUSION: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.

Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial.

BACKGROUND: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment. AIMS: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer. MATERIALS/METHODS: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression. RESULTS: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly. CONCLUSIONS: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.

Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence.

Ductal carcinoma in situ (DCIS) of the breast constitutes about 10% of all diagnosed breast cancers and, despite surgical removal, it may recur, either as DCIS or invasive breast cancer. Nuclear grade and growth pattern according to Andersen et al as well as surgical margins are factors that have been used to predict local recurrence, but ideally a set of tumour-specific factors should be identified and used as prognostic markers. Many cell cycle regulatory gene products have been shown to be involved in the formation of tumours and are either oncogenes or suppressor genes and involved in key processes in the transformation. We therefore characterised the cell cycle regulators cyclin E, cyclin D1, p27 and p16 in a material of DCIS cases arranged in a tissue microarray. With a manual tissue arrayer, 52% of the initial 177 DCIS samples were successfully targeted allowing immunohistochemical analyses of all four proteins in 92 cases of DCIS. As also observed in invasive breast cancer, there was a trend indicating that DCIS cases with high cyclin D1 were cyclin E low and oestrogen receptor-positive, whereas cyclin E high DCIS cases were cyclin D1 low and oestrogen receptor-negative. For the 64 patients that did not receive postoperative radiotherapy, there were 16 local recurrences (eight DCIS and eight invasive breast cancer) during a mean follow-up time of 63 months. Cyclin E, p27 or p16 were not associated with local recurrence, but interestingly cyclin D1 was significantly and inversely associated with local recurrence, both using univariate and multivariate analyses. In summary, using a tissue array approach we have shown that cyclin D1, besides growth pattern, is a prognostic marker for local recurrence in DCIS.

Are cellular polarisation and mitotic frequency prognostic factors for local recurrence in patients with ductal carcinoma in situ of the breast?

There is still no generally accepted histopathological classification system for ductal carcinoma in situ (DCIS) of the breast. Nuclear grade, with or without other histopathological parameters (i.e. comedo-type necrosis and cellular polarisation), has been demonstrated to yield prognostic information. A detailed method for the evaluation of the mitotic frequency in DCIS, based on an approach by Contesso, was used in this study. We also investigated if cellular polarisation and mitotic frequency were important for the ipsilateral local recurrence-free interval (IL-RFI) in 121 DCIS patients who had been operated upon with breast-conserving treatment (BCT) without radiotherapy. Both cellular polarisation and the mitotic frequency were associated with histopathological and cellular biological factors (in previous evaluations), and were of borderline significance for IL-RFI in the univariate analyses. However, when nuclear grade was included in the multivariate analyses (with or without the growth pattern), neither cellular polarisation nor the mitotic frequency were of any independent prognostic value.

Relation between the rate of tumour cell proliferation and latency time in radiation associated breast cancer.

BACKGROUND: Patients with possible radiation induced cancer could be used to study if the rate of tumour cell proliferation is related to latency time. Such a finding could help researcher to find time periods when other initiating risk factors operate. METHODS: Seventeen women with breast cancer, with a prior history of radiation treatment towards the parts or the whole breast, exclusive of the primary treatment of a breast cancer were identified. Most women had received treatment for benign disorders as hemangiomas, shoulder pain or skin infections. Three patients had been treated with mantle radiation for Hodgkin's disease prior to developing breast cancer. DNA analysis were performed, on remaining tumour tissue after hormone receptor analysis had been done, measuring the fraction of tumour cells in S-phase. Latency time (time between diagnosis and previous radiation treatment) was calculated and related to the S-phase fraction. RESULTS: A significant inverse relationship between latency time and S-phase was found (p < 0.0025), indicating that tumours with a high S-phase had a short latency time and vice versa. Among the possible radiation induced tumours, median S-phase was 14%, comparable with a median latency time of 22 years. Very high S-phase values were associated with short latency times (eg a S-phase of 35% would be compatible with a latency time of 7 years). CONCLUSION: Our preliminary results indicate that S-phase is related to latency time and that the median latency time maybe as long as 22 years. Our data may also explain why breast cancer is rare before 30 years of age and if patients are diagnosed at early ages, tumours often show high S-phase values and bad prognostic signs. We postulate that these results from radiation induced breast cancer may be used to extrapolate possible latency times in patients with non radiation induced breast tumours in order to isolate possible time periods for research after other initiating events.

TP53 protein expression analysis by luminometric immunoassay in comparison with gene mutation status and prognostic factors in early stage endometrial cancer.

Mutations in the TP53 tumor suppressor gene have been shown to significantly correlate with poor prognosis in endometrial cancer. In the present study we have evaluated a luminometric immunoassay (LIA) for quantitative estimation of TP53 protein expression in 65 cytosol preparations from endometrial cancer, previously analyzed for mutations in TP53 exons 4-10. LIA showed high (> or = 0.6 ng/mg protein) expression of TP53 protein in all eight tumors with missense mutation, but high protein levels were also detected in 15 tumors with normal TP53 sequence. All four tumors with nonsense or frameshift mutations had low or no TP53 protein expression. LIA was further evaluated in a retrospective study of 201 cytosol samples from endometrial cancer. TP53 overexpression (> = 0.6 ng/mg protein) was observed in 22% of the tumors and correlated with nonendometrioid histology types (P = 0.005), poorly differentiated tumors (P = 0.001), higher FIGO grade (P = 0.001), DNA nondiploidy (P = 0.002), and high S-phase fraction (P = 0.03). After a median follow-up time of 6.8 years (range 0.7-9.9 years), 22 (13%) progressions were observed in the 175 patients with early stage (I-II) disease. TP53 overexpression (P = 0.04), FIGO grade 3 vs. 1 + 2 (P = 0.01), higher age (P = 0.02), and DNA nondiploidy (P < 0.001) showed significant correlation to shorter progression-free survival in these patients. We conclude that TP53 protein analysis by LIA provides an incomplete correlation to mutation status and cannot substitute for mutation analysis in assessment of prognosis in endometrial carcinoma. In comparison to TP53 overexpression and higher FIGO grades, DNA nonploidy status seems to be a better prognostic indicator to define a subset of early stage endometrial cancer patients who may benefit by adjuvant chemotherapy/radiotherapy.