Tamoxifen Citrate or Z-Endoxifen Hydrochloride in Treating Patients With Locally Advanced or Metastatic, Estrogen Receptor-Positive, HER2-Negative Breast Cancer

Inclusion Criteria:

PRE-REGISTRATION ELIGIBILITY CRITERIA
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

Patient must have been previously treated with an aromatase inhibitor (either letrozole, anastrozole or exemestane) either in the adjuvant or metastatic setting, and have one of the following types of primary or secondary endocrine resistant disease

Primary clinical resistance is defined as one of the following:

Recurrence within the first 2 years of adjuvant endocrine therapy while on aromatase inhibitor therapy
Progression within first 6 months of initiating first-line endocrine therapy (either aromatase inhibitor or fulvestrant containing regimen) for the treatment of metastatic breast cancer

Secondary clinical resistance is defined as one of the following:

Recurrence after year 2 while receiving adjuvant aromatase inhibitor therapy, or within 12 months of completing adjuvant aromatase inhibitor therapy
Progression occurring 6 or more months after initiating the first endocrine therapy for metastatic disease (either fulvestrant or aromatase inhibitor containing regimen)
Patients with a history of measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with non-measurable disease and bone metastases are eligible
No history of tumors involving spinal cord or heart
No current evidence of visceral crisis or lymphangitic spread
No known brain metastases

Women must be postmenopausal

Postmenopausal status is verified by:

Prior bilateral surgical oophorectomy, or
Age >= 60 years, or
Age < 60 with no menses for > 1 year with follicle-stimulating hormone (FSH) and estradiol levels within post menopausal range, according to institutional standard

Prior treatment

No more than two prior chemotherapy regimens in the metastatic setting
Prior treatment with an aromatase inhibitor (either anastrozole, letrozole or exemestane), either in the adjuvant or metastatic setting is required
Unlimited prior endocrine regimens in the metastatic setting, which may have included an everolimus or cyclin dependent kinase (CDK) 4/6 inhibitor (such as palbociclib, abemaciclib or ribociclib) containing regimen
Prior tamoxifen treatment is allowed in the adjuvant setting, but patients must not have experienced relapse within 1 year of stopping tamoxifen
No prior treatment with tamoxifen in the metastatic setting
No prior treatment with endoxifen

Patients who have not fully recovered from acute, reversible effects of prior therapy regardless of interval since last treatment are not eligible to participate in this study

EXCEPTION: neuropathies-if grade 2 neuropathies have been stable for at least 3 months since completion of prior treatment patient is eligible
Not receiving any medications or substances that are strong inhibitors of cytochrome P450 family 2, subfamily D, polypeptide 6 (CYP2D6)
Not receiving any other investigational agents

No uncontrolled intercurrent illness including, but not limited to:

Ongoing or active infection
Symptomatic congestive heart failure
Unstable angina pectoris
Uncontrolled symptomatic cardiac arrhythmia
Uncontrolled hypertension (defined as blood pressure > 160/90)

None of the following co-morbid conditions:

Cataracts of grade 2 or greater as per Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Retinopathy of grade 2 or greater as per CTCAE version 4.0

Note: patients that have cataracts that do not require surgery are eligible
Note: serious adverse events will be reported on CTEP-Adverse Event Reporting System (AERS) using CTCAE version (v)5.0

Deep vein thrombosis/pulmonary embolism (DVT/PE) within the past 6 months

Note: patients that are on anticoagulant therapy for maintenance are eligible as long as the DVT and/or PE occurred > 6 months prior to enrollment, and there is no evidence for active thrombosis (either DVT or PE)
No other active second malignancy other than non-melanoma skin cancers within 3 years of pre-registration; a second malignancy is not considered active if all treatment for that malignancy is completed and the patient has been disease-free for at least 3 years prior to pre-registration
Eastern Cooperative Oncology Group (ECOG) performance status: 0-2
Able to swallow oral formulation of the study agent
Hemoglobin >= 9 g/dL
Platelet count >= 75,000/mm^3
Creatinine =< 1.5 x upper limits of normal (ULN)
Total bilirubin =< 1.5 x upper limits of normal (ULN)
Aspartate aminotransferase (AST) =< 2.5 x upper limits of normal (ULN); for patients with liver metastasis: =< 5 x upper limits of normal (ULN)
REGISTRATION ELIGIBILITY CRITERIA

Patients with either measurable disease as defined by RECIST criteria or bone only disease are eligible; Note: those patients with both non-measurable disease and bone metastases are eligible

Non-measurable bone only disease: Non-measurable bone only disease may include any of the following: blastic bone lesions, lytic bone lesions without a measurable soft-tissue component, or mixed lytic-blastic bone lesions without a measurable soft-tissue component
Lytic bone lesions, with an identifiable soft tissue component, evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), can be considered as measurable lesions if the soft tissue component otherwise meets the definition of measurability previously described
No tumors involving spinal cord or heart
No visceral crisis, lymphangitic spread or known brain metastases: visceral crisis is not the mere presence of visceral metastases, but implies severe organ dysfunction as assessed by symptoms and signs, laboratory studies, and rapid progression of disease
Histologic confirmation, from the A011203 pre-registration biopsy, by institutional/local pathologist of either locally advanced or metastatic breast cancer that is estrogen receptor positive and HER2 negative; those patients with bone only disease with either no tumor or insufficient tumor for ER/progesterone receptor (PR) and HER2 staining after the bone biopsy are still eligible to participate in this study
Estrogen receptor positive disease is defined as > 10% nuclear staining

HER2 negative disease as per 2013 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, one of the following must apply:

0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH)
0 or 1+ by IHC and ISH not done
2+ by IHC and not amplified by ISH or
IHC not done and not amplified by ISH

None of the following therapies are allowed prior to registration:

Chemotherapy =< 2 weeks
Immunotherapy =< 2 weeks
Biologic therapy =< 2 weeks
Hormonal therapy =< 2 weeks
Monoclonal antibodies =< 2 weeks
Radiation therapy =< 2 weeks

Anti-Her-2 or other "targeted" (e.g. mammalian target of rapamycin [mTOR]) therapy =< 2 weeks

NOTE : Any toxicities derived from these therapies must be =< grade 2 prior to starting study therapy