Pharmacy & Therapeutics - February 2009 - (Page 101)

MEETING HIGHLIGHTS: San Antonio Breast Cancer Symposium 2008 San Antonio Breast Cancer Symposium The symposium attracted approximately 9,000 researchers and clinicians from December 10 to 14, 2008. Antitumor effects of the bisphosphonate zoledronic acid, along with hormone and combination therapies and strategies to overcome treatment resistance, attracted keen interest. Finally, the proportion of patients requiring mastectomy was lower in those receiving chemotherapy plus zoledronic acid (65.3%) than with chemotherapy alone (77.9%). The combination was well tolerated, and no increase in serious adverse events was reported in the neoadjuvant treatment period. “AZURE suggests a possible direct antitumor effect of zoledronic acid in combination with neoadjuvant chemotherapy and warrants a formal evaluation in prospective studies,” Dr. Johnston concluded. In an interview, lead author Dr. Winter said, “This is clearly exploratory and not practice-changing. Next, we are assessing biological effects in serial biopsies to see if there are changes in apoptosis and proliferation.” Zoledronic Acid (Zometa) plus Neoadjuvant Chemotherapy Have Antitumor Activity • Matthew C. Winter, MD, Weston Park Hospital, Sheffield, U.K., • Presented at a press conference by Robert Coleman, MD, Cancer Research Centre, Weston Park Hospital, Sheffield, U.K. Zoledronic acid (Zometa, Novartis) is a bisphosphonate indicated for the treatment of hypercalcemia of malignancy in patients with multiple myeloma or in patients with bone metastases from solid tumors. Explorator y evidence from the AZURE trial (Adjuvant Zoledronic acid redUce REcurrence), however, suggests direct antitumor activity when zoledronic acid is added to neoadjuvant chemotherapy in patients with breast cancer. The AZURE investigators recruited 3,360 women with stage II/III breast cancer. Preclinical studies of nitrogen-containing bisphosphonates showed antitumor activity, and adding zoledronic acid to adjuvant endocrine therapy in premenopausal women with hormone receptor–positive (HR+) breast cancer has significantly prolonged disease-free survival. This new analysis focused on the AZURE subgroup receiving neoadjuvant chemotherapy. The study was designed to determine whether adding zoledronic acid to standard neoadjuvant therapy improved disease-related outcomes. The main endpoint was pathological response in the primary tumor. Eligible patients received neoadjuvant chemotherapy (N = 206, 6.1%) according to local practice. They were randomly assigned to receive chemotherapy alone or zoledronic acid 4 mg IV three to four times weekly for six months in the neoadjuvant period in addition to chemotherapy. The primary surrogate endpoint for response was pathologically assessed residual invasive tumor size (RITS) at surgery. All of the women had tumors larger than 50 mm (5 cm, or stage T3) or features of locally advanced disease (T4) or biopsyproven lymph node involvement (stage N1). The patients were scheduled to undergo definitive surger y or radical radiotherapy, or both, with curative intent within six months of starting neoadjuvant therapy. Among 188 evaluable women, the median RITS was 30 mm (3 cm) with chemotherapy alone and 20.5 mm (2.05 cm) with chemotherapy plus zoledronic acid. A multivariate analysis found a 14.1-mm difference in mean RITS with chemotherapy alone (42.4 mm, or 4.24 cm) and a difference of 28.2 mm with chemotherapy plus zoledronic acid (P = 0.002). An analysis of the number of women achieving pathological complete response also revealed a significant difference favoring the addition of zoledronic acid: for chemotherapy alone, 5.8%, and for chemotherapy plus zoledronic acid, 10.3% (P = 0.03). RAD001 (Everolimus) in HER-2 Overexpressing Metastatic Breast Cancer with Prior Trastuzumab (Herceptin) • Ruth O’Regan, MD, Emory University, Atlanta, Ga. (Paclitaxel) • A. Fasolo, MD, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy (Vinorelbine) Two early, multicenter clinical trials suggest that RAD001 (everolimus) may help overcome resistance to trastuzumab (Herceptin, Genentech) in women with HER-2–positive (HER-2+) metastatic breast cancer. It is thought that everolimus, an inhibitor of mammalian target of rapamycin (mTOR) signaling, acts on the pathway that mediates trastuzumab resistance and that it may help restore response in these patients. Dr. O’Regan assessed weekly everolimus, combined with weekly trastuzumab and paclitaxel (Taxol, Bristol-Myers Squibb) among 27 women with disease that was resistant to trastuzumab. Trastuzumab resistance was defined as disease progression of three months or less after trastuzumab was given for metastasis or 12 months or less if it was given in a neoadjuvant setting. Most women had disease that was also resistant to taxanes. The median number of previous therapies was six. Everolimus 5 mg and 10 mg daily or 30 mg weekly was generally well tolerated, but the investigators recommended 10 mg daily as the dose for further study. For 22 evaluable patients, Dr. O’Regan reported one complete response (5%), eight partial responses (36%), and stable disease in 11 patients (50%). The rate for disease control (i.e., complete response, partial response, and stable disease) for more than 16 weeks was 77%. In another study, Dr. Fasolo evaluated weekly everolimus in 37 similarly trastuzumab-resistant patients receiving weekly trastuzumab and vinorelbine (Navelbine, GlaxoSmithKline). These patients had undergone a median of 4.5 previous regimens. Vol. 34 No. 2 • February 2009 • P&T® 101

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Pharmacy & Therapeutics - February 2009 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Pushing an Expanded Role for Pharmacists Better Asthma Management with Advanced Technology Pharmaceutical Approval Update 58th Annual Meeting, American Society of Human Genetics, 2008 American Society of Hematology, 50th Annual Meeting and Exposition 2008 San Antonio Breast Cancer Symposium Stahl’s Essential Psychopharmacology, 3rd Edition Author Guidelines

Pharmacy & Therapeutics - February 2009

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