NSABP B-47 - "A Randomized Phase III Trial of Adjuvant Therapy Comparing Chemotherapy Alone (Six Cycles of Docetaxel Plus Cyclophosphamide or Four Cycles of Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel) to Chemotherapy Plus Trastuzumab in Women with Node-Positive or High-Risk Node-Negative HER2-Low Invasive Breast Cancer"

NOTE:  AT STUDY ENTRY, INVESTIGATOR MUST DESIGNATE WHICH CHEMO REGIMEN WILL BE ADMINISTERED.

Treatment Plan    (Supplied Drug:  Trastuzumab)

Chemo Regimen A for Groups 1A & 2A

TC (q 3 wks x 6 cycles)

Docetaxel:  75/mg,2, IV

Cyclophosphamide:  600mg/m2, IV

Chemo Regimen B for Groups 1B & 2B

AC à WP

Doxorubicin:  60mg/m2, IV, q 3 wks x 4 cycles

Cyclophosphamide:  600mg/m2, IV, q 3 wks x 4 cycles

Followed by

Paclitaxel:  80mg/m2, IV, weekly x 12 doses (at investigator's discretion, may use Doxorubicin/Cyclophosphamide q 2 wks x 4 cycles)

Trastuzumab Regimen for Group 2A (Given w/TC)

8mg/kg (loading dose), IV, Day 1, Cycle 1 of TC

6mg/kg, IV, Cycles 2-6

6mg/kg (after completion of TC), IV, q 3 wks x 11 doses

Trastuzumab Regimen for Group 2B (Given w/AC à WP)

4mg/kg (loading dose), IV, beginning w/1st dose of weekly Paclitaxel

2mg/kg (subsequent doses), IV, weekly x 12 doses

6mg/kg (after completion of WP), IV, q 3 wks x 13 doses max

ARM 1 - GROUPS 1A & 1B

Chemo (TC or AC à WP)

ARM 2 - GROUPS 2A & 2B

Chemo (TC or AC à WP)

Trastuzumab x 1 yr

Eligibility

• Female, age >18.

• ECOG perf status 0-1.

• Unilateral invasive breast adenocarcinoma on histol exam.

• All of following must be met (7th edition, AJCC Cancer Staging Manual):

  • pT1-3

  • Ipsilateral nodes pN0, pN1 (N1mi, N1a, N1b, N1c), pN2a, pN2b, pN3a, pN3b

    If pN0, 1 of following must be met:

    • pT2 & ER- & PgR- or

    • pT2 & ER+ (PgR may be + or -) & either Grade 3 histology or Oncotype DX Recurrence Score >25

    • pT3 regardless of hormone receptor status, histologic grade, & Oncotype DX Recurrence Score

• HER2 status of prim tumor must be evaluated pre-randomiz.  All testing must show the tumor is HER2-Low as defined:

  • IHC must be performed & the IHC staining results score 1+ (in situ hybridization [ISH] testing is not required) or 2+ (FISH or CISH must also be performed & indicate the tumor is HER2-Low as described below).

  • If ISH is performed, test results must be as follows & IHC must be 1+ or 2+.  Ratio of HER2 to CEP17 must be <2.0 or, if a ratio was not performed, the HER2 gene copy number must be <4 per nucleus.  NOTE:  If IHC staining intensity is reported as a range, the higher intensity score in the range should be used to determine eligibility.

• Must have undergone total mastectomy or breast-conserving surgery (lumpectomy).  Pts w/nipple-sparing mastectomy are eligible.

• Pts undergoing lumpectomy:  Margins of resected specimen must be histologically free of invasive tumor & DCIS (by local pathologist).  If path shows tumor at line of resection, additional operative procedures may be performed to obtain clear margins.  If tumor is still present at resected margin after re-excision(s), pt must undergo total mastectomy to be eligible.  Pts w/margins positive for LCIS are eligible w/o additional resection.

• Pts undergoing mastectomy:  Margins must be free of gross residual tumor.  Microscopic positive margins are allowed if post-mastectomy RT of chest wall will be administered.

• Must have had 1 of the following for eval of pathologic nodal status:

  • Sentinel lymphadenectomy alone:

    • If path nodal staging based on sentinel lymphadenectomy is pN0 or pN1b

    • If path nodal staging based on sentinel lymphadenectomy is pN1mi or pN1a, the prim tumor must be T1 or T2 by path eval & limited to 1 or 2 positive nodes.

  • Sentinel lymphadenectomy followed by removal of additional non-sentinel LNs if the SN is positive

  • Axillary lymphadenectomy w/ or w/o SN isolation procedure

• <84 days from last breast cancer surgery (tx or staging) and randomiz.

• Must have ER analysis performed on prim tumor pre-randomiz.  If ER-, then PgR analysis must also be performed (either core bx or surgical resection specimen can be used for ER/PgR testing).  Prim tumors that are hormone receptor + or hormone receptor -  are allowed.

• Within 6 wks pre-randomiz:  ANC >1200/mm3; platelets >100,000/mm3; Hgb>10g/dL; total bili <ULN for lab (unless bili >ULN to >1.5x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bili); alk phos <2.5x ULN for lab; SGOT <1.5x ULN for lab; & serum creat <ULN.  NOTES:  1) Alk phos & SGOT may not both be >ULN; 2) If SGPT is done instead of SGOT, the SGPT must be <1.5x ULN (if both were performed, SGOT must be <1.5x ULN).

• Pts w/SGOT or alk phos >ULN are eligible if liver imaging done w/i 90 days pre-randomiz does not show mets disease and hepatic function requirements above are met.

• Pts w/alk phos >ULN but <2.5x ULN or unexplained bone pain are eligible if a bone scan, PET-CT, or PET w/i 90 days pre-randomiz does not show mets disease.

• LVEF asmt w/i 90 days pre-randomiz (2D echo is preferred, but MUGA may be used based on institut preference).  For pts who will get TC chemo regimen, the LVEF must be >50% regardless of cardiac imaging facility's LLN.  For pts who will get AC à WP chemo regimen, LVEF must be >55% regardless of facility's LLN.  NOTE:  It is critical that baseline LVEF be accurate - if it is >70%, investigator is encouraged to have accuracy confirmed & test repeated if necessary.

• No prim tumor w/any of following HER2 results:

  • IHC staining intensity:

    • 0 on all evaluations of specimens

    • 3+ on eval of any specimen

  • ISH w/ratio of HER2 to CEP17>2.0 on eval of any specimen

  • ISH indicating HER2 gene copy number >4 per nucleus on eval of any specimen

• No T4 tumors including inflammatory breast cancer.

• No definitive clinical or radiologic evidence of mets.  Chest imaging (mandatory) & other imaging (if required) must be performed w/i 90 days pre-randomiz.

• No synchronous or prior contralateral invasive breast cancer (synchronous &/or prior contralateral DCIS or LCIS is allowed).

• No prior ipsilateral invasive breast cancer or ipsilateral DCIS.  Synchronous or prior ipsilateral LCIS is allowed.

• No prior non-breast malignancies (except in situ cancers treated only by local excision & basal or squamous cell skin cancers) w/i 5 yrs pre-randomiz.

• No prior therapy w/anthracyclines, taxanes, or Trastuzumab for any malignancy.

• No chemo or HER2-targeted therapy administered for currently diagnosed breast cancer prior to randomiz.

• No whole breast RT prior to randomiz or partial breast RT that cannot be completed on or b/f randomiz.

• No continued endocrine therapy or aromatase inhibitor.  Pts are eligible if these meds are DC'd pre-randomiz.

• No continued sex hormonal therapy.  Pts are eligible if these meds are DC'd pre-randomiz.

• No prior or current cardiac disease to preclude use of drugs in the tx regimens.  Includes, but not confined to:

  Active cardiac disease

  • Angina pectoris that requires current use of anti-anginal meds

  • Ventricular arrhythmias except for benign premature ventricular contractions

  • Supraventricular & nodal arrhythmias requiring a pacemaker or not controlled w/meds

  • Conduction abnormality requiring a pacemaker

  • Valvular disease w/documented compromise in cardiac function

  • Symptomatic pericarditis

  Prior cardiac disease

  • MI documented by elevated cardiac enzymes or persistent regional wall abnormalities on asmt of LV function

  • Documented CHF

  • Documented cardiomyopathy

• No HTN as defined below:

  • For pts receiving TC (regardless of pt's age):  Uncontrolled HTN of sustained systolic >150mmHg or diastolic >90mmHg.  Pts w/initial BP elevations are eligible if initiation/adjustment of BP med lowers pressure to eligible range.

  • For pts <50 yrs old who will receive AC à WP:  Uncontrolled HTN of sustained systolic >150mmHg or diastolic >90mmHg.  Pts w/initial BP elevations are eligible if initiation/adjustment of BP med lowers pressure to eligible range.

  • For pts 50 yrs or older who will receive AC à WP:  Uncontrolled HTN of sustained systolic >150mmHg or diastolic >90mmHg or controlled HTN (systolic <150mmHg & diastolic <90mmHg) if anti-hypertensive meds are needed.

  • Pts who are not eligible based on AC à WP regimen BP criteria, but who meet TC regimen's BP criteria are eligible if chemo regimen is changed to TC.

• No active Hep B or C w/abnormal liver function tests.

• No intrinsic lung disease resulting in dyspnea.

• No poorly controlled diabetes mellitus.

• No active or chronic infection requiring chronic suppressive antibiotics.

• No nervous system disorder (paresthesia, perip motor neuropathy, or perip sensory neuropathy) >Grade 2 (CTCAE v4.0).

• No conditions prohibiting administration of corticosteroids.

• No chronic daily tx w/corticosteroids >10mg/day methylprednisolone equiv (excluding inhaled steroids).

• No known hypersensitivity to any study drug or excipient (i.e., polysorbate 80 & Cremophor EL).

• No pregnant or nursing women at study entry.  Pregnancy testing required w/i 2 wks pre-randomiz, if applicable).

• No other non-malig systemic disease that precludes pt from receiving study tx or completing follow-up.

• No psychiatric or addictive disorders or other conditions to preclude completion of study requirements (investigator's opinion).

• No use of any investigational product w/i 30 days pre-randomiz.

• PRESTUDY REQUIREMENTS:

  • Determination of local path dept's policy re:  submission of tumor samples

  • Determination of hormone receptor status

  • HER2 analysis

  • H&P (by Dr or other healthcare professional), ht, wt, perf status*

  • Menstrual hx (identifies women who will be included in the Menstrual Hx Study after randomiz)*

  • Menopausal status (estradiol level may be required)*

  • Asmt of BP & BP meds*

  • Asmt of concomitant meds*

  • Asmt of alcohol & tobacco use and comorbid conditions (pt-completed questionnaire after signing B-47 consent)*

  • CBC/diff/platelets**

  • Total bili/alk phos/SGOT or SGPT**

  • Serum creat**

  • Pregnancy test (if applicable, w/i 2 wks pre-randomiz)

  • 2D echo (preferred) or MUGA***

  • ECG***

  • Chest CT or CXR (PET or PET-CT also permitted)***

  • Liver imaging (CT, MRI, PET-CT or PET to r/o mets only if alk phos or SGOT >ULN)***

  • Bone nuclear imaging (bone scan, PET, or PET-CT only if unexplained bone pain or alk phos >ULN)***

  • Bilat breast imaging (Mammogram or MRI [not US]; unilateral if applicable.  Within 180 days pre-randomiz.)

  • Submission of tumor sample(s) - MANDATORY#

  • Submission of blood samples for pts in Menstrual Hx study population - Contact KCCOP for kit##@%

  • Submission of blood samples for all consenting B-47 pts - Contact KCCOP for kit##$%

  *      Within 4 wks pre-randomiz (must be post-op)

  **    Within 6 wks pre-randomiz (most recent post-op test results)

  ***  Within 90 days pre-randomiz

  #     Within 90 days post-randomiz.  >1 paraffin block from prim tumor (preferably more than 1) & 1 block from >1 positive lymph node (if applicable).  If possible, submitted block should be the one used for original HER2 testing & should contain largest tumor volume.  No alternative samples allowed.  Send via standard ground delivery to:  NSABP Biostat Center; Pittsburgh, PA.

  ##   Post-randomiz, but b/f therapy begins. 

  @   Only pts determined to be in the Menstrual Hx study population & who agree to optional blood sample collections. 

  $     For Correlative science studies & Host Factors Study. 

  %  Ship same day as collected.  Send on cold packs (frozen at -20^oC overnight b/f shipping ) on Mon-Thurs only via overnight delivery to:  Baylor College of Medicine Breast Center; Houston, TX. 

• Signed informed consent.