Neoadjuvant Zoledronate and Atorvastatin in Triple Negative Breast Cancer
Status:
Unknown status
Trial end date:
2020-07-25
Target enrollment:
Participant gender:
Summary
Recent evidences suggest that zoledronate, 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. The ABCSG-12 clinical trial have reported
improved Disease Free Survival (DFS) and Overall Survival (OS) in mostly chemotherapy naive
premenopausal patients after a 3-years of treatment with zoledronate (zol) and
ovarian-suppression therapy. The ZO-FAST study showed better DFS for immediate use of zol in
postmenopausal patients receiving adjuvant hormonal treatment. Preliminary evidences support
the role of zoledronate also in neoadjuvant setting reporting better responses in cases of
treatment with zol and chemotherapy (cht) compared with cht alone. The anticancer mechanism
of action of BPs still remains not well understood. Basically, BPs are mevalonate (MVA)
pathway inhibitors and one of the most intriguing hypothesis supporting their anticancer
activity relies on the modulation of the mevalonate downstream metabolism. Selected cancer
subtypes may present a more pronounced mevalonate activity able to confer an aggressive
phenotype. It has been shown that a mutant p53 acts as promoter of MVA upregulation. One of
the most important biological implications of MVA pathway upregulation in cancer cells is the
aberrant activation of the Hippo pathway, a molecular axis with a central role in
carcinogenesis. Two Hippo pathway related transcriptional coactivators, YAP and TAZ, promote
tissue proliferation and the self-renewal of normal and cancer stem cells, and incite
metastasis. Due to the strong interplay between the MVA and Hippo pathways, the modulation of
MVA axis has deep impact on the function of YAP/TAZ as transcriptional regulators of tumour
growth. These findings implicate the mevalonate pathway as a therapeutic target for selected
tumors with up-regulation of these pathways.
Preclinical and clinical evidences suggest that BPs are able to interfere with YAP/TAZ
expression, via MVA pathway. This kind of activity may be part of the mechanism of action of
BPs as antitumor drugs. Others medications are able to modulate the MVA pathway. Statins, a
first-class of lipid-lowering medications that inhibit the enzyme HMG-CoA reductase, inhibit
the sterol biosynthesis via the mevalonate pathway. A possible anti-tumor effect of statins
can be predicted with the same mechanism of action described for BPs, through the
interference with the MVA axis. Actually, the anti-tumor activity of statins have been
investigated in different retrospective analyses. In breast cancer a more robust signal has
been retrospectively reported and 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
triple-negative breast cancer (TNBC). 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.
The primary clinical objective is to assess the anti-tumor activity of the combination of
neoadjuvant standard cht associated with zol and atorvastatin, measured by the proportion of
pCR obtained after neoadjuvant treatment in patients with TNBC.
Secondary objectives are: 1) to evaluate the anti-tumor activity of pre-operative standard
chemotherapy associated or not with zol and atorvastatin according to high/low p53 levels 2)
to address the efficacy of neoadjuvant cht associated or not with zol/atorvastatin combo in
terms of disease free survival and overall survival); 3) to study the safety profile of study
treatments; 4) to investigate the treatment modulation of YAP and TAZ gene expression
(RNA-Seq) in tumor tissues collected at the time of core-biopsy and definitive surgery; 5) to
address the modulation of Ki67expression by IHC in the FFPE diagnostic core biopsy tumor
block and in the tumor tissue collected at surgery.
Patients fulfilling the eligibility criteria will be randomized to receive standard
anthracyclines/taxanes based neoadjuvant cht (ARM A) or the combination of zol and
atorvastatin associated with the above mentioned neoadjuvant cht (ARM B).
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research