Please select the eligibility criteria that correspond to the clinical trial below.
Title: Impact of Neoadjuvant Chemotherapy With or Without Zometa on Occult Micrometastases and Bone Density in Women With Locally Advanced Breast Cancer
Brief Summary: This study is designed to evaluate the impact of Zometa on clearance of bone marrow micrometastases; the protective effect on chemotherapy-induced loss of bone mineral density; and quality of life in women undergoing treatment for locally advanced breast cancer.


Options:
A: Inclusion Criteria:

* Stage I-IIIa breast cancer
* Postmenopausal or recently postmenopausal
* Recent surgery for breast cancer
* Estrogen Receptor positive and/or progesterone receptor positive hormone receptor status
* No prior treatment with letrozole

Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

* Metastatic disease
* Invasive bilateral disease
* Clinical or radiological evidence of existing fracture in spine or hip
* Prior treatment with IV bisphosphonates in the past 12 months
* Current treatment with oral bisphosphonates ( must be discontinued within 3 weeks of baseline evaluation)
* Use of Tibolone within 6 months
* Prior use of parathyroid hormone for more than 1 week
* Previous or concomitant malignancy
* Abnormal renal function
* History of disease effecting bone metabolism

Other protocol-defined exclusion criteria may apply.
B: Inclusion Criteria:

* Newly diagnosed primary invasive ductal or invasive lobular breast adenocarcinoma
* Tumor classified as clinically large T2 (2-5 cm), T3, T4 or any T with N1, N2
* Prior malignancies: limited to curatively treated basal or squamous carcinoma of the skin or history of previous malignancies, treated and now \> 5 years disease free
* \>= 18 years of age
* Normal left ventricular function by echocardiogram or radioventriculogram
* Karnofsky Performance \>= 70

Exclusion Criteria:

* No evidence of distant metastasis present by CT, Bone scan, or physical exam
* If the bone scan or CT scans demonstrate indeterminate lesions, the nature of these lesions may be further clarified by additional testing such as PET or MRI
* No current treatment with Zometa or other bisphosphonates
* No serious functional disorders of the liver or kidneys:
* Serum Creatinine \<=2
* ALT/AST/ALK Phos \<= 1.5 x upper limit of institutional normal.
* Bili \<= 1.5 x upper limit of institutional normal.
* Currently not pregnant
C: Inclusion Criteria:

* Pre- and newly postmenopausal (up to 8 years) women ages 18 and older
* Breast cancer treated with chemotherapeutic agents, with or without tamoxifen/aromatase inhibitors
* Negative pregnancy test

Exclusion Criteria:

* Stage 4 breast cancer
* Any illness or medications known to affect bone metabolism
* History of osteoporosis or history of vertebral or hip fractures
* Kidney stones in the past 5 years
* Active peptic ulcer disease
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