Trends in Breast Health Newsletter
IN THIS ISSUE VOL. 2  |  AUG. 2011
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Manage the Axilla with Z11 Data
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Next Generation MammoSite Multi-Lumen
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Accelerated Partial Breast Irradiation Tech Bulletin
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Literature Corner
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Editors' Bios

TRENDS' Editors
Pamela Benitez, MD
Dr. Benitez is a general surgeon focusing exclusively on diseases of the breast and breast cancer at William Beaumont Hospital in Royal Oak, Michigan

Martin Keisch, MD
Dr. Keisch is a board-certified radiation oncologist at University of Miami Hospital and President of Cancer HealthCare Associates (CHCA)

Literature Corner

1. J Clin Oncol 29: 2011 (suppl; abstr 588) 2011 ASCO Annual Meeting
Preliminary results of centralized HER2 testing in DCIS of the breast: NSABP B-43.

K. P. Siziopikou, M. A. Cobleigh, S. J. Anderson, T. B. Julian, D. W. Arthur, P. Zheng, E. P. Mamounas, E. R. Pajon, R. J. Behrens, L. Chu, N. C. Leasure, J. N. Atkins, J. Polikoff, T. E. Seay, W. J. McCaskill-Stevens, R. Rabinovitch, N. Wolmark

Abstract
Background: NSABP-B-43 is the first prospective, randomized phase III multi-institution clinical trial targeting high-risk, HER-2-positive DCIS. It compares whole breast irradiation (WBI) alone (Group [G] 1) with WBI given concurrently with trastuzumab (Group [G] 2) in women with HER-2 positive DCIS treated by lumpectomy. The primary aim is to determine trastuzumab's value in preventing ipsilateral breast cancer recurrence. Historically, the rate of HER-2 positive DCIS has been estimated as >50%; it is seen primarily in ER-negative, comedo-type DCIS of high nuclear grade. In that population HER-2 positivity was thought to be >70%, based mainly on single-institution studies with relatively few DCIS patients. There has been no documented centralized multi-institutional HER-2 analysis of DCIS. B-43 provides a unique opportunity to evaluate this question in a large cohort of DCIS patients.
Methods: Patients who have undergone lumpectomy for DCIS without evidence of an invasive component are eligible to participate. A central review of each patient's pure DCIS lesion is first carried out by IHC analysis. If the lesion is 1+ or 2+, FISH analysis is performed. Patients who are HER-2 3+ or FISH positive can then be entered into the trial and randomly assigned to receive 2 doses of trastuzumab during WBI or WBI alone.

Results: NSABP B-43 opened 11/9/08. As of 12/31/10, 1816 patients' specimens have been received centrally; 613 (33.8%) were HER-2 positive. The average time on study as of 12/31/10 for the 452 patients who were randomly assigned was 10.8 months. No grade 4 or 5 toxicity has been observed. Lower toxicity grades were equally balanced between groups. Nuclear grade for G 1 and G 2 were: low (0.4 vs 0.9%), intermediate (17.8 vs 14.9%), and high (81.8 vs 84.2 %), respectively. Negative ER status for G 1 and G 2 were 41.3% vs 41.9%, respectively.
Conclusions: In B-43 the HER2-positive rate for pure DCIS is 33.8%, lower than previously reported. No trastuzumab-related safety signals have been observed. Interest in this trial has been robust, as demonstrated by an average specimen submission rate of about 70/month. Funded by NCI PHS grants U10-CA-37377, U10-CA-69974, U10-CA-12027, and U10-CA-69651, with additional support from Genentech. 2. Lancet Oncol. 2011 Jun 3. [Epub ahead of print]
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial.

Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; on behalf of the Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. SourceMedical University of Vienna, Vienna, Austria.

Abstract
Background: Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.

Methods: ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3·6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.

FINDINGS: At a median follow-up of 62 months (range 0–114·4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0·68, 95% CI 0·51-0·91; p=0·009), although the difference was not significant in the tamoxifen (HR 0·67, 95% CI 0·44-1·03; p=0·067) and anastrozole arms (HR 0·68, 95% CI 0·45-1·02; p=0·061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0·67, 95% CI 0·41-1·07; p=0·09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1·08, 95% CI 0·81-1·44; p=0·591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1·75, 95% CI 1·08-2·83; p=0·02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).

INTERPRETATION: Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.

 
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