Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase II Trial Investigating the Addition of Carboplatin to Neoadjuvant Therapy for Triple-negative and HER2-positive Early Breast Cancer
Brief Summary: Study participants with primary breast cancer will receive a standard chemotherapy with an anthracycline and a taxane as well as trastuzumab in case of HER2-positive tumors at doses and duration in concordance to current treatment guidelines. Patients will be receive and benefit in addition currently not in the neoadjuvant setting registered medication as lapatinib or bevacizumab of which significant increases of cure (pCR) rates have been reported in previous phase III studies. Patients randomized to carboplatin will receive in addition to the described backbone therapies a potentially active agent which suggested synergy of efficacy with chemotherapies as well as targeted agents. Patients might have the risk of an increase in toxicities due to the added agents and will have additional burden due to investigations required for study participation. However, due to the severity of the underlying disease and the high risk of relapse and death due to the stage of disease, this increase in toxicity and burden appears less relevant compared to the potential higher efficacy and finally cure rate by the incorporated treatments.


Options:
A: Inclusion Criteria:

* Female patients, age at diagnosis 18 years and above (consider patients at 70 years and above for ADAPT Elderly)
* Histologically confirmed unilateral primary invasive carcinoma of the breast
* Clinical T1 - T4 (except inflammatory breast cancer)
* All clinical N (cN)
* No clinical evidence for distant metastasis (M0)
* Known HR status and HER2 status (local pathology) Tumor block available for central pathology review
* Performance Status ECOG ≤ 1 or KI ≥ 80%
* Negative pregnancy test (urine or serum) within 7 days prior to start of induction treatment in premenopausal patients
* Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
* The patient must be accessible for treatment and follow-up

Additional Inclusion criteria for participation in the HER2+/HR+ sub-protocol:

* Confirmed ER and/or PR positive and HER2+ by central pathology
* Clinical cT1c - T4a-c (participation of patients with tumors \>cT2 is strongly recommended)
* All clinical N (participation of patients with cN0, if cT1c is strongly recommended)
* Patients must qualify for neoadjuvant treatment
* LVEF \> 50%; LVEF within normal limits of each institution measured by echocardiography and normal ECG (within 42 days prior to induction treatment)

Exclusion Criteria:

* Known hypersensitivity reaction to the compounds or incorporated substances
* Prior malignancy with a disease-free survival of \< 10 years, except curatively treated basalioma of the skin, pTis of the cervix uteri
* 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 than 1% failure rate) non-hormonal contraceptive measures during the study treatment
* Breast feeding woman
* Sequential breast cancer
* Reasons indicating risk of poor compliance Patient not able to consent

Additional Exclusion Criteria for participation in the HER2+/HR+ sub-protocol:

* Known polyneuropathy ≥ grade 2
* Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study
* Inadequate organ function (e.g. hepatic impairment, pulmonary disease, etc.)
* Uncompensated cardiac function (current unstable ventricular arrhythmia
* requiring treatment, history of symptomatic CHF NYHA classes II-IV), history of myocardial infarction or unstable angina pectoris within 6 months of enrollment, history of severe hypertension, CAD - coronary artery disease)
* Severe dyspnea
* Pneumonitis

Abnormal blood values:

* Thrombocytopenia \> CTCAE grade 1
* Increases in ALT/AST \> CTCAE grade 1
* Hypokalaemia \> CTCAE grade 1
* Neutropenia \> CTCAE grade 1
* Anaemia \> CTCAE grade 1
B: Inclusion Criteria:

* Female patients, age at diagnosis 18 years and above (consider patients at 70 years and above for ADAPT Elderly)
* Histologically confirmed unilateral primary invasive carcinoma of the breast
* Clinical T1 - T4 (except inflammatory breast cancer)
* All clinical N (cN)
* No clinical evidence for distant metastasis (M0)
* Known HR status and HER2 status (local pathology)
* Tumor block available for central pathology review
* Performance Status ECOG \<= 1 or KI \>= 80%
* Negative pregnancy test (urine or serum) within 7 days prior to start of induction treatment in premenopausal patients
* Written informed consent prior to beginning specific protocol procedures, including expected cooperation of the patients for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
* The patient must be accessible for treatment and follow-up

Exclusion Criteria:

* Known hypersensitivity reaction to the compounds or incorporated substances
* Prior malignancy with a disease-free survival of \< 10 years, except curatively treated basalioma of the skin or pTis of the cervix uteri
* 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 interventional clinical trial with or without 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 than 1% failure rate) non-hormonal contraceptive measures during the study treatment
* Breast feeding woman
* Sequential breast cancer
* Reasons indicating risk of poor compliance
* Patients not able to consent
C: Inclusion Criteria:

* Pathologic confirmation of invasive breast cancer
* Stage: Clinical T1 \>/= 1.0 cm, T2 or T3, N0-3, M0
* HER2 negative
* ER and PgR status by immunohistochemistry must be known. ER positive patients are allowed if physicain has determined neoadjuvant chemo is appropriate.
* Life expectancy greater than six months
* Use of an effective means of contraception is required

Exclusion Criteria:

* Pregnant or breastfeeding
* Prior anthracycline or platinum based therapy
* Prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy
* Ipsilateral breast recurrence, unless prior treatment consisted of excision alone for DCIS or breast-conserving treatment and hormonal therapy for DCIS or invasive cancer
* Peripheral neuropathy of any etiology that exceeds grade 1
* Significant hearing loss
* Renal dysfunction
* Use of other investigational or study agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study drugs
* Uncontrolled intercurrent illness
* Any condition that would prohibit administration of corticosteroids
* Uncontrolled diabetes
* Pre-existing medical condition that would represent toxicity in excess of grade 1 as measured by CTCAE (unless not considered medically significant by the physician)
* Known HIV positive individuals on combination antiretroviral therapy
D: Inclusion Criteria:

* 1.Written informed consent for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
* 2.Complete baseline documentation must be submitted via Medcodes® and approved by GBG Forschungs GmbH.
* 3.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.
* 4.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.
* 5.Patients should be in the following stages of disease: cT2 - cT4a-d or cT1c and cN+ or pNSLN+
* 6.In patients with multifocal or multicentric breast cancer, the largest lesion should be measured.
* 7.Centrally confirmed ER/PR/HER-2 and Ki-67 status detected on core biopsy. ER/PR positive is defined as \>1% stained cells and HER2-positive is defined as HercepTest IHC 3+ or FISH ratio ≥ 2.2. 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.
* 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. LVEF must be above 55%.
* 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. Renal function
* Creatinine ≤ 175 µmol/L (2 mg/dL) \< 1.5x UNL
* Proteinuria: Urine dipstick for proteinuria \< 2+. Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis should undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours. If creatinine is between 140 - 175 umol/L (1.6-2.0 mg/dL), the creatinine clearance (calculated or measured) should be ≥ 45 mL/min.
* 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), breast MRI (optional), chest X-ray (PA and lateral), abdominal ultrasound or CT scan or MRI, and bone scan done. In case of positive bone scan, bone X-ray (or CT or MRI) is mandatory. Other tests may be performed as clinically indicated.
* 14.Patients must be available and compliant for central diagnostics, treatment and follow-up.

Exclusion Criteria:

1. Prior chemotherapy for any malignancy.
2. Prior radiation therapy for breast cancer.
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 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 \>160 / 90 mm Hg under treatment with two antihypertensive drugs), rhythm abnormalities requiring permanent treatment, clinically significant valvular heart disease.
7. Previous thromboembolic event (except when thrombophily screening is negative).
8. Known hemorrhagic diathesis or coagulopathy with increased bleeding risk.
9. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
10. Pre-existing motor or sensory neuropathy of a severity ≥ grade 2 by NCI-CTC criteria v 4.0.
11. Currently active infection.
12. Active peptic ulcer.
13. Incomplete wound healing or unhealed bone fracture.
14. Disease significantly affecting gastrointestinal function, e.g. malabsorption syndrome, resection of the stomach or small bowel, ulcerative colitis.
15. History of abdominal fistula or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment.
16. Severe pulmonary condition / illness.
17. Major surgery within the last 28 days or anticipation of the need for major surgery during study treatment with bevacizumab. Minor surgeries including insertion of an indwelling catheter or sentinel lymph node biopsy within 24 h prior to chemotherapy.
18. Definite contraindications for the use of corticosteroids except inhalative corticoids.
19. Known hypersensitivity reaction to one of the compounds or incorporated substances used in this protocol;
20. Concurrent treatment with:

    * chronic corticosteroids unless initiated \> 6 months prior to study entry and at low dose (≤ 10 mg methylprednisolone or equivalent).
    * sex hormones. Prior treatment must be stopped before study entry.
    * virostatic agents like sorivudine or analogs like brivudine, concurrent treatment with aminoglycosides.
    * anticoagulants: heparin, warfarin as well as acetylic acid (e.g. Aspirin®) at a dose of \> 325 mg/day or clopidogrel at a dose of \> 75 mg/day.
    * other experimental drugs or any other anti-cancer therapy.
    * drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A, e.g. Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Ritonavir, Telithromycin, Erythromycin, Verapamil, Diltiazem within the last 5 days or the expected need for these treatments during study participation.
21. Participation in another clinical trial with any investigational, not marketed drug within 30 days prior to study entry.
22. Male patients.

Answer: D