Neoadjuvant Therapy in Clinical Stage I-III HER2-positive Breast Cancer.

See summary above

• paclitaxel (Drug), also known as taxel, onxal: 80 mg/m2 (or nab-paclitaxel 80-100 mg/m2) weekly
• Trastuzumab (Drug), also known as Herceptin: Either every 3 weeks (8 mg/kg cycle 1 then 6 mg/kg cycles 2-4) or weekly (4 mg/kg week 1 then 2 mg/kg weeks 2-12)
• Pertuzumab (Drug), also known as Perjeta: every 3 weeks (840 mg cycle 1 then 420 mg cycles 2-4) or weeks 1 and 2 cycle 1 (420 mg each dose) during the first 3-6 weeks of treatment, then 420 mg day 1 of cycles 2-4.
• carboplatin (Drug), also known as paraplatin: AUC 2 administered weekly with no planned treatment breaks
• Breast surgery (Procedure): breast conserving or mastectomy
• AC (Drug): doxorubicin and cyclophosphamide (AC) every 2 or 3 weeks for 4 cycles Dose-dense AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 every 2 weeks x 4 cycles Standard AC: Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 IV day 1 r every 3 weeks x 4 cycles

Primary outcomes

• Percent of Patients Who Achieve a pCR [at surgery post approximately 18 weeks of treatment]: pCR is pathologic complete response defined as ypT0/isN0 on pathology report
• Number of of Patients Who Develop Major Toxicities as Defined in Protocol. [From start of neo-adjuvant treatment through approximately 18 weeks.]: Defined based on CTCAE version 4: 1. Neutropenia (grade>2) 2. Thrombocytopenia (grade >2) 3. Anemia (grade >2) 4. Diarrhea (any grade, grade >3) 5. Neuropathy (any grade, grade 2, grade >3) 6. Vomiting (any grade, grade >3)

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

1 Histologically confirmed adenocarcinoma of the breast, with sufficient tissue available from needle or incisional biopsy (excisional biopsy not permitted) for ER, PR and HER2 testing.

2\. Resectable - clinical stage I (only with T=2.0 cm), IIA-IIIA - T2 N0-T3N0 or T1-3 N1-N2a - or unresectable - clinical stage IIIB-C - T4 or N2b-3 - disease. No evidence of M1 disease. Pretreatment clinical stage will be recorded by the treating physician.

3\. Breast tumor measuring at least 1 cm in greatest dimension by ultrasound or MRI; patients without measurable disease in the breast (TX) by imaging studies are eligible if they have measurable disease (a node measuring at least 1 cm along its short axis, and histologically confirmed to contain metastatic disease) in the axilla.

4\. HER2+, defined by either IHC 3+ or amplification of the HER2 gene by FISH analysis (ratio >2.0 or >6 HER2 targets per cell; patients with equivocal HER2 testing, 2+ by IHC with a FISH ratio of <2.0 and 4-6 HER2 signals per nucleus, are not eligible).

5\. Patients with multiple foci of invasive cancer in the same breast are eligible if any single lesion meets the above size criteria and all sampled lesions > 1 cm in maximum dimension are histologically similar and HER2+. Patients are also eligible , or if there is a focus of HER2- invasive cancer that is <1 cm in maximum dimension and in a different quadrant of the breast from the HER2+ cancer, such that its presence will not interfere with clinical or pathologic assessment of response of the HER2+ cancer. The presence of DCIS or LCIS in either breast will not render a patient ineligible. Patients with a small focus of invasive cancer detected in the contralateral breast (clinical T1a/bN0) are eligible, whether the contralateral tumor is HER2+ or HER2-, while patients with a more advanced invasive cancer in the contralateral breast are not eligible; in patients with a small focus of invasive cancer in the contralateral breast or a small focus of HER2- cancer in the same breast only the histologic response in the HER2+ target lesion will be considered in determining the patient's pathologic response.

6 It is recommended that patients have a pretreatment echocardiogram or MUGA scan with an LVEF above the institutional lower limit of normal.

7\. Female, age >18, Zubrod PS 0-1. 8. It is recommended that patients have adequate bone marrow, renal and hepatic function. Examples of this include: ANC > 1000/ul, platelet count >100,000/ul, HGB> 9.0 g/dl, serum creatinine <1.5 mg/dl or measured creatinine clearance of >30 ml/min and AST <5 x ULN.

9\. Signed informed consent.

Exclusion Criteria:

1. Prior chemotherapy, hormonal therapy, or radiation therapy for this cancer
2. Patients with congestive heart failure, unstable angina pectoris, absolute exclusion for BP >180 (systolic) or >100 (diastolic); for BP 160-180/90-100, assurance from the treating MD that this is being addressed and that the MD is comfortable initiating study treatment despite the elevated value(s)uncontrolled clinically significant arrhythmia or grade II or greater peripheral vascular disease are not eligible. Patients with BP >180 (systolic) or >100 (diastolic) are excluded; patients with BP 160-180/90-100 are eligible with assurance from the treating MD that this is being addressed and that the MD is comfortable initiating study treatment despite the elevated value(s).
3. Patients with myocardial infarction, stroke or arterial thrombotic event within the past 12 months are not eligible.
4. Pregnant and lactating women are not eligible. All patients of reproductive potential should have a negative pregnancy test at baseline and be advised to use an effective barrier method of contraception if sexually active during treatment on the study and for 2 months post the last treatment. Sites will be asked to confirm the patient's menopausal status at study entry and that premenopausal women had a negative pregnancy test performed within 7 days of starting treatment, but will not be required to submit test results.
5. Active (defined as symptomatic, currently requiring treatment or likely to require treatment within the 6 months following study enrollment, or likely to affect the efficacy or tolerability of the study treatment) non-breast malignancy.
6. Baseline grade >2 peripheral neuropathy

Participant flow

Outcome results

• Percent of Patients Who Achieve a pCR (Primary), Count of participants, Participants: Experimental: Optimal- 18 Weeks 19; Experimental: Sub-optimal With AC 2; Experimental: Optimal With AC 0; Experimental: Sub-optimal no AC 0
• Number of of Patients Who Develop Major Toxicities as Defined in Protocol. (Primary), Count of participants, Participants: Experimental: Optimal- 18 Weeks 19; Experimental: Sub-optimal With AC 3; Experimental: Optimal With AC ; Experimental: Sub-optimal no AC 2

Adverse events

Time frame: Adverse events were collected from the time a signed and dated ICF is obtained until 3 months post-operative, or until the subject withdrew consent from study participation, whichever occurs first.

Serious adverse events by term

Other adverse events by term

• Results publication: Lopresti ML, Bian JJ, Sakr BJ, Strenger RS, Legare RD, Fenton M, Witherby SM, Dizon DS, Pandya SV, Stuckey AR, Edmondson DA, Gass JS, Emmick CM, Graves TA, Cutitar M, Olszewski AJ, Sikov WM. Neoadjuvant weekly paclitaxel and carboplatin with trastuzumab and pertuzumab in HER2-positive breast cancer: a Brown University Oncology Research Group (BrUOG) study. Breast Cancer Res Treat. 2021 Aug;189(1):93-101. doi: 10.1007/s10549-021-06266-9. Epub 2021 Jun 4. PMID 34086171

• Study Protocol and Statistical Analysis Plan (PDF, 2018-05-07)

• Howard Safran, MD, Study chair, BrUOG Study Chair