Please select the eligibility criteria that correspond to the clinical trial below.
Title: Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients With High Risk Localized Breast Cancer?
Brief Summary: RATIONALE: Zoledronate may delay or prevent the formation of bone metastases. It is not yet known whether chemotherapy and/or hormone therapy are more effective with or without zoledronate in preventing cancer recurrence and bone metastases in women with breast cancer.

PURPOSE: This randomized phase III trial is studying giving chemotherapy and/or hormone therapy together with zoledronate to see how well they work compared to chemotherapy and/or hormone therapy alone in preventing cancer recurrence and bone metastases in women with stage II or stage III breast cancer.


Options:
A: Inclusion Criteria:

1. Metastatic breast cancer to the bone with radiologically confirmed bone metastases
2. High-risk of subsequent SRE as reflected through either: elevated serum CTX (\> 400ng/L) and/or bone pain (using BPI) and/or prior SRE while on bisphosphonate therapy and/or progressive bone metastasis (by imaging)
3. On pamidronate therapy for at least 3 months
4. ECOG ≤ 2 and life expectancy \> 3 months
5. Serum creatinine ≤ 2.0 × ULN (zoledronic acid or pamidronate to be renal dosed as per institution standard)
6. No changes in systemic treatment in the 4 weeks prior to study entry or anticipated changes in the 4 weeks after entering the study. Markers of bone formation can be affected by a change in systemic therapies
7. Ability to take calcium and Vitamin D as per Health Canada recommended daily doses for the duration of the study
8. Ability to provide informed consent and complete study evaluations.

Exclusion Criteria:

1. Patients with acute symptomatic pathological fractures or acute spinal cord compression until such time as the appropriate management (surgery and/or radiotherapy) has been completed
2. Acute hypercalcemia (\>3.5 mmol/L)
3. Hypersensitivity to any bisphosphonate
4. Patients with rapidly progressive non-bone metastases for whom delaying a change in systemic anti-cancer treatment for the 1 month biochemical marker evaluation period could have a detrimental impact on patient outcome.
5. Renal dysfunction (≥ 2x creatinine of the upper limit of normal )
6. Pregnancy or lactation
7. Patients with dental abscesses or patients potentially requiring tooth extraction while on study
B: DISEASE CHARACTERISTICS:

* Diagnosis of primary breast cancer, meeting 1 of the following staging criteria:

  * Stage II
  * Stage III
  * T stage ≥ T1
* Receiving OR scheduled to receive chemotherapy and/or endocrine therapy

  * For patients receiving neoadjuvant therapy

    * Tumor \> 5 cm (T3), features of locally advanced disease (T4), OR biopsy-proven lymph node involvement (N1)
    * Scheduled to proceed to definitive surgery and/or radical radiotherapy with curative intent within 6 months of starting neoadjuvant therapy
    * No more than 30 days between initiation of neoadjuvant therapy and start of study drug
  * For patients receiving adjuvant therapy

    * Must have undergone complete primary tumor resection and treatment of axillary lymph nodes\*
    * Must have lymph node involvement
    * No prior neoadjuvant therapy\*\*
    * No more than 60 days since prior definitive surgery NOTE: \*Patients whose treatment plan includes further primary tumor resection and/or treatment of the axillary lymph nodes (e.g., clearance or radiotherapy) with curative intent after completion of chemotherapy are eligible provided the treatment is completed within 9 months of study entry

NOTE: \*\*Preoperative endocrine therapy with a duration of \< 30 days is not considered prior neoadjuvant therapy

* No evidence of recurrent or metastatic disease
* No history of breast cancer, except ductal carcinoma in situ or lobular carcinoma in situ
* Hormone receptor status:

  * Not specified

PATIENT CHARACTERISTICS:

Age

* 18 and over

Sex

* Female

Menopausal status

* Premenopausal or postmenopausal

Performance status

* Karnofsky 80-100% OR
* ECOG 0-1

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* Not specified

Renal

* Creatinine ≤ 1.5 times upper limit of normal

Other

* Not pregnant or nursing
* Fertile patients must use effective contraception
* No active dental problems, including dental abscess or infection of the jaw bone (e.g., maxilla or mandible)
* No prior or current diagnosis of osteonecrosis of the jaw
* No other malignancy within the past 5 years (including prior contralateral breast cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the cervix
* No history of disease with influence on bone metabolism, including any of the following:

  * Paget's disease of the bone
  * Primary hyperparathyroidism
  * Osteoporosis requiring treatment or likely to require treatment within the next 6 months
* No other severe physical or psychological disease that would preclude study compliance
* No known hypersensitivity to bisphosphonates

PRIOR CONCURRENT THERAPY:

Chemotherapy

* See Disease Characteristics

Endocrine therapy

* See Disease Characteristics

Radiotherapy

* See Disease Characteristics

Surgery

* See Disease Characteristics
* More than 4 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants)

  * Dental fillings, teeth scaling and polishing, or minor gingival surgery within the past 4 weeks are allowed

Other

* More than 1 year since prior bisphosphonates
* More than 30 days since prior investigational drugs
* No concurrent investigational drugs (i.e., not locally approved for any indication)
C: Inclusion Criteria:

* Women with histological diagnosis of invasive breast cancer requiring neoadjuvant chemotherapy
* T2 tumour or above
* WHO Performance status of 0,1 or 2
* Must consent to or have undergone a core biopsy for diagnosis of breast cancer AND consent to undergo an additional core biopsy prior to the second cycle of chemotherapy (Day 5 +/- Day 21)
* Written informed consent

Exclusion Criteria:

* Previous chemotherapy or radiotherapy to treated breast
* Evidence of metastatic disease or recurrent breast cancer or previous malignancy (some exceptions)
* Calculated creatinine clearance \< 40mls/min
* Prior treatment with bisphosphonates in last year or known contraindications to bisphosphonate therapy
* Concurrent tamoxifen or aromatase inhibitor medication
* Pregnant or lactating women
* Cardiac dysfunction that precludes use of anthracycline chemotherapy
* Unwilling to have extra interim biopsy
D: Inclusion Criteria for Double Blinded Phase:

* Histologically or cytologically confirmed adenocarcinoma of the breast;
* Female subjects with non-metastatic disease who are estrogen receptor (ER) and/or progesterone receptor (PR) positive, and who have completed their treatment pathway;
* Subjects who are currently on, or will initiate an approved non-steroidal aromatase inhibitor therapy (eg, anastrazole) in the adjuvant setting;
* Postmenopausal woman, defined as a woman fulfilling any one of the following criteria:

  * Having undergone a bilateral oophorectomy;
  * Age ≥ 60 years;
  * Aged \< 60 years meeting the following requirements:
* Follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range;
* A negative pregnancy test within 7 days prior to randomization. Subjects who have undergone a hysterectomy do not require a pregnancy test.
* More criteria may apply.

Exclusion Criteria for Double Blinded Phase:

* Aromatase inhibitor therapy for more than 24 months;
* Prior or concurrent treatment with Selective Estrogen Receptor Modulators (eg, tamoxifen);
* Evidence of metastatic disease;
* Current or prior intravenous (IV) bisphosphonate administration;
* Oral bisphosphonate treatment greater than or equal to 3 years continuously OR greater than 3 months but less than 3 years unless there was a washout period of at least 1 year prior to randomization OR any use during the 3-month period prior to randomization;
* Prior administration of denosumab;
* Known liver or renal deficiency;
* Recurrence of the primary malignancy (e.g., during the allowed interval of pretreatment with aromatase inhibitor);
* Diagnosis of any second non-breast malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri;
* Any kind of disorder that compromises the ability to give written informed consent and/or comply with study procedures.

Inclusion Criteria to Receive Open-label Phase Denosumab:

* Obtain signed and dated written informed consent prior to performing any study-specific procedure;
* Subjects currently taking an approved non-steroidal AIT (eg, anastrazole) or who have completed or discontinued AIT within 12 months prior to participation in the OLP;
* Randomized to placebo arm during the double-blind phase (as determined by unblinding procedures);

Exclusion Criteria to Receive Open-label Phase Denosumab:

* Current or prior IV bisphosphonate administration;
* Subjects meeting the following criteria for oral bisphosphonate treatment:

  * Greater than or equal to 3 years continuously,
  * Greater than 3 months but less than 3 years unless subject has had a washout period of at least 1 year prior to participation in the OLP,
  * Any use during the 3-month period prior to participation in the OLP;
* Prior or concurrent treatment with SERMs (eg, tamoxifen);
* Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase; Treatment with commercial denosumab (Prolia or Xgeva) prior to participation in the OLP.

Eligibility for ZA substudy Inclusion Criteria

* Obtain signed and dated written informed consent prior to performing any substudy-specific procedure
* Subjects that received OLP denosumab and completed OLP treatment
* Last OLP denosumab administration no longer than 9 months ago Exclusion Criteria
* Current or prior ZA administration.
* Subjects who ended treatment with investigational product (IP) prematurely in the double-blind phase and OL phase
* Known sensitivity or intolerance to any of the products to be administered during the substudy (eg, ZA, calcium or vitamin D)
* Known history of any of the following conditions either by subject self report or chart review

  * Paget's disease (bone), Cushing's disease, hyperprolactinemia or other active metabolic bone disease
  * Known history of hypocalcemia
  * Major surgery, or significant traumatic injury occurring within 4 weeks prior to randomization
  * Parathyroid glands in neck surgically removed.
  * Any sections of intestine removed.
  * Known human immunodeficiency virus infection
  * Active infection with hepatitis B or hepatitis C virus
* Known liver or renal disease as determined by the investigator and indicated by the following criteria:

  * Aspartate aminotransferase ≥ 2.5 x ULN
  * Alanine transaminase ≥ 2.5 x ULN
  * Serum creatinine ≥ 2 x ULN
  * Creatine clearance \< 35ml/min Subjects that are pregnant or breastfeeding
  * All subjects with reproductive potential must have a negative pregnancy test within 7 days before randomization
* Subjects who are osteoporotic in baseline BMD

Answer: B