Neoadjuvant Therapy in Clinical Stage I-III HER2-positive Breast Cancer.
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: paclitaxel; Trastuzumab; Pertuzumab; carboplatin; Breast surgery; AC
Intervention description: 80 mg/m2 (or nab-paclitaxel 80-100 mg/m2) weekly; 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); 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.; AUC 2 administered weekly with no planned treatment breaks; breast conserving or mastectomy; 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
Intervention MeSH terms: Paclitaxel; Carboplatin; Trastuzumab; Pertuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: neoadjuvant breast cancer; stage I-III breast cancer; HER 2 positive breast cancer

Summary:

      Neoadjuvant therapy is given to breast cancer patients whose cancers are relatively large or
      have spread to lymph nodes or both. The primary goal of this treatment is to prevent the
      cancer from coming back (recurring) elsewhere in the body, but if it makes the cancer in the
      breast and lymph nodes shrink it might be easier to remove. This could allow a patient to
      have a lumpectomy instead of a mastectomy and reduce the number of lymph nodes that the
      surgeon has to remove. In some cases, the neoadjuvant therapy works so well that it kills all
      of the cancer in the breast and lymph nodes. This is referred to as a pathologic complete
      response (pCR). Patients who achieve a pCR have a much lower risk of the cancer recurring
      elsewhere in their bodies.

      Investigators aren't sure which chemotherapy drugs work best with the HER2-targeted drugs,
      and what combination of these drugs causes the fewest side effects.Thus, this study has two
      main goals:

        1. To find out if treatment with wPCbTP, weekly paclitaxel and carboplatin given with
           trastuzumab and pertuzumab every 3 weeks, leads to as many pCRs as TCHP in patients with
           HER2-positive breast cancer, but has fewer side effects.

        2. To find out if HER2-positive patients whose cancers are not responding well after 12
           weeks of wPCbTP get a better response when they are switched to a doxorubicin-containing
           regimen called AC for 4 cycles (8-12 weeks).
    

Eligibility criteria:

        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