Pharmacokinetic evaluation of the vinorelbine–lapatinib combination in the treatment of breast cancer patients

Purpose  

The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients.     

lapatinib治疗乳腺癌研究进展

lapatinib是一种口服酪氨酸激酶抑制剂,同时作用于表皮生长因子受体（EGFR）和HER- 2。无论单药还是与曲妥珠单抗联合,lapatinib在体外与活体试验中均显示出抑制曲妥珠耐药细胞株增殖的活性。在难治性乳腺癌,特别是炎性乳腺癌和乳腺癌脑转移的治疗中,lapatinib的临床试验结果令人鼓舞。     

A randomized phase II study of lapatinib + pazopanib versus lapatinib in patients with HER2+ inflammatory breast cancer

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib–pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.     

新药lapatinib治疗乳腺癌初探

新型药物lapatinib可同时抑制表皮生长因子受体(EGFR)和表皮生长因子受体-2(HER- 2)酪氨酸激酶活性,在体外细胞和动物实验模型中显示具有一定抗肿瘤效应。Ⅰ期临床研究显示,lapa- tinib剂量达到1 800 mg/d仍显示出良好的耐受性,无4级毒性,最常见的不良反应为1级或2级腹泻和皮疹,临床显示出一定的疗效。生物学相关性研究显示,lapatinib促进肿瘤细胞凋亡与临床疗效相关。lapatinib在转移性乳腺癌的Ⅱ、Ⅲ期临床研究正在进行中。     

新药lapatinib治疗乳腺癌初探

新型药物lapatinib可同时抑制表皮生长因子受体（EGFR）和表皮生长因子受体-2（HER-2）酪氨酸激酶活性,在体外细胞和动物实验模型中显示具有一定抗肿瘤效应。Ⅰ期临床研究显示,lapatinib剂量达到1800mg／d仍显示出良好的耐受性,无4级毒性,最常见的不良反应为1级或2级腹泻和皮疹,临床显示出一定的疗效。生物学相关性研究显示,lapatinib促进肿瘤细胞凋亡与临床疗效相关。lapatinib在转移性乳腺癌的Ⅱ、Ⅲ期临床研究正在进行中。     

Does lapatinib,a small-molecule tyrosine kinase inhibitor,constitute a breakthrough in the treatment of breast cancer?

ErbB/HER receptor or its signal transduction pathway is an attractive therapeutic target for breast cancer. Lapatinib, an orally administered dual inhibitor of ErbB1 (EGFR) and ErbB2 (HER2) receptor tyrosine kinases has shown promising results for metastatic breast cancer (MBC). Lapatinib exhibited activity against trastuzumab-refractory MBC and showed an acceptable adverse event profile such as transient mild rash, diarrhea and nausea. The addition of lapatinib to capecitabine resulted in significantly prolonged time to progression. Large randomized trials using lapatinib following chemotherapy and surgery are ongoing for early stage HER2-overexpressing breast cancer. Various combinations with agents such as paclitaxel, aromatase inhibitors, or other molecular targeted agents are currently being investigated in clinical trials. If these approaches overcome the limitations of trastuzumab, lapatinib will become an effective treatment option for breast cancer in the near future.     

β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib

Introduction  

The overexpression of human epidermal growth factor receptor (HER)-2 in 20% of human breast cancers and its association with aggressive growth has led to widespread use of HER2-targeted therapies, such as trastuzumab (T) and lapatinib (L). Despite the success of these drugs, their efficacy is limited in patients whose tumors demonstrate de novo or acquired resistance to treatment. The β1 integrin resides on the membrane of the breast cancer cell, activating several elements of breast tumor progression including proliferation and survival.     

Cost-effectiveness of lapatinib plus letrozole in her2-positive,hormone receptor–positive metastatic breast cancer in Canada

Background

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.

Methods

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 ({"type":"clinical-trial","attrs":{"text":"NCT00073528","term_id":"NCT00073528"}}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.

Results

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.

Conclusions

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.     

High serum TGF-�� predicts poor response to lapatinib and capecitabine in HER2-positive breast cancer

Lapatinib and capecitabine combination therapy is effective in trastuzumab-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We investigated the biomarkers from serum of patients receiving lapatinib and capecitabine Patients received lapatinib 1,250 mg once daily and capecitabine 2,000 mg/m(2)/day, day 1-14, every 3 weeks. Serum samples were obtained before treatment initiation. Levels of transforming growth factor-α (TGF-α), epidermal growth factor (EGF), extracellular domains of EGFR and HER2 were measured by enzyme-linked immunosorbent assay. The effect of TGF-α on in vitro sensitivity of SK-BR-3 cells to lapatinib was investigated. Sixty-four patients were included. Response rate was significantly higher in patients with low serum TGF-α (≤ 3.75 pg/ml) compared to high TGF-α (>3.75 pg/ml) [61.1% (11/18) vs. 17.4% (8/46), respectively; P = 0.001]. Low serum TGF-α was independently associated with better response in multivariate analysis [adjusted odds ratio, 8.96; 95% confidence interval (CI) 2.4-34.2]. Time-to-progression tended to be shorter in patients with high serum TGF-α compared to low TGF-α [median 3.8 months (95% CI 2.3-5.4) vs. 6.5 (95% CI 6.1-6.8), respectively; P = 0.067]. We confirmed that TGF-α diminished the sensitivity of SK-BR3-cells to lapatinib in vitro. The in vitro antiproliferative effect of cetuximab in combination with lapatinib was higher than that of lapatinib alone in SK-BR3-cells exposed to TGF-α. These data suggest that TGF-α plays a role in resistance to lapatinib and capecitabine therapy among HER2-positive breast cancer.     

Phase II study assessing lapatinib added to letrozole in patients with progressive disease under aromatase inhibitor in metastatic breast cancer—Study BES 06

This trial evaluated the effect of adding lapatinib to letrozole after clinical resistance to aromatase inhibitor (IA) treatment in hormone receptor-positive metastatic breast cancer. Postmenopausal women received daily letrozole plus lapatinib (1,500 mg). The primary end point was objective rate response (ORR) at week 12. Secondary objectives included time to response, duration of response, clinical benefit (CB), progression-free survival (PFS), overall survival, and safety. Twenty-four human epidermal growth factor receptor 2 (HER2)-negative patients were included with secondary resistance to IA. ORR at 12 weeks was 4 % (95 % confidence interval (CI), 0.7–20). Stable and progression diseases were reported in 25 % (95 % CI, 12–45) and 71 % (95 % CI, 51–85) of cases, respectively. At 24 weeks, the ORR increased to 8 %. CB was 21 % (95 % CI, 9–40). At a median follow-up of 27 months, median PFS was 3.4 months (95 % CI, 2.8–5.4). Grade 3 or 4 adverse events were rarely reported. No clinical cardiac toxicity was observed. Lapatinib was discontinued in two patients due to severe diarrhea. This trial was prematurely closed due to low recruitment. These preliminary results suggest that the addition of lapatinib to letrozole has a favorable safety profile and could overcome tumoral resistance to letrozole among HER2-negative tumors.     

mTOR inhibitors and the anti-diabetic biguanide metformin: new insights into the molecular management of breast cancer resistance to the HER2 tyrosine kinase inhibitor lapatinib (Tykerb®)

The small molecule HER2 tyrosine kinase inhibitor (TKI) lapatinib (Tykerb®) is approved for the therapy of patients with HER2-positive breast carcinomas who have progressed on trastuzumab (Herceptin®). Unfortunately, the efficacy of this HER2 TKI is limited by both primary (inherent) and acquired resistance, the latter typically occurring within 12 months of starting therapy. One of the key factors limiting our understanding of the mechanisms involved in lapatinib resistance is the lack of published preclinical models. We herein review lapatinib-refractory models recently developed at the bench and the survival pathways discovered. As hyperactivation of the pharmacologically targetable PI3K/mTOR/p70S6K1 axis appears to be central to the occurrence of lapatinib resistance, preclinical data showing enhanced antitumour effects when combining lapatinib with mTOR inhibitors (e.g., rapamycin analogues and NVP-BEZ235) highlight the importance of translational work to yield clinically useful regimens capable of delaying or treating lapatinib resistance. The unexpected ability of the anti-type II diabetes drug metformin to inactivate mTOR and decrease p70S6K1 activity further reveals that this biguanide, generally considered non-toxic and remarkably inexpensive, might be considered for new combinatorial lapatinib-based protocols in HER2-overexpressing breast cancer patients.     

Hypoxia/HIF1α induces lapatinib resistance in ERBB2-positive breast cancer cells via regulation of DUSP2

ERBB2/HER2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can promote tumor progression. Breast cancer patients with ERBB2 amplifications are currently treated with lapatinib, a small-molecule kinase inhibitor that specifically blocks EGFR/ERBB2 signaling. Here, we show that hypoxia, via HIF-1, induces resistance to lapatinib-mediated effects in ERBB2-expressing mammary epithelial and ERBB2-positive breast cancer cells. Lapatinib-mediated growth inhibition and apoptosis in three-dimensional (3D) cultures are decreased under hypoxic conditions. Hypoxia can maintain activation of signaling pathways downstream from ERBB2 including AKT and ERK in the presence of lapatinib. HIF-1 is both required and sufficient to induce lapatinib resistance as overexpression of stable HIF-1 in ERBB2-expressing cells blocks lapatinib-mediated effects and maintains ERBB2-downstream signaling under normoxic conditions. Under hypoxia, activation of ERK signaling is required for lapatinib resistance as treatment with MEK inhibitor trametinib reverses hypoxia-mediated lapatinib resistance. HIF-1 can bypass the lapatinib-treated inhibition of the ERK pathway via inhibition of the dual-specificity phosphatase 2 (DUSP2). Indeed, overexpression of DUSP2 in ErbB2-positve breast cancer cells reverses hypoxia-mediated lapatinib resistance. Thus, our results provide rationale for therapeutic evaluation of the treatment of hypoxic ERBB2 expressing breast tumors with a combination of lapatinib and MEK inhibitors.     

What caused the decline in breast cancer mortality in the united kingdom?

BACKGROUND: The marked improvement in breast cancer mortality in the United Kingdom (UK) has attracted worldwide interest. To understand the details of this phenomenon the morbidity and mortality rates of breast cancer in the UK during the past 30 years were analyzed. METHODS: The official publications and statistical data were available and downloaded at the official UK Web sites of the National Health Service, National Statistics and Cancer Research Organization. Parts of the data were obtained directly from the National Cancer Intelligence Centre of UK. RESULTS: After the beginning of breast screening the morbidity of the subject age group soared up to the level of an age group that was 10 years older. Noninvasive carcinoma was often discovered in the subject age group after the beginning of breast screening and constituted 8.3%of all cases. The mortality rates, however, began to decrease before the start of screening and fell clearly even in age groups other than that of the study group and particularly in elderly women. CONCLUSIONS: Not only the prevalence of breast screening but also the increase of early stage cancer in all age groups have probably resulted from improvements in diagnostic technology and heightened social interest and awareness. In addition, the development of adjuvant endocrine therapy must have influenced the evident improvement in mortality of breast cancer in the UK.     

Targeted therapies in oncology: in the crosshairs or at the crossroads?

Normal cellular behavior depends on functional integration of extracellular stimuli with intracellular signal transduction pathways. Coupling cell surface message reception to nuclear gene expression is no longer a linear model constructed with molecular components acting merely as conduits to relay signals that cascade toward the nucleus. What has emerged instead is a highly integrated circuit comprised of numerous molecular components harmoniously programmed to communicate a multitude of internal signals that controls cellular response. Despite increasing understanding of cell signaling, mutinous elements embedded in these pathways have defied complete resolution. Research indicates that propagation of signals emanating from the extracellular environment to the cell nucleus follows a complex internal circuit equipped with sophisticated molecular components that provide rigid control over a variety of cellular responses. Although increasing understanding of genetic aberrations and signaling pathway transgressions can lead to novel strategies for targeting cancer cells, the disappointing results from clinical trials suggest that the occult processes responsible for neoplastic transformation remain largely unexplained.     

Was the drop in mammography rates in 2005 associated with the drop in hormone therapy use?

BACKGROUND:

In 2005, mammography rates in the United States dropped nationally for the first time among age‐eligible women. An increased risk of breast cancer related to hormone therapy (HT) use reported in 2002 led to a dramatic drop in its use by 2005. Because current users of HT also tend to have higher mammography rates, the authors examined whether concurrent drops in HT and mammography use were associated.

METHODS:

Multivariate logistic regression was used to test for an interaction between HT use and survey year, controlling for a range of measurable factors in data from the 2000 and 2005 National Health Interview Surveys (NHIS).

RESULTS:

Women ages 50 to 64 years were more likely to report a recent mammogram if they also reported more education, a usual source of care, private health insurance, any race except non‐Hispanic Asian, talking with an obstetrician/gynecologist or other physician in the past 12 months, or were currently taking HT. Women aged ≥65 years were more likely to report a recent mammogram if they also reported younger age (ages 65‐74 years), more education, a usual source of care, having Medicare Part B or other supplemental Medicare insurance, excellent health, any race except non‐Hispanic Asian, talking with an obstetrician/gynecologist or other physician in the past 12 months, or were currently taking HT.

CONCLUSIONS:

The change in HT use was associated with the drop in mammography use for women ages 50 to 64 years but not for women aged ≥65 years. NHIS data explained 70% to 80% of the change in mammography use. Cancer 2011;. © 2011 American Cancer Society.     

Potential biomarkers of long‐term benefit from single‐agent trastuzumab or lapatinib in HER2‐positive metastatic breast cancer

In 2009 a prospective, randomized Phase II trial ({"type":"clinical-trial","attrs":{"text":"NCT00842998","term_id":"NCT00842998"}}NCT00842998) was initiated to evaluate the activity of HER2‐targeting agents without chemotherapy (CT) in HER2‐positive metastatic breast cancer (MBC) patients. The primary tumors of the patients enrolled in this study offered a unique opportunity to identify biomarkers that could predict durable clinical benefit from CT‐free anti‐HER2 therapy.Patients with HER2‐positive MBC were randomized to trastuzumab or lapatinib as first‐line therapy. CT was added to anti‐HER2 therapy in patients failing to achieve tumor regression at the 8‐week evaluation and in those progressing at any time. Expression analysis of 105 selected genes was performed from formalin‐fixed paraffin‐embedded primary tumor samples. The research‐based PAM50 intrinsic subtypes were also identified. Additionally, quantitative HER2 (H2T) and p95HER2 (p95) protein expression were evaluated by HERmark® and VeraTag® assay, respectively. Predictors of persistence on protocol (PP) were studied by Cox univariate and multivariate analysis.Nineteen patients were enrolled. Median overall survival was 43 months and median PP was 3.8 months (0.8–38.8+), with 4 patients (21.1%) persisting on single agent trastuzumab or lapatinib for longer than 12 mo (14.9–38.8 + mo). Seventeen patients were evaluable for PP. Gene expression analysis revealed that high expression of the 17q12‐21 amplicon genes HER2 and GRB7, and the PAM50 HER2‐enriched intrinsic profile, were significantly associated with longer PP. Conversely, high expression of luminal‐related genes such as PGR, MDM2 or PIK3CA, or the PAM50 luminal intrinsic profile correlated with reduced PP. Moreover, increasing H2T/p95 ratio was found to be significantly associated with longer PP (HR 0.56 per 2‐fold increase in H2T/p95, P = 0.0015).Our data suggest that patients belonging to the “HER2‐enriched” subtype and/or having high H2T/p95 protein expression ratio are exquisitely sensitive to anti‐HER2 agents. MBC patients with these tumors could be candidates for studies aimed at establishing chemotherapy‐free regimens.