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T Aas

Publications and source records attributed to T Aas.

17 recordsLinked to original sources
PubMed2003

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy.

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin (P = 0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 (P = 0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations (P = 0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death (P = 0.001 and P = 0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Adult↗
PubMed2001

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Algorithms↗
PubMed2001

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.

Adult↗
PubMed2001

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer.

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.

Adult↗
PubMed1997

Absence of p21 expression is associated with abnormal p53 in human breast carcinomas.

The p53 tumour-suppressor gene is important in the regulation of cell growth and apoptosis, and loss of functional wild-type activity may be associated with tumour formation and resistance to therapy. Differentiation of functionally normal wild-type protein from mutant or abnormal protein remains difficult using either immunohistochemical assays or mutational DNA sequencing. p21(WAF1/CIP1) (p21) is induced by wild type p53 and plays an important role in promoting cell cycle arrest. To test the hypothesis that p21 protein expression may act as a downstream marker of tumours from patients with locally advanced breast cancer before treatment with doxorubicin, pretreatment p53 status had been characterized in 63 tumours by p53 protein immunostaining and DNA mutational analysis. There was a significant association between immunostaining for p53 and the presence of p53 mutations (P = 0.01). Of 56 patients available for determination of p21, 31 (55%) expressed p21 protein. Twenty-eight out of 31 patients (90%) positive for p21 had low negative p53 protein expression, whereas only 3 of 13 patients (23%) with high p53 expressed p21 (P = 0.009). No association was seen between p21 protein expression and p53 mutations (P = 0.24). The combination of p53 and p21 immunostaining results improved the specificity of the immunostaining but at a cost of significant reduction in sensitivity. Immunohistochemical assessment of p21 protein expression is inversely associated with abnormal p53 protein in human breast cancer. The detection of p21 protein expression in combination with p53 protein expression did not improve the ability of immunohistochemistry (IHC) to differentiate between normal and mutant p53 protein.

Adult↗
PubMed1996

Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients.

The mechanisms causing resistance to chemotherapeutic drugs in cancer patients are poorly understood. Recent evidence suggests that different forms of chemotherapy may exert their cytotoxic effects by inducing apoptosis. The tumor suppressor gene P53 has a pivotal role inducing apoptosis in response to cellular damage. In vitro investigations have shown intact p53 to play a critical role executing cell death in response to treatment with cytotoxic drugs like 5-fluorouracil, etoposide and doxorubicin. Recently, mutations in the P53 gene were found to confer resistance to anthracyclines in a mouse sarcoma tumor model, and overexpression of the p53 protein (which, in most cases, is due to a mutated gene) was found to be associated with lack of response to cisplatin-based chemotherapy in non-small cell lung cancer. Previous studies have shown mutations in the P53 gene or overexpression of the p53 protein to predict a poor prognosis, but also a beneficial effect of adjuvant radiotherapy or chemotherapy in breast cancer. In this study we present data linking specific mutations in the P53 gene to primary resistance to doxorubicin therapy and early relapse in breast cancer patients.

Adult↗
PubMed1996

Primary systemic treatment with weekly doxorubicin monotherapy in women with locally advanced breast cancer; clinical experience and parameters predicting outcome.

Sixty-three patients (median age 64 years) with locally advanced breast cancer (T3, T4 and/or N2) were treated with primary 'neoadjuvant' chemotherapy given as weekly doxorubicin monotherapy (14 mg/m2 per dose). Seven patients had solitary distant metastasis at the time of diagnosis. Twenty-eight patients (45%) achieved 'partial response' to primary chemotherapy. Twenty-nine patients (46%) had 'stable disease', and 6 patients (9%) had 'progressive disease' during treatment. Following chemotherapy, 52 patients were subjected to surgery and another 4 patients had surgery performed after radiotherapy. Surgery was considered impossible in only three patients. After a median observation time of 23 months, local recurrences were observed in 2 patients, one with progressive disease and one with stable disease during chemotherapy. Univariate analyses revealed that large tumour size, high histological grade and high mitotic frequency were associated with poor primary response to chemotherapy. Recent studies have demonstrated a correlation between p53-mutations and chemotherapy response.

Adult↗
PubMed1994

[Primary treatment of locally advanced breast cancer with neoadjuvant chemotherapy].

Since February 1991, in Health Region 3, patients with recently diagnosed Stage III breast cancer have been treated with neoadjuvant chemotherapy. This treatment includes 16 weeks of chemotherapy prior to local treatment, usually consisting of mastectomy and postoperative radiotherapy. 48 patients have so far undergone this treatment. The majority (43 patients) received chemotherapy consisting of weekly doses of Adriamycin. Even with a high average age the therapy has been well tolerated. 60% of the patients partially responded to the therapy, an additional 15% experienced minimal response. At this point it would be premature to evaluate the long term effect of the therapy. It is very interesting, however, that at this stage we have not observed any local recidive in patients who showed primary response to chemotherapy. Following primary treatment of this group of patients, local recidive is usually a frequent and early observation.

Aged↗
PubMed1991

The Effect of Gastric Banding on Weight Loss in Patients with Morbid Obesity.

The results following operation for morbid obesity in 41 patients (8 men and 33 women) during the period 1983-1989 are reported. The median preoperative body mass index (BMI) was 43.6 (median excess weight 81%). All patients were preoperatively evaluated at the Department of Internal Medicine, and they had all tried several conservative regimens in order to lose weight. They were all operated on with gastric banding, creating a gastric stoma of 15 mm. Pneumonia developed in 10 patients, one patient got a wound infection, and one patient died postoperatively from a massive coronary embolism. The immediate postoperative weight loss was satisfactory, median BMI being reduced from 43.6 preoperative to 30.5 after 9 months. Median BMI after 3 and 5 years was 34 and 32 (median excess weight 42 and 41%, respectively). Six patients were reoperated, four having their band removed, two being converted to vertical gastric banding. In conclusion, gastric banding gives satisfactory results for most of the patients. The reoperation rate is, however, high and the long-term result is not favorable for all patients

Journal Article↗
PubMed1990

[Breast conserving surgery in breast cancer. Experiences from the Haukeland Hospital 1983-88].

From 1983-88, 97 breast cancers in 94 women were treated with breast conserving surgery at Haukeland University Hospital. 71% of the tumours were less than 2 cm in diameter and 94% less than 3 cm. 65% had negative axillary nodal status. 90 patients had ductal carcinoma, three of whom also had extensive intraductal carcinoma. Pathological findings in the resection margins (invasive carcinoma, intraductal carcinoma or atypical epithelial hyperplasia) were reasons for reoperation in 14 patients, eight of them by mastectomy. Thus, after completion of initial treatment the breast was preserved in 89 patients. Postoperative irradiation to the breast was given as a routine. Three elderly patients were excepted. Two patients developed ipsilateral breast recurrences after six and 24 months respectively. The first was treated by re-resection and the second by mastectomy. Neither of these showed evidence of distant metastases. Distant metastases were discovered in five patients, two of these have since died.

Adult↗
PubMed1990

[Breast-preserving surgery in breast cancer. Experiences from Haukeland Hospital 1983-1988].

From 1983-88, 97 breast cancers in 94 women were treated with breast-conserving surgery at Haukeland University Hospital. 71 per cent of the tumours were less than 2 cm in diameter and 94 per cent less than 3 cm. 65 had negative axillary nodal status. 90 patients had ductal carcinoma, three of whom also had extensive intraductal carcinoma. Pathological findings in the resection margins (invasive carcinoma, intraductal carcinoma or atypical epithelial hyperplasia) were reasons for reoperation in 14 patients, eight of them by mastectomy. Thus, after completion of initial treatment the breast was preserved in 89 patients. Postoperative irradiation to the breast was given as a routine. Three elderly patients were excepted. Two patients developed ipsilateral breast recurrences after six and 24 months respectively. The first was treated by re-resection and the second by mastectomy. Neither of these showed evidence of distant metastases. Distant metastases were discovered in five patients, two of these have since died.

Adult↗
PubMed1989

[Breast sarcoma. Diagnostic and therapeutic problems].

From 1981 to 1988 six patients, five females and one male, with breast sarcoma were treated in the Department of Surgery, University Hospital, Bergen. Four of them had phyllodes tumour, one a malignant myoepithelioma and one a liposarcoma. Metastases to axillary lymph nodes or distant metastases were not observed. Sarcomas account for about 1% of malignant breast tumours in our department. The cases demonstrate diagnostic and therapeutical problems in dealing with breast sarcomas.

Aged↗
PubMedDate not supplied

Progesterone binding cyst protein in hormone receptor positive breast cancer; a predictive factor for effect of adjuvant tamoxifen treatment.

Progesterone binding cyst protein (PBCP) was measured in breast cancer cytosols from 128 pre- and post-menopausal women with operable node positive (pN+) breast cancer Stage II. All patients were included in a national multicenter study on the effect of adjuvant tamoxifen treatment in hormone sensitive breast cancer, i.e. estrogen receptor content of at least 10 pmol/g cytosol protein. Patients were randomised to receive adjuvant tamoxifen 20 mg once daily for two years or no endocrine treatment. At a median follow-up of 60 months, we found PBCP content in the primary tumor to be an important factor with regard to the effect of adjuvant tamoxifen treatment. The benefit of adjuvant tamoxifen treatment on relapse-free survival and overall survival was confined to the subpopulation of patients with PBCP negative tumors. PBCP should be further evaluated as a predictive factor for the effect of tamoxifen treatment.

Adult↗