Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Multi-center Randomized Phase III Study Evaluating 4 Cycles of Docetaxel, Doxorubicin and Cyclophosphamide Versus 4 Cycles of Vinorelbine and Capecitabine in Patients Not Sufficiently Responding to 2 Cycles of TAC and 4 Cycles of TAC Versus 6 Cycles of TAC in Patients Sufficiently Responding to 2 Cycles of TAC as Preoperative Treatment of Locally Advanced or Operable Primary Breast Cancer
Brief Summary: Primary objective of the study in patients without a sufficient sonographic response (i.e. iNC) to 2 cycles of TAC as preoperative treatment of operable (T\>/= 2cm, N0-2,M0) primary breast cancer: To determine the response rate determined by sonography (iRR = iCR+iPR) of further 4 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) and of 4 cycles of vinorelbine and capecitabine (NX) (TAC vs. NX)

Primary objective of the study in patients with a sufficient sonographic response (i.e. iRR = iPR or iCR) to the first 2 cycles of TAC as preoperative treatment of operable (T\>/=2cm, N0-2,M0) primary breast cancer: To determine the pCR rate of 6 cycles vs. 8 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC x 6 vs. TAC x 8)


Options:
A: Inclusion Criteria:

* Written informed consent.
* Histological diagnosis of operable invasive adenocarcinoma of the breast (T1-T3). Tumours must be HER2 negative. Time window between surgery and study randomization must be less than 60 days.
* Surgery must consist of mastectomy or conservative surgery with axillary lymph node dissection. Margins free of disease and ductal carcinomas in situ (DCIS) are required. Lobular carcinoma is not considered a positive margin.
* Positive axillary lymph nodes defined as at least 1 out of 10 nodes with presence of disease. If sentinel node technique is used, sentinel node can be the only node affected. Patients belonging to the following classifications are eligible: TNM pathologic stage N1a, TNM pathologic stage N2a, TNM pathologic stage N3a.
* Status of hormone receptors in primary tumour. Results must be available before the end of adjuvant chemotherapy.
* Patients must not present evidence of metastatic disease. Status of HER2 in primary tumour, known before randomization. Patients with immune histochemistry (IHC) 0 or +1 are eligible. For patients with IHC 2+, fluorescence in situ hybridization (FISH) is mandatory and result must be negative.
* Age \>= 18 and \<= 70 years old.
* Performance status (Karnofsky index) \>= 80.
* Normal electrocardiogram (EKG) in the 12 weeks prior to randomization. If needed, normal cardiac function must be confirmed by left ventricular ejection fraction (LVEF).
* Laboratory results (within 14 days prior to randomization):

  * Hematology: neutrophils \>= 1.5 x 10\^9/l; platelets \>= 100 x 10\^9/l; hemoglobin \>= 10 mg/dl;
  * Hepatic function: total bilirubin \<= 1 upper normal limit (UNL); serum glutamic-oxaloacetic transaminase (SGOT) and Serum glutamic pyruvic transaminase (SGPT) \<= 2.5 UNL; alkaline phosphatase \<= 2.5 UNL. If values of SGOT and SGPT \> 1.5 UNL are associated to alkaline phosphatase \> 2.5 UNL, patient is not eligible;
  * Renal function: creatinine \<= 175 mmol/l (2 mg/dl); creatinine clearance \>= 60 ml/min;
  * Pharmacogenetics: one blood sample is needed for single nucleotide polymorphism (SNP) assessment.
* Complete stage workup during the 12 weeks prior to randomization (mammograms are allowed within a 20 week window). All patients must have a bilateral mammogram, thorax x-ray, abdominal echography and/or computed tomography (CT)-scan. If bone pain, and/or alkaline phosphatase elevation, a bone scintigraphy is mandatory. This test is recommended for all patients. Other tests: as clinically indicated.
* Patients able to comply with treatment and study follow-up.
* Negative pregnancy test done in the 14 prior days to randomization.

Exclusion Criteria:

* Prior systemic therapy for breast cancer.
* Prior therapy with anthracyclines or taxanes (paclitaxel or docetaxel) for any malignancy.
* Prior radiotherapy for breast cancer.
* Bilateral invasive breast cancer.
* Pregnant or lactating women. Adequate contraceptive methods must be used during chemotherapy and hormone therapy treatments.
* Any T4 or M1 tumour.
* Axillary lymph nodes: patients belonging to the following classifications are excluded: TNM pathologic stage N1b, TNM pathologic stage N1c, TNM pathologic stage N2b, TNM pathologic stage N3b, TNM pathologic stage N3c.
* HER2 positive breast cancer (IHC 3+ or positive FISH result).
* Pre-existing grade \>= 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria version 2.0 \[NCICTC v-2.0\]).
* Any other serious medical pathology, such as congestive heart failure; unstable angina; history of myocardial infarction during the previous year; uncontrolled hypertension or high risk arrhythmias.
* History of neurological or psychiatric disorders, which could preclude the patients from free informed consent.
* Active uncontrolled infection.
* Active peptic ulcer; unstable diabetes mellitus.
* Previous or current history of neoplasms different from breast cancer, except for skin carcinoma, cervical in situ carcinoma, or any other tumour curatively treated and without recurrence in the last 10 years; ductal in situ carcinoma in the same breast; lobular in situ carcinoma.
* Chronic treatment with corticosteroids.
* Contraindications for corticosteroid administration.
* Concomitant treatment with raloxifene, tamoxifen or other selective estrogen receptor modulators (SERMs), either for osteoporosis treatment or for prevention. These treatments must stop before randomisation.
* Concomitant treatment with other investigational products; participation in other clinical trials with a non-marketed drug in the 20 previous days before randomization.
* Concomitant treatment with another therapy for cancer.
* Males.
B: Inclusion Criteria:

* Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures.
* Complete baseline documentation sent to SKM CRS.
* Unilateral or bilateral primary carcinoma of the breast, confirmed histologically by core biopsy. Fine-needle aspiration 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.
* Tumor lesion in the breast with a palpable size of \> 2 cm in maximum diameter. The leasion has to be measurable in two-dimensions by sonography. In case of inflammatory disease the extent of inflammation can be used as measurable lesion. The following tumor stages are eligible:

  * Palpable breast tumor size of \> 2 cm without involvement of the skin or muscle or evidence of inflammatory disease (T2-3). Clinical N0-2. (Study population I)
  * Primary tumor with clinical involvement of skin or muscle or clinically evidence of inflammatory breast cancer (T4 a-d) or clinical N3 including supraclavicular nodes. (Study population II). In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
* Age \> 18 years.
* Karnofsky Performance status index \> 80%.
* Normal cardiac function must be confirmed by LVEF or shortening fraction (echocardiography or MUGA scan respectively) within 3 months prior to registration. The result must be above the normal limit of the institution.
* Laboratory requirements (within 14 days prior to registration):

  * Hematology:

    * Neutrophils \> 2.0 x 109/L and
    * Platelets \> 100 x 109/L and
    * Hemoglobin \> 10 g/dL
  * Hepatic function:

    * Total bilirubin \< 1 x UNL and
    * ASAT (SGOT) and ALAT (SGPT) \< 2.5 x UNL and
    * Alkaline phosphatase \< 5 UNL. Patients with ASAT and/or ALAT \> 1.5 x UNL associated with alkaline phosphatase \> 2.5 x UNL are not eligible for the study.
  * Renal function:

    * Creatinine \< 175 µmol/L (2 mg/dL)
* Tissue block centrally available for further biological tests.
* Negative pregnancy test (urine or serum) within 14 days prior to registration for all women of childbearing potential.
* Complete staging work-up within 3 months prior to registration. All patients must have bilateral mammography, breast ultrasound, breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound and/or CT scan, and bone scan. In case of positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated.
* Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center which can be the Principal or the Co- Investigator's site.

Exclusion Criteria:

* Early breast cancer with a tumor size of \< 2 cm measured by palpation.
* Patients with low or moderate risk. These patients are defined as having none of the following risk factors: Age \< 36 years, cT\> 5cm, ER and PR negative, cN+, or Grade III.
* Evidence of distant metastasis.
* Prior chemotherapy for any malignancy.
* Pregnant or lactating patients. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment.
* Pre-existing motor or sensory neuropathy of a severity \> grade 2 by NCI criteria.
* Other serious illness or medical condition:

  * previous malignant disease with a disease-free survival of less than 5 years (except CIS of the Cervix and non-melanomatous skin cancer.
  * congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year prior to study entry, uncontrolled arterial hypertension or high-risk uncontrolled arrhythmias.
  * history of significant neurologic or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent.
  * active uncontrolled infection.
  * active peptic ulcer, unstable diabetes mellitus.
* Chronic treatment with corticosteroids unless initiated \> 6 months prior to study entry and at low dose (\</= 20 mg methylprednisolone or equivalent).
* Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry.
* Definite contraindications for the use of corticosteroids.
* Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
* Concurrent treatment with any other anti-cancer therapy.
* Known hypersensitivity reaction to one of the investigational compounds or incorporated substances.
* Male patients.
C: Key Inclusion Criteria:

- Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above.

Key Exclusion Criteria:

- Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors.
D: DISEASE CHARACTERISTICS:

* Histologically or cytologically confirmed adenocarcinoma of the breast

  * Locally advanced, recurrent, or metastatic disease
* HER2-negative disease
* Measurable or evaluable disease
* Candidate for taxane-based chemotherapy
* No presence or history of CNS metastasis

  * Clinical suspicion of CNS metastasis must be confirmed by CT or MRI scan
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* Menopausal status not specified
* WHO performance status 0-2
* Neutrophil count ≥ 1.5 x 10\^9/L
* Platelet count ≥ 100 x 10\^9/L
* Hemoglobin ≥ 80 g/L
* Bilirubin ≤ 1.5 times upper limit of normal (ULN)
* AST ≤ 5 times ULN
* Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in case of liver metastases or ≤ 10 times ULN in case of bone metastases)
* Serum creatinine ≤ 1.5 times ULN
* Urine protein \< 2+ by dipstick OR ≤ 1 g by 24-hour urine collection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception during and for 12 months after completion of study therapy
* Patients with INR \> 1.5 (or Quick ≤ 70%) OR aPTT \> 1.5 times ULN within 7 days prior to expected first trial treatment must be receiving anticoagulant medication

  * Patients receiving full-dose oral or parental anticoagulants may be included in the trial provided anticoagulant dosing has been stable for at least 2 weeks prior to trial entry and the appropriate coagulation monitoring tests are within local therapeutic limits
* Must be compliant and geographically proximal for staging and follow-up
* No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
* No known hypersensitivity to trial drugs or its active compound (e.g., fluoropyrimidine), any other components of the trial drugs, or drugs formulated with cremophor EL including hypersensitivity to Chinese hamster ovary cell products or any other humanized recombinant antibodies
* No preexisting peripheral motor or sensory neuropathy \> NCI CTCAE grade 2 (i.e., moderate symptoms or limiting instrumental activities of daily living)
* No history or evidence of inherited bleeding diathesis, coagulopathy with the risk of bleeding, serious nonhealing wound, active peptic ulcer, nonhealing bone fracture, or bleeding metastases
* No history of abdominal fistula, grade 4 bowel obstruction, or gastrointestinal perforation or intra-abdominal abscess within the past 6 months
* No evidence of other medical conditions that would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs, including any of the following:

  * DPD deficiency
  * Severe respiratory, cardiac, hepatic, or renal disease
  * Active infection
  * Uncontrolled diabetes mellitus
  * Uncontrolled hypertension ≥ 140/100 mm Hg
  * Myocardial infarction within the past 12 months
  * Cerebrovascular accident or stroke within the past 6 months
  * History of hemorrhagic disorders
* No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, filling out quality-of-life forms, or interfering with compliance for oral drug intake

PRIOR CONCURRENT THERAPY:

* No prior chemotherapy for metastatic or locally recurrent breast cancer
* No prior radiotherapy for metastatic disease

  * Prior radiotherapy for the relief of metastatic bone pain allowed provided no more than 30% of marrow-bearing bone was irradiated
* At least 12 months since prior bevacizumab or other anti-VEGF therapy
* At least 12 months since prior capecitabine, continuous (\> 24 hours) fluorouracil infusion, or other oral fluoropyrimidine (e.g., eniluracil/fluorouracil, uracil/tegafur, S1, or emitefur)
* At least 12 months since prior taxane-based chemotherapy
* At least 6 months since other prior (neo)adjuvant chemotherapy
* At least 30 days since prior treatment in another clinical trial
* At least 24 hours since prior minor surgical procedures
* At least 28 days since prior and no concurrent major surgical procedures (including open biopsy) and no anticipation of the need for major surgery during the first course of this trial
* At least 10 days since prior hormone therapy for metastatic disease
* No continuous daily treatment with corticosteroid except for inhaled steroids
* No concurrent chronic daily aspirin \> 325 mg/day
* No concurrent chronic daily clopidogrel \> 75 mg/day
* No other concurrent anticancer treatments
* No other concurrent investigational treatments or experimental drugs
* No other concurrent drug therapy contraindicated for use with the trial drugs

Answer: B