To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Try the modernized ClinicalTrials. Learn more about the modernization effort. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information. Search for terms. Save this study. Warning You have reached the maximum number of saved studies The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. Results First Posted : May 26, Last Update Posted : April 16, Study Description. Post-menopausal breast cancer patients will receive letrozole 2. Delayed start zoledronic acid will be initiated when either the Bone Mineral Density T-score is below -2 Standard Deviations at either the lumbar spine or hip or any clinical fracture unrelated to trauma or an asymptomatic fracture discovered at the month 36 scheduled visit.
Letrozole 2. Drug Information available for: Letrozole Zoledronic acid. In the same line of the neoAzure trial a more recently randomized clinical trial the JONIE study clearly confirmed the benefit of adding zol to neoadjuvant chemotherapy in HER2 negative early breast cancers. Zol 4 mg was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response pCR rate. The pCR rate in postmenopausal patients was The authors concluded the addition of zol to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and in particular in the patients with triple-negative breast cancer.
Actually, other clinical trials analyzed the role of BPs in breast cancer and, according to a recent meta-analysis of all randomized controlled trials 13 RCTs including more than In line with this observation, Valachis A. In the meta-analysis fifteen studies were considered eligible and were further analyzed. The use of zol resulted in a statistically significant better overall survival outcome five studies, 6, patients; hazard ratio [HR], 0.
Even though different explanations have been proposed over-time, the exact anticancer mechanism of action of BPs still remains not well understood. FPP is also converted to geranylgeranyl pyrophosphate, and these lipids are used for post-translational modification of proteins that are involved in various aspects of tumor development and progression.
Many studies showed that the MVA pathway is up-regulated in several cancers such as leukemia, lymphoma, multiple myeloma, as well as prostate, hepatic, pancreatic, esophageal and breast cancers. Several mechanisms may be involved in dysregulation of this pathway. It has been shown that mevalonate pathway is significantly upregulated in case of mutant p Sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture.
It has been shown that the enzymes of the mevalonate pathways are under transcriptional control of SREBPs. In breast cancer cells oncogenic mutant p53 acts as a transcriptional cofactor for SREBPs, leading to elevated expression of mevalonate enzymes. Strikingly, YAP and TAZ are controlled by the same architectural features that first inhibit and then foster cancer growth, such as ECM elasticity, cell shape, and epithelial-to-mesenchymal transition.
Statins, also known as HMG-CoA reductase inhibitors, are a first-class of lipid-lowering medications that inhibit the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol. Statins inhibit the sterol biosynthesis via the mevalonate pathway. From above, a possible anti-tumor effect of statins can be predicted exactly with the same mechanism of action already described for BPs, i. Actually, the anti-tumor activity of statins have been investigated over-time in different retrospective analyses with conflicting results.
In breast cancer a more robust signal has been retrospectively reported and, more recently, prospective studies have enquired the exquisite antitumor activity of statins in pre-operative breast cancer setting. From above, the clinical trial herein proposed aims to investigate the antitumoral clinical activity of zoledronate zol and statins atorvastatin combination, in patients receiving neoadjuvant chemotherapy for TNBC.
The results of this project may eventually contribute to unveil a novel combined treatment in TNBC through the repositioning of clinical approved low toxic drugs, able to target relevant masterpieces of breast cancer cells metabolism.
The primary objective of the study is to address in patients with TNBC the antitumor activity of pre-operative standard chemotherapy associated or not with zoledronate zol and atorvastatin measured through its effect on YAP and TAZ immunochemistry IHC expressions, which are considered co-primary objectives proof of concept objective. The primary clinical objective is to assess the anti-tumor activity of the combination of neoadjuvant standard chemotherapy associated with zoledronate and atorvastatin, measured by the proportion of pathological complete response pCR obtained after neoadjuvant treatment in patients with TNBC.
Prior to enrolment, the formalin fixed paraffin embedded FFPE diagnostic core biopsy specimens will be analyzed by investigational site pathologists to determine the presence of invasive TNBC and the p53 and Ki67 values by IHC. The same evaluations will be then repeated at the time of definitive surgery.
The study is composed by two phases. Within the first phase patients will be randomized to one of the two study treatment arms described above. Moreover the anti-tumor activity of the combination of neoadjuvant standard chemotherapy associated with zoledronate and atorvastatin measured by the proportion of patients with pCR obtained after neoadjuvant treatment will be assessed as primary clinical endpoint.
The post treatment follow-up procedure required for all patients consists in disease assessment with mammography and breast ultrasound scan, according to RECIST criteria version 1. From 1st phase to 2nd phase patients will be registered in this clinical trial. The overall duration of the project, is expected to be 36 months, including 20 months for the execution of the first phase recruitment, patients follow-up and data analysis , followed by 12 months for the running of the second phase.
Fifteen experimental centers will take part into the study. The proportion of responded patients [ Time Frame: After 6 months of study treatment ] The clinical primary activity endpoint of the second phase of study is the proportion of responder patients, defined as those obtaining a pCR, defined as ypT0ypN0 or as the absence of any residual tumor burden at surgery. Subjects alive not having relapse or recurrence or second cancer by the end of the study will be censored at the last disease assessment date.
Overall survival - Efficacy endpoint [ Time Frame: Date of death from any cause, assessed up to 36 months ] Overall survival OS , calculated for each patient as the time from the date of treatment start to the date of death from any cause. Patients not reported as having died at the end of the study will be censored at the date they were last known to be alive.
Relative reduction of Ki67 in tumor samples - Efficacy endpoint [ Time Frame: At surgery, after 6 months of study treatment ] Relative reduction of Ki67 IHC expression in tumour tissue samples collected at definitive surgery with respect to tumour tissue collected at the time of diagnostic core-biopsy for responder and non-responders patients.
In order to address the safety endpoint the study will evaluate:. Information from the National Library of Medicine Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below.
For general information, Learn About Clinical Studies. Inadequate bone marrow, hepatic or renal function including the following:. Try the modernized ClinicalTrials.
Learn more about the modernization effort. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.
Search for terms. Save this study. Warning You have reached the maximum number of saved studies Listing a study does not mean it has been evaluated by the U. Federal Government. Exploratory analyses of the women who were postmenopausal for more than 5 years or older than 60 years at study entry showed that immediate zoledronic acid treatment significantly improved disease-free survival, with a hazard ratio of 0.
In a comparison of patients who did and did not initiate therapy, "the hazard ratio for disease-free survival was in favor of those who did initiate treatment, suggesting a delay in bisphosphonate initiation could still have an impact on disease outcomes," Dr.
In terms of safety, there were three confirmed cases of osteonecrosis of the jaw in the trial, all in the immediate group. The findings of this study, together with those of other recent studies including the AZURE trial, "support the hypothesis that the anticancer benefits of zoledronic acid may best be realized in a low-estrogen environment," Dr.
The additional anticancer benefit observed in the truly vs. Skip to main content.
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