Jørn Andersen

Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study

PURPOSEnIntergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events.nnnPATIENTS AND METHODSnPatients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors.nnnRESULTSnIn all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115).nnnCONCLUSIONnThe protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer.

Purpose and patients. During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment. Results. During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75–1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur. Conclusion. The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.

Dynamics of the meningococcal carrier state and characteristics of the carrier strains: a longitudinal study within three cohorts of military recruits

Three cohorts of Danish male military recruits (n = 1069) were studied for pharyngeal meningococcal carriage during 3 months at different seasons: 39-47% of entrants were meningococcal carriers and the carriage rate remained constant over time and season. However, individual changes in the carrier state occurred frequently, and after 3 months 34% had changed carrier state on one or more occasions. Initially, a loss of carriage predominated; on the other hand almost 20% of non-carriers had acquisition of meningococci within the first month. The serological phenotypes of the 670 carrier strains were compared with those of 261 invasive strains recovered concurrently from patients with meningococcal disease country-wide. Both carrier strains and invasive strains were phenotypically heterogeneous. Almost 60% of the invasive strains belonged to three phenotypes: B:15:P1.7, 16, C:2a:P1.2, 5 and C:2b:P1.2, 5. In contrast, these phenotypes only amounted to 3.2% of the carrier strains, among which no phenotype was found with a prevalence above 4.9%. However, 30% of the carrier strains had serological phenotypes identical to those of 80% of the invasive strains. Our results indicated that the transmission rate of potential pathogenic carrier strains did not differ from that of other carrier strains.

MIB-1 expression in breast carcinomas with medullary features. An immunohistological study including correlations with p53 and bcl-2.

Abstractu2002Typical medullary carcinoma (TMC) is usually considered to have a more favourable prognosis than other types of infiltrating breast carcinomas. This is a biological paradox, since its clinical behaviour is not in agreement with its anaplastic morphology and high mitotic rate. It should be remembered that neoplastic growth reflects cell production minus cell loss, the latter being achieved by apoptosis. At present, bcl-2 oncogene (apoptosis inhibitor) and p53 gene are assumed to be involved in the regulation of cell death and tumour proliferation. Sixty breast carcinomas, initially indexed as medullary carcinomas, were re-classified using the diagnostic criteria given by Ridolfi. This review yielded 13 typical (TMC), 24 atypical (AMC), and 23 non-medullary carcinomas (NMC). Following antigen retrieval by microwave treatment, immunohistochemical analyses, using MIB-1, p53 and bcl-2 monoclonal antibodies were performed on serial sections from formalin-fixed, paraffin-embedded specimens. TMC revealed the highest incidence of intense p53 positivity, and the highest mean MIB-1 index, and absence of the apoptosis-inhibitor protein bcl-2. These results suggest the presence of a higher overall cell turnover in TMC than in AMC and NMC. Increased apoptosis balancing the increased cell proliferation might be among the possible explanations for the more favourable prognosis in TMC.

Long-Term Follow-Up of the Intergroup Exemestane Study.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

648 Prognostic significance of UPA and PAI-1 in relation to other prognosticators for the clinical outcome of breast cancer

In a retrospective study, uPA and PAI-I were assayed by enzyme-linked immunosorbent assay (ELISA) in detergent extracts prepared from 400 primary breast tumours. The patients were followed for a mediati of 9 years and for all patients relevant clinical findings were recorded. We found a correlation between uPA/PAI-1 and classical prognostic factors such as number of lymph nodes involved, grade, tumour size, hormone receptor status and histology, but no correlation according to menopause or age. Disease-free (DFS) and over-all survival (OS) were analyzed using a Coxs proportional hazard model. As cut-off point the median uPA and PAI-I values were used. Breast cancer patients with high content of PAI-I (>xa011.0xa0ng/mg protein) have an increased risk of relapse and death (RR: 1.74 (1.27–2.39), while high uPA (>xa04.3xa0ng/mg protein) had no impact. Despite PAI-ls correlation to other prognosticators, PAI-I retained its independent significance in the Cox-model in contrast to uPA.