ER(+) and/or PR(+) by IHC (? 10% staining or Allred score ? 4)
Eligible tumor-node-metastasis (TNM) stages include:\r\n* Estrogen receptor (ER) and progesterone receptor (PR) negative (defined as < 1% staining for ER and PR by IHC): T2 or T3 N0, T0-3N1-3\r\n** Note: Patients with T1, N1mi disease are NOT eligible\r\n* ER and/or PR positive (defined as >= 1% staining for ER and/or PR on IHC): T0-3N1-3 or T3N0\r\n** Note: Patients with T0N0, T1N0 and T1, N1mi disease are NOT eligible\r\n* ER and/or PR positive (defined as >= 1% staining for ER and/or PR on IHC): T0-3N1-3 or T3N0\r\n** Note: Patients with T0N0, T1N0, T2N0 and T1-2, N1mi disease are NOT eligible\r\n* The eligibility of neo-adjuvant subjects can be assessed on the basis of clinical (c)TNM or pathologic (yp)TNM; the same eligible TNM combinations apply; patients may be eligible if they meet eligibility requirements at either time point, as long as they do not have T4 disease prior to therapy
Invasive breast cancer is estrogen receptor (ER) positive with an Allred score of 6, 7 or 8 by local institution standard protocol; if an Allred score is not reported on the diagnostic pathology report, ER positivity in > 66% cells is eligible; if ER positivity is =< 66%, the staining intensity (weak, intermediate, strong) is needed to calculate the Allred score to determine eligibility
Tumor ER Allred score between 0-5 or HER2 positive by IHC (3+) or amplified by FISH > 2.0
Patients must have histologically confirmed estrogen receptor (ER)-, progesterone receptor (PR)- and HER2-negative (triple-negative, TNBC) or ER, PR, and HER2 equivocal status and must not have received and not be planning to receive adjuvant anti-HER2 or endocrine therapies after completion of neoadjuvant chemotherapy; patients who are HER2 positive by American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines are ineligible; HER2 negative and HER2 equivocal cases as per ASCO CAP guidelines that do not receive HER2-targeted therapy are eligible; patients with weekly ER or PR positive disease, defined as ER and/or PR < 5% by immunohistochemistry, are eligible if the treating physician considers the patient not eligible for adjuvant endocrine therapy; residual disease must be >= 1 cm in greatest dimension, and/or have positive lymph nodes (ypN+) observed on pathologic exam\r\n* NOTE: Immunohistochemistry (IHC)-positive isolated tumor cells in the lymph node (N0 [i+]) are not considered node-positive and these patients also must have >= 1 cm residual invasive cancer in the breast in order to be eligible
Patients with multicentric and/or multifocal and/or bilateral early invasive breast cancer are eligible if all histopathologically examined tumors meet pathologic criteria for ER+ and/or PR+ and HER2-.
SAFETY RUN-IN: Patients with hormone-receptor positive breast cancer (ER and/or PR > 5%), and with HER-2 positive breast cancer (by means of immunohistochemistry with 3+ indicating positive status or fluorescence in situ hybridization with amplification ratio >= 2.0 indicating positive status)
RANDOMIZED PHASE II CLINICAL TRIAL: Patients with hormone-receptor positive breast cancer (ER and/or PR > 5%), and with HER-2 positive breast cancer (by means of immunohistochemistry with 3+ indicating positive status or fluorescence in situ hybridization with amplification ratio >= 2.0 indicating positive status)
Evidence of hormone sensitive, ER rich primary tumor defined by an Allred score of >= 6
Local testing on the diagnostic core must have determined the tumor to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP guidelines. (If local testing has determined a tumor to be HER2 equivocal or to have a borderline ER/PgR status (% IHC staining < 10% for both) and other eligibility criteria are met, material may be submitted for central testing to determine eligibility.)
Central testing for ER, PgR, and HER2 will be performed, and the tumor must be determined to be ER-negative, PgR-negative, and HER2-negative by current ASCO/CAP Guidelines Recommendations. Material from either the diagnostic core biopsy or the research biopsy can be used for central testing depending on local preferences and standards.
Patients with synchronous bilateral or multicentric HER2-negative breast cancer are eligible as long as the highest risk tumor is ER-negative and PgR-negative and meets stage eligibility criteria. All of the other invasive tumors must also be HER2-negative by ASCO/CAP Guidelines based on local testing. Central testing to confirm TNBC status is only required for the highest risk tumor.
Histologically confirmed metastatic ER positive (+) and/or PR+ and HER2 negative (-) breast cancer who are candidates for palbociclib in combination with either letrozole or fulvestrant per treating physician
Part E) ER-positive and/or PR-positive/HER2- disease and received no more than 1 prior non-hormonally-directed or cytotoxic therapy in the MBC setting.
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed; in addition, ER and/or progesterone receptor (PR) positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED BY WASH U GPS LABORATORY): To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with fulvestrant is not allowed; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen if biopsy was done unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
INCLUSION CRITERIA FOR REGISTRATION (HER2 MUTATION IDENTIFIED AT AN OUTSIDE CLIA CERTIFIED LOCATION): To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease progression on fulvestrant is required; in addition, ER and/or PR positivity by institutional standard is required on pathology from the most recent tumor specimen unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may yield false negative ER and/or PR result, in which case the pathology from an earlier time point could be used and a discussion with the study chair is required
Newly diagnosed ER-positive, HER2-negative breast cancer. ER-positive is defined as ? 1% immunohistochemical (IHC) staining of any intensity. HER2 test result is negative if a single test (or both tests) performed show:
Known HER2-, ER-positive, or PR-positive breast cancer by local laboratory assessment
Histologic confirmation of invasive breast cancer with any measures of ER, PR and HER2neu
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™)
Have a diagnosis of ER+ breast cancer (defined as ER > 1% by IHC)
Women diagnosed with pathologically confirmed HER2-overexpressing breast cancer, that is locally recurrent, unresectable or metastatic (negative or positive for ER/PR, and positive for HER2)
Histologic confirmation of ER+ breast cancer
Patients must have histologically or cytologically confirmed ER and/or PR positive, HER-2/neu negative metastatic breast cancer; they can be enrolled in any line of therapy without investigational agents and should have stable disease or a partial response (which can be determined clinically) on current systemic treatment; patients must also have pathologic OR radiographic evidence of bone metastases and >= 5 CTCs; (Note: the pathology report that is used by the physician to determine diagnosis, will be used to determine patient eligibility; ER and PR status should be available at the time of registration)
Known ER, PgR and HER2 statuses.
Patients must have histologically or cytologically confirmed invasive breast cancer that is estrogen receptor positive (ER+) (> 1% staining) with radiographical or clinical evidence of metastatic disease \r\n* Measurable and/or non-measurable disease
History of ER positive (+) (>= 10% of cells positive on hematoxylin and eosin stain [H&E]), HER2 negative (?) breast cancer disease, either as a\r\n* History of primary, operable ER+/HER2? invasive breast cancer OR\r\n* History of de novo metastatic breast cancer that is ER+/HER2?\r\n** Note: HER2? (negative) disease defined as one of the following:\r\n*** HER2 immunohistochemistry (IHC) expression of 0, 1+ and in-situ hybridization (ISH) non-amplified\r\n*** HER2 IHC expression of 0, 1+ and ISH not done\r\n*** HER2 IHC expression of 2+ and ISH non-amplified\r\n*** IHC not done and ISH non-amplified; Note: supporting documentation such as a pathology report from their primary diagnosis that indicates ER+/Her2- invasive breast cancer or a biopsy report of de novo metastatic breast cancer that is ER+/HER2? should be submitted through the RAVE database
Central ER determination on pre-registration biopsy completed
The invasive cancer must be estrogen receptor alpha (ER)-positive, defined as having ER staining by IHC in >= 10% of malignant tumor cells
Patients with histologically confirmed diagnosis of locally-advanced, inoperable, metastatic and/or treatment-refractory triple negative breast cancer (TNBC). *Treatment refractory disease is defined as the persistence of tumor lesions following at least one intervention that may include chemotherapy, radiation and/or surgery, or any combination thereof. *Patients must have both ER and PR staining < 5% and be HER2-negative. Patients with ER or PR staining of 5-10%, but who have historically been treated as TNBC may also be enrolled. *Patients must not have disease that, in the opinion of the investigator, is considered amenable to potentially curative treatment.
ER+ status
Disease must be ER+ and HER2-
Women with previously untreated, unilateral stage II-III breast cancer, ER/PgR/HER2 negative (ER =< 5%, PgR =< 5%, HER2 0-1+ by immunohistochemistry [IHC] or fluorescence in situ hybridization [FISH] =< 2.0); if clinically negative lymph nodes, tumor size should be minimum 1.0 cm and identifiable under office-based ultrasound guidance
Estrogen receptor (ER) less than Allred score of 3 or less than 1% positive staining cells in the invasive component of the tumor
Must have ER positive disease with ER/PR report available.
Addition inclusion for Part A (A6 & A7) Has a histological confirmation of either metastatic breast (ER+ve for Arm A6, 50% ER +ve and 50% HER2+ve metastatic breast cancer patients for Arm A7) or castrate-resistant prostate cancer
ER+ve tumours defined as ?1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ?3
ER with <1% of cells positive on IHC or an IHC score (Allred) of ?2
PR with <1% of tumour cells positive on IHC or an Allred score of ?2
Part E3 dose expansion: must have advanced or metastatic ER-negative, PR-negative, and HER-2 non-overexpressing breast cancer
The tumor specimen obtained at the time of diagnosis used for HER2 testing must also have central testing for estrogen receptor (ER) and progesterone receptor (PgR) according to current ASCO/CAP guideline; patients with < 1% ER and PgR staining by IHC will be classified as negative
The tumor specimen obtained at the time of diagnosis used for HER2 and ER/and PgR testing must also have central testing for PD-L1 status; patients who are negative or positive are eligible
Patients who will participate in the endocrine therapy cohort must have invasive breast cancer that is estrogen receptor (ER)+ (? 1% ER staining by immunohistochemistry [IHC])
Head and neck cancer OR metastatic breast for which standard therapy is not curative\r\n* NOTE: Patients with ER/PR positive, HER2 negative breast cancer must have progressed through at least one prior cytotoxic regimen for advanced disease and no longer be candidates for standard endocrine therapy; patients with HER2 positive breast cancer irrespective of ER/PR status must have received or no longer be candidates for standard HER2 directed therapy (i.e., trastuzumab, pertuzumab, trastuzumab emtansine, and lapatinib); patients with ER/PR/HER2 negative breast cancer must have progressed through at least one prior cytotoxic regimen for advanced disease; ER/PR and HER2 status are defined by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
Patients must have known ER, PR, and HER2 status defined as either:\r\n* Triple-negative breast cancer, defined as: ER and PR < 10% by immunohistochemistry, and HER2-negative (defined as IHC 0 or 1+, or FISH ratio < 2.0)\r\n* Or, inflammatory breast cancer with any ER, PR, HER2 status
Estrogen (ER) and/or progesterone (PR)-positive at primary diagnosis and at metastatic diagnosis where tissue is available (defined as > or = 1% of staining nuclei)
National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic breast cancer “…biopsy documentation of first recurrence, if possible, and determination of hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status….”; therefore, histologic and/or cytologic confirmation of metastatic disease is encouraged whenever feasible, but not required; in some circumstances, histologic confirmation may not be feasible (eg, bone metastases not amenable to biopsy and elevated cancer antigen [CA]27-29 tumor marker); for patients who have had histologic confirmation of metastatic disease, it is required that the biopsy confirm that the metastatic tumor is ER and/or PR positive, and HER2/neu negative; for patients in whom biopsy confirmation of metastatic disease is not feasible, it is required that the primary tumor be ER and/or PR-positive and HER2/neu negative
Centrally confirmed hormone-receptor-positive (?1% ER and/or PR positive stained cells) and HER2-normal (IHC score 0-1 or FISH negative (in-situ hybridization (ISH) ratio) <2.0 status) assessed preferably on tissue from post-neoadjuvant residual invasive disease or core biopsy of the breast, or if no other tissue is available the residual tumor of the lymphnode can be assessed. In case of bilateral breast cancer hormonreceptor positivity and HER2-normal status has to be centrally confirmed for both sides.
Histological or cytological confirmation of ER+ BC as assessed by a local laboratory using slides, paraffin blocks, or paraffin sample or by medical history: ER+ (confirmed as ER expression more than or equal to 1% positive tumor nuclei)
Willing to provide tissue samples for ER and retinoblastoma (RB) staining
Primary tumor was negative for ER, PR (cut-off for positivity is >10% positive tumor cells with nuclear staining) and negative for Her2-neu (0 or 1+ on immunohistochemistry and/or normal gene copy number by in-situ hybridization); Central review is not required.
ER-positive tumor, HER2-negative breast cancer
Women who agree to undergo a standard of care core biopsy of recurrent or metastatic breast cancer to confirm the ER+ (>= 10% nuclear staining) and HER2 negative status
Documentation of ER positive (? 1% positive stained cells by local standards) based on the most recent tumor biopsy, unless bone-only disease
ER/PgR negativity to follow local guidelines
Pre and postmenopausal women or men with stage IV estrogen receptor positive (ER+) breast cancer histological or cytological confirmation\r\n* ER-positive tumors\r\n** Progressed after at least one line of hormonal therapy\r\n** Any number of prior chemotherapy in the metastatic setting\r\n** Any number of prior hormonal therapies\r\n* ER-negative tumors\r\n** PD-L1 low, high or unknown\r\n** Progression after prior PD-1 or PD-L1 inhibitors allowed\r\n** HER2 positive or negative
Confirmed diagnosis of ER positive breast cancer
ER positive breast cancer. Central testing (required for all subjects) must demonstrate that the tumor is ER+ with low expression (H-score [1-159]).
Confirmed diagnosis of ER positive breast cancer
Concomitant active malignancy other than ER+ breast cancer.
Invasive breast cancer must be estrogen receptor-positive (ER+) in > 66 % of the cells or ER allred score 6-8; if ER is positive in >= 66%, the staining intensity (weak, intermediate, strong) is needed to calculate the allred score to determine eligibility; in institutions where ER expression is classified only by < 1%, 1-10%, and > 10% cut-offs, > 10% expression is required for inclusion
Estrogen receptor (ER)+ (ER- DCIS meeting other eligibility criteria are eligible)
ER/PR determination assays performed by IHC methods according to the local institution standard protocol
Patients with both ER positive and ER negative breast cancer are eligible for this study; patients with human epidermal growth factor receptor 2 (HER2) positive disease will be excluded from participation in this study
Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer, clinical stage I-III at diagnosis (AJCC 6th edition) based on initial evaluation by physical examination and/or breast imaging prior to study registration. NOTE: ER, PR and HER2 status will be confirmed by central pathology review prior to randomization. ER and PR will be considered negative if ? 1% of cells stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of < 2.0 or < 6 copies per cell.
Patient must have histologically confirmed (by routine hematoxylin and eosin [H&E] staining) estrogen receptor (ER)-negative invasive adenocarcinoma of the breast
Participants must have histologically or cytologically confirmed inoperable locally advanced or metastatic ER+ breast cancer; to fulfill the requirement for ER+ disease, a breast cancer must express, by immunohistochemistry (IHC), ER in >= 10% of cells, on the most recent biopsy; central confirmation of ER status is not required
ER/progesterone receptor (PR) determination is required; ER- and PR-assays should be performed by immunohistochemical methods according to the local institution standard protocol
Confirmed pathologic diagnosis of triple negative breast cancer (TNBC), OR estrogen receptor (ER) positive with immunohistochemistry (IHC) staining of 1-9%, irrespective of progesterone receptor (PR) staining, and human epidermal growth factor receptor (HER)2 negative, OR prior diagnosis of ER positive (>= 10%) (HER2 negative) breast cancer that is demonstrated to be ER < 10% on the patient’s most recent biopsy\r\n* NOTE: patients with a diagnosis of TNBC who are found to have ER or PR positive staining on any additional biopsies since diagnosis remain eligible
Tumors are positive for ER, PgR, or both
Patients with the following types of histologically documented solid tumors:\r\n* Estrogen receptor (ER) positive (+)/progesterone receptor (PR)+, ER+/PR negative (-), or ER-/PR+ breast cancer\r\n* Gynecologic tumors (endometrial, ovarian, uterine, fallopian tube, peritoneal, etc.)\r\n* Desmoid tumors\r\n* Tumors that are ER+ or PR+ by immunohistochemistry (including low-level expression) such as non-small cell lung, colorectal, and prostate
Patients enrolled based on tumor ER/PR status must have ER/PR status confirmed by the Laboratory of Pathology, National Institutes of Health (NIH); ER/PR status will be determined on a metastatic site, if possible; otherwise, the original site or available tissue will be acceptable
Patients must have tumors that demonstrate ER/PR+ (positivity by immunohistochemistry [IHC] staining >= 1%)
Invasive carcinoma should be ER alpha receptor positive
The invasive cancer must be estrogen receptor alpha (ER)-positive, with ER staining present in greater than 50% of invasive cancer cells by immunohistochemistry (IHC)
Estrogen receptor (ER)/progesterone receptor (PR) status (ER or PR defined as positive if >= 1%; ER/PR is defined as negative if 0%): \r\n* PHASE I: Patients may have ER/PR(+) or negative (-) breast cancer; ER(+) patients must have progression of disease following 1 prior line of endocrine therapy; progression of disease within 6 months of adjuvant endocrine therapy will be considered 1 line of prior endocrine therapy\r\n* PHASE II: Patients must have ER/PR(-) breast cancer
Tumors must express ER positivity by immunohistochemistry (ER expression >10% by immunohistochemistry).
Diagnosis of TNBC: < 1% cells positive for ER/progesterone receptor, and HER2 IHC score of 0 or 1, or FISH HER2+ ratio of less than 1.8; patients with low ER IHC (> 1% but < 10% cells positive), but negative by genomic assay are eligible
Patients who are ER+ and/or PR+ and who are receiving anti-hormone therapy for at least three months may continue to receive such therapy during the course of the trial
Patients must have histologically confirmed HR+ breast cancer; HR+ is defined as either ERa or PgR being positive, or both; positivity is defined for the purposes of this protocol as:\r\n* Allred >= 4\r\n* IHC 1+, 2+, 3+\r\n* Percentage of positive staining > 10%\r\n** When there is discrepancy between the metastatic and primary tumor results with respect to ERA or PgR status, the metastatic results will hold precedence; when there is discrepancy between the local and University of Wisconsin (UW) pathology results with respect to ER? or PgR status, the UW results will hold precedence
ER and/or PR-positive disease. Tumors must be HER-2/neu negative or equivocal.
Patients must be ER >= 1% and HER2 negative on local testing
Biopsy proven ER/PR positive tumor
Screen-detected, estrogen receptor (ER) positive DCIS of the breast proven on core needle biopsy, defined as 10% ER positive cells; the presence of a focus suspicious for microinvasion will be allowed; the size of the DCIS in the core biopsy sample must total 5 mm (multiple cores can be summed) and must be estimated on the deepest step section (if step sections are taken)
The study will be conducted in women who have been diagnosed with a first primary invasive estrogen receptor (ER) positive (+) breast cancer (stages I-IIIa) who are within the first 3 years post-treatment
The patient was proven to have TNBC, defined from standard pathologic assays as negative for ER and PR (< 10% tumor staining) and negative for HER2 (immunohistochemistry [IHC] score < 3, gene copy number not amplified)
HR (ER and/or PgR) positive disease based on local testing: ASCO/CAP guidelines should be utilized for assessing HR status.
Confirmed histologic diagnosis of operable HER2 overexpressing (ER < 10%, progesterone receptor [PR] < 10%, and HER2 2+ or fluorescence in situ hybridization [FISH] amplified) OR triple negative (ER < 10%, PR < 10%, and HER2 0/1+ or 2+/FISH not amplified) OR ER positive invasive ductal breast cancer, including Memorial Sloan Kettering Cancer Center (MSKCC) pathology confirmation
Histologically confirmed estrogen receptor positive (ER+) breast cancer either from a metastatic biopsy or from a primary breast tumor with imaging evidence of metastatic disease. The pathology report and either (1) tumor tissue (blocks or unstained slides) or (2) a photomicrograph of the ER immunohistochemistry (IHC) slide from at least one site of metastatic disease and/or from primary breast cancer must be available for review and analysis.
No or equivocal ER, PR or HER2 testing performed prior to surgery if biopsy indicates invasive cancer
Patient must have any one of the following types of breast cancer (primary or metastatic): estrogen receptor (ER)+/PgR+/human epidermal growth factor receptor 2 negative (HER2-) or ER+/PgR-/HER2-\r\n* ER+ is defined as Allred score of at least 4 and greater\r\n* PgR+ is defined as Allred score of at least 4 and greater\r\n* IHC is the primary assay methodology for HER2; HER2- refers to HER2 of 0, 1+ by IHC or negative by fluorescence in situ hybridization (FISH)
History of ER+ pathology (ER+ may be confirmed from surgery or biopsy of primary breast cancer or lymph nodes, and/or surgery or biopsy of a metastatic site, metastatic biopsy is not required)
Patients with histologic/immunochemical proof of estrogen receptor (ER)+ primary or metastatic malignancy (positive staining in >= 1% of cells by immunohistochemistry)
Patients who are to be treated with clinically approved or experimental regimens where ER has an important role
Breast cancer from ER+ primary that is seen on other imaging tests; tumor ER expression must have been confirmed by immunohistocytochemistry of primary tumor or recurrent disease
PHASE II: Women with a first primary ER+, HER2-, LN-, breast cancer < 3 cm immediately after their initial surgical consultation
Patients must have estrogen receptor (ER) positive, HER2 negative metastatic breast\n             cancer (MBC) with at least one non-irradiated distant site of metastasis.