Significance Of Breast Cancer Adjuvant Therapy With Bisphosphonates

Objective: Bisphosphonates are standard drugs for preventingskeletal-related events in patients with bone metastatic cancer and for treatingosteoporosis. Increasing data suggest that the adjuvant use of bisphosphonatesreduces recurrence rates and death in patients with breast cancer. This studyretrospectively analyze the medical records of patients with breast cancer, andaims at assessing the impact of adjuvant treatment with bisphosphonates ondisease-free survival, rate of osteoporosis/osteopenia, the drug safety andfactors affecting efficacy.Methods: The first part of this study retrospectively analyzed stageI-stage III breast cancer patients’ clinical data who had received standardadjuvant therapy at Fourth Hospital of Hebei Medical University fromSeptember2008to September2013, the bisphosphonates group comprised allpatients who started bisphosphonates treatment within1year after breastcancer mastectomy and lasted3months, depending on this criterion, patientswere divided into bisphosphonates group and control group. The primaryendpoint was disease-free survival. The second part of this studyretrospectively analyzed stage I-stage III breast cancer patients’ clinical datawho had received standard adjuvant therapy, all of them had bone mineraldensity examination in June2012to November2013period.Osteoporosis/osteopenia was set to positive result. Analyze the impact ofbisphosphonates on positive result. This study used SPSS19.0statisticalsoftware for analysis. Disease-free survival was estimated using theKaplan-Meier method. Hazard ratios and95%confidence intervals wereobtained via Cox regression models. Logistic regression model analyzed theimpacts of adjuvant therapy with bisphosphonates, age, menopausal status,et.al on the incidence of osteoporosis/osteopenia. Results: In the first part, a total of301stage I-stage III cases wereeligible for inclusion in the analysis, bisphosphonates group was57cases andcontrol group was244cases, follow-up rate was98%. The follow up timerange was2-62months (the median time:27months). Recurrence andmetastasis occurred in63cases, the rate was20.9%. The median time torecurrent and metastasis was13months (1-56months). The most commonmetastasis sites in this study were bone, lymph node, liver, lung, chest wall,and brain.6cases (10.5%) in bisphosphonates group occurred recurrence ormetastasis, and the control group was57cases (23.4%). The recurrence rate ofcontrol group was higher than bisphosphonates group (2=4.599, P=0.032),the difference was statistically significant.The mean disease-free survival of bisphosphonates group was55.6months (95%CI：49.9-61.3months), the control group was44.1months(95%CI：41.4-46.8months), difference between the groups was statisticallysignificant(2=4.363, P=0.037), disease-free survival of bisphosphonatesgroup was significantly longer than control group. Univariate analysis showedthat disease-free survival was longer among the patients with bisphosphonatesadjuvant therapy (HR=2.438，95%CI：1.027-5.786，P=0.043), less number ofaxillary lymph nodes metastasis (HR=1.852，95%CI：1.470-2.333，P=0.000)and Luminal A (HR=1.332，95%CI：1.118-1.586，P=0.001) in this study, theresult was statistically significant. Menopausal status, age or tumor stage hadno significant effect on disease-free survival. Multivariate analysis indicatedthat the independent factors to improve disease-free survival of301cases ofbreast cancer included bisphosphonates adjuvant therapy (HR=2.198，95%CI：0.935-5.171，P=0.071), less number of axillary lymph nodes metastasis(HR=1.847，95%CI：1.476-2.311，P=0.000) and ER/PR+(HR=1.522，95%CI：1.192-1.944，P=0.001).Stratified analysis showed that in women with postmenopausal (2=4.571,P=0.033) and under60years old (2=5.194, P=0.023), treated withbisphosphonates had a better disease-free survival. Hormone receptor status,number of positive axillary lymph nodes, the existence of high recurrent risk factors or pathologic stage had no effect on whether patients benefit frombisphosphonates (P>0.05) in this study.Of301cases of breast cancer,24cases (8.0%) had bone metastasis,2inbisphosphonates group (3.5%),22in control group (9.0%). The incidence ofbone metastases in both groups were similar (P=0.274). Mean time of onset ofbone metastasis in bisphosphonates group was60.1months (95%CI：57.3-62.9months), and control group was52.0months (95%CI：50.1-53.9months),there was no significant difference between the two groups (P=0.180).Number of positive axillary lymph nodes (HR=1.617,95%CI1.103-2.372,P=0.014) and menopausal status (HR=0.443,95%CI：0.192-1.024, P=0.057)were important factors affecting the time of onset of bone metastasis in thestudy. Bone metastasis occurred late among patients with less number ofpositive axillary and postmenopause. Bisphosphonates, molecular subtypes,age or tumor stage in this study had no effect on bone metastasis in breastcancer patients.In the second part, a total of52stage I-stage III breast cancer cases hadbone mineral density examination, in which34cases (65.4%) occurredosteoporosis/osteopenia. Between cases adjuvant therapy withbisphosphonates (23cases) or without (29cases), the rates ofosteoporosis/osteopenia were significantly different (29.4%vs.70.6%,2=8.744, P=0.003). Compared to negative results group, bisphosphonates usein positive results group was lower (68%vs.29.4%, P<0.05). Statisticalresults showed that bisphosphonates adjuvant therapy (OR=0.239,95%CI：0.062-0.915) and age (OR=1.081,95%CI：0.995-1.174) were main factorsaffecting whether patients occurred osteopenia/osteoporosis or not in thisstudy, the result was statistically significant.In this study, a total of bisphosphonates use was365cycles,6.4cyclesper cases, in which292cycles (80.0%) was zoledronic acid, the remaining20%was ibandronate acid. Approximately60%of patients completed per3-4weeks last5-6cycle. Among bisphosphonates-treated patients, only1patientexperienced rash. Give general symptomatic treatment could be alleviated. No confirmed cases of renal dysfunction or osteonecrosis of the jaw werereported.Conclusions:1Breast cancer patients can benefit from adjuvant therapy(chemotherapy, endocrine therapy) combined with bisphosphonates.2Postmenopausal breast cancer patients benefit most frombisphosphonates adjuvant therapy irrespective of pathological stage, estrogen/progesterone receptor status.3Breast cancer patients with premenopause, high risk factors ofrecurrence are more likely metastases to bone. Bisphosphonates were notobserved to delay the onset of bone metastasis, pending further research toconfirm.4Bisphosphonates adjuvant therapy in patients with breast cancereffectively prevent bone mineral density decrease, thereby reducing rates ofosteoporosis/osteopenia.5Bisphosphonates were well tolerated and safe in clinical practice,however, the optimal duration and regularity requires further studies toconfirm.