Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Phase III Trial Comparing Two Dose-dense, Dose-intensified Approaches (ETC and PM(Cb)) for Neoadjuvant Treatment of Patients With High-risk Early Breast Cancer (GeparOcto)
Brief Summary: Two regimen are currently considered to have highest efficacy for patients with high-risk early stage breast cancer: sequential treatment of high dose epirubicin, taxane, and cyclophosphamide concomitantly with a dual HER2-blockade, and weekly treatment with paclitaxel/non-pegylated liposomal doxorubicin with dual HER2-blockade or carboplatin. The aim of the GeparOcto study is to compare those two regimen/strategies.

Both regimens are myelosuppressive with a significant incidence of chemotherapy induced anaemia.

The second aim of the GeparOcto study is therefore to compare the use of parental ferric carboxymaltose versus physician's choice for the treatment of chemotherapy-induced anemia in patients with iron deficiency.


Options:
A: 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.
B: ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)

Inclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening
* Female and male patients must have histologically confirmed invasive breast cancer that meets the following criteria:

  * Clinical stage II-III (American Joint Committee on Cancer \[AJCC\] 7th edition) at diagnosis, based on initial evaluation by clinical examination and/or breast imaging; no metastatic disease allowed
  * ER- and PR- should meet one of the following criteria:

    * =\< 10% cells stain positive, with weak intensity score (equivalent to Allred score =\< 3)
    * =\< 1% cells stain positive, with weak or intermediate intensity score (equivalent to Allred score =\< 3)
  * HER2 negative (not eligible for anti-HER2 therapy) will be defined as:

    * Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR
    * IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number \< 6 signals/cells OR
    * ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number \< 6 signals/cells without IHC
    * NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol; multifocal or multicentric breast cancers are eligible as long as all tumors fulfill eligibility criteria
    * NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not eligible for study participation (i.e. ER/PR/HER2 has to fulfill above criteria in both scenarios)
* Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen

  * NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll
  * NOTE: Patients that were not able to complete their planned neoadjuvant chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate as long as no further systemic standard of care therapy is planned by the treating physician
* Must have completed definitive resection of primary tumor

  * Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible
  * Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable
  * Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) are allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory
* Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery; residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring \>= 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination; this is required due to constraints in deoxyribonucleic acid (DNA) extraction for PAM50 analysis

  * NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast
  * NOTE: Despite lymph node involvement if residual invasive cancer in the breast is \< 1 cm in diameter patients are not eligible for participation
* Radiotherapy may be given before or after protocol treatment per standard of care guidelines; when radiotherapy is planned prior to protocol treatment administration, patients may be registered and screened while receiving radiation

  * Post-mastectomy radiotherapy is required for all patients with the following:

    * Primary tumor \>= 5 cm (prior to neoadjuvant chemotherapy \[clinically\] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery
    * For patients with primary tumors \< 5 cm or with \< 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician
    * Radiation of regional nodal basins is at the discretion of the treating radiation oncologist
  * NOTE: Breast radiotherapy (whole breast or partial) is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy
* Hemoglobin (Hgb) \> 9.0 g/dL
* Platelets \> 100,000 mm\^3
* Absolute neutrophil count (ANC) \> 1500 mm\^3
* Calculated creatinine clearance of \> 50 mL/min using the Cockcroft-Gault formula
* Bilirubin =\< 1.5 x ULN upper limit of normal (except in patients with documented Gilbert?s disease, who must have a total bilirubin =\< 3.0 mg/dL)
* Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase \[SGOT\]) =\< 2.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN
* Patients with active \>= Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade 2 neuropathy are ineligible
* Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant bisphosphonate or denosumab use is allowed
* Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification

  * Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery
  * The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will perform the PAM50 analysis and notify the ECOG-American College of Radiology Imaging Network (ACRIN) operations office within three (3) weeks of receipt of the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN database; results will not be reported to the submitting institution
  * NOTE: Tissue must be submitted any time during screening period, even if patient is getting radiation
  * NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately

Exclusion Criteria:

* History of TNBC invasive breast cancer within 5 years of enrollment, no concurrent malignancies of any sort
* Clinically significant infections as judged by the treating investigator

ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1):

* No specific timeframe between registration and randomization needs to be observed, as long as:

  * Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum based or capecitabine) start within 3 weeks (15 working days) following randomization date
  * Randomization occurs no more than 24 weeks from surgery date
* Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed
* ECOG performance status 0 or 1 within 2 weeks prior to randomization
* Radiotherapy may be given before or after protocol treatment. when radiotherapy is planned prior to protocol treatment administration, patients must have completed adjuvant radiotherapy \>= 2 weeks prior to randomization for protocol therapy, if applicable
* Patients must have completed treatment with any investigational agent \>= 30 days prior to randomization for protocol therapy, if applicable
* Patients must be randomized within 24 weeks from surgery
* Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy

  * A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
* Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
* Hemoglobin (Hgb) \> 9.0 g/dL
* Platelets \> 100,000 mm\^3
* Absolute neutrophil count (ANC) \> 1500 mm\^3
* International normalized ratio (INR) =\< 3 (to be done/tested only for subjects on warfarin)
* Calculated creatinine clearance of \> 50 mL/min using the Cockcroft-Gault formula
* Bilirubin =\< 1.5 x ULN (except in patients with documented Gilbert?s disease, who must have a total bilirubin =\< 3.0 mg/dL)
* Aspartate aminotransferase (AST, SGOT) =\< 2.5 x ULN
* Alanine aminotransferase (ALT, SGPT) =\< 2.5 x ULN
C: Inclusion Criteria:

* Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the following phenotypes:

  1. Triple negative breast cancer defined as: ER and PgR negative AND HER2 negative (not eligible for anti-HER2 therapy)
  2. ER and/or PgR positive, HER2 negative
* Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
* Completed adequate breast and axilla surgery.
* Completed at least 6 cycles neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes or the combination of both. Prior platinum as potentially curative treatment for prior cancer (e.g. ovarian) or as adjuvant or neoadjuvant treatment for breast cancer is allowed.
* ECOG 0-1.

Exclusion criteria:

* Any previous treatment with a PARP inhibitor, including olaparib and/or known hypersensitivity to any of the excipients of study treatment.
* Patients with second primary malignancy. EXCEPTIONS are:

  1. adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, Ductal Carcinoma in situ (DCIS) of the breast, stage 1 grade 1 endometrial carcinoma
  2. other solid tumours and lymphomas (without bone marrow involvement) diagnosed ≥ 5 years prior to randomisation and treated with no evidence of disease recurrence and for whom no more than one line of chemotherapy was applied.
* Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout period prior to starting study treatment is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents.
* Evidence of metastatic breast cancer
D: 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.

Answer: D