Pre-operative Zoledronate in Triple Negative Breast Cancer

Recent evidences suggest that zoledronate (zol), one of the most used bisphosphonates (BPs) in the clinical setting for the prevention and treatment of bone metastasis in cancer patients, may have antitumor activity in early breast cancer in terms of improved disease free survival, overall survival and better response in BPs treated patients. BPs are mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer activity relies on the modulation of the mevalonate downstream metabolism. Biologically active mevalonate metabolites are involved in tumour cell proliferation and invasion and selected cancer subtypes may present a more pronounced mevalonate activity, able of maintaining an aggressive phenotype. The mevalonate pathway has deep impact on the function of YAP/TAZ, transcriptional regulators of tumour growth, and preclinical evidences suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients selected by the level of mevalonate pathway regulation, namely the p53 expression. This study is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor activity of pre-operative zol measured through its effect on the Ki67 proliferative biomarker, in TNBC patients classified according to the p53 expression (high vs low p53 expression). Patients with newly diagnosed, untreated, operable TNBC, intended to definitive breast surgery and suitable for pre-operative therapy with zoledronate will receive a pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast surgery. Ki67 levels will be assessed in tumor samples collected at the time of diagnosis and after zoledronate treatment at the time of definitive surgery. The secondary objective of the study is to investigate the effect of zoledronate on critical genes/proteins related to p53 and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue collected at the time of diagnosis and at definitive surgery. Zol safety profile will be evaluated by the NCI-CTCAE scale, version 4.0, and by the occurrence of serious adverse reactions. The total number of patients required is forty. The overall duration of the project is 32 months (30 months for accrual, followed by 2 months of follow-up after the recruitment of the last patient).

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* Histologically confirmed diagnosis of non-metastatic operable primary invasive TN breast cancer subjected to diagnostic core biopsy
* TNBC defined as HER2/ER/PgR negative receptors
* Ki67 and p53 expression determined by IHC
* Tumour tissue availability at time of diagnosis for IHC evaluation of p53/PIN1, YAP/TAZ and Ki67 protein expression and for RT-PCR molecular testing of critical genes: p53/PIN1, YAP/TAZ
* Age ≥ 18 years old
* ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
* Patients with reproductive potential. Female patients must have a negative serum pregnancy test within 7 days prior to start of trial. Patients must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months (female patients) and 6 months (male patients) after discontinuation of treatment
* Written informed consent signed prior to enrolment according to ICH/GCP.

Exclusion Criteria:

* Presence of metastatic disease
* Clinical indication of debulking neo-adjuvant treatment
* Previous investigational treatment for any condition within 4 weeks from study registration
* Treatment with bisphosphonates, denosumab or other drug that, in the Investigator's judgment, affects bone metabolism
* Treatment with statins or other drugs that, in the Investigator's judgment, potentially affect the mevalonate pathway
* Any previous treatment for the currently diagnosed breast cancer, including radiation therapy, chemotherapy, biotherapy and/or hormonal therapy
* Inadequate bone marrow, hepatic or renal function including the following

  1. Hb\< 9.0 g/dL, absolute neutrophil count \< 1.5 x 109/L, platelets \<100 x 109/L
  2. Total bilirubin \> 1.5 x ULN, excluding cases where elevated bilirubin can be attributed to Gilberts Syndrome
  3. AST (SGOT), ALT (SGPT) \> 2.5 x ULN Creatinine \> 1.2 x ULN, calcium \<8.6mg/dL
* Co-existing active infection or serious concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study
* Co-existing dental diseases that form a contraindication to the use of zol or need for immediate dental work
* Any medical or other condition that in the investigator's opinion renders the patient unsuitable for this study due to unacceptable risk
* Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures
* Anticipation of need for major surgical procedure during the course of the trial
* Known hypersensitivity to any excipients of zoledronate
* Pregnant or breast feeding women.

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