Staff Writer, Oncology Specialty Group

San Antonio, TX—For patients with early breast cancer, peripheral neurotoxicity is an unfortunate side effect of treatment with taxanes, but there may be a silver lining, according to an analysis of the landmark N9831 trial by the North America Breast Intergroup consortium. “Patients who developed peripheral neuropathy on adjuvant paclitaxel-containing chemotherapy had a significantly better disease-free survival (DFS) than patients who did not develop neuropathy,” said Alvaro Moreno, MD, of the Mayo Clinic in Jacksonville, Florida.

Edith Perez, MD, senior author of the study and principal investigator of N9831, commented, “Our data are very solid. Patients are concerned about developing neuropathy with these commonly used drugs, but it turns out that peripheral neuropathy may be a surrogate marker for a better outcome.” 

The study analyzed 1967 patients with HER2-positive early breast cancer who received only paclitaxel-containing chemotherapy (Arm A) or trastuzumab (Herceptin) plus the same chemotherapy regimen (Arm C). Patients in Arm B received sequential chemotherapy and trastuzumab but were not included in this analysis. 

Patients in Arm A who developed neuropathy had better 3-year DFS than those who did not develop neuropathy, at 84.2% versus 77.8%, respectively. This translates to a 36% reduction in risk (

“We saw better DFS, in spite of the fact that patients with neuropathy received lower doses of paclitaxel,” he said. The lower doses might have resulted from dose reduction to address neuropathy. The grade of neuropathy did not appear to affect DFS, he added.

For Arm C, the same differences were not observed with patients receiving trastuzumab along with the taxane. Three-year DFS in this arm was 89.8% for patients with neuropathy and 87.6% for those without neuropathy. While this represented a 28% reduction in risk, it was not statistically significant (

“The effect was possibly abrogated somehow by the use of trastuzumab in Arm C,” Dr Moreno said. 

The comparison between patients without neuropathy (n = 852) and those with neuropathy that persisted >6 months (n = 792) was most robust, he continued. In this group, the risk of events was reduced by 42% compared with patients who had neuropathy lasting ≤6 months, which was highly statistically significant (

Dr Moreno explained that microtubules are crucial for spindle formation during mitosis and for cellular proliferation. The antineoplastic effect of paclitaxel is mainly related to its ability to bind the beta subunit of tubulin, thus preventing tubulin chain depolarization and inducing apoptosis. Tubulins are expressed in human peripheral nerves, and the binding of paclitaxel to tubulin may lead to neuropathy. 

“This side effect may represent effective binding of paclitaxel to the target tubulin, lack of point mutations in tubulin at the paclitaxel binding site, increased depletion of target genes at the microtubule site, or lack of selective overexpression of 

-III tubulin, which confers resistance to paclitaxel,” he suggested. “If drugs attach to the tubulin site in both cancer cells and nerves, the hypothesis is this could lead to better outcomes.”

To confirm these observations, the investigators are examining the E1199 data for this correlation. Findings from the two studies will be combined for future publication. 

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For patients with early breast cancer, peripheral neurotoxicity is an unfortunate side effect of treatment with taxanes, but there may be a silver lining.

Taxane-related Peripheral Neuropathy Associated with Better Outcomes

	San Antonio, TX—The multi-targeted kinase inhibitor sorafenib (Nexavar), approved to treat kidney and liver cancer, may also benefit patients with metastatic breast cancer, according to a phase IIb study presented at the 32nd annual San Antonio Breast Cancer Symposium. “We saw a signal of potential activity,” said principal investigator William S. Gradishar, MD, Professor of Medicine at Northwestern University School of Medicine, Chicago. The principal endpoint, progression-free survival (PFS), showed a trend favoring sorafenib combined with paclitaxel versus single-agent paclitaxel in patients with locally advanced or metastatic breast cancer.   

	The double-blind randomized placebo-controlled phase IIb trial included 237 patients from the United States, India, and Brazil. It is the second in a series of four worldwide phase IIb clinical trials testing the use of sorafenib in advanced HER2-negative breast cancer in a program called TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer).

	To evaluate the benefit of sorafenib when paired with chemotherapy, the study randomized 119 patients to paclitaxel (90 mg/m2 weekly) plus oral sorafenib (400 mg twice daily) and 118 patients to the same dose of paclitaxel plus placebo.

	Median PFS was 6.9 months with the combination and 5.6 months with single-agent paclitaxel, for a 21% relative reduction in risk of death or progression (P = .0857). The lack of statistical significance may have been due, according to Dr Gradishar, to the excess number of deaths in the sorafenib arm, none believed to be related to treatment; out of 20 deaths, 17 occurred in patients receiving sorafenib. Most of the deaths occurred among the 170 patients from India who died from malaria, tuberculosis, and other conditions not typical of patients treated in the United States, he explained.  

	“We think these deaths skewed the PFS,” he said at a press briefing. “Time to progression, which does not include deaths, showed a 3-month spread that looks more impressive.”

	Time to progression was reduced by 33% with sorafenib. Median duration of response was 5.6 months with sorafenib and 3.7 months in the control arm (P = .0079), and objective response rates were 67% versus 54%, respectively (P = .0234), he reported.

	Press briefing moderator Kent Osborne, MD, professor of Medicine at Baylor College of Medicine, Houston, Texas, and director of the Dan L. Duncan Cancer Center at Baylor, explained that the purpose of a phase IIb trial is to obtain “a hint of activity.” This does not require the number of patients needed to show statistical significance at the .05 level, he said, noting, “This study did meet the statistical guidelines” needed to show activity, which was a 20% improvement over the control arm. No unexpected toxicities were observed, though ~30% of patients receiving sorafenib developed serious hand-foot syndrome, he said.  

	Dr Osborne said to use sorafenib effectively, “we need to find a dose that will lower the side effects, and to do an expanded trial showing definitively that the addition of this oral drug to chemotherapy is advantageous.” SABCS Abstract 44.

The multi-targeted kinase inhibitor sorafenib, approved to treat kidney and liver cancer, may also benefit patients with metastatic breast cancer.

Sorafenib Active in Metastatic Breast Cancer

San Antonio, TX—In a head-to-head comparison of two bone-protective agents, the 

ligand inhibitor denosumab was superior to the standard-of-care bisphosphonate, zoledronic acid (Zometa), in a study of breast cancer patients with bone metastases. The study was reported at the 32nd annual San Antonio Breast Cancer Symposium. 

The randomized comparison of 2048 breast cancer patients with bone metastases evaluated the two agents for the prevention of skeletal-related events (SRE), defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression. “Denosumab prevented more events, was better tolerated, and was more convenient for patients in this randomized double-blind trial against what has been the standard of care for treating bone metastasis,” said Alison Stopeck, MD, of the University of Arizona Cancer Center, Tucson, who described the study at a press briefing. 

Patients with bone metastases not previously treated with intravenous (IV) bisphosphonates were randomized to treatment with subcutaneous (SC) denosumab (120 mg every 4 weeks) and IV placebo, or SC placebo and IV zoledronic acid (4 mg every 4 weeks), in addition to supplemental calcium and vitamin D. 

The primary endpoint of time to first on-study SRE was 

reduced by 18% with denosumab treatment. Patients receiving ZA experienced their first SRE in 26.5 months, but the median time to first SRE has not been reached in the denosumab group. 

The study also evaluated the benefit of continued treatment with denosumab, since patients with SREs are at increased risk for a second event.

Denosumab was also superior in that comparison, with time to first-and-subsequent on-study SREs reduced by 23%, Dr Stopeck said. Importantly for patients, she added, denosumab was associated with a delay in the onset of moderate or severe pain, which was extended from 64 days with ZA to 88 days with denosumab, a statistically significant difference. 

Adverse events were reported by over 95% of patients in each arm.

Patients receiving ZA had a higher incidence of acute phase reactions (27.3% vs 10.4%, respectively) and more renal toxicity (8.5% vs 4.9%, respectively). Osteonecrosis of the jaw, a concern with bisphosphonate use, was uncommon in each arm, occurring in 14 patients (1.4%) taking ZA and 20 (2.0%) taking denosumab, a difference that was not significant. The majority of patients who developed osteonecrosis had risk factors for the condition, such as dental extraction and dental appliances, Dr Stopeck said. 

Press briefing moderator Theresa Guise, MD, Professor of Medicine at Indiana University School of Medicine, called the findings “very important.” She said they demonstrate that the inhibition of bone resorption through 

 ligand, which regulates osteoclast activity and function, may offer improved protection against SREs in patients with bone metastases. 

The RANK ligand inhibitor denosumab was better than the standard-of-care bisphosphonate, zoledronic acid in breast cancer patients with bone metastases.

Denosumab Tops Zometa for Bone Protection in Breast Cancer Patients

 — Cancer patients are at high risk for venous thromboembolism (VTE), a leading cause of death in patients with cancer. Fixed-dose dabigatran may be a replacement for warfarin in the treatment of VTE, according to results of the large Phase III RE-COVER trial. The study was published online to coincide with its presentation at the 51

 Annual Meeting of the American Society of Hematology (

RE-COVER found that fixed-dose dabigatran significantly reduced major or clinically relevant bleeding. In addition, it was as effective as dose-adjusted warfarin in preventing recurrent symptomatic VTE and VTE-related death in patients treated for acute VTE. 

The new oral direct thrombin inhibitor has several important advantages over warfarin, the current standard for anticoagulation. Dabigatran does not require frequent monitoring and dosing adjustments to keep patients in a therapeutic range. Unlike warfarin, dabigatran does not interact with food and other drugs, so no dietary adjustments are needed. 

“Dabigatran is a potential replacement for warfarin, explained Sam Schulman, MD, Professor at McMaster University in Hamilton, Ontario, Canada. 

The global, prospective, double-blind, double-dummy study randomized 2539 patients 1:1 to 6 months of treatment with a fixed 150-mg dose of dabigatran twice daily or warfarin (International Normalized Ratio, 2.0-3.0). Mean age of patients was 55 years, and ~ 42% were female, ~69% had deep vein thrombosis (DVT) as the index event, ~22% had pulmonary embolism (PE) only, and ~10% had DVT and PE. One-quarter of patients had a history of previous VTE.

The cumulative risk of recurrent or fatal VTE after 6 months of treatment was similar for both groups. Recurrent VTE occurred in 30 patients (2.4%) in the dabigatran-treated group and 27 patients (2.1%) in the warfarin group. This difference in risks of 0.4 percentage points established that dabigatran was non-inferior to warfarin.

Dabigatran reduced the risk of any bleeding event by 29% compared with warfarin (

 = .0002). Any bleeding event occurred in 205 patients (16.1%) in the dabigatran group and 277 (21.9%) assigned to warfarin. Major bleeding occurred in 20 patients (1.6%) in the dabigatran group and in 24 (1.9%) in the warfarin group. Major or clinically relevant bleeds were reduced by 37% in the dabigatran group (5.6% versus 8.8%, respectively, 

Deaths, acute coronary syndromes, and abnormal liver function tests were similar in the two arms of the study. Discontinuations due to adverse events occurred in 9% of those assigned to dabigatran and in 6.8% of those assigned to warfarin (

“There is no signal of danger in the liver with dabigatran. Ximelegatran, a predecessor, was killed by elevations in ALTs and bilirubin,” Dr Schulman said. 

Cancer patients are at high risk for venous thromboembolism (VTE), a leading cause of death in patients with cancer. Fixed-dose dabigatran may be a replacement for warfarin in the treatment of VTE, according to results of the large Phase III RE-COVER trial. 