Patients must have a histologically confirmed diagnosis of invasive breast carcinoma with positive estrogen and/or progesterone receptor status, and negative HER-, for whom standard adjuvant endocrine therapy is planned; estrogen and progesterone receptor positivity must be assessed according to American Society of Clinical Oncology (ASCO)/College of American Pathologist (CAP) guidelines as either estrogen receptor (ER) or progesterone receptor (PR) >= % positive nuclear staining; HER- test result negativity must be assessed as per ASCO/CAP  guidelines using immunohistochemistry (IHC), in situ hybridization (ISH) or both; HER- is negative if a single test (or all tests) performed in a tumor specimen show: a) IHC negative ( or +) or b) ISH negative using single probe or dual probe (average HER- copy number < . signals per cell by single probe or HER-/chromosome enumeration probe [CEP] ratio < . with an average copy number < . signals per cell by dual probe); if HER- IHC is +, evaluation for gene amplification (ISH) must be performed and the ISH must be negative; ISH is not required if IHC is  or +; HER- equivocal is not eligible
The tumor must have been determined to be human epidermal growth factor receptor  (HER)-negative as follows:\r\n* Immunohistochemistry (IHC) -+; or\r\n* IHC + and in situ hybridization (ISH) non-amplified with a ratio of HER to centromere enumerator probe  (CEP) < ., and if reported, average HER gene copy number <  signals/cells; or\r\n* ISH non-amplified with a ratio of HER to CEP < ., and if reported, average HER gene copy number <  signals/cells
Patients whose tumors have HER immunohistochemistry (IHC) +, in situ hybridization (ISH) >= ., or average HER copy number >= . signals per cell are not eligible; receptor status may be based on any time during treatment prior to study randomization, and from any site (i.e. primary, recurrent, or metastatic)
Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast that is one of the two following phenotypes:\r\n* TNBC defined as:\r\n** ER and PgR negative defined as immunohistochemistry (IHC) nuclear staining < %\r\n** HER negative (not eligible for anti-HER therapy) defined as:\r\n*** IHC , + without in situ hybridization (ISH) OR \r\n*** IHC + and ISH non-amplified with ratio less than . and if reported, average HER copy number <  signals/cells OR \r\n*** ISH non-amplified with ratio less than . and if reported, average HER copy number <  signals/cells (without IHC)\r\n* ER and/or PgR positive, HER negative breast cancer defined as:\r\n** ER and/or PgR positive defined as IHC nuclear staining >= %; AND\r\n** HER negative (not eligible for anti-HER therapy) defined as:\r\n*** IHC , + without ISH OR\r\n*** IHC + and ISH non-amplified with ratio less than . and if reported, average HER copy number <  signals/cells OR\r\n*** ISH non-amplified with ratio less than . and if reported, average HER copy number <  signals/cells (without IHC)
Primary tumors and/or metastatic lesions must demonstrate HER-neu overexpression by immunohistochemistry (IHC +) or amplification by in situ hybridization based on the following:\r\n* Single-probe average HER copy number >= . signals/cell\r\n* Dual-probe HER/chromosome enumeration probe  (CEP) ratio >= . with an average HER copy number >= . signals/cell\r\n* Dual-probe HER/CEP ratio >= . with an average HER copy number < . signals/cell\r\n* Dual-probe HER/CEP ratio < . with an average HER copy number > . signals/cell\r\nPatients may be estrogen and/or progesterone positive (>= %) or negative (< %); hormone receptor status will be a stratification factor
Evidence of HER positive metastatic breast cancer in either a primary or metastatic site, if + by an immunohistochemistry (IHC) method defined as uniform membrane staining for HER in % or more of tumor cells or demonstrate HER gene amplification by an in situ hybridization (ISH) method (single probe, average HER copy number >= . signals/cell; dual probe HER/chromosome enumeration probe [CEP]  ratio >= . with an average HER copy number >= . signals/cell; dual probe HER/CEP  ratio >= . with an average HER copy number < . signals/cell; and HER/CEP ratio < . with an average HER copy number >= . signals/cell) or amplified by fluorescence in situ hybridization (FISH) > .; high average copy number of HER (>= . signals/cell) is considered positive regardless of the HER/CEP ratio
Participants must NOT have HER positive status based on American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines defined as:\r\n* Immunohistochemistry (IHC) + based on circumferential membrane staining that is complete, intense -AND/OR  \r\n* Fluorescence in situ hybridization (FISH) positive based on one of the three following criteria:\r\n** Single-probe average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/CEP ratio < . with an average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/CEP ratio >= .
Recovery to baseline or =< grade  Common Terminology Criteria for Adverse Events version . (CTCAE v..) from toxicities related to any prior treatments, unless adverse event(s) (AE[s]) are clinically nonsignificant and/or stable on supportive therapy:\r\n* Cohort : HER-positive, defined by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP)  guidelines: \r\n** IHC + based on circumferential membrane staining that is complete, intense OR\r\n** FISH positive based on one of the three following criteria:\r\n*** Single-probe average HER copy number >= . signals/cell; OR\r\n*** Dual-probe HER/chromosome  centromere (CEP) ratio < . with an average HER copy number >= . signals/cell; OR\r\n*** Dual-probe HER/CEP ratio >= .\r\n* Cohort : Hormone receptor positive (estrogen receptor [ER]-positive and/or progesterone receptor [PR]-positive, defined as >= % staining by immunohistochemistry) and HER-negative\r\n* Cohort : Triple negative (ER-negative, PR-negative, HER-negative)
Pathologically confirmed HER-positive MBC by local laboratory with the following requirements: HER overexpressed or amplified (immunohistochemistry of + or HER gene amplification by in situ hybridization with a ratio of HER-gene signals to centromere  signals ? . or average HER copy number ? . signals/cells)
Single-probe average HER copy number < . signals/cell
Dual-probe HER/CEP ratio <  with an average HER copy number < . signals/cell.
Metastatic triple negative breast cancer (TNBC), as defined by: \r\n* Estrogen receptor (ER) and progesterone receptor (PR) negative as defined as ER < % and PR < % by immunohistochemistry according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for hormone receptor testing\r\n* Human epidermal growth factor receptor  (HER) non-amplified per ASCO/CAP guidelines, defined as: \r\n** immunohistochemistry (IHC) score /+\r\n** IHC + and in situ hybridization (ISH) non-amplified with a ratio of HER to CEP < ., and if reported, average HER gene copy number <  signals/cells; or\r\n** ISH non-amplified with a ratio of HER to chromosome enumeration probe  (CEP) < ., and if reported, average HER gene copy number <  signals/cells
Has confirmed HR+ and HER negative breast cancer with known metastatic disease. HR defined as positive if expression greater than % by immunohistochemistry (IHC). HER negative or non-amplified is determined by the current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows: HER testing by IHC as  or +. If HER is +, ISH (in situ hybridization) must be performed. HER is positive if: i. IHC + based on circumferential membrane staining that is a. complete, intense ii. ISH positive based on: a. single-probe average HER copy number >= . signals/cell. b. Dual-probe HER/CEP ratio >= . with an average HER copy number >= . signals/cell c. Dual-probe HER/CEP ratio >= . with an average HER copy number < . signals/cell d. Dual-probe HER/CEP ratio < . with an average HER copy number >= . signals/cell.
COHORT : HORMONE RECEPTOR POSITIVE BREAST CANCER: Patients must have histologically confirmed persistent or recurrent invasive metastatic hormone receptor positive, HER normal breast cancer for which standard curative measures do not exist or are no longer effective; hormone receptor positive is defined as estrogen receptor (ER) positive >= % by immunohistochemistry (IHC) and/or progesterone receptor (PR) positive >= % by IHC; HER will be considered negative per American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines (HER test result as negative if a single test (or both tests) performed show: ) IHC + as defined by incomplete membrane staining that is faint/barely perceptible and within >% of the invasive tumor cells; ) IHC  as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< % of the invasive tumor cells; or ) in situ hybridization (ISH) negative based on: a) single-probe average HER copy number < . signals/cell or b) dual-probe HER/CEP ratio < . with an average HER copy number < . signals/cell)and HER testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity
COHORT : TRIPLE NEGATIVE BREAST CANCER: Patients must have histologically or cytologically confirmed persistent or recurrent invasive, metastatic triple negative breast cancer (TNBC) for which standard curative measures do not exist or are no longer effective; TNBC, defined as ER negative (ER < %), PR negative (PR < %); HER will be considered negative per ASCO-CAP guidelines (HER test result as negative if a single test (or both tests) performed show: ) IHC + as defined by incomplete membrane staining that is faint/barely perceptible and within > % of the invasive tumor cells; ) IHC  as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< % of the invasive tumor cells; or ) ISH negative based on: a) single-probe average HER copy number < . signals/cell or b) dual-probe HER/CEP ratio < . with an average HER copy number < . signals/cell) and HER testing must have been performed in a laboratory accredited by the College of American Pathologists (CAP) or another accrediting entity
Hormone receptor positive (defined as estrogen receptor [ER] and/or progesterone receptor [PR] positive), HER negative breast cancer that is clinically staged II-III with no known metastatic disease. ER and/or PR defined as positive if expression > % by immunohistochemistry (IHC). HER negative or non-amplified as determined by the current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows: HER testing by immunohistochemistry (IHC) as  or +. If HER is +, ISH (in situ hybridization) must be performed. HER is positive if: IHC + based on circumferential membrane staining that is complete, intense ISH positive based on: ) Single-probe average HER copy number >= . signals/cell, ) Dual-probe HER/CEP ratio >= .; c,e with an average HER copy number >= . signals/cell, ) Dual-probe HER/CEP ratio >= .; c,e with an average HER copy number < . signals/cell, ) Dual-probe HER/CEP ratio < .; c,e with an average HER copy number >= . signals/cell
HER status confirmed positive by means of immunohistochemistry (IHC) or in situ hybridization (ISH) according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)  guidelines; it is considered positive if scored as + by an IHC method defined as uniform membrane staining for HER in % or more of tumor cells or demonstrate HER gene amplification by an ISH method (single probe, average HER copy number >= . signals/cell; dual probe HER/CEP ratio >= . with an average HER copy number >= . signals/cell; dual probe HER/chromosome enumeration probe (CEP) ratio >= . with an average HER copy number < . signals/cell; HER/CEP ratio < . with an average HER copy number >= . signals/cell)
Cohort : Phase b: subject must have HER + (regardless of hormonal receptor status) primary metastatic or locally advanced breast cancer (IBC or Non-IBC); HER positive status is defined as strongly positive (+) staining score by immunohistochemistry (IHC), or gene amplification using fluorescence in situ hybridization (FISH), if performed; if IHC is equivocal (+), assays using FISH require gene amplification based on recent American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guideline: dual-probe HER/CEP ratio is >= . and/or an average HER copy number >= . signals/cell; IBC is determined by using international consensus criteria: onset: rapid onset of breast erythema, edema and/or peau dorange, and/or warm breast, with/without an underlying breast mass; duration: history of such findings no more than  months; extent erythema occupying at least / of whole breast; pathology: pathologic confirmation of invasive carcinoma
Breast cancer determined to be HER-negative per current American Society of Clinical Oncologists/College of American Pathologists (ASCO/CAP) HER guidelines (if immunohistochemistry [IHC] was performed, IHC  or +; if fluorescence in situ hybridization [FISH] or other in situ hybridization test, dual probe HER/CEP ratio < . with an average HER copy number < . signals/cell)
Estrogen receptor (ER) and progesterone receptor (PR) expression both < % by immunohistochemistry (IHC) and human epidermal growth factor receptor  (HER) negative or non-amplified as determined by the current American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) criteria which are as follows: HER testing by IHC as  or +; if HER is +, ISH (in situ hybridization) must be performed; HER is positive for gene amplification if: - IHC + based on circumferential membrane staining that is complete, intense - ISH positive based on: \r\n* Single-probe average HER copy number >= . signals/cell\r\n* Dual-probe HER/chromosome enumeration probe (CEP) ratio >= .; with an average HER copy number >= . signals/cell\r\n* Dual-probe HER/CEP ratio >= .; with an average HER copy number < . signals/cell\r\n* Dual-probe HER/CEP ratio < .; with an average HER copy number >= . signals/cell
Hormone receptor positive and HER negative breast cancer; patients with HER/neu positive tumors irrespective of their hormone receptor status will be excluded; at least % of tumor cell nuclei should be immunoreactive for hormone receptors (ER and/or PR) to be deemed eligible for the study; Her/neu negative is defined as:\r\n* Immunohistochemistry (IHC) score of  (no staining is observed or membrane staining that is incomplete and is faint/barely perceptible and within =< % of tumor cells) OR\r\n* IHC score of  (incomplete membrane staining that is faint/barely perceptible and within < % of tumor cells) OR\r\n* Fluorescence in situ hybridization (FISH) HER/chromosome enumeration probe  (CEP) ratio of < . or average HER gene copy number of <  signals/nucleus for test systems without an internal control probe\r\n* Equivocal results for HER/neu (defined as: IHC + or FISH HER/CEP ratio of .-. or average HER gene copy number - HER signals/nucleus for test systems without an internal control probe) should prompt reflex test (same specimen using an alternative method) or order a new test (new specimen if available, using IHC or FISH)
The tumor specimen obtained at the time of diagnosis of locally recurrent or metastatic disease must have been demonstrated to be HER-positive based on central testing; HER-positive is defined as HER/chromosome enumeration probe  (CEP) ratio >= . or >=  average HER copy number per cell by in situ hybridization (ISH) or IHC + by current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines; sites must send biopsy specimens for central testing which have been determined to be HER-positive or HER-equivocal on local testing
HER negative in the primary or metastatic tumor tissue defined as:\r\n* Immunohistochemistry (IHC) grade  as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< % of the invasive tumor cell; OR\r\n* IHC + as defined by incomplete membrane staining that is faint/barely perceptible and within > % of the invasive tumor cell; OR\r\n* IHC grade + staining intensity by means of IHC analysis with no gene amplification below; OR\r\n* No gene amplification on in situ hybridization (ISH) based on:\r\n** Single-probe average HER copy number < . signals/cell OR\r\n** Dual-probe HER/CEP ratio < . with an average HER copy number < . signals/cell
The tumor must have been determined to be HER-postive as follows:\r\n* Immunohistochemistry (IHC) + or\r\n* In situ hybridization (ISH)-positive (defined by ratio of HER to circulating endothelial progenitors [CEP] >= . or HER gene copy number >=  per nucleus)
Patients must have a histologically confirmed diagnosis of node positive (- nodes) invasive breast carcinoma with positive estrogen and/or progesterone receptor status, and negative HER- status; estrogen and progesterone receptor positivity must be assessed according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as either estrogen receptor (ER) or progesterone receptor (PR) >= % positive nuclear staining; HER- test result negativity must be assessed as per ASCO/CAP  guidelines using immunohistochemistry (IHC), in situ hybridization (ISH) or both; HER- is negative if a single test (or all tests) performed in a tumor specimen show: a) IHC negative ( or +) or b) ISH negative using single probe or dual probe (average HER- copy number < . signals per cell by single probe or HER-/CEP ration < . with an average copy number < . signals per cell by dual probe); if HER- IHC is +, evaluation for gene amplification (ISH) must be performed and the ISH must be negative; ISH is not required if IHC is  or +; HER- equivocal is not eligible
HER- positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP)  guidelines, confirmed by central testing confirmed by central testing (NeoGenomics Laboratories): \r\n* Immunohistochemistry (IHC) + based on circumferential membrane staining that is complete, intense AND/OR\r\n* FISH positive based on one of the three following criteria:\r\n** Single-probe average HER copy number >= . signals/cell OR\r\n** Dual-probe HER/chromosome  centromere (CEP) ratio < . with an average HER copy number >= . signals/cell OR\r\n** Dual-probe HER/CEP ratio >= .\r\n* NOTE: HER- status must be confirmed to be positive by central review prior to patient starting protocol therapy; patients previously having had HER testing at NeoGenomics Laboratories, Inc. (formerly Clarient Laboratories) do not need to undergo retesting for central confirmation of HER status; ductal carcinoma in situ (DCIS) components should not be counted in the determination of HER status
Documented HER-negative tumor based on local testing on most recent tumor biopsy (immunohistochemistry score /+ or negative by in situ hybridization HER/CP ratio <  or for single probe assessment HER copy number < )
Invasive breast cancer must be HER negative; HER negative is defined as a single test or both tests used to determine HER status (in situ hybridization [ISH] and immunohistochemistry [IHC]) show:\r\n* IHC + as defined by incomplete membrane staining that is faint/barely perceptible and within > % of the invasive tumor cells\r\n* IHC  as defined by no staining observed or membrane staining that is incomplete and is faint/barely perceptible and within =< % of the invasive tumor cells\r\n* ISH single-probe average HER copy number < . signals/cell\r\n* ISH dual-probe HER/chromosome  centromere probe (CEP) ratio < . with an average HER copy number < . signals/cell
HER negative, defined as -+ by immunohistochemistry or fluorescence in situ hybridization (FISH)-negative (HER copy number <  and HER/chromosome enumeration probe [CEP] ratio < .); central confirmation is not required
HER positive breast cancer (+ by immunohistochemistry or Her gene amplification by in situ hybridization with a ratio of HER gene signals to centromere  signals > . or average HER copy number > . signals/cell)
Participants must have invasive primary tumor or metastatic tissue confirmation of HER-positive status, defined as presence of one or more of the following criteria: HER-positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP)  guidelines\r\n* Immunohistochemistry (IHC) + based on circumferential membrane staining that is complete, intense OR\r\n* Fluorescent in situ hybridization (FISH) positive based on one of the three following criteria:\r\n** Single-probe average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/chromosome  centromere (CEP) ratio < . with an average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/CEP ratio >= .\r\n* Note: participants with a negative or equivocal overall result (FISH ratio of < . or =< . HER gene copies per nucleus) and IHC staining scores of , +, + are not eligible for enrollment
HER- positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP)  guidelines, confirmed by central testing (Clarient laboratories [labs]):\r\n* IHC + based on circumferential membrane staining that is complete, intense OR\r\n* Fluorescence in situ hybridization (FISH) positive based on one of the three following criteria:\r\n** Single-probe average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/chromosome  centromere (CEP) ratio < . with an average HER copy number >= . signals/cell; OR\r\n** Dual-probe HER/CEP ratio >= .\r\n* NOTE: ductal carcinoma in situ (DCIS) components should not be counted in the determination of HER status\r\n* NOTE: HER- status must be confirmed to be positive by central review prior to patient starting protocol therapy; patients previously having had HER testing at Clarient Laboratories do not need to undergo retesting for central confirmation of HER status; a pathology report documenting testing at Clarient should be provided at time of patient registration
HER-positive breast cancer, defined as by American Society of Clinical Oncology College of American Pathologists (ASCO CAP)  guidelines\r\n* Immunohistochemistry (IHC) + based on circumferential membrane staining that is complete, intense AND/OR\r\n* Fluorescence in situ hybridization (FISH) positive based on one of the following three criteria: \r\n** Single-probe average HER copy number >= . signals/cell OR\r\n** Dual-probe HER/CEP ratio < . with an average HER copy number >= .signals/cell; OR \r\n** Dual-probe HER/CEP ratio >= .
Histologically proven diagnosis HER-positive breast cancer; Her-positive is defined as follows:\r\n* Validated immunohistochemistry (IHC) assay score of + (defined as uniform, intense staining of > % of invasive tumor cells)\r\n* Average HER gene copy number of > \r\n* Gene amplified (HER:DZ ratio > .)
Patients must have either:\r\n* Estrogen receptor (ER) negative/progesterone receptor (PR) negative (< % by immunohistochemistry [IHC] staining) and HER- negative breast cancer OR\r\n* ER negative/PR negative (< % by IHC staining) and HER- positive tumors\r\n* HER status will be determined per the  American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines:\r\n** HER is considered positive if a) there is IHC + staining or b) positive using either single probe in situ hybridization (ISH) or dual probe ISH\r\n** HER is considered negative if a) there is IHC  or + staining or b) ISH negative using either single probe ISH or dual probe ISH\r\n* For patients enrolling after neoadjuvant therapy, the ER, PR, and HER markers are based on assessment prior to initiating neoadjuvant treatment
Clinical stage IV ER, PR, HER negative invasive mammary carcinoma, previously documented by histological analysis and that meets the following criteria:\r\n* HER negativity is defined as any of the following by local laboratory assessment: in-situ hybridization (ISH) non-amplified (ratio of HER to CEP < . or single probe average HER gene copy number <  signals/cell), or IHC  or IHC + (if more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the protocol chair to establish eligibility of the patient)\r\n* ER and PR negativity are defined as =< % of cells expressing hormonal receptors via IHC analysis