| 1. |
- Stenmark-Askmalm, Askmalm Marie, 1966-
(författare)
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p53 Alterations in Breast Cancer Related to Prognosis and Results of Therapy
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignant tumour disease and also the main cause of cancer-related deaths among women. The lifetime risk in western countries is 10%. The basic treatment for a patient with a localised tumour is surgery. In addition, different pathobiological variables are considered and an estimation of the risk of recurrence is made before deciding whether adjuvant therapy should be recommended. This therapy can be chemotherapy, which mainly prevents distant recurrence, or radiotherapy, which is effective against local recurrence. The treatment can be combined with anti-oestrogen, which prevents distant recurrence among patients exhibiting an oestrogen-receptor-positive tumour. However, breast cancer remains the chief cause of cancerrelated deaths and there is a need· for further pathobiologica! variables that, at an early stage, both can be prognostic and predict the outcome of adjuvant therapy.The p53 gene and its product p53 have been shown to play a central role in tumour suppression by regulating the cell cycle or initiating apoptosis. Certain mutations are associated with a stabilisation of the protein, leading to an accumulation that is detectable by immunohistochemistry.The main purposes of this study were to analyse p53 protein accumulation and gene mutation in exons 5-8 and to investigate the prognostic and predictive role of p53.p53 protein accumulation was investigated with immunohistochemistry in frozen tumour samples from 776 patients; 164 patients with stage U, 205 patients with stage I and 407 patients with either lymph node metastases and/or a tumour diameter exceeding 30mm. Of the latter, 139 were premenopausal and 268 were postmenopausal. These 407 patients had been randomiscd to adjuvant CMF chemotherapy or postoperative radiotherapy. Gene analyses with PCR-SSCP followed by direct sequencing were performed in the 268 postmenopausal patients. The predictive value of p53 was only analysed in the randomised patient material.The results showed that nuclear p53 accumulation ranged between 9% and 25%. p53 accumulation was significantly associated with several pathobiological variables, "indicating an aggressive tumour, which was more likely to be oestrogen receptor negative, DNA aneuploid, and have a high S-phase fraction. p53 accumulation was also significantly correlated with an increased rate of distant recurrence, whereas mutations that were found in 16% of the 268 cases investigated were not significantly correlated with an increased risk of distant recurrence. However, the investigation of both protein accumulation and gene mutation in exons 5-8 contributed further information than was achieved with one of the methods alone. The protein accumulation reflected to a certain extent mutations of the gene, mainly missense mutations. A majority of the severe mutations that included alteration of the reading frame did not lead to any protein accumulation. Sixty-one per cent of the tumours exhibiting protein accumulation did not show any mutation in exons 5-8. Subgroups of different p53 alteration patterns seemed to be related to different prognoses.The patients with p53 altered tumours, either showing protein accumulation, gene mutation or both, benefited significantly from CMF chemotherapy compared with the radiotherapy group. This benefit could not be seen among the patients without p53 alterations. The test for interaction between p53 status and relative rate was significant. This response was most pronounced among premenopausal patients. Postmenopausal patients seemed to benefit although not significantly.In conclusion, the present study suggests that p53 accumulation is a prognostic factor associated with an increased risk of distant recurrence. p53 alteration defined as protein accumulation, gene mutation in exons 5-8, or both, was a predictor of good response to CMF chemotherapy as compared to postoperative radiotherapy. This benefit could not be seen among patients without p53-altered tumours.
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| 2. |
- Malmström, Annika, 1957-
(författare)
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Studies for Better Treatment of Patients with Glioma
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden annually over 500 people will be diagnosed with the malignant brain tumor glioma. They are graded from I-IV. The majority are glioblastoma (grade IV) (GBM), these being the most aggressive type. Median survival for those treated with standard of care is expected to be around 15 months. This tumor will mainly affect those 60 years or older.The studies in this thesis focus on treatment of patients with malignant gliomas grade III and IV. The aim of the studies is to improve the care of glioma patients. Papers I and II explored different therapeutic options in randomized trials, to facilitate individualized treatment recommendations. Findings from studies I and II, together with additional trials, demonstrated the importance of analyzing the tumor marker O6-methylguanine DNA methyltransferase (MGMT) methylation status for survival of GBM patients treated with Temozolomide (TMZ). The third paper investigated how the analysis of this marker is implemented internationally.The first study (paper I, Nordic trial) investigated treatment options for patients 60 years or older with GBM. The trial compared standard radiotherapy (SRT) over 6 weeks versus hypofractionated radiotherapy (HRT) over 2 weeks versus single agent TMZ administered in up to six 4 weekly cycles. In all, 342 patients were included in the trial. This study demonstrated that those randomized to TMZ had superior survival as compared to SRT. In addition, quality of life (QoL) data also suggested a better QoL for TMZ treatment than for radiotherapy. The benefit of TMZ treatment seemed to be limited to those with the tumor molecular marker MGMT methylated (inactivated).The second trial (paper II, Neoadjuvant trial) studied whether integrating TMZ treatment with SRT for patients younger than 60 years with GBM (grade IV) and astrocytoma grade III would confer a survival benefit, if administered postoperatively, before the start of SRT (neoadjuvant). TMZ was provided for 2-3 four weekly cycles followed by SRT to patients randomized to neoadjuvant treatment and was compared to postoperative SRT alone. Although this trial could not illustrate any advantage of delaying the start of SRT while administering TMZ for the study cohort in general, for those included as astrocytoma grade III the median survival was found to be superior by 5 years when randomized to neoadjuvant TMZ. This trial also confirmed the importance of MGMT promoter methylation for the efficacy of TMZ.The third study (paper III) investigated international practices for analyzing tumor MGMT promoter methylation status. MGMT analysis can be conducted by various laboratory methods, which in some cases can provide opposing results regarding the MGMT methylation status of the patient´s tumor. This can lead to incorrect treatment recommendations. To establish which methods and cut-offs that are regularly used to determine tumor MGMT status in the clinic, an international survey was provided to those working in the field. We also inquired about opinions regarding an international consensus on how MGMT should be tested. The 152 respondents reported several methodologies and different cut-off levels also for the same method. A majority of respondents warrant international guidelines.In conclusion, the results of the 2 randomized trials contribute to individualized treatment recommendations for patients affected by GBM or astrocytoma grade III. The results of the survey regarding analyses of MGMT clarify the current problematic situation. The request of the respondents regarding international guidelines might contribute to their future development, so that personalized treatment recommendations can be improved.
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| 3. |
- Söderlund Leifler, Karin, 1979-
(författare)
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DNA repair pathways and the effect of radiotherapy in breast cancer
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A large proportion of breast cancer patients are treated with radiotherapy. Ionising radiation induces different DNA damages, of which double-strand breaks are the most severe. They are mainly repaired by homologous recombination or non-homologous end-joining. Different protein complexes have central roles in these repair processes. In addition to the ability to repair DNA damage, cellular radiosensitivity is also affected by mitogenic signals that stimulate survival and inhibit apoptosis. The phosphatidylinositol 3-kinase (PI3-K)/AKT pathway controls cell proliferation, invasiveness and cell survival. AKT is regulated by upstream growth factor receptors, one of them being HER2 (also called ErbB2). HER2 is overexpressed in 15-30% of all breast cancers and associated with poor prognosis.In this thesis, we have studied factors that affect tumour cell resistance to ionising radiation. In Paper I, the role of HER2/PI3-K/AKT signalling in radiation resistance was investigated in two breast cancer cell lines. The results support the hypothesis that the HER2/PI3-K/AKT pathway is involved in resistance to radiation-induced apoptosis in breast cancer cells in which this signalling pathway is overstimulated.We also investigated if the protein expression of several DNA repair-associated proteins influence the prognosis and treatment response in early breast cancer. Moderate/strong expression of the MRE11/RAD50/NBS1 (MRN) complex predicted good response to radiotherapy, whereas patients with negative/weak MRN had no benefit from radiotherapy as compared to chemotherapy (Paper II). These results suggest that an intact MRNcomplex is important for the tumour-eradicating effect of radiotherapy. In Paper III, low expression of the BRCA1/BRCA2/RAD51 complex was associated with an aggressive phenotype, an increased risk of local recurrence and good response to radiotherapy.In Paper IV, we studied if a single nucleotide polymorphism, RAD51 135G/C, was related to RAD51 protein expression, prognosis and therapy resistance. We found that genotype was not correlated to neither protein expression nor prognosis. Patients who were G/G homozygotes had a significant benefit from radiotherapy. The results also suggested that the RAD51 135G/C polymorphism predicts the effect of chemotherapy in early breast cancer.In conclusion, DNA repair proteins are potential prognostic and predictive markers. The results indicate that proteins in different repair pathways may contribute differently to the effect of radiotherapy. Also, the HER2/PI3-K/AKT signalling pathway protects cells from radiation-induced apoptosis. In the future, it might be possible to target some of these proteins with inhibitory drugs to sensitise tumours to radiotherapy.
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