Phase III randomized trial with neoadjuvant chemotherapy (TAC) with or without zoledronic acid for patients with large resectable or locally advanced HER2-negative breast cancer.

Neoadjuvant chemotherapy is an effective alternative to adjuvant chemotherapy
in both early and locally advanced breast cancer. Neoadjuvant chemotherapy has
the advantage that it potentially downstages the tumor, facilitating breast
conserving surgery instead of a mastectomy. Additionally it provides
information of response of the tumor to treatment and it allows research of
pathological and molecular predictors of response and tumor biology. In the
neoadjuvant setting the regimen using six cycles of docetaxel, adriamycin and
cyclofosfamide (TAC) is generally accepted as standard care.
It has been recently discovered that bisphosphonates (BPs), especially the most
potent BP zoledronic acid, might have both anti tumor effects and a synergistic
effect when given sequential with chemotherapy. Clinically, after previous
discordant data using less potent bisphosphonates in the adjuvant setting the
ABCSG-12 trial was the first adjuvant clinical trial to notice an improvement
of disease-free survival, a reduction in distant metastasis other than bone,
loco-regional and contra lateral relapses and a trend to reduces risk of death,
with zoledronic acid (4mg every 6 months for 3years) added to endocrine
treatment.
In a large trial (AZURE) investigating the anti tumor effects of zoledronic
acid in the neoadjuvant and adjuvant treatment of breast cancer, an interim
analysis of the subset treated with neoadjuvant chemotherapy showed an
significant improvement in pathological complete response (10,9 % vs. 5,8%)
when zoledronic acid was added.The mechanism of this synergy is currently
unknown.

In this study we want to investigate whether the submission of zoledronic acid
to neoadjuvant chemotherapy benefits the pathological complete response, and
thus favors a better clinical outcome in patients with large ressectable or
locally advanced HER2-negative breast cancer.
Further we want to evaluate the clinical response, DFS and OS in correlation
with the pathological response. We also evaluate the toxicity of both treatment
arms en the heterogeneity of the core biopsy and operation specimen.
By means of translational research, we try to investigate the mechanism of
action of zoledronic acid en try to detect methods for early respons detection
in neoadjuvant treatment.

This study is designed as a randomized, open-label, multi centre phase III
trial.

Arm A: Zoledronic acid 4 mg i.v in 15 minutes every 3-weeks within 24 hours
after infusion of chemotherapy, repeated every 21 days for 6 cycles

Patients are randomised in group A (TAC with zoledronic acid) or group B (TAC).
Patients in group A will receive 4 mg of zometa in 15 minutes, within 24 hours
after infusion of all chemotherapeutic agents. No extra visits or
investigations are planned unless patients particpate in one or more of the
side studies.
The most common treatment-related adverse event is an acute phase reaction, a
transient flu-like syndrome of fever, arthralgias and myalgias starting within
24 hours after treatment. Paracetamol can be used to prevent this flu-like
syndrome.Zoledronic acid dosis > 4 mg, especially when infused over < 15
minutes, were associated with a greater risk of serum creatinine increase.
Rarely, osteonecrosis of the jaw is seen especially in combination with dental
surgery and is associated with high cumulative dosage en longer treatment
periods. In case of poor dental health, patients should visit their dentist
before starting the neoadjuvant therapy. Dental surgery during neoadjuvant
treatment with zoledronic acid is strongly advised against.
If our hypothesis that adding zoledronic acid to neoadjuvant chemotherapy
improves pCR is correct, patients could benefit because a pCR is related with
a better clinical survival and an increased disease free survivall. Patients
could also benefit by being able to receive a breast conserving operation
instead of a mastectomy if the tumor shrinks more when treatment is in
combination with Zometa.