Please select the eligibility criteria that correspond to the clinical trial below.
Title: I-SPY Trial (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2)
Brief Summary: The purpose of this study is to further advance the ability to practice personalized medicine by learning which new drug agents are most effective with which types of breast cancer tumors and by learning more about which early indicators of response (tumor analysis prior to surgery via magnetic resonance imaging (MRI) images along with tissue and blood samples) are predictors of treatment success.


Options:
A: Inclusion Criteria:

* Histologically confirmed invasive cancer of the breast
* Clinically or radiologically measureable disease in the breast after diagnostic biopsy, defined as longest diameter greater than or equal to 25 mm (2.5cm)
* No prior cytotoxic regimens are allowed for this malignancy. Patients may not have had prior chemotherapy or prior radiation therapy to the ipsilateral breast for this malignancy. Prior bis-phosphonate therapy is allowed
* Age ≥18 years
* ECOG performance status 0-1
* Willing to undergo core biopsy of the primary breast lesion to assess baseline biomarkers
* Non-pregnant and non-lactating
* No ferromagnetic prostheses. Patients who have metallic surgical implants that are not compatible with an MRI machine are not eligible.
* Ability to understand and willingness to sign a written informed consent (I-SPY TRIAL Screening Consent)
* Eligible tumors must meet one of the following criteria: Stage II or III, or T4, any N, M0, including clinical or pathologic inflammatory cancer or Regional Stage IV, where supraclavicular lymph nodes are the only sites metastasis
* Any tumor ER/PgR status, any HER-2/neu status as measured by local hospital pathology laboratory and meets any tumor assay profile described in protocol section 4.1.2F
* Normal organ and marrow function: Leukocytes ≥ 3000/μL, Absolute neutrophil count ≥ 1500/μL, Platelets ≥ 100,000/μL, Total bilirubin within normal institutional limits, unless patient has Gilbert's disease, for which bilirubin must be ≤ 2.0 x ULN, AST(SGOT)/ALT (SGPT) ≤ 1.5 x institutional ULN, creatinine \< 1.5 x institutional ULN
* No uncontrolled or severe cardiac disease. Baseline ejection fraction (by nuclear imaging or echocardiography) must by ≥ 50%
* No clinical or imaging evidence of distant metastases by PA and Lateral CXR, Radionuclide Bone scan, and LFTs including total bilirubin, ALT, AST, and alkaline phosphatase
* Tumor assay profile must include on of the following: MammaPrint High, any ER status, any HER2 status, or MammaPrint Low, ER negative (\<5%), any HER2 status, or MammaPrint Low, ER positive, HER2/neu positive by any one of the three methods used (IHC, FISH, TargetPrint™)
* Ability to understand and willingness to sign a written informed consent document (I-SPY 2 TRIAL Consent #2)

Exclusion Criteria:

* Use of any other investigational agents within 30 days of starting study treatment
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study agent or accompanying supportive medications.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
B: Inclusion Criteria:

Patients will be eligible for study participation only if they comply with the following criteria:

* Written informed consent according to local regulatory requirements prior to beginning specific protocol procedures.
* Complete baseline documentation must be submitted via MedCODES to GBG Forschungs GmbH.
* Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration from the breast lesion alone is not sufficient. Incisional biopsy or axillary clearance is not allowed.

In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.

* Tumor lesion in the breast with a palpable size of 2 cm or a sonographical size of 1 cm in maximum diameter. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
* Patients must have stage cT1c - cT4a-d disease. Patients with HER2- positive or TNBC are eligible irrespective of nodal status (cN0-cN3). Patients with luminal B-like tumors (defined here as ER and/or PgR \>1% stained cells, HER2 negative, Ki-67 \>20%) only with histologically (sentinel-node biopsy, core- or fine-needle biopsy) involved lymph nodes (pN1-3).
* In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
* Centrally confirmed ER, PR and HER2 status. Central pathology includes also assessment of Ki-67 and LPBC status on core biopsy. ER/PR negative is defined as \<=1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridization (ISH) and according to ASCO-CAP guidelines as of 2013). Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the GBG central pathology laboratory prior to randomization.
* Age \>=18 years.
* Karnofsky Performance status index 90%.
* Confirmed normal cardiac function by ECG and cardiac ultrasound (LVEF or shortening fraction) within 4 weeks prior to randomization. LVEF must be above 55%.
* Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
* Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (21 days), breast MRI (optional). Chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan in case of high risk for primary metastasis. In case of a positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
* Patients must agree with central pathology testing of core biopsy specimen and final pathology specimen and be available and compliant for treatment and follow-up.
* In addition for patients to be randomized to the two supportive anemia treatment arms:
* Hemoglobin level \<10g/dl.
* Body weight ≥ 40 kg.
* No need for immediate red blood cell transfusion.
* Transferrin saturation (TSAT) ≤20% and serum ferritin \<300ng/ml.

Exclusion Criteria:

* Patients with ER- and/or PR-positive, HER2-negative breast cancer and Ki- 67 \<= 20% (any luminal A-like subtype) or luminal B-like (Ki67\>20%) subtype without nodal involvement.
* Patients with stages cT1a, cT1b, or any M1.
* Patients with pure lobular invasive breast cancer.
* Prior chemotherapy for any malignancy.
* Prior radiation therapy for breast cancer.
* Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
* Inadequate general condition (not fit for dose-dense, dose-intensified anthracycline-taxane-targeted agents-based chemotherapy).
* Previous malignant disease being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
* Known or suspected congestive heart failure (\>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \>140/90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
* History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
* Pre-existing motor or sensory neuropathy of a severity grade 2 by NCI-CTC criteria v 4.0.
* Currently active infection.
* Incomplete wound healing.
* Definite contraindications for the use of corticosteroids.
* Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
* Concurrent treatment with:
* chronic corticosteroids unless initiated \> 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).
* sex hormones. Prior treatment must be stopped before study entry.
* other experimental drugs or any other anti-cancer therapy.
* Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
* Male patients.

In addition for patients to be randomized to the two supportive anemia treatment arms:

* Iron substitution (oral or IV) or blood transfusions or treatment with r-HuEPO with the last 4 weeks prior to study start.
* Known hypersensibility or contraindication against ferric carboxymaltose.
C: Inclusion Criteria:

1. Written informed consent for all study specific procedures according to local regulatory requirements prior to beginning specific protocol procedures.
2. Complete baseline documentation must be sent to GBG Forschungs GmbH.
3. Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration alone is not sufficient. Incisional biopsy is not allowed. In case of bilateral cancer, the investigator has to decide prospectively which side will be evaluated for the primary endpoint.
4. Centrally confirmed negative HER2-status. Centrally confirmed estrogen and progesterone receptor, and Ki-67 status detected on core biopsy. ER/PR positive is defined as ≥1% stained cells and HER2-positive is defined as IHC 3+ or in-situ hybridisation (ISH) ratio ≥2.0. Formalin-fixed, paraffin-embedded (FFPE) breast tissue from core biopsy has therefore to be sent to the Dept. of Pathology at the Charité, Berlin prior to randomization.
5. Centrally confirmed tumor Homologous Recombinant Deficiency score (tBRCA positive/mutated and/or HRD high). Patients with known gBRCA and/or tBRCA status can be enrolled prior to the central test results available.
6. Tumor lesion in the breast with a palpable size of \> 2 cm or a sonographical size of \>1 cm in maximum diameter. If the tumor is not detectable with sonography mammography assessment can be considered. The lesion has to be measurable in two dimensions, preferably by sonography. In case of inflammatory disease, the extent of inflammation can be used as measurable lesion.
7. Patients must be in the following stages of disease:

   * cT2 - cT4a-d or
   * cT1c and cN+ or cT1c and pNSLN+ or
   * cT1c and ER-neg and PR-neg or
   * cT1c and Ki67\>20% In patients with multifocal or multicentric breast cancer, the largest lesion should be measured and at least one lesion has to meet the above criteria
8. Age \> 18 years.
9. Karnofsky Performance status index ≥ 80%.
10. Normal cardiac function must be confirmed by ECG and cardiac ultrasound (LVEF or shortening fraction) within 3 months prior to randomization. Results must be above the normal limit of the institution.
11. Laboratory requirements:

    Hematology
    * Absolute neutrophil count (ANC) ≥2.0 x 109 / L and
    * Platelets ≥100 x 109 / L and
    * Hemoglobin ≥10 g/dL (≥ 6.2 mmol/L) Hepatic function
    * Total bilirubin ≥1.5x UNL and
    * ASAT (SGOT) and ALAT (SGPT) ≥1.5x UNL and
    * Alkaline phosphatase ≥2.5x UNL.
12. Negative pregnancy test (urine or serum) within 14 days prior to randomization for all women of childbearing potential.
13. Complete staging work-up within 3 months prior to randomization. All patients must have bilateral mammography, breast ultrasound (≥21 days, and in no case exceed 6 weeks prior to randomization) (Note MRI/ CT scan may be used as an alternative imaging technique). In case of high risk according to guidelines: chest X-ray (PA and lateral) or as an alternative breast MRI/CT, abdominal ultrasound or CT scan or MRI, and bone scan in case of high risk for primary metastasis according to guidelines. In case of positive bone scan, bone X-ray or CT scan is mandatory. Other tests may be performed as clinically indicated.
14. Male or female patients
15. Patients must be available and compliant for central diagnostics, treatment and follow-up.

Exclusion Criteria:

1. Prior chemotherapy for any malignancy within 5 years.
2. Prior radiation therapy for breast cancer within 5 years.
3. Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures (barrier methods, intrauterine contraceptive devices, sterilization) during study treatment.
4. Inadequate general condition (not fit for anthracycline-taxane-targeted agents-based chemotherapy).
5. Previous malignant disease without being disease-free for less than 5 years (except CIS of the cervix and non-melanomatous skin cancer).
6. Known or suspected congestive heart failure (\>NYHA I) and / or coronary heart disease, angina pectoris requiring antianginal medication, previous history of myocardial infarction, evidence of transmural infarction on ECG, uncontrolled or poorly controlled arterial hypertension (i.e. BP \>140 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
7. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
8. Patients currently in an institution by order of jurisdictional or governmental grounds.
9. Currently active infection.
10. Definite contraindications for the use of corticosteroids.
11. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol.
12. Concurrent treatment with:

    * chronic corticosteroids unless initiated \> 6 months prior to study entry and at low dose (10 mg or less methylprednisolone or equivalent).
    * sex hormones. Prior treatment must be stopped before study entry.
    * other experimental drugs or any other anti-cancer therapy.
13. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
14. Prior use of a PARP-Inhibitor
D: Inclusion Criteria(Screening):

* Female patients, age at diagnosis 18 - 75 years
* Histological confirmed unilateral primary invasive carcinoma of the breast
* Adequate surgical treatment with complete resection of the tumor (R0) and resection of \> or = 10 axillary nodes or SLN in clinically N0 patients
* T1 - T4 (if operable, inflammatory breast cancer is excluded)
* Her-2 non-over expressing tumor confirmed by IHC/FISH
* Estrogen and/or progesterone receptor analysis performed on the primary tumor prior to randomization. Results must be known at the time of randomization
* Node positive disease or node negative disease with at least one other risk factor (tumor size \> or = 2 cm, grade \> or = 2, ER and PR negative, high uPA//PAI-1 levels)
* No evidence for distant metastasis (M0) after conventional staging
* Performance Status ECOG \< or = 1 or KI \> or = 80 %
* The patient must be accessible for treatment and follow-up
* Written informed consent for central pathology review and evaluation of Recurrence Score (HR positive) and participation in the planB trial prior to beginning specific protocol procedures

HR positive patients:

* Patient willingness to participate in adjuvant chemotherapy planB trial if RS \> 11
* Indication for chemotherapy given provided either \> 4 involved lymph nodes or RS \> 11 in 1-3 lymph nodes or N0 disease

Additional Inclusion Criteria (Randomisation to chemotherapy):

* Laboratory requirements (within 21 days prior to randomization):

  * Leucocytes \> or = 3.5 109/L
  * platelets \> or = 100 109/L
  * haemoglobin \> or = 10 g/dL
  * total bilirubin \< or = 1 ULN
  * ASAT (SGOT) and ALAT (SGPT) \< or = 2.5 UNL
  * creatinine \< 175 ymol/L (2 mg/dL)
* Negative pregnancy test (urine or serum) within 7 days prior to randomization in premenopausal patients
* LVEF within normal limits of each institution measured by echocardiography or MUGA scan and

Exclusion Criteria(Screening):

* HER2 over expression confirmed by IHC/FISH/CISH
* Known hypersensitivity reaction to the compounds or incorporated substances
* Known polyneuropathy \> or = grade 2
* Severe and relevant comorbidity that would interact with the application of cytotoxic agents or the participation in the study including acute cystitis and ischuria and chronic kidney disease.
* Prior malignancy with a disease-free survival of \< 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri or ipsilateral ductal carcinoma in-situ (DCISpTis of the breast)
* Non-operable breast cancer including inflammatory breast cancer
* Previous or concurrent treatment with cytotoxic agents for any reason after consultation with the sponsor
* Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry
* Male breast cancer
* Concurrent pregnancy; patients of childbearing potential must implement a highly effective (less then 1% failure rate) non-hormonal contraceptive measures during the study treatment
* Breast feeding woman
* Sequential breast cancer
* Lack of patient compliance

Additional Exclusion Criteria (Randomisation):

* Inadequate organ function including:

  * Leucocytes \< 3,5 G/l
  * platelets \< 100 G/l
  * creatinine or bilirubin above normal limits
  * alkaline phosphatise \> 5 UNL
  * ASAT and/or ALAT associated with AP \> 2.5 UNL
  * uncompensated cardiac function
* Time since axillary dissection \> 42 days

Answer: A