To the Editor: Gnant et al. (Feb. 12 issue)1 report on the AustrianBreast and Colorectal Cancer Study Group trial 12 (ABCSG-12)(ClinicalTrials.gov number, NCT00295646
[ClinicalTrials.gov]
), which looked at theuse of goserelin plus either tamoxifen or anastrozole with orwithout zoledronic acid in premenopausal women with breast cancer.The authors conclude that the addition of zoledronic acid improveddisease-free survival and that treatment with tamoxifen andtreatment with anastrozole were associated with similar ratesof disease-free survival. However, a separate analysis of thegroup of patients who received anastrozole without zoledronicacid would be of interest.
Frederik Wenz, M.D. University Medical Center Mannheim 68167 Mannheim, Germany frederik.wenz{at}medma.uni-heidelberg.de
References
Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679-691. [Free Full Text]
To the Editor: Gnant et al. report a 4-year rate of 90.8% fordisease-free survival in the group of premenopausal women withbreast cancer who received endocrine therapy alone and a rateof 94.0% in the group that received endocrine therapy plus zoledronicacid. Data from this trial that were presented at the AmericanSociety of Clinical Oncology meeting in 2008 showed that theeffect of zoledronic acid was driven almost exclusively by thefindings in the cohort of patients who received anastrozole,whereas little effect was discernible for the patients who receivedtamoxifen. With only 137 events contributing to these analyses,the test for interaction comparing the effectiveness of zoledronicacid between the anastrozole group and the tamoxifen group isexpected to be nonsignificant. What was the effect of zoledronicacid on the anastrozole and tamoxifen groups?
Richard D. Gelber, Ph.D. Dana–Farber Cancer Institute Boston, MA 02115
Stefan Aebi, M.D. Bern University Hospital CH-3010 Bern, Switzerland
To the Editor: Gnant et al. describe the results of the combinationof tamoxifen plus goserelin; however, this combined therapyis not a standard option for the typical premenopausal patientwith breast cancer enrolled in this study. In most centers,outside the context of a clinical trial, such patients wouldbe offered 5 years of tamoxifen plus or minus chemotherapy,1with the possible addition of ovarian ablation for women underthe age of 35 years who did not have chemotherapy-induced amenorrhea.2,3The combination of ovarian suppression and tamoxifen is beingprospectively addressed in the Suppression of Ovarian FunctionTrial (SOFT) (Clinical Trials.gov number, NCT00066690
[ClinicalTrials.gov]
). In addition,the duration of the tamoxifen exposure (3 years) cannot be considereda standard, level I, evidence-based form of adjuvant hormonaltherapy.
Artur Katz, M.D. Aknar Calabrich, M.D. Hospital Sirio Libanes 01308-050 São Paulo, Brazil artkatz{at}uol.com.br
Everardo D. Saad, M.D. Dendrix Research 04534-000 São Paulo, Brazil
References
Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol 2007;18:1133-1144. [Erratum, Ann Oncol 2007;18:1917.] [Free Full Text]
Rabaglio M, Aebi S, Castiglione-Gertsch M. Controversies of adjuvant endocrine treatment for breast cancer and recommendations of the 2007 St Gallen Conference. Lancet Oncol 2007;8:940-949. [CrossRef][Web of Science][Medline]
Goldhirsch A, Gelber RD, Yothers G. Adjuvant therapy for very young women with breast cancer: need for tailored treatments. In: The National Institutes of Health Consensus Development Conference: adjuvant therapy for breast cancer. Journal of the National Cancer Institute Monographs. No. 30. Bethesda, MD: National Cancer Institute, December 2001:44-51.
To the Editor: Gnant et al. did not compare disease-free survivalbetween the group of patients who received goserelin plus tamoxifenplus zoledronic acid and the group that received goserelin plusanastrozole plus zoledronic acid. An uneven distribution ofHER-2/neu overexpression among the groups might have influencedthe outcomes of this study. Predictive markers such as HER-2/neuoverexpression should be included in the analysis.
Lin Nan Li, Ph.D. Peng Wen Dong, M.D. Xijing Hospital Xi'an 710032, China linanlin{at}fmmu.edu.cn
To the Editor: In Table 2 of the article by Gnant et al., thereis a trend favoring tamoxifen with respect to distant recurrenceand death. In the two groups of patients who received endocrinetherapy, there were 15 deaths in the tamoxifen group, as comparedwith 27 in the anastrozole group (hazard ratio, 1.80; 95% confidenceinterval, 0.95 to 3.38). The P value of 0.70 for overall survival(as presented in Fig. 2E of the article) is not understandable;we would expect a P value of 0.07 on the basis of the 95% confidenceinterval and event numbers.
Toralf Reimer, M.D. Bernd Gerber, M.D., Ph.D. University of Rostock 18059 Rostock, Germany toralf.reimer{at}med.uni-rostock.de
To the Editor: Gnant et al. report that six doses of zoledronicacid prolonged disease-free survival in premenopausal patientswith breast cancer who were undergoing adjuvant endocrine therapy.Bisphosphonates are commonly prescribed in association withvitamin D supplementation. However, there is no mention as towhether vitamin D was prescribed to patients in this trial.
Vitamin D decreases the cellular proliferation of cancer cells,1so that vitamin D supplementation represents a potential confounderin the interpretation of the study results. In addition, hypovitaminosisD is relatively common in premenopausal women,2 and this conditionmay be worsened by estrogen deprivation.3 Vitamin D deficiencyin early breast cancer has been found to be associated withan increased risk of distant recurrence and death.4
On these grounds, it would be interesting to know whether anyof the patients who were treated with zoledronic acid receivedvitamin D supplementation, whether these patients had a differentoutcome, and whether there was an interaction in terms of outcomebetween zoledronic acid and anastrozole.
Alfredo Berruti, M.D. Consuelo Buttigliero, M.D. Luigi Dogliotti,M.D. University of Turin 10043 Orbassano, Italy alfredo.berruti{at}gmail.com
Nesby-O'Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002;76:187-192. [Free Full Text]
Dick IM, Prince RL, Kelly JJ, Ho KK. Oestrogen effects on calcitriol levels in post-menopausal women: a comparison of oral versus transdermal administration. Clin Endocrinol (Oxf) 1995;43:219-224. [CrossRef][Medline]
Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Frequency of vitamin D (Vit D) deficiency at breast cancer (BC) diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, N0-1, M0 BC. J Clin Oncol 2008;26:Suppl:9s-9s. [CrossRef]
To the Editor: The pharmacokinetic properties of zoledronicacid do not support the hypothesis of Gnant et al. that thisdrug has antitumor effects in tissue other than bone. Afterintravenous administration, bisphosphonates spread in calcifiedand noncalcified tissues, but their levels decline quickly innoncalcified tissues, and the decline is proportionate to thedecrease in the plasma concentration.1,2 In animal models, repeatedinjections of zoledronic acid (every 4 days) were required toreduce the number of metastatic foci outside bone, in whichzoledronic acid did not induce apoptosis.3
Bone marrow–derived mesenchymal stem cells are recruitedto the stroma of developing tumors. Karnoub et al.4 demonstratedthat mesenchymal stem cells greatly increase the metastaticpotential of breast-cancer cells by secreting chemokines andgrowth factors that sustain breast-cancer migration, invasion,and metastases. In this regard, we have recently shown thatzoledronic acid affects the ability of mesenchymal stem cellsto secrete angiogenic factors that promote breast-cancer metastasis.5We propose that the antitumor activity of zoledronic acid inpatients with breast cancer is related to its action on mesenchymalstem cells within the bone marrow microenvironment.
Antonella De Luca, Ph.D. Nicola Normanno, M.D. Istituto Nazionale Tumori Fondazione Pascale 80131 Naples, Italy nicnorm{at}yahoo.com
References
Chen T, Berenson J, Vescio R, et al. Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 2002;42:1228-1236. [Abstract]
Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone 1996;18:75-85. [CrossRef][Medline]
Hiraga T, Williams PJ, Ueda A, Tamura D, Yoneda T. Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res 2004;10:4559-4567. [Free Full Text]
Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007;449:557-563. [CrossRef][Web of Science][Medline]
De Luca A, Gallo M, Maiello M, et al. Zoledronic acid affects the expression of VEGF in breast cancer cells and in bone marrow stromal cells through direct and indirect mechanisms. Presented at the 99th Annual Meeting of the American Association for Cancer Research, San Diego, CA, April 12–16, 2008.
The author replies: In response to Wenz, Gelber and Aebi, Katzet al., Li and Dong, and Reimer and Gerber: according to St.Gallen and National Comprehensive Cancer Network guidelines,goserelin plus tamoxifen is an accepted treatment for premenopausalpatients with endocrine-responsive breast cancer, and luteinizinghormone–releasing hormone agonists alone are associatedwith a strong trend toward reduced rates of recurrence and death.1In the ABCSG-12 study, the selection of 3 years of endocrinetherapy was based on the findings of the ABCSG-5 trial (ClinicalTrials.govnumber, NCT00309478
[ClinicalTrials.gov]
) (which examined 3 years of goserelin, then5 years of tamoxifen).2 However, 5 years of continuous endocrinetherapy may not be necessary in this low-risk population, sinceit would be difficult to improve the 98.2% 4-year overall survivalachieved in the group receiving zoledronic acid in the ABCSG-12trial. We agree that long-term follow-up of SOFT and Triptorelinwith Exemestane on Tamoxifen (TEXT) (NCT00066703
[ClinicalTrials.gov]
) may providemore definitive guidance on the use of aromatase inhibitorsin premenopausal patients with breast cancer.
The ABCSG-12 study was designed and powered to show whetherthe addition of zoledronic acid to endocrine therapy improvedoutcomes, as compared with endocrine therapy alone. A specificinteraction test did not reveal any difference in the treatmenteffect between the group receiving anastrozole plus zoledronicacid and the group receiving tamoxifen plus zoledronic acid.Therefore, at this time, it is not possible to conclude thatthe effect of zoledronic acid was driven primarily by the findingsin one cohort. Longer follow-up of the zoledronic acid effectmay help to determine whether meaningful differences exist.
Reimer and Gerber are correct in pointing out that there wasa nonsignificant trend favoring tamoxifen over anastrozole forsurvival, and both P values in Figure 2E should be 0.07 ratherthan 0.70. (The article has been corrected at NEJM.org.)
In response to Li and Dong: we did not prospectively determinethe HER-2/neu status of patients in our study. However, sincepatients underwent randomization, the proportion of HER-2/neu–positivepatients is likely to have been balanced among the study groupsand is unlikely to have confounded the trial outcomes.
In response to Berruti et al.: vitamin D levels and vitaminD supplementation were not part of our protocol and thereforewere not prospectively recorded. However, we agree that thiscould be an important factor and should be elucidated in futuretrials of adjuvant bisphosphonates.
We agree with De Luca and Normanno that the antitumor effectsof zoledronic acid may be mediated by preventing the secretionof angiogenic factors by mesenchymal stem cells in bone marrow.This is entirely consistent with the idea that zoledronic acidmakes the bone-and-marrow microenvironment less favorable "soil"for tumor-cell growth. One hypothesis is that bone may providea sanctuary for dormant micrometastases that may later seeddistant metastases. Preliminary clinical data suggest that theantitumor activity of zoledronic acid may include the inhibitionof angiogenesis, immunostimulatory effects through the activationof gamma delta T cells,3 and a reduction in the number of disseminatedtumor cells in bone marrow.4 In addition, recent results fromthe neoadjuvant subgroup analysis of the Adjuvant ZoledronicAcid to Reduce Recurrence (AZURE) (NCT00072020
[ClinicalTrials.gov]
) trial indicatethat zoledronic acid has direct antitumor activity.5 Therefore,stimulation of a wide array of antitumor effects by zoledronicacid may inhibit disease progression in areas other than bonein patients with breast cancer.
Michael Gnant, M.D. Medical University of Vienna A-1090 Vienna, Austria michael.gnant{at}meduniwien.ac.at
for the ABCSG-12 Trial Investigators
References
Cuzick J, Ambroisine L, Davidson N, et al. Use of luteinising-hormone-releasing hormone agonists as adjuvant treatment in premenopausal patients with hormone-receptor-positive breast cancer: a meta-analysis of individual patient data from randomised adjuvant trials. Lancet 2007;369:1711-1723. [CrossRef][Web of Science][Medline]
Jakesz R, Hausmaninger H, Kubista E, et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer -- Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol 2002;20:4621-4627. [Free Full Text]
Santini D, Martini F, Fratto ME, et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother 2009;58:31-38. [CrossRef][Web of Science][Medline]
Lin AY, Park JW, Scott J, et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol 2008;26:Suppl:20s-20s. [CrossRef]
Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response — exploratory evidence for direct anti-tumor activity in breast cancer. Presented at the 31st Annual San Antonio Breast Cancer Symposium (SABCS), San Antonio, TX, December 11–13, 2008. poster.
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