Tommy Fornander

ADJUVANT TAMOXIFEN IN EARLY BREAST CANCER: OCCURRENCE OF NEW PRIMARY CANCERS

The frequency of new primary cancers was studied in 1846 postmenopausal patients included in a randomised trial of tamoxifen as an adjunct to primary surgery for early breast cancer. The median follow-up was 4.5 years (range 0.5-10.5 years). The number of new cancers in the tamoxifen group (n = 57) did not differ significantly from that in the control group (n = 70). However, in tamoxifen patients second breast cancers occurred less often and endometrial cancer occurred more often than in the controls. The increase in endometrial cancers was probably related to the agonistic oestrogenic effects of tamoxifen and was most pronounced in those treated for over 2 years.

Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer

One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium. The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a randomized trial of pre- or postoperative radiation therapy (45 Gy/5 weeks) versus surgery alone. All patients were treated with a modified radical mastectomy. The mean follow-up was 16 years (range: 13-19 years). During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance (p = 0.09). There was no increase in intercurrent mortality due to any cause. However, when the results were analyzed according to estimated doses of radiation to the myocardium, the subset of patients who received the highest doses, that is, those treated with tangential 60Co fields for left-sided tumors, were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls (relative hazard: 3.2, p less than 0.05). No such increase was observed among the patients who received less radiation to the myocardium, that is, whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors, irrespective of the treatment technique. It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume. All of the following factors are thus important: laterality of the tumor, portal arrangements, radiation energy, fractionation, and total dose. The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment.

Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden.

PURPOSE To study incidence of radiation-related heart disease in a large population of breast cancer patients followed for up to 30 years. MATERIAL AND METHODS 72,134 women diagnosed with breast cancer in Denmark or Sweden during 1976-2006 and followed prospectively. Radiation-related risk was studied by comparing women with left-sided and right-sided tumours. RESULTS 34,825 women (48%) received radiotherapy. Among unirradiated women tumour laterality had little relevance to heart disease. Among irradiated women mean dose to the whole heart was 6.3 Gy for left-sided tumours and 2.7 Gy for right-sided tumours. Mortality was similar in irradiated women with left-sided and right-sided tumours, but incidence ratios, left-sided versus right-sided, were raised: acute myocardial infarction 1.22 (95% CI 1.06-1.42), angina 1.25 (1.05-1.49), pericarditis 1.61 (1.06-2.43), valvular heart disease 1.54 (1.11-2.13). Incidence ratios for all heart disease were as high for women irradiated since 1990 (1.09 [1.00-1.19]) as for women irradiated during 1976-1989 (1.08 [0.99-1.17]), and were higher for women diagnosed with ischaemic heart disease prior to breast cancer than for other women (1.58 [1.19-2.10] versus 1.08 [1.01-1.15], p for difference=0.01). CONCLUSIONS Breast cancer radiotherapy has, at least until recently, increased the risk of developing ischaemic heart disease, pericarditis and valvular disease. Women with ischaemic heart disease before breast cancer diagnosis may have incurred higher risks than others.

Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer

BACKGROUND AND PURPOSE Some types of radiation therapy have been associated with an increased risk of cardiac mortality and morbidity in patients with early-stage breast cancer. A relationship has been observed between cardiac radiation dose-volume and the level of excess risk of cardiac mortality. However, relatively few data are available on the morbidity from myocardial infarction associated with adjuvant radiotherapy. PATIENTS AND METHODS From 1971 to 1976, a total of 960 patients with operable breast cancer were randomly allocated to preoperative radiation therapy, postoperative radiation therapy or to surgery alone. A previous analysis of the cardiac dose-volumes with the treatment techniques used in the trial indicated that the irradiated patients could roughly be divided into three groups. Information on the number of myocardial infarctions was obtained through computerized record linkage with a population-based registry of myocardial infarctions in Stockholm County. Information on cause-specific mortality was obtained from the Swedish Cause-of-Death Registry. The median follow-up was 20 years (range 17-23 years). RESULTS A total of 58 patients developed an acute myocardial infarction during the period of follow-up. The number of myocardial infarction cases was not significantly different between the three treatment groups. When analyzed according to estimated cardiac radiation dose-volumes, patients in the highest dose-volume subgroup exhibited a hazard of myocardial infarction of 1.3 (95% CI 0.7-2.6) relative to that of the surgical controls, whereas the corresponding relative hazard for the intermediate and low dose-volume subgroups was below unity. Data on death due to cardiovascular disease showed that patients in the high dose-volume group exhibited a hazard of 2.0 (95% CI 1.0-3.9, P = 0.04) relative to that of the surgical controls. Concerning death due to ischemic heart disease, the relative hazard for the same subgroup was 2.5 (95% CI 1.1-5.7, P = 0.03). The difference between the groups was established after 4-5 years. The cumulative incidence curves continued to diverge up to about 10-12 years. No further divergence appeared after 12 years, but the number of events was low. CONCLUSIONS This analysis confirms and extends previous results from the trial. Cardiac mortality was positively correlated with the cardiac dose-volume. Patients receiving high dose-volumes exhibited an increased mortality of ischemic heart disease, but not of myocardial infarction, which implies another mechanism, e.g. radiation-induced microvascular damage to the heart.

Late effects of adjuvant chemotherapy and postoperative radiotherapy on quality of life among breast cancer patients

Late effects of adjuvant treatment on perceived health and quality of life were assessed through a questionnaire mailed to 448 premenopausal and postmenopausal breast cancer patients, free from recurrence 2-10 years after primary therapy. The patients had been randomised to postoperative radiotherapy or adjuvant chemotherapy as adjuncts to primary surgery. The differences between the two treatments were generally small. However, the radiotherapy patients had significantly greater problems with decreased stamina, symptoms related to the operation scar and anxiety. The chemotherapy patients had significantly more problems with smell aversion. Activity level inside and outside the home, anxiousness and depressive symptoms were similar in both groups. The chemotherapy patients scored their overall quality of life higher than the radiotherapy patients.

Evaluation of irradiated heart volumes in stage I breast cancer patients treated with postoperative adjuvant radiotherapy.

PURPOSE To quantify the proportion of heart volumes that received at least 25 Gy with tangential photon fields in patients with left-sided stage I (T1 NOMO) breast cancer treated with breast-conserving surgery. METHODS AND MATERIALS The dose planning of 100 consecutive patients was reviewed. All were irradiated with tangential photon fields that covered the left breast only. A three-dimensional computed tomographic (CT)-based dose planning was made for each patient. The prescribed dose to the tumor was 50 Gy. For each patient, the proportion of the heart included in the 50% isodose was determined from the cumulative dose-volume histogram (DVH). The same volume determination was made for the left-sided breast cancer patients treated with tangential fields during the first Stockholm Breast Cancer Trial. RESULTS The mean irradiated heart volume that received at least 25 Gy was 5.7% (SD = 4.5%) for the whole group and 11.9% (SD = 3.7%) in those with the highest volumes. The mean irradiated heart volume included in the 50% isodose for patients in the Stockholm Trial was 25% (SD = 11.9%). CONCLUSION In this study, the majority of patients with left-sided T1NOMO breast cancer did not receive irradiation to substantial heart volumes. However, in 6% of all studied patients, the proportion of irradiated heart volume was close to the irradiated heart volumes with one of the treatment techniques used in the Stockholm Trial for patients with left-sided tumors. That technique has been associated with significantly increased cardiac mortality during long-term follow-up evaluation in a previous study. The CT-based three-dimensional treatment-planning system (TMS) represents a valuable tool in identifying such patients; thus, treatment may be conformed to reduce the irradiated heart volume.

Myocardial damage in breast cancer patients treated with adjuvant radiotherapy : A prospective study

PURPOSE To look for early and late signs of cardiac side effects of postoperative radiotherapy in patients with left-sided breast cancer. METHODS AND MATERIALS Seventeen left-sided primary (Stage I-III) breast cancer patients considered eligible were recruited. Their computer tomography-based dose planning showed a part of the hearts left ventricle irradiated with at least 85-95% of the total dose. Twelve patients were examined both before treatment and an average of 13 months later, at a first follow-up. In partially mastectomized patients tangential opposed photon fields were used to the breast tissue, while in patients with modified radical mastectomy electrons were given to the thorax. Echocardiography and a bicycle ergometry stress test with myocardial perfusion scintigraphy were carried out before and after radiotherapy to assess if any myocardial damage could be detected. RESULTS Six of the 12 patients exhibited new fixed scintigraphic defects after radiotherapy indicating regional hypoperfusion. Four of them received treatment only to the breast after breast-conserving surgery. The localization of the defects corresponded well with the irradiated volume of the left ventricle. No deterioration in left ventricular systolic or diastolic function could be detected by echocardiography. CONCLUSIONS In this study half of the patients exhibited new scintigraphic defects that indicate radiation-induced myocardial damage, probably affecting the microcirculation. There were no changes on electrocardiography or any deterioration of the left ventricular function at this stage. Long-term follow-up is necessary to assess whether this finding is a prognostic sign for developing radiation-induced coronary artery disease.

Long-term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women.

The decrease in sex steroid hormone levels after the onset of menopause is associated with bone loss and subsequent osteoporosis. Tamoxifen has antiestrogenic properties and may thus theoretically decrease bone mineral density, particularly after long-term treatment. Bone mineral density (BMD) was assessed in 75 recurrence-free postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen (40 mg daily) for 2 or 5 years versus no adjuvant endocrine therapy. The measurements were done about 7 years after the initial randomization. BMD was measured with single-photon absorptiometry (SPA) at two levels of the distal forearm representing cortical and trabecular bone. The BMD was found to be similar among tamoxifen patients compared with the controls. For cortical bone, the BMD was 1.03 g/cm2 (95% confidence interval [Cl], 0.97 to 1.09) among tamoxifen patients and 1.03 g/cm2 (95% Cl, 0.96 to 1.11) in controls. For trabecular bone, the values were 0.74 g/cm2 (95% Cl, 0.70 to 0.79) and 0.73 g/cm2 (95% Cl, 0.68 to 0.79), respectively. The results thus did not indicate an accelerated postmenopausal bone loss with long-term adjuvant tamoxifen.

Amplification of CCND1 and PAK1 as predictors of recurrence and tamoxifen resistance in postmenopausal breast cancer

The 11q13 region is amplified in approximately 15% of all breast tumors. Situated in this region are the cyclin D1 gene (CCND1) and the p-21-activated kinase 1 (PAK1) gene. Both genes encode proteins shown to activate the estrogen receptor (ER), leading to transcription of CCND1 and other ER-responsive genes. Here, we investigate the prognostic and treatment predictive role of CCND1 and PAK1 gene amplification in postmenopausal breast cancer patients randomized to tamoxifen treatment or no adjuvant treatment. Amplification of CCND1 and PAK1, assessed by real-time PCR, was observed in 12.5 and 9.3%, respectively. Amplification of PAK1 was seen in 37% of the CCND1-amplified tumors, indicating coamplification (P<0.001). In ER-positive patients, amplification of at least one of the genes indicated a reduced recurrence-free survival (P=0.025). When response to tamoxifen treatment was analysed, patients with PAK1 amplification showed decreased benefit from the drug (ER+; relative risk ratio (RR)=1.62; 95% confidence interval (CI), 0.47–5.55) compared to patients without amplification (ER+; RR=0.53; 95% CI, 0.32–0.88). This was not evident for CCND1 amplification. We show that PAK1 may be a predictor of tamoxifen resistance and furthermore, we do not discard PAK1 as a potential candidate oncogene in the 11q13 amplicon. In addition, we show that high pak1 protein levels may predict tamoxifen insensitivity.

Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: A population-based study

Background:We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries.Methods:We analysed the data on 257 362 women diagnosed with breast cancer during 2000–7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis.Results:Age-standardised 3-year net survival was 87–89% in the UK and Denmark, and 91–94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42–45% elsewhere. Women in the UK had low survival for TNM stage III–IV disease compared with other countries.Conclusion:International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.