Chemotherapy With or Without Trastuzumab After Surgery in Treating Women With Invasive Breast Cancer

<p>Inclusion Criteria:</p><ul><li>Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer; (comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer)</li><li>Women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, tubal ligation, vasectomized partner, or abstinence) during therapy and for at least 6 months after the last dose of study therapy (chemotherapy or trastuzumab)</li><li>Submission of tumor samples from the breast surgery is required for all patients; therefore, the local pathology department policy regarding release of tumor samples must be considered in the screening process; patients whose tumor samples are located in a pathology department that by policy will not submit any samples for research purposes should not be approached for participation in the B-47 trial</li><li>The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines</li><li>Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1</li><li>The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination</li><li><p>All of the following staging criteria (according to the 7th edition of the American Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met:</p><ul><li>By pathologic evaluation, primary tumor must be pT1-3</li><li><p>By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b</p><ul><li><p>If pN0, one of the following criteria must be met:</p><ul><li>pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR) negative; or</li><li>pT2 and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX Recurrence Score of &gt;= 25; or</li><li>pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX Recurrence Score</li></ul></li></ul></li></ul></li><li><p>HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low as defined below</p><ul><li>IHC must be performed and the IHC staining results must indicate a score of 1+ (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be performed and must indicate that the tumor is HER2-low as described below)</li><li>If ISH testing is performed, test results must be as follows and IHC must be 1+ or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be &lt; 2.0 or, if a ratio was not performed, the HER2 gene copy number must be &lt; 4 per nucleus</li><li>Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the higher intensity score in the range should be used to determine eligibility</li></ul></li><li>The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)</li><li>For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible; (patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection)</li><li>For patients who undergo mastectomy, margins must be free of gross residual tumor; (patients with microscopic positive margins are eligible as long as post-mastectomy radiation therapy [RT] of the chest wall will be administered)</li><li><p>The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below:</p><ul><li><p>Sentinel lymphadenectomy alone:</p><ul><li>If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b</li><li>If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes</li></ul></li><li>Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or</li><li>Axillary lymphadenectomy with or without SN isolation procedures</li></ul></li><li>The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days</li><li>The patient must have ER analysis performed on the primary tumor prior to randomization; if ER analysis is negative, then PgR analysis must also be performed (either the core biopsy or surgical resection specimen can be used for ER&#x2F;PgR testing); patients with a primary tumor that is hormone receptor-positive or receptor-negative are eligible</li><li>Absolute neutrophil count (ANC) must be &gt;= 1,200&#x2F;mm^3</li><li>Platelet count must be &gt;= 100,000&#x2F;mm^3</li><li>Hemoglobin must be &gt;= 10 g&#x2F;dL</li><li>Total bilirubin must be =&lt; upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation &gt; ULN to 1.5 x ULN due to Gilbert disease or similar syndrome involving slow conjugation of bilirubin</li><li>Alkaline phosphatase must be =&lt; 2.5 x ULN for the lab</li><li>Aspartate aminotransferase (AST) must be =&lt; 1.5 x ULN for the lab (if alanine aminotransferase [ALT] is performed instead of AST [per institution&#x27;s standard practice], the alanine aminotransferase [ALT] value must be =&lt; 1.5 x ULN; if both were performed, the AST must be =&lt; 1.5 x ULN)</li><li>Alkaline phosphatase and AST may not both be &gt; the ULN</li><li>Patients with AST or alkaline phosphatase &gt; ULN are eligible for inclusion in the study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the above requirements are met</li><li>Patients with alkaline phosphatase that is &gt; ULN but =&lt; 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease</li><li>The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be =&lt; ULN for the lab</li><li><p>Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-dimensional (D) echocardiogram is preferred, however, multi-gated acquisition (MUGA) scan maybe substituted based on institutional preferences</p><ul><li>For patients who will receive the TC chemotherapy regimen, the LVEF must be &gt;= 50% regardless of the cardiac imaging facility&#x27;s lower limit of normal</li><li>For patients who will receive the AC--&gt;WP chemotherapy regimen, the LVEF must be &gt;= 55% regardless of the cardiac imaging facility&#x27;s lower limit of normal</li><li>NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment; if the baseline LVEF is &gt; 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain</li></ul></li></ul><p>Exclusion Criteria:</p><ul><li><p>Primary tumor with any of the following HER2 testing results:</p><ul><li><p>IHC staining intensity:</p><ul><li>0 on all evaluations of specimens</li><li>3+ on evaluation of any specimen</li></ul></li><li>ISH with a ratio of HER2 to CEP17 &gt;= 2.0 on evaluation of any specimen</li><li>ISH result indicating HER2 gene copy number &gt;= 4 per nucleus on evaluation of any specimen</li></ul></li><li>T4 tumors including inflammatory breast cancer</li><li><p>Definitive clinical or radiologic evidence of metastatic disease</p><ul><li>NOTE: Chest imaging (mandatory for all patients) and other imaging (if required) must have been performed within 90 days prior to randomization</li></ul></li><li>Synchronous or previous contralateral invasive breast cancer (patients with synchronous and&#x2F;or previous contralateral DCIS or LCIS are eligible)</li><li>Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS; (patients with synchronous or previous ipsilateral LCIS are eligible)</li><li>History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization</li><li>Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy</li><li>Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization</li><li>Whole-breast RT prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization</li><li>Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible if these medications are discontinued prior to randomization</li><li>Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy; patients are eligible if these medications are discontinued prior to randomization</li><li><p>Cardiac disease (history of and&#x2F;or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:</p><ul><li><p>Active cardiac disease:</p><ul><li>Angina pectoris that requires the current use of anti-anginal medication</li><li>Ventricular arrhythmias except for benign premature ventricular contractions</li><li>Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication</li><li>Conduction abnormality requiring a pacemaker</li><li>Valvular disease with documented compromise in cardiac function</li><li>Symptomatic pericarditis</li></ul></li><li><p>History of cardiac disease:</p><ul><li>Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricle (LV) function</li><li>History of documented congestive heart failure (CHF)</li><li>Documented cardiomyopathy</li></ul></li></ul></li><li><p>Hypertension defined according to the following ineligibility criteria:</p><ul><li>For patients who will receive TC (regardless of the patient&#x27;s age): uncontrolled hypertension defined as sustained systolic blood pressure (BP) &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)</li><li>For patients &lt; 50 years old who will receive AC--&gt;WP: uncontrolled hypertension defined as sustained systolic BP &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg; patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria</li><li><p>For patients &gt;= 50 years old who will receive AC--&gt;WP:</p><ul><li>Uncontrolled hypertension defined as sustained systolic BP &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg</li><li>Controlled hypertension (systolic BP =&lt; 150 mm Hg and diastolic BP =&lt; 90 mmHg), if anti-hypertensive medication(s) are needed</li></ul></li><li>NOTE: Patients who are not eligible based on the AC-WP regimen BP criteria but who meet the TC regimen BP criteria are eligible for B-47, if the intended chemotherapy regimen is changed to TC</li></ul></li><li>Active hepatitis B or hepatitis C with abnormal liver function tests</li><li>Intrinsic lung disease resulting in dyspnea</li><li>Poorly controlled diabetes mellitus</li><li>Active infection or chronic infection requiring chronic suppressive antibiotics</li><li>Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) &gt;= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0</li><li>Conditions that would prohibit administration of corticosteroids</li><li>Chronic daily treatment with corticosteroids with a dose of &gt;= 10 mg&#x2F;day methylprednisol one equivalent (excluding inhaled steroids)</li><li>Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL</li><li>Pregnancy or lactation at the time of study entry; (Note: pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential)</li><li>Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up</li><li>Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements</li><li>Use of any investigational product within 30 days prior to randomization</li></ul>

<p>Inclusion Criteria:</p><ul><li>Patients should have a life expectancy of at least 10 years, excluding their diagnosis of breast cancer; (comorbid conditions should be taken into consideration, but not the diagnosis of breast cancer)</li><li>Women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, tubal ligation, vasectomized partner, or abstinence) during therapy and for at least 6 months (Arm 1 patients) and for at least 7 months (Arm 2 patients) after the last dose of study therapy (chemotherapy or trastuzumab)</li><li>Submission of tumor samples from the breast surgery is required for all patients; therefore, the local pathology department policy regarding release of tumor samples must be considered in the screening process; patients whose tumor samples are located in a pathology department that by policy will not submit any samples for research purposes should not be approached for participation in the B-47 trial</li><li>The patient must have signed and dated an Institutional Review Board (IRB)-approved consent form that conforms to federal and institutional guidelines</li><li>Eastern Cooperation Oncology Group (ECOG) performance status of 0 or 1</li><li>The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination</li><li><p>All of the following staging criteria (according to the 7th edition of the American Joint Committee on Cancer [AJCC] Cancer Staging Manual) must be met:</p><ul><li>By pathologic evaluation, primary tumor must be pT1-3</li><li><p>By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b</p><ul><li><p>If pN0, one of the following criteria must be met:</p><ul><li>pT2 and estrogen receptor (ER) negative and progesterone receptor (PgR) negative; or</li><li>pT2 and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX Recurrence Score of &gt;= 25; or</li><li>pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX Recurrence Score</li></ul></li></ul></li></ul></li><li><p>HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low as defined below</p><ul><li>IHC must be performed and the IHC staining results must indicate a score of 1+ (in situ hybridization [ISH] testing is not required) or 2+ (ISH must also be performed and must indicate that the tumor is HER2-low as described below)</li><li>If ISH testing is performed, test results must be as follows and IHC must be 1+ or 2+: the ratio of HER2 to chromosome enumeration probe 17 (CEP17) must be &lt; 2.0 or, if a ratio was not performed, the HER2 gene copy number must be &lt; 4 per nucleus</li><li>Note: If the IHC staining intensity is reported as a range, e.g., 0 to 1+ or 1+ to 2+, the higher intensity score in the range should be used to determine eligibility</li></ul></li><li>The patient must have undergone either a total mastectomy or breast-conserving surgery (lumpectomy); (patients who have had a nipple-sparing mastectomy are eligible)</li><li>For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist; if pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins; if tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible; (patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection)</li><li>For patients who undergo mastectomy, margins must be free of gross residual tumor; (patients with microscopic positive margins are eligible as long as post-mastectomy radiation therapy [RT] of the chest wall will be administered)</li><li><p>The patient must have completed one of the procedures for evaluation of pathologic nodal status listed below:</p><ul><li><p>Sentinel lymphadenectomy alone:</p><ul><li>If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b</li><li>If pathologic nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal involvement must be limited to 1 or 2 positive nodes</li></ul></li><li>Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or</li><li>Axillary lymphadenectomy with or without SN isolation procedures</li></ul></li><li>The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days</li><li>The patient must have ER analysis performed on the primary tumor prior to randomization; if ER analysis is negative, then PgR analysis must also be performed (either the core biopsy or surgical resection specimen can be used for ER&#x2F;PgR testing); patients with a primary tumor that is hormone receptor-positive or receptor-negative are eligible</li><li>Absolute neutrophil count (ANC) must be &gt;= 1,200&#x2F;mm^3</li><li>Platelet count must be &gt;= 100,000&#x2F;mm^3</li><li>Hemoglobin must be &gt;= 10 g&#x2F;dL</li><li>Total bilirubin must be =&lt; upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation &gt; ULN to 1.5 x ULN due to Gilbert disease or similar syndrome involving slow conjugation of bilirubin</li><li>Alkaline phosphatase must be =&lt; 2.5 x ULN for the lab</li><li>Aspartate aminotransferase (AST) must be =&lt; 1.5 x ULN for the lab (if alanine aminotransferase [ALT] is performed instead of AST [per institution&#x27;s standard practice], the alanine aminotransferase [ALT] value must be =&lt; 1.5 x ULN; if both were performed, the AST must be =&lt; 1.5 x ULN)</li><li>Alkaline phosphatase and AST may not both be &gt; the ULN</li><li>Patients with AST or alkaline phosphatase &gt; ULN are eligible for inclusion in the study if liver imaging (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]-CT, or PET scan) performed within 90 days prior to randomization does not demonstrate metastatic disease and the above requirements are met</li><li>Patients with alkaline phosphatase that is &gt; ULN but =&lt; 2.5 x ULN or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan performed within 90 days prior to randomization does not demonstrate metastatic disease</li><li>The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be =&lt; ULN for the lab</li><li><p>Left ventricular ejection fraction (LVEF) assessment must be performed within 90 days prior to randomization; LVEF assessment performed by 2-dimensional (D) echocardiogram is preferred, however, multi-gated acquisition (MUGA) scan maybe substituted based on institutional preferences</p><ul><li>For patients who will receive the TC chemotherapy regimen, the LVEF must be &gt;= 50% regardless of the cardiac imaging facility&#x27;s lower limit of normal</li><li>For patients who will receive the AC--&gt;WP chemotherapy regimen, the LVEF must be &gt;= 55% regardless of the cardiac imaging facility&#x27;s lower limit of normal</li><li>NOTE: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment; if the baseline LVEF is &gt; 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain</li></ul></li></ul><p>Exclusion Criteria:</p><ul><li><p>Primary tumor with any of the following HER2 testing results:</p><ul><li><p>IHC staining intensity:</p><ul><li>0 on all evaluations of specimens</li><li>3+ on evaluation of any specimen</li></ul></li><li>ISH with a ratio of HER2 to CEP17 &gt;= 2.0 on evaluation of any specimen</li><li>ISH result indicating HER2 gene copy number &gt;= 4 per nucleus on evaluation of any specimen</li></ul></li><li>T4 tumors including inflammatory breast cancer</li><li><p>Definitive clinical or radiologic evidence of metastatic disease</p><ul><li>NOTE: Chest imaging (mandatory for all patients) and other imaging (if required) must have been performed within 90 days prior to randomization</li></ul></li><li>Synchronous or previous contralateral invasive breast cancer (patients with synchronous and&#x2F;or previous contralateral DCIS or LCIS are eligible)</li><li>Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS; (patients with synchronous or previous ipsilateral LCIS are eligible)</li><li>History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization</li><li>Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy</li><li>Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization</li><li>Whole-breast RT prior to randomization or partial-breast RT that cannot be completed on or before the date of randomization</li><li>Continued endocrine therapy such as raloxifene or tamoxifen (or other selective estrogen receptor modulator [SERM]) or an aromatase inhibitor; patients are eligible if these medications are discontinued prior to randomization</li><li>Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy; patients are eligible if these medications are discontinued prior to randomization</li><li><p>Cardiac disease (history of and&#x2F;or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:</p><ul><li><p>Active cardiac disease:</p><ul><li>Angina pectoris that requires the current use of anti-anginal medication</li><li>Ventricular arrhythmias except for benign premature ventricular contractions</li><li>Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication</li><li>Conduction abnormality requiring a pacemaker</li><li>Valvular disease with documented compromise in cardiac function</li><li>Symptomatic pericarditis</li></ul></li><li><p>History of cardiac disease:</p><ul><li>Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricle (LV) function</li><li>History of documented congestive heart failure (CHF)</li><li>Documented cardiomyopathy</li></ul></li></ul></li><li><p>Hypertension defined according to the following ineligibility criteria:</p><ul><li>For patients who will receive TC (regardless of the patient&#x27;s age): uncontrolled hypertension defined as sustained systolic blood pressure (BP) &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)</li><li>For patients &lt; 50 years old who will receive AC--&gt;WP: uncontrolled hypertension defined as sustained systolic BP &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg; patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria</li><li><p>For patients &gt;= 50 years old who will receive AC--&gt;WP:</p><ul><li>Uncontrolled hypertension defined as sustained systolic BP &gt; 150 mm Hg or diastolic BP &gt; 90 mm Hg</li><li>Controlled hypertension (systolic BP =&lt; 150 mm Hg and diastolic BP =&lt; 90 mmHg), if anti-hypertensive medication(s) are needed</li></ul></li><li>NOTE: Patients who are not eligible based on the AC-WP regimen BP criteria but who meet the TC regimen BP criteria are eligible for B-47, if the intended chemotherapy regimen is changed to TC</li></ul></li><li>Active hepatitis B or hepatitis C with abnormal liver function tests</li><li>Intrinsic lung disease resulting in dyspnea</li><li>Poorly controlled diabetes mellitus</li><li>Active infection or chronic infection requiring chronic suppressive antibiotics</li><li>Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) &gt;= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0</li><li>Conditions that would prohibit administration of corticosteroids</li><li>Chronic daily treatment with corticosteroids with a dose of &gt;= 10 mg&#x2F;day methylprednisol one equivalent (excluding inhaled steroids)</li><li>Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor EL</li><li>Pregnancy or lactation at the time of study entry; (Note: pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards for women of childbearing potential)</li><li>Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up</li><li>Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements</li><li>Use of any investigational product within 30 days prior to randomization</li></ul>

University of South Alabama Mitchell Cancer Institute

Alaska Breast Care and Surgery LLC

Mobile

Anchorage

Alabama

Alaska

36688

99508

30.69436

61.21806

-88.04305

-149.90028

Alaska Breast Care and Surgery LLC

Alaska Women's Cancer Care

Alaska Women's Cancer Care

Anchorage Oncology Centre

Anchorage Oncology Centre

Katmai Oncology Group

Katmai Oncology Group

Providence Alaska Medical Center

Providence Alaska Medical Center

Fairbanks Memorial Hospital

Anchorage

Fairbanks

99508

99701

61.21806

64.83778

-149.90028

-147.71639

Fairbanks Memorial Hospital

Arizona Oncology Associates-Biltmore Cancer Center

Fairbanks

Phoenix

Alaska

Arizona

99701

85016

64.83778

33.44838

-147.71639

-112.07404

Arizona Oncology Associates-Biltmore Cancer Center

Pinnacle Oncology Hematology

Phoenix

Scottsdale

85016

85258

33.44838

33.50921

-112.07404

-111.89903

Pinnacle Oncology Hematology

Fowler Family Center for Cancer Care

Scottsdale

Jonesboro

Arizona

Arkansas

85258

72401

33.50921

35.8423

-111.89903

-90.70428

Fowler Family Center for Cancer Care

NEA Baptist Memorial Hospital

NEA Baptist Memorial Hospital

University of Arkansas for Medical Sciences

Jonesboro

Little Rock

72401

72205

35.8423

34.74648

-90.70428

-92.28959

University of Arkansas for Medical Sciences

Kaiser Anaheim Medical Center

Little Rock

Anaheim

Arkansas

California

72205

92807

34.74648

33.83529

-92.28959

-117.9145

Kaiser Anaheim Medical Center

Kaiser Permanente-Deer Valley Medical Center

Anaheim

Antioch

92807

94531

33.83529

38.00492

-117.9145

-121.80579

Kaiser Permanente-Deer Valley Medical Center

Sutter Auburn Faith Hospital

Antioch

Auburn

94531

95602

38.00492

38.89657

-121.80579

-121.07689

Sutter Auburn Faith Hospital

Sutter Cancer Centers Radiation Oncology Services-Auburn

95602

95603

Sutter Cancer Centers Radiation Oncology Services-Auburn

Kaiser Permanente Medical Group - Baldwin Park

Auburn

Baldwin Park

95603

91706

38.89657

34.08529

-121.07689

-117.9609

Kaiser Permanente Medical Group - Baldwin Park

Kaiser Foundation Hospital

Baldwin Park

Bellflower

91706

90706

34.08529

33.88168

-117.9609

-118.11701

Kaiser Foundation Hospital

Alta Bates Summit Medical Center-Herrick Campus

Bellflower

Berkeley

90706

94704

33.88168

37.87159

-118.11701

-122.27275

Alta Bates Summit Medical Center-Herrick Campus

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Berkeley

Burbank

94704

91505

37.87159

34.18084

-122.27275

-118.30897

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Mills - Peninsula Hospitals

Burbank

Burlingame

91505

94010

34.18084

37.5841

-118.30897

-122.36608

Roy and Patricia Disney Family Cancer Center

Sutter Cancer Centers Radiation Oncology Services-Cameron Park

Burbank

Cameron Park

91505

95682

34.18084

38.66879

-118.30897

-120.98716

Mills - Peninsula Hospitals

East Bay Radiation Oncology Center

Burlingame

Castro Valley

94010

94546

37.5841

37.6941

-122.36608

-122.08635

Sutter Cancer Centers Radiation Oncology Services-Cameron Park

Valley Medical Oncology Consultants-Castro Valley

Cameron Park

Castro Valley

95682

94546

38.66879

37.6941

-120.98716

-122.08635

East Bay Radiation Oncology Center

John Muir Medical Center-Concord Campus

Castro Valley

Concord

94546

94520

37.6941

37.97798

-122.08635

-122.03107

Valley Medical Oncology Consultants-Castro Valley

Sutter Davis Hospital

Castro Valley

Davis

94546

95616

37.6941

38.54491

-122.08635

-121.74052

John Muir Medical Center-Concord Campus

Epic Care-Dublin

Concord

Dublin

94520

94568

37.97798

37.70215

-122.03107

-121.93579

Sutter Davis Hospital

Northbay Cancer Center

Davis

Fairfield

95616

94533

38.54491

38.24936

-121.74052

-122.03997

Epic Care-Dublin

Kaiser Permanente Hospital

Dublin

Fontana

94568

92335

37.70215

34.09223

-121.93579

-117.43505

Northbay Cancer Center

Kaiser Permanente, Fremont

Fairfield

Fremont

94533

94538

38.24936

37.54827

-122.03997

-121.98857

Kaiser Permanente Hospital

Valley Medical Oncology Consultants-Fremont

Fontana

Fremont

92335

94538

34.09223

37.54827

-117.43505

-121.98857

Kaiser Permanente, Fremont

Kaiser Permanente

Fremont

Fresno

94538

93720

37.54827

36.74773

-121.98857

-119.77237

Valley Medical Oncology Consultants-Fremont

Glendale Memorial Hospital and Health Center

Fremont

Glendale

94538

91204

37.54827

34.14251

-121.98857

-118.25508

Kaiser Permanente

Marin Cancer Care Inc

Fresno

Greenbrae

93720

94904

36.74773

37.94854

-119.77237

-122.5247

Glendale Memorial Hospital and Health Center

Marin General Hospital

Glendale

Greenbrae

91204

94904

34.14251

37.94854

-118.25508

-122.5247

Marin Cancer Care Inc

Kaiser Permanente - Harbor City

Greenbrae

Harbor City

94904

90710

37.94854

33.79002

-122.5247

-118.29785

Marin General Hospital

Southern California Permanente Medical Group

Greenbrae

Irvine

94904

92618

37.94854

33.66946

-122.5247

-117.82311

Kaiser Permanente - Harbor City

Long Beach Memorial Medical Center-Todd Cancer Institute

Harbor City

Long Beach

90710

90806

33.79002

33.76696

-118.29785

-118.18923

Southern California Permanente Medical Group

Kaiser Permanente Los Angeles Medical Center

Irvine

Los Angeles

92618

90027

33.66946

34.05223

-117.82311

-118.24368

Long Beach Memorial Medical Center-Todd Cancer Institute

Kaiser Permanente-West Los Angeles

Long Beach

Los Angeles

90806

90034

33.76696

34.05223

-118.18923

-118.24368

Kaiser Permanente Los Angeles Medical Center

Contra Costa Regional Medical Center

Los Angeles

Martinez

90027

94553-3156

34.05223

38.01937

-118.24368

-122.13413

Kaiser Permanente

Memorial Medical Center

Los Angeles

Modesto

90027

95355

34.05223

37.6391

-118.24368

-120.99688

Kaiser Permanente-West Los Angeles

Kaiser Permanente-Modesto

Los Angeles

Modesto

90034

95356

34.05223

37.6391

-118.24368

-120.99688

Contra Costa Regional Medical Center

Community Hospital of Monterey Peninsula

Martinez

Monterey

94553-3156

93940

38.01937

36.60024

-122.13413

-121.89468

Memorial Medical Center

El Camino Hospital

Modesto

Mountain View

95355

94040

37.6391

37.38605

-120.99688

-122.08385

Kaiser Permanente-Modesto

Palo Alto Medical Foundation-Gynecologic Oncology

Modesto

Mountain View

95356

94040

37.6391

37.38605

-120.99688

-122.08385

Community Hospital of Monterey Peninsula

Sutter Cancer Research Consortium

Monterey

Novato

93940

94945

36.60024

38.10742

-121.89468

-122.5697

El Camino Hospital

Highland General Hospital

Mountain View

Oakland

94040

94602

37.38605

37.80437

-122.08385

-122.2708

Palo Alto Medical Foundation-Camino Division

Alta Bates Summit Medical Center - Summit Campus

Mountain View

Oakland

94040

94609

37.38605

37.80437

-122.08385

-122.2708

Palo Alto Medical Foundation-Gynecologic Oncology

Bay Area Breast Surgeons Inc

Mountain View

Oakland

94040

94609

37.38605

37.80437

-122.08385

-122.2708

Sutter Cancer Research Consortium

Bay Area Tumor Institute

Novato

Oakland

94945

94609

38.10742

37.80437

-122.5697

-122.2708

Highland General Hospital

Larry G Strieff MD Medical Corporation

94602

94609

Alta Bates Summit Medical Center - Summit Campus

Tom K Lee Inc

Bay Area Breast Surgeons Inc

Kaiser Permanente Oakland-Broadway

94609

94611

Bay Area Tumor Institute

Kaiser Permanente-Oakland

94609

94611

Larry G Strieff MD Medical Corporation

Epic Care-Oakland

94609

94612

Tom K Lee Inc

Saint Joseph Hospital - Orange

Oakland

Orange

94609

92868

37.80437

33.78779

-122.2708

-117.85311

Kaiser Permanente Oakland-Broadway

Ventura County Hematology Oncology Specialists

Oakland

Oxnard

94611

93030

37.80437

34.1975

-122.2708

-119.17705

Kaiser Permanente-Oakland

Desert Regional Medical Center

Oakland

Palm Springs

94611

92262

37.80437

33.8303

-122.2708

-116.54529

Epic Care-Oakland

Kaiser Permanente - Panorama City

Oakland

Panorama City

94612

91402

37.80437

34.22473

-122.2708

-118.44981

Saint Joseph Hospital - Orange

Palchak David MD

Orange

Pismo Beach

92868

93449

33.78779

35.14275

-117.85311

-120.64128

Ventura County Hematology Oncology Specialists

Valley Medical Oncology Consultants

Oxnard

Pleasanton

93030

94588

34.1975

37.66243

-119.17705

-121.87468

Desert Regional Medical Center

Kaiser Permanente-Rancho Cordova Cancer Center

Palm Springs

Rancho Cardova

92262

95670

Palo Alto Medical Foundation Health Care

Eisenhower Medical Center

Palo Alto

Rancho Mirage

94301

92270

37.44188

33.73974

-122.14302

-116.41279

Kaiser Permanente - Panorama City

Kaiser Permanente-Redwood City

Panorama City

Redwood City

91402

94063

34.22473

37.48522

-118.44981

-122.23635

Palchak David MD

Kaiser Permanente-Richmond

Pismo Beach

Richmond

93449

94801

35.14275

37.93576

-120.64128

-122.34775

Valley Medical Oncology Consultants

Kaiser Permanente Medical Center

Pleasanton

Riverside

94588

92505

37.66243

33.95335

-121.87468

-117.39616

Pomona Valley Hospital Medical Center

Rohnert Park Cancer Center

Pomona

Rohnert Park

91767

94928

34.05529

38.33964

-117.75228

-122.7011

Kaiser Permanente-Rancho Cordova Cancer Center

Kaiser Permanente-Roseville

Rancho Cardova

Roseville

95670

95661

Eisenhower Medical Center

Sutter Cancer Centers Radiation Oncology Services-Roseville

Rancho Mirage

Roseville

92270

95661

33.73974

38.75212

-116.41279

-121.28801

Kaiser Permanente-Redwood City

Sutter Roseville Medical Center

Redwood City

Roseville

94063

95661

37.48522

38.75212

-122.23635

-121.28801

Kaiser Permanente-Richmond

The Permanente Medical Group-Roseville Radiation Oncology

Richmond

Roseville

94801

95678

37.93576

38.75212

-122.34775

-121.28801

Kaiser Permanente Medical Center

Sutter General Hospital

Riverside

Sacramento

92505

95816

33.95335

38.58157

-117.39616

-121.4944

Rohnert Park Cancer Center

Kaiser Permanente-South Sacramento

Rohnert Park

Sacramento

94928

95823

38.33964

38.58157

-122.7011

-121.4944

Kaiser Permanente-Roseville

South Sacramento Cancer Center

Roseville

Sacramento

95661

95823

38.75212

38.58157

-121.28801

-121.4944

Sutter Cancer Centers Radiation Oncology Services-Roseville

Kaiser Permanente - Sacramento

Roseville

Sacramento

95661

95825

38.75212

38.58157

-121.28801

-121.4944

Sutter Roseville Medical Center

Salinas Valley Memorial

Roseville

Salinas

95661

93901

38.75212

36.67774

-121.28801

-121.6555

The Permanente Medical Group-Roseville Radiation Oncology

Kaiser Permanente at San Diego

Roseville

San Diego

95678

92120

38.75212

32.71571

-121.28801

-117.16472

Sutter General Hospital

Kaiser Permanente

Sacramento

San Diego

95816

92120

38.58157

32.71571

-121.4944

-117.16472

Kaiser Permanente-South Sacramento

Kaiser Permanente-San Francisco

Sacramento

San Francisco

95823

94115

38.58157

37.77493

-121.4944

-122.41942

South Sacramento Cancer Center

California Pacific Medical Center-Pacific Campus

Sacramento

San Francisco

95823

94118

38.58157

37.77493

-121.4944

-122.41942

Kaiser Permanente - Sacramento

Kaiser Permanente-Santa Teresa-San Jose

Sacramento

San Jose

95825

95119

38.58157

37.33939

-121.4944

-121.89496

Salinas Valley Memorial

Kaiser Permanente San Leandro

Salinas

San Leandro

93901

94577

36.67774

37.72493

-121.6555

-122.15608

Kaiser Permanente at San Diego

Coastal Integrative Cancer Care

San Diego

San Luis Obispo