Efficacy of tucatinib for HER2-positive metastatic breast cancer after HER2-targeted therapy: a network meta-analysis.

Aim: A systematic literature review and network meta-analysis of randomized controlled trials in patients receiving therapy for HER2+ unresectable/metastatic breast cancer after ≥1 HER2-directed therapy was conducted to compare progression-free survival (PFS) and overall survival (OS). Methods: Hazard ratios (HRs) and relative differences from fractional polynomials (FPs) for PFS and OS were assessed by Bayesian network meta-analyses. Results: For PFS, surface under the cumulative rankogram (SUCRA) ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by T-DM1 monotherapy and neratinib plus capecitabine. For OS, SUCRA ranked tucatinib plus trastuzumab with capecitabine as highest in both HR and FP analyses, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1 monotherapy, with similar scores. Conclusion: Tucatinib plus trastuzumab with capecitabine, and T-DM1 monotherapy, consistently showed improved PFS and OS versus lapatinib/trastuzumab plus capecitabine and non-targeted treatments.

Lay abstract Although several therapies are used in HER2-positive metastatic breast cancer, direct head-to-head comparisons of these therapies are lacking. We conducted a network meta-analysis, a way of indirectly comparing the results of different clinical trials, to compare how long patients receiving therapy had no disease progression, and also how long patients survived. In terms of avoiding disease progression, tucatinib plus trastuzumab with capecitabine ranked highest, followed by T-DM1 monotherapy and neratinib plus capecitabine. In terms of survival, tucatinib plus trastuzumab with capecitabine ranked highest, followed by pertuzumab plus trastuzumab with capecitabine and T-DM1. Tucatinib in combination with trastuzumab plus capecitabine and also T-DM1 monotherapy consistently demonstrated improved progression-free and overall survival outcomes compared with other therapies.

Clinical burden and incremental cost of fractures in postmenopausal women in the United Kingdom.

This cohort study of postmenopausal women in the United Kingdom aged ≥50years determined the incremental cost of health care and clinical outcomes in the 12months following incident, selected fractures (non-vertebral non-hip [NVNHF], vertebral [VF] and multiple [MF]). Incremental costs and outcomes of the fracture cohorts were compared with those of cohorts comprised of women without fractures who were individually matched on age and comorbidity. Cohorts were identified from The Health Improvement Network database, a primary health care database, from 2001 to 2005. We estimated 1-year incremental costs (hospitalizations; general practice, accident/emergency, and referral visits; and prescription medications) associated with each fracture type. Descriptive analyses examined occurrence of subsequent fractures and death. No long-term health care costs or outcomes were assessed. Overall, 14,030 women had NVNHF, 1471 had VF, and 193 had MF. The risk of death was greater for women with fractures than for women in the non-fracture cohorts. Mean incremental cost for fractures compared with no fractures was £1152 for VF; £690 for NVNHF, and £2581 for MF. Of the total incremental cost, hospitalizations represented 54%-90% and medications represented 7%-29%. In all fracture cohorts, most of the total annual costs were concentrated in the 6months after the date of fracture. Fractures among postmenopausal women represent an important burden to the health system due to the increase in health resource utilization and related costs. In this study, hospitalizations were the main driver of the overall incremental cost during the 12months following the fracture. Mortality in women in the selected fracture cohorts was higher than in women in the non-fracture cohorts.

Study of the incremental cost and clinical burden of hip fractures in postmenopausal women in the United Kingdom.

OBJECTIVE: To determine the incremental cost of healthcare and clinical outcomes in the 12 months following incident hip fractures among postmenopausal women in the UK. METHODS: Retrospective cohort study of women aged 50 years or older hospitalized for an incident hip fracture within 1 week of the fracture date who were age- and comorbidity-matched to women without fracture. Cohorts were identified in the Health Improvement Network database, and followed up for 1 year. RESULTS: Among 2,427 women who had a hip fracture and a recorded hospitalization, the mean [SD] age was 81 [9.3] years. About 18% of women without fractures were hospitalized during follow-up and 18% of women with hip fractures and 4% of women without fractures had at least one emergency admission (RR, 4.7; 95% CI, 3.8-5.8). There were no major differences in use of general practitioner visit, referral visits, or in prescription of medications. Mortality was 18% in the hip fracture cohort and 7% in the non-fracture cohort (RR, 2.5; 95% CI, 2.1-3.0). The overall 1-year mean incremental cost of hip fractures was £4,222 (95% CI, £4,105-4,339); most of this cost (97%) was for hospitalizations, with an increment of £4,095. About 98% of the incremental cost occurred in the first 6 months following hip fracture. CONCLUSIONS: The results of this study indicate that the cost and clinical burden associated with hip fractures in postmenopausal women in the UK are considerable. The incremental cost is mostly related to the cost of hospitalization and treatment of the hip fracture. Key limitations were the inclusion of only those women with a recorded hospitalization, and that costs associated with rehabilitation services, social services, and long-term care were not recorded in this study, although these are important contributors to the total cost of fractures.

Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity.

In the Human Gene Mutation Database (www.hgmd.org), microdeletions and microinsertions causing inherited disease (both defined as involving < or = 20 bp of DNA) account for 8,399 (17%) and 3,345 (7%) logged mutations, in 940 and 668 genes, respectively. A positive correlation was noted between the microdeletion and microinsertion frequencies for 564 genes for which both microdeletions and microinsertions are reported in HGMD, consistent with the view that the propensity of a given gene/sequence to undergo microdeletion is related to its propensity to undergo microinsertion. While microdeletions and microinsertions of 1 bp constitute respectively 48% and 66% of the corresponding totals, the relative frequency of the remaining lesions correlates negatively with the length of the DNA sequence deleted or inserted. Many of the microdeletions and microinsertions of more than 1 bp are potentially explicable in terms of slippage mutagenesis, involving the addition or removal of one copy of a mono-, di-, or trinucleotide tandem repeat. The frequency of in-frame 3-bp and 6-bp microinsertions and microdeletions was, however, found to be significantly lower than that of mutations of other lengths, suggesting that some of these in-frame lesions may not have come to clinical attention. Various sequence motifs were found to be over-represented in the vicinity of both microinsertions and microdeletions, including the heptanucleotide CCCCCTG that shares homology with the complement of the 8-bp human minisatellite conserved sequence/chi-like element (GCWGGWGG). The previously reported indel hotspot GTAAGT and its complement ACTTAC were also found to be overrepresented in the vicinity of both microinsertions and microdeletions, thereby providing a first example of a mutational hotspot that is common to different types of gene lesion. Other motifs overrepresented in the vicinity of microdeletions and microinsertions included DNA polymerase pause sites and topoisomerase cleavage sites. Several novel microdeletion/microinsertion hotspots were noted and some of these exhibited sufficient similarity to one another to justify terming them "super-hotspot" motifs. Analysis of sequence complexity also demonstrated that a combination of slipped mispairing mediated by direct repeats, and secondary structure formation promoted by symmetric elements, can account for the majority of microdeletions and microinsertions. Thus, microinsertions and microdeletions exhibit strong similarities in terms of the characteristics of their flanking DNA sequences, implying that they are generated by very similar underlying mechanisms.

Breakpoints of gross deletions coincide with non-B DNA conformations.

Genomic rearrangements are a frequent source of instability, but the mechanisms involved are poorly understood. A 2.5-kbp poly(purine.pyrimidine) sequence from the human PKD1 gene, known to form non-B DNA structures, induced long deletions and other instabilities in plasmids that were mediated by mismatch repair and, in some cases, transcription. The breakpoints occurred at predicted non-B DNA structures. Distance measurements also indicated a significant proximity of alternating purine-pyrimidine and oligo(purine.pyrimidine) tracts to breakpoint junctions in 222 gross deletions and translocations, respectively, involved in human diseases. In 11 deletions analyzed, breakpoints were explicable by non-B DNA structure formation. We conclude that alternative DNA conformations trigger genomic rearrangements through recombination-repair activities.

Gross Rearrangement Breakpoint Database (GRaBD).

Translocations and gross gene deletions are an important cause of both cancer and inherited disease. Such DNA rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be particularly susceptible to breakage and recombination. The Gross Rearrangement Breakpoint Database (GRaBD; http://www.uwcm.ac.uk/uwcm/mg/grabd/) was established primarily for the analysis of the sequence context of translocation and deletion breakpoints in a search for characteristics that might have rendered these sequences prone to rearrangement. GRaBD, which contains 397 germline and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer, is the only comprehensive collection of gross gene rearrangement breakpoint junctions currently available.

Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs.

Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion breakpoints were found to be AT-rich whereas by comparison, translocation breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion breakpoints while polypyrimidine tracts were over-represented at translocation breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the chi element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion breakpoints. Alu sequences were found to span both breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations.

Translocation and gross deletion breakpoints in human inherited disease and cancer II: Potential involvement of repetitive sequence elements in secondary structure formation between DNA ends.

Translocations and gross deletions are responsible for a significant proportion of both cancer and inherited disease. Although such gene rearrangements are nonuniformly distributed in the human genome, the underlying mutational mechanisms remain unclear. We have studied the potential involvement of various types of repetitive sequence elements in the formation of secondary structure intermediates between the single-stranded DNA ends that recombine during rearrangements. Complexity analysis was used to assess the potential of these ends to form secondary structures, the maximum decrease in complexity consequent to a gross rearrangement being used as an indicator of the type of repeat and the specific DNA ends involved. A total of 175 pairs of deletion/translocation breakpoint junction sequences available from the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] were analyzed. Potential secondary structure was noted between the 5' flanking sequence of the first breakpoint and the 3' flanking sequence of the second breakpoint in 49% of rearrangements and between the 5' flanking sequence of the second breakpoint and the 3' flanking sequence of the first breakpoint in 36% of rearrangements. Inverted repeats, inversions of inverted repeats, and symmetric elements were found in association with gross rearrangements at approximately the same frequency. However, inverted repeats and inversions of inverted repeats accounted for the vast majority (83%) of deletions plus small insertions, symmetric elements for one-half of all antigen receptor-mediated translocations, while direct repeats appear only to be involved in mediating simple deletions. These findings extend our understanding of illegitimate recombination by highlighting the importance of secondary structure formation between single-stranded DNA ends at breakpoint junctions.

Human Gene Mutation Database (HGMD): 2003 update.

The Human Gene Mutation Database (HGMD) constitutes a comprehensive core collection of data on germ-line mutations in nuclear genes underlying or associated with human inherited disease (www.hgmd.org). Data catalogued includes: single base-pair substitutions in coding, regulatory and splicing-relevant regions; micro-deletions and micro-insertions; indels; triplet repeat expansions as well as gross deletions; insertions; duplications; and complex rearrangements. Each mutation is entered into HGMD only once in order to avoid confusion between recurrent and identical-by-descent lesions. By March 2003, the database contained in excess of 39,415 different lesions detected in 1,516 different nuclear genes, with new entries currently accumulating at a rate exceeding 5,000 per annum. Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease-associated and functional polymorphisms, as well as links to data present in publicly available online locus-specific mutation databases. Although HGMD has recently entered into a licensing agreement with Celera Genomics (Rockville, MD), mutation data will continue to be made freely available via the Internet.