http://www.oncologynursingnews.com/B...rticle/126636/
The increasing complexity of breast cancer treatments, including targeted therapies and combinations of new drugs, were highlighted by Patti Kwok, ARNP, in a concurrent session at the Advanced Practice Nurse meeting. In addition, a review of the latest findings concerning vitamin D's role in breast cancer were presented.
Among targeted therapies (which include epidermal growth factor receptor [EGFR] inhibitors, vascular endothelial growth factor, monoclonal antibodies, small molecule inhibitors, endocrine therapy, and selective estrogen receptor modulators [SERMs]), this session paid particular attention to the EGFR family (comprised of the HER1-4 receptors). This is important, Ms Kwok pointed out, because “what they're really trying to do is develop drugs that target all 4 members of the EGFR family.” To do this effectively, drug therapies increasingly involve combinations of multiple agents.
Lapatinib (Tykerb) is one such drug being used in combination with others. Although lapatinib works differently than trastuzumab (Herceptin), having specificity for both HER1 and HER2 receptors, it seems to have synergy with herceptin. Referring to data on this combination presented at the 2008 American Society of Clinical Oncology (ASCO) meeting, Ms Kwok noted that the lapatinib and trastuzumab group had significantly improved progression-free survival and clinical benefit rate.
Combining lapatinib with capecitabine has also shown promise, as Ms Kwok noted in referring to data presented in the
New England Journal of Medicine (Geyer CE, et al.
N Engl J Med. 2006;355:2733- 2743). Although this study did not show an overall survival benefit, there was improved time-to-progression and overall response rate in the group treated with the combination. Common side effects included nausea, diarrhea, vomiting, and, like many of the other EGFR inhibitors, rash. Studies indicate that cardiotoxicity may be less with lapatinib when compared with herceptin.
A third combination, lapatinib with hormone therapy (specifically letrozole), also shows promise in a Phase 3 trial of patients with metastatic disease. Ms Kwok said that this combination “may restore sensitivity to tamoxifen.” The overall thought, Ms Kwok pointed out, is that by “decreasing EGFR expression, perhaps you can improve tolerance to hormone therapy.” Investigations of gefitinib and erlotinib in combination with hormones have not shown significant results.
Lapatinib may also have benefit for central nervous system (CNS) metastases, which develop in about 1/3 of patients on continuous trastuzumab therapy, Ms Kwok noted. “Because lapatinib is a small molecule, it's better about getting into the CNS,” she pointed out. “Many of our therapies do not get across the blood-brain barrier, often resulting in CNS metastases.”
Optimizing an Old Treatment
Although tamoxifen is a long-time breast cancer treatment, new research from a pharmacogenomic perspective can help extend the value of this drug. Because patients have differing genetic makeups that influence metabolizing of drugs, an effort to screen patients prior to therapy to optimize drug therapy may be helpful. Some current research focuses on the CYP2D6 enzyme, which is involved in metabolizing 25% of all drugs, and that acts as a rate-limiter for converting tamoxifen into metabolites. The goal is to better individualize hormonal therapy for breast cancer. “We know our patients don't have equal responses and outcomes with the same drugs,” said Ms Kwok.
Some patients are not just wondering, but acting too. Ms Kwok reported that one of her patients, who is taking tamoxifen, paid $300 to have her metabolic activity tested. Although this patient was relieved to learn that she is an “extensive metabolizer,” Ms Kwok cautioned that “there's no consensus whether or not to recommend testing women.”
Ms Kwok discussed how such information might be helpful in decision making. If a patient was determined to be an extensive or ultra metabolizer, optimal treatment might include 5 years of tamoxifen followed by an aromatase inhibitor (AI). Alternatively, she might recommend “2 1/2 years of tamoxifen, 2 1/2 of an AI, and I like that way because there is less build up of side effects either way.”
Ms Kwok also urged caution when taking tamoxifen with other drugs, especially selective serotonin reuptake inhibitors (SSRIs), which are frequently prescribed to control hot flashes. SSRIs have the effect of converting extensive metabolizers to poor metabolizers, and can reduce plasma concentrations of tamoxifen. Although SSRIs are the primary culprit, “there are many other drugs that might have the same effect on tamoxifen,” Ms Kwok pointed out.
Triple Negative Breast Cancers and Other Treatments
“What about breast cancer that doesn't have any targeted therapies, or at least not any targets that we currently recognize?” asked Ms Kwok. For the aggressive cancer known as triple negative breast cancer, which represents about 15% of breast cancers, some potential treatment targets have emerged. EGFR overexpression happens in about 50% of all triple negative cancers and therefore is a compelling target for therapy. Frequent mutation of P53, overexpression of c-Kit, and abundant signaling through the MAP kinase pathway make these potential targets for therapy and are under investigation. Other potential triple negative therapies include cetuximab (alone or in combination with carboplatin), gefitinib, erlotinib, and other chemotherapy agents including anthrocyclines and taxanes. Ms Kwok did not uncover any recent trials with bevacizumab in triple negative cancer; however, 2 trials with this drug (combined with paclitaxel and docetaxel, respectively) found improved progression-free survival for patients with metastatic disease.
With the current emphasis on new biologic agents and combinations, Ms Kwok noted that today “we really don't see that much in terms of new chemotherapy agents.” One agent recently approved is ixabepilone (Ixempra), an epothilone B analog. “You don't want to give it to patients with a history of paclitaxel or docetaxel allergic reaction,” Ms Kwok said, and she noted when ixabepilone was used in combination with capecitabine, there was a higher incidence of myocardial ischemia and ventricular dysfunction.
Ms Kwok indicated that bisphosphonates are “a hot topic.” Although these drugs have been previously used for bone metastases, citing the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial data that was presented at the ASCO meeting, Ms Kwok posited that “there is emerging data that biphosphonates could possibly decrease the risk of recurrent breast cancer when used in the adjuvant setting.” She cautioned, however, that this trial is “awaiting mature data.” Another trial of bisphosphonates, Southwest Oncology Group (SWOG) 0307, is still currently enrolling patients, and Ms Kwok argued that “it would be great to get people on this trial.” It is important “not to overwhelm patients at the beginning of their therapy,” she stated, “but they're eligible to go on this within 3 months after completing chemotherapy.”
The Debate on Vitamin D
A final area of discussion centered on vitamin D and the controversies surrounding its use in breast cancer. Acknowledging the inconsistent or conflicting trial results involving vitamin D, Ms Kwok pointed out that nevertheless, vitamin D deficiency is common at breast cancer diagnosis and is associated with a poor prognosis. “I think we should monitor vitamin D levels during therapy, especially in patients that are on bisphosphonates,” she advocated, because if the patient's vitamin D level is too low they might not get the full benefit of the bisphosphonate.
As part of the monitoring, she emphasized the importance of measuring vitamin D properly. Measuring the active form of vitamin D (1,25 dihydroxy vitamin D) rather than the inactive form (25- hydroxy vitamin D), will result in readings indicating that the patient's levels are fine, and this will be in error. Citing a Canadian study on vitamin D deficiency in breast cancer patients, and her own clinical experience, Ms Kwok argued that “we really just need better guidelines on dosing and monitoring, especially in our cancer patients.”
Hybrid Mode
