Cost effectiveness of letrozole in the treatment of advanced breast cancer in postmenopausal women in the UK.

OBJECTIVE: To simulate the treatment of postmenopausal women with advanced breast cancer from second-line hormone therapy to death, and to generate estimates of the cost and effectiveness of letrozole and megestrol in order to determine the incremental cost effectiveness of letrozole, expressed as cost per life-years gained. DESIGN: A decision-analytic model, using Markov process techniques, was designed to evaluate the lifetime clinical and economic consequences of treatment with letrozole compared with standard care with megestrol. The model was based on clinical trial results showing a clear advantage of letrozole in terms of time to progression and duration of response. SETTING: The setting of the study was that of the UK healthcare system in 1996. PATIENTS AND PARTICIPANTS: A hypothetical cohort of patients, identical to the patients recruited for the AR/BC2 clinical trial, who were postmenopausal women with advanced breast cancer who had previously failed to respond to first-line or adjuvant anti-estrogen therapy. INTERVENTIONS: The dosages of medications were 2.5 and 160 mg/day for letrozole and megestrol, respectively. The analysis covered the period from treatment initiation until death (lifetime model). Effectiveness was expressed as survival and time without progression, and the model also included all relevant economic measures. MAIN OUTCOME MEASURES AND RESULTS: Based on the model, the average survival time of the letrozole group was 2.1 years (25.3 months) versus 1.9 years (21.5 months) for the megestrol group, a gain in survival of 2.4 months (10.5%). The average time without progression, cumulatively calculated over the different treatment options, amounted to 20.2 months for letrozole and 17.8 months for megestrol, an increase of 13.7% for the former patients. The total average cost per patient for the treatment of advanced breast cancer starting from second-line hormone therapy until death was higher in the letrozole group at 7547 Pounds versus 6820 Pounds for the megestrol group (discounted at an annual rate of 5%), leading to an incremental cost-effectiveness ratio of 3588 Pounds per life-year gained (1996 values). CONCLUSIONS: Based on the assumptions used in this model, letrozole offers a suitable alternative to megestrol in the treatment of second-line hormone therapy.

RNA-polymerase specificity of transcription of Arabidopsis U snRNA genes determined by promoter element spacing.

Although most eukaryotic genes known to be transcribed by RNA polymerase III have intragenic promoter elements, some are similar to genes transcribed by RNA polymerase II in that they have upstream promoters (reviewed in refs 1-4). Transcription of the vertebrate U6 and 7SK RNA genes by RNA polymerase III depends exclusively upon upstream signals, some of which are indistinguishable from the elements essential for polymerase II-specific genes. In the plant Arabidopsis thaliana the promoter elements for the U6 and U2 small nuclear RNA genes, transcribed by RNA polymerases III and II respectively, are identical, comprising a -30 TATA box and an upstream element specific for small nuclear RNA genes. The distance between these elements differs, however. Here we report evidence that this separation is crucial in determining whether the genes are transcribed by polymerase II or III.

U6 snRNA genes of Arabidopsis are transcribed by RNA polymerase III but contain the same two upstream promoter elements as RNA polymerase II-transcribed U-snRNA genes.

Previously we have demonstrated that the U2 snRNA genes from the higher plant Arabidopsis thaliana contain two upstream elements, the USE with sequence RTCCCACATCG and a -30 'TATA' box, which are essential for transcription by RNA polymerase II, and that the conserved spacing of about four helical DNA turns between these elements is important for optimal promoter function. We have now isolated three genes encoding U6 RNA in Arabidopsis. Transcription of these genes in transfected protoplasts of Nicotiana plumbaginifolia is resistant to alpha-amanitin indicating that they are transcribed by RNA polymerase III. The upstream regions of three Arabidopsis U6 genes contain USE and -30 TATA-like elements similar to those found to be important for transcription of U2 RNA genes but the spacing between the two elements is about 10 bp closer than in the U2 genes. Using synthetic U6 genes we demonstrate that the USE and TATA elements are indispensable for their transcription, the TATA boxes of U2 and U6 genes are interchangeable, and that the intragenic A box-like sequence of U6 gene is not essential. Increasing the distance between the USE and TATA by 10 bp inactivates U6 gene transcription, demonstrating that proper positioning of the elements is also important for transcription by RNA polymerase III. The data indicate that the structure of U-snRNA gene promoters and the determinants of polymerase specificity are completely different between vertebrates and plants.

Economic evaluation of letrozole in the treatment of advanced breast cancer in postmenopausal women in Canada.

OBJECTIVE: To determine the cost-effectiveness of initiation of second-line hormone therapy with letrozole in the treatment of advanced breast cancer in postmenopausal women in Canada, compared to megestrol acetate. METHODS: A modified Markov model, incorporating seven health states, was designed to simulate the treatment of patients with advanced breast cancer from second-line hormone therapy to death. The model was constructed with data from a clinical trial, literature sources, and interviews with breast cancer treatment experts. Canadian experts provided information on resource utilization patterns and local costs were attached to these resources. The model was used to calculate mean survival time, time without progression, and total direct medical costs for patients initiating treatment with letrozole 2.5 mg or megestrol acetate 160 mg. RESULTS: The mean survival time and time without progression for letrozole 2.5 mg patients were 28.3 months and 19.0 months, respectively, compared to 25.7 months and 16.5 months for megestrol acetate 160 mg patients. Total treatment costs for both groups were similar with the letrozole 2.5 mg group costing dollar 20,068 per patient, dollar 1061 more than the megestrol acetate 160 mg group (dollar CAN, 1996). The cost-effectiveness ratio for letrozole 2.5 mg with respect to megestrol was dollar 5051 per year of life gained. Sensitivity analysis showed that this ratio was sensitive to variations in the probabilities governing disease progression. CONCLUSIONS: Advanced breast cancer patients initiating second-line hormone therapy with letrozole 2.5 mg have better clinical outcomes than patients receiving megestrol acetate 160 mg. Furthermore, this benefit comes at an acceptable cost to the Canadian health care system.

Characterization of the genes encoding U4 small nuclear RNAs in Arabidopsis thaliana.

Three genes encoding U4 small nuclear RNA (U4 snRNA) in the higher plant Arabidopsis thaliana have been isolated and characterized. Two of the genes, AtU4.1 and AtU4.2, contain all the transcriptional signals known to be essential for U-snRNA gene activity in dicot plants: the Upstream Sequence Element (USE), the -30 TATA box and the downstream 3' end formation sequence. The USE and TATA elements are centered approximately four helical DNA turns apart, a feature characteristic of RNA polymerase II-transcribed U-snRNA genes of plants. The genes AtU4.1 and AtU4.2 are actively transcribed in transfected plant protoplasts and in Arabidopsis plants. Expression of the third gene, AtU4.3, could not be demonstrated. Since this gene is missing the downstream signal important for RNA 3' end formation, it probably represents a pseudogene. The genes AtU4.1 and AtU4.2 encode 152-153 nt long RNAs which show 85-89% sequence similarity with broad bean and pea U4 RNAs and 60-65% similarity with mammalian U4 RNAs. Arabidopsis U4 and U6 snRNAs can be folded into the base-paired Y-shaped model supporting the importance of the U4/U6 interaction during pre-mRNA splicing in plants as well as animals.

Absence of Y-specific DNA sequences in human 46,XX true hermaphrodites and in 45,X mixed gonadal dysgenesis.

A search for Y-specific DNA sequences has been performed in a sample of seven 46,XX true hermaphrodites and one 45,X mixed gonadal dysgenesis case and compared with a sample of 11 XX males. Using six Y-specific DNA probes no hybridization signal was obtained in the hermaphrodite group; in contrast, all XX males gave a positive signal with at least one probe. This difference is statistically highly significant. We conclude that the aetiology of true hermaphroditism is different from that of the XX male syndrome. As all cases of the hermaphrodite group are positive for the serological sex-specific antigen (Sxs) it is concluded that this antigen can be present even in the absence of Y-specific DNA.

A 45,X male with a Yp/18 translocation.

A patient described as a 45,X male (Forabosco et al. 1977) was examined for the presence of Y-specific DNA by using various probes detecting restriction fragments from different regions of the Y chromosome. Positive hybridization signals were obtained for Yp fragments only. In situ hybridization with two different probes, pDP31 and the pseudoautosomal probe 113F, led to a clear assignment of the Yp sequences to the short arm of one chromosome 18. Cytogenetically, the presence of all of Yp including the Y centromere on 18p could be demonstrated replacing a segment of similar size of 18p. Thus, the Y/18 translocation chromosome is dicentric structurally, but it was shown to be monocentric functionally with the no. 18 centromere active. Gene dosage studies with the probe B74 defining a sequence at 18p11.3 demonstrated a single dose of this sequence in the patient. In agreement with these observations, the patient shows clinical signs of the 18p-syndrome. It is concluded that in XO males in general, the X is of maternal origin while the maleness is due to a de novo Y/autosome translocation derived from the father. Depending on the nature of the autosomal deficiency caused by the Y/autosome translocation, the patient may have congenital malformations.