Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy.

BACKGROUND: Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified. METHODS: We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome. RESULTS: The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene. CONCLUSIONS: This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.

Genetic markers of bevacizumab-induced hypertension.

PURPOSE: There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension. EXPERIMENTAL DESIGN: Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates. RESULTS: Ten SNPs were associated with bevacizumab-induced hypertension (P ≤ 0.05), but none surpassed the threshold adjusted for multiple testing (P < 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028). CONCLUSIONS: The genes described in this large genetic analysis using pooled datasets warrant further functional investigation regarding their role in mediating bevacizumab-induced hypertension.

Safety of bevacizumab in metastatic breast cancer patients undergoing surgery.

BACKGROUND: Evaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials. PATIENTS AND METHODS: The incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6 weeks before elective surgery and to wait 28 days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy. RESULTS: In AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n=46, 2.2%), bevacizumab 7.5mg/kg (n=57, 1.8%) and bevacizumab 15mg/kg (n=52, 1.9%). Incidence of grade 3-4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively. CONCLUSIONS: Surgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to.

Efficacy and safety of bevacizumab in combination with docetaxel for the first-line treatment of elderly patients with locally recurrent or metastatic breast cancer: results from AVADO.

BACKGROUND: Oncologic treatment in elderly patients is challenging, due to comorbidities, often impaired organ function, limited clinical trial evidence, inadequate guidelines and no consistent 'elderly' definition. We report exploratory sub-analyses of safety and efficacy in elderly patients, defined as ⩾ 65years old, in AVastin And DOcetaxel (AVADO) receiving first-line bevacizumab plus docetaxel for metastatic breast cancer (mBC). PATIENTS AND METHODS: Patients with HER2-negative, locally recurrent or mBC were randomised to 3-weekly docetaxel (100mg/m(2)) with placebo, bevacizumab 7.5mg/kg or bevacizumab 15 mg/kg, for 9 cycles or until disease progression or unacceptable toxicity. Patients had no prior chemotherapy for mBC. RESULTS: Progression-free survival (PFS) was increased with bevacizumab in the elderly subpopulation (n=127), the effect being greater with higher dose (hazard ratio=0.63 [95% confidence interval (CI) 0.383-1.032] versus 0.76 [95% CI: 0.46-1.262], respectively). PFS was numerically similar in the elderly and overall populations, but the former failed to achieve statistical significance. Overall response rates for docetaxel plus placebo, bevacizumab 7.5mg/kg and 15 mg/kg were 44.7%, 36.6% and 50.0%, respectively. Effects on survival were not statistically significant. Bevacizumab was well tolerated in elderly patients, the most common adverse effects were neutropenia and febrile neutropenia; there was no excess of grade⩾3 cardiovascular events. There was no clear correlation between baseline hypertension and its development during study treatment. CONCLUSIONS: In this exploratory sub-analysis in AVADO, bevacizumab plus docetaxel showed efficacy in elderly patients similar to the overall study population. There were no unexpected safety signals in patients aged 65 years or older.

Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE: The efficacy and safety of combining bevacizumab (7.5 and 15 mg/kg) with docetaxel as first-line therapy for human epidermal growth factor receptor 2 (HER2) -negative, locally recurrent or metastatic breast cancer (MBC) was investigated in a three-arm, placebo-controlled, phase III trial. PATIENTS AND METHODS: Patients (N = 736) were randomly assigned to docetaxel 100 mg/m(2) plus either placebo or bevacizumab 7.5 or 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS); secondary end points included best overall response, duration of response, time to treatment failure, overall survival, and safety. RESULTS: Combination of bevacizumab 15 mg/kg, but not 7.5 mg/kg, with docetaxel showed superior median PFS (mPFS) to placebo plus docetaxel in unstratified analysis (placebo mPFS, 8.2 months; 7.5 mg/kg mPFS, 9.0 months [hazard ratio (HR), 0.86; P = .12]; 15 mg/kg mPFS, 10.1 months [HR, 0.77; P = .006]) and stratified analysis (placebo mPFS, 8.1 months; 7.5 mg/kg mPFS, 9.0 months [HR, 0.80; P = .045]; 15 mg/kg mPFS, 10.0 months [HR, 0.67; P < .001]). Response rates in patients with measurable disease at baseline also increased with bevacizumab 15 mg/kg (46% [placebo] v 55% [7.5 mg/kg; P = .07] and 64% [15 mg/kg; P < .001]). Combination with bevacizumab had limited impact on the known toxicity profile of docetaxel. CONCLUSION: Combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased PFS when combined with docetaxel as first-line therapy for MBC compared with docetaxel plus placebo.

Recent advances in systemic therapy. When HER2 is not the target: advances in the treatment of HER2-negative metastatic breast cancer.

The anti-human epidermal growth factor receptor 2 (HER2) agent trastuzumab has improved outcomes in breast cancer patients with HER2 over-expressing tumours. However, systemic treatment for patients with HER2-negative disease is still limited to endocrine and cytotoxic therapies. The increasing use of the anthracyclines and taxanes in early stage disease has reduced the available therapeutic options for patients with relapsed disease, and choices are further limited for patients with triple-negative tumours, who typically have a poor prognosis. The novel agents bevacizumab and ixabepilone were recently approved for metastatic breast cancer, and numerous other agents are currently in clinical development that may contribute further valuable therapeutic options.

A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer.

BACKGROUND: Docetaxel has significant activity in metastatic breast cancer and weekly schedules are associated with less myelosuppression than 3-weekly schedules. We evaluated the toxicity and the activity of weekly docetaxel in anthracycline-pretreated patients. PATIENTS AND METHODS: A total of 42 patients were studied. Treatment consisted of docetaxel 35 mg/m2 weekly as a 30-min infusion for 6 weeks followed by a 2-week rest, with dexamethasone 8 mg i.v. pre-medication and 4 mg orally 12-hourly for 48 h following treatment. RESULTS: The median age of the patients was 53 years (range 34-74). Twenty-six (62%) patients had received prior chemotherapy for advanced disease. Patients received a median 10 weeks of treatment (range 1-24). 11 had a partial response (ORR 26%; 95% CI 13-39%), five of whom had relapsed <12 months since the end of previous anthracycline-based chemotherapy. In addition six patients (14%) had stable disease for >16 weeks. Myelosuppression was rare with only 2 patients (5%) experiencing grade 3 neutropenia (no grade 4 neutropenia). Non-haematological grade III toxicities were as follows: fatigue 17%, neuropathy 0%, hyperlacrimation 5%, stomatitis 7%, diarrhoea 14%, and cutaneous toxicity 19%. Skin toxicity consisted of limb/palmar-plantar erythematous reactions, or fixed-plaque erythrodysaesthesia. CONCLUSIONS: Weekly docetaxel has moderate activity in women with anthracycline pre-treated breast cancer. Although the level of myelosuppression is lower than 3-weekly regimens, this weekly regimen cannot be recommended due to the significant non-haematological toxicities associated with the treatment.

Quality of life in women with advanced breast cancer treated with docetaxel.

A survey was conducted to address the question of whether overall quality of life (QOL) in women with advanced breast cancer is significantly impaired by treatment with docetaxel in routine clinical practice. Health-related QOL (HRQOL) measured by the European Organisation for Research and Treatment of Cancer QOL Questionnaire C30, as well as performance status (PS) and tumor response, were assessed at baseline, then after every 2 cycles of treatment. The 209 evaluable patients received a median of 5 treatment cycles (range, 2-9), with a response rate of 35% (95% CI, 28.5%-41.4%). There were significant adverse changes in fatigue (P = 0.002) and diarrhea (P = 0.0002). However, HRQOL scores for emotional function (P < 0.0001), pain (P = 0.0001), constipation (P = 0.01), and nausea and vomiting (P = 0.03) all showed significant beneficial changes. Several QOL parameters improved during docetaxel therapy even in patients who did not have an objective tumor response. Overall, PS was maintained during docetaxel treatment. Following the encouraging QOL data from clinical trials of docetaxel in breast cancer, the authors conclude that, in actual clinical practice, docetaxel does not have an overall detrimental effect on QOL.

Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice.

The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.