Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for hormone receptor positive(HR+) and HER2+ advanced or metastatic breast cancer(MBC).
ABSTRACT Third-generation aromatase inhibitors (letrozole, anastrozole) have shown superior efficacy in early and advanced breast cancer compared with tamoxifen. For HR+, HER2+ MBC, combination of an AI with an anti-HER2 agent (lapatinib or trastuzumab) has shown clinical benefit.
Six databases were searched until January 2009 for randomized controlled clinical trials, assessing the safety and efficacy of first-line treatments for postmenopausal women with HR+ and HER2 (ErbB2) positive MBC, who have not received prior therapy for advanced or metastatic disease. Relevant interventions were lapatinib, aromatase inhibitors, tamoxifen, and trastuzumab. Outcomes included overall survival (OS), progression-free-survival (PFS), time-to-progression (TTP), and objective response rate (ORR).
Eighteen studies (62 papers) were included. Lapatinib + letrozole was significantly superior to letrozole alone based on a direct head-to-head study in terms of PFS/TTP and ORR. Using a network meta-analysis, compared with lapatinib + letrozole, tamoxifen (HR = 0.45 (95% CI: 0.32, 0.65) and anastrozole (HR = 0.53 (0.36, 0.80)) scored significantly worse in terms of PFS/TTP and ORR (tamoxifen: OR = 0.25 (0.12, 0.53), anastrozole: OR = 0.27 (0.12, 0.58). The combination also seemed significantly superior to exemestane in terms of PFS/TTP (HR = 0.52 (0.34, 0.79)). Lapatinib + letrozole also seemed better, although not significantly, in terms of OS versus tamoxifen: HR = 0.74 (0.49, 1.12), anastrozole: HR = 0.71 (0.45, 1.14) and exemestane: HR = 0.65 (0.39, 1.11). When compared with trastuzumab + anastrozole, lapatinib + letrozole seemed to be better in terms of OS (HR = 0.85 (0.47, 1.54)), PFS/TTP (HR = 0.89 (0.54, 1.47)) and ORR (OR = 0.92 (0.24, 3.48)), although, none of these results were significant.
Lapatinib + letrozole was significantly superior to letrozole in terms of PFS/TTP and ORR based on a direct head-to-head study. Indirect comparisons appeared to favor lapatinib + letrozole versus other first-line treatments used in this patient population in terms of three main outcomes: OS, PFS/TTP and ORR. Indirect comparison results are based on a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the fact that these are the best available data, the results need to be interpreted with caution.
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ABSTRACT: The ErbB or HER family is a group of membrane bound tyrosine kinase receptors that initiate signal transduction cascades, which are critical to a wide range of biological processes. When over-expressed or mutated, members of this kinase family form homomeric or heteromeric kinase assemblies that are involved in certain human malignancies. Targeted therapy evolved from studies showing that monoclonal antibodies to the ectodomain of ErbB2/neu would reverse the malignant phenotype. Unfortunately, tumors develop resistance to targeted therapies even when coupled with genotoxic insults such as radiation. Radiation treatment predominantly induces double strand DNA breaks, which, if not repaired, are potentially lethal to the cell. Some tumors are resistant to radiation treatment because they effectively repair double strand breaks. We and others have shown that even in the presence of ionizing radiation, active ErbB kinase signaling apparently enhances the repair process, such that transformed cells resist genotoxic signal induced cell death. We review here the current understanding of ErbB signaling and DNA double strand break repair. Some studies have identified a mechanism by which DNA damage is coordinated to assemblies of proteins that associate with SUN domain containing proteins. These assemblies represent a new target for therapy of resistant tumor cells.Experimental and Molecular Pathology 09/2012; 93(3). DOI:10.1016/j.yexmp.2012.09.007 · 2.88 Impact Factor
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ABSTRACT: The treatment and prevention of solid tumors have proved to be a major challenge for medical science. The paradigms for success in the treatment of childhood leukemia, Hodgkin's disease, Burkett's lymphoma, and testicular carcinoma with cytotoxic chemotherapy did not translate to success in solid tumors-the majority of cancers that kill. In contrast, significant success has accrued for patients with breast cancer with antihormone treatments (tamoxifen or aromatase inhibitors) that are proved to enhance survivorship, and remarkably, there are now two approved prevention strategies using either tamoxifen or raloxifene. This was considered impossible 40 years ago. We describe the major clinical advances with nonsteroidal antiestrogens that evolved into selective estrogen receptor modulators (SERMs) which successfully exploited the ER target selectively inside a woman's body. The standard paradigm that estrogen stimulates breast cancer growth has been successfully exploited for over 4 decades with therapeutic strategies that block (tamoxifen, raloxifene) or reduce (aromatase inhibitors) circulating estrogens in patients to stop breast tumor growth. But this did not explain why high-dose estrogen treatment that was the standard of care to treat postmenopausal breast cancer for 3 decades before tamoxifen caused tumor regression. This paradox was resolved with the discovery that breast cancer resistance to long-term estrogen deprivation causes tumor regression with physiologic estrogen through apoptosis. The new biology of estrogen action has been utilized to explain the findings in the Women's Health Initiative that conjugated equine estrogen alone given to postmenopausal women, average age 68, will produce a reduction of breast cancer incidence and mortality compared to no treatment. Estrogen is killing nascent breast cancer cells in the ducts of healthy postmenopausal women. The modulation of the ER using multifunctional medicines called SERMs has provided not only significant improvements in women's health and survivorship not anticipated 40 years ago but also has been the catalyst to enhance our knowledge of estrogen's apoptotic action that can be further exploited in the future.Vitamins & Hormones 01/2013; 93C:1-49. DOI:10.1016/B978-0-12-416673-8.00007-1 · 1.78 Impact Factor
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ABSTRACT: The cost-effectiveness of first-line treatment with lapatinib plus letrozole for postmenopausal women with hormone receptor-positive (hr+), human epidermal growth factor receptor 2-positive (her2+) metastatic breast cancer (mbc) has not been assessed from the Canadian health care system and societal perspectives. A partitioned survival analysis model with 3 health states (alive, pre-progression; alive, post-progression; dead) was developed to estimate direct and indirect costs and quality-adjusted life years (qalys) with lapatinib-letrozole, letrozole, anastrozole, or trastuzumab-anastrozole as first-line treatment. Clinical inputs for lapatinib-letrozole and letrozole were taken from the EGF30008 trial (NCT00073528). Clinical inputs for anastrozole and trastuzumab-anastrozole were taken from a network meta-analysis of published studies. Drug costs were obtained from the manufacturer's price list, the Quebec list of medications, and imsBrogan. Other costs were taken from the Ontario Health Insurance Plan's Schedule of Benefits and Fees and published studies. A 10-year time horizon was used. Costs and qalys were discounted at 5% annually. Deterministic and probabilistic sensitivity analyses were performed to assess the effects of changes in model parameters. Quality-adjusted life years gained with lapatinib-letrozole were 0.236 compared with trastuzumab-anastrozole, 0.440 compared with letrozole, and 0.568 compared with anastrozole. Assuming a health care system perspective, incremental costs were $5,805, $67,029, and $67,472 respectively. Given a cost per qaly threshold of $100,000, the probability that lapatinib-letrozole is preferred was 21% compared with letrozole, 36% compared with anastrozole, and 68% compared with trastuzumab-anastrozole. Results from the societal perspective were similar. In postmenopausal women with hr+/her2+ mbc receiving first-line treatment, lapatinib-letrozole may not be cost-effective compared with letrozole or anastrozole, but may be cost-effective compared with trastuzumab-anastrozole.Current Oncology 10/2013; 20(5):e371-87. DOI:10.3747/co.20.1394 · 1.64 Impact Factor