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A Study Evaluating Pertuzumab (Perjeta) Combined With Trastuzumab (Herceptin) and Standard Anthracycline-based Chemotherapy in Participants With Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Locally Advanced, Inflammatory, or Early-stage Breast Cancer (BERENICE)

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ClinicalTrials.gov Identifier: NCT02132949
Recruitment Status : Completed
First Posted : May 7, 2014
Results First Posted : April 13, 2017
Last Update Posted : September 17, 2021
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Brief Summary:
This multicenter, non-randomized, open-label, phase 2 study is designed to evaluate the safety and efficacy of pertuzumab (Perjeta) in combination with trastuzumab (Herceptin) and anthracycline-based chemotherapy as neoadjuvant treatment in participants with HER2-positive locally advanced, inflammatory, or early-stage breast cancer. Each investigator will choose a treatment regimen (A or B) for all of their participants to follow. Treatment regimen A (for Cohort A) will include dose-dense doxorubicin and cyclophosphamide (ddAC), followed by paclitaxel, with pertuzumab and trastuzumab given from the start of paclitaxel. Treatment regimen B (for Cohort B) will include 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), followed by docetaxel, with pertuzumab and trastuzumab given from the start of docetaxel. Participants in both cohorts will subsequently undergo surgical treatment and then resume pertuzumab and trastuzumab treatment.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: 5-Fluorouracil Drug: Cyclophosphamide Drug: Docetaxel Drug: Doxorubicin Drug: Epirubicin Drug: Paclitaxel Drug: Pertuzumab Drug: Trastuzumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 401 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Multinational, Phase II Study to Evaluate Perjeta in Combination With Herceptin and Standard Neoadjuvant Anthracycline-Based Chemotherapy in Patients With HER2-Positive, Locally Advanced, Inflammatory, or Early-Stage Breast Cancer
Actual Study Start Date : July 14, 2014
Actual Primary Completion Date : March 3, 2016
Actual Study Completion Date : August 25, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Cohort A: ddAC, Paclitaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with dose-dense doxorubicin and cyclophosphamide (ddAC), with administration of doxorubicin 60 milligrams per square meter (mg/m^2) intravenously (IV) once every 2 weeks (q2w) and cyclophosphamide 600mg/m^2 IV q2w for 4 cycles, followed by paclitaxel 80mg/m^2 IV once weekly (qw) for 12 weeks. Pertuzumab (840 milligrams [mg] IV loading dose then 420mg IV q3w) and trastuzumab (8 milligrams per kilogram [mg/kg] IV loading dose then 4mg/kg IV q3w) were administered along with paclitaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Drug: Cyclophosphamide
Participants will receive cyclophosphamide 600 milligrams per square meter (mg/m^2) intravenous (IV) given on Day 1 of each cycle q2w.

Drug: Doxorubicin
Participants will receive doxorubicin 60 mg/m^2 IV on Day 1 of each cycle q2w.

Drug: Paclitaxel
Participants will receive paclitaxel 80 mg/m^2 IV given weekly.

Drug: Pertuzumab
Participants will receive pertuzumab at a loading dose of 840 milligrams (mg) IV loading dose, then 420 mg IV q3w.
Other Name: Perjeta

Drug: Trastuzumab
Participants will receive trastuzumab at a loading dose of 8 milligrams per kilogram (mg/kg) IV, then 6 mg/kg IV q3w.
Other Name: Herceptin

Experimental: Cohort B: FEC, Docetaxel, Pertuzumab, Trastuzumab
Participants received neoadjuvant treatment with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC), with administration of 5-fluorouracil 500mg/m^2 intravenously (IV) q3w, epirubicin 100mg/m^2 IV q3w, and cyclophosphamide 600mg/m^2 IV q3w for 4 cycles, followed by docetaxel (with starting dose of 75mg/m^2 in Cycle 5, then 100mg/m^2 for Cycles 6-8) q3w for 4 cycles. Pertuzumab (840 mg IV loading dose then 420mg IV q3w) and trastuzumab (8 mg/kg IV loading dose then 4mg/kg IV q3w) were given along with doectaxel for 4 cycles (8 cycles of chemotherapy in total prior to surgery). Following surgery, participants received adjuvant treatment with pertuzumab and trastuzumab IV q3w (up to 13 cycles), for a total of 17 cycles of pertuzumab and trastuzumab therapy during the study. Radiotherapy and adjuvant hormonal therapy were also given as clinically indicated. Following treatment completion/discontinuation, participants were followed for safety and efficacy for up to 5 years.
Drug: 5-Fluorouracil
Participants will receive 5-fluorouracil 500 mg/m^2 IV on Day 1 of each cycle q3w.

Drug: Cyclophosphamide
Participants will receive cyclophosphamide 600 milligrams per square meter (mg/m^2) intravenous (IV) given on Day 1 of each cycle q2w.

Drug: Docetaxel
Participants will receive docetaxel at a starting dose of 75 mg/m^2 IV for the first cycle and the dose may be escalated to 100 mg/m^2 for subsequent cycles q3w.

Drug: Epirubicin
Participants will receive epirubicin 100 mg/m^2 IV on Day 1 of each cycle q3w.

Drug: Pertuzumab
Participants will receive pertuzumab at a loading dose of 840 milligrams (mg) IV loading dose, then 420 mg IV q3w.
Other Name: Perjeta

Drug: Trastuzumab
Participants will receive trastuzumab at a loading dose of 8 milligrams per kilogram (mg/kg) IV, then 6 mg/kg IV q3w.
Other Name: Herceptin




Primary Outcome Measures :
  1. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Neoadjuvant Treatment Period [ Time Frame: From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks) ]
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from first dose of pertuzumab/trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab/trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever was later.

  2. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Neoadjuvant Treatment Period [ Time Frame: From day of first dose of pertuzumab or trastuzumab until the end of the neoadjuvant treatment period (as defined in the description; up to 25 weeks) ]
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals (CIs) were calculated using the Clopper-Pearson method. Results include events with onset from the first dose of pertuzumab or trastuzumab prior to surgery through the day before the first dose of any study drug after surgery. If participant withdrew without entering adjuvant period, results included all events with onset from first dose of pertuzumab or trastuzumab through 42 days after last dose of any study drug or on the day of target surgery whichever is later.


Secondary Outcome Measures :
  1. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Adjuvant Treatment Period [ Time Frame: From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) ]
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.

  2. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Adjuvant Treatment Period [ Time Frame: From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) ]
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method. Results included events with onset from the first dose of any study drug after surgery through 42 days after the last dose of any study drug.

  3. Percentage of Participants With at Least One Event of New York Heart Association (NYHA) Class III or IV Heart Failure During the Treatment-Free Follow-Up Period [ Time Frame: From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years) ]
    Symptomatic left ventricular systolic dysfunction (otherwise referred to as heart failure) is a serious adverse event. The NYHA Functional Classification System for Heart Failure considers the patient's symptoms: Class III: Marked limitation of physical activity; Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV: Unable to carry on any physical activity without discomfort; Symptoms of heart failure at rest; If any physical activity is undertaken, discomfort increases. The 95% CIs were calculated with the Clopper-Pearson method.

  4. Percentage of Participants With at Least One Left Ventricular Ejection Fraction (LVEF) Significant Decline, Defined as a Drop in LVEF of at Least 10 Percentage Points From Baseline and to Below 50%, During the Treatment-Free Follow-Up Period [ Time Frame: From 42 days after the last dose of study treatment until the end of treatment-free follow-up (up to 5 years) ]
    LVEF significant decline was defined as the decline in LVEF of >/= 10%-points from baseline to an LVEF of < 50%. A Confirmed LVEF Significant Decline was defined as at least two consecutive readings of significant declines in LVEF. A Single LVEF Significant Decline was defined as only one reading of a significant decline (no consecutive readings) in LVEF. The category of 'At Least one LVEF Significant Decline Event' was defined as the total of confirmed and single LVEF significant declines. The 95% confidence intervals were calculated using the Clopper-Pearson method.

  5. Overview of the Number of Participants With at Least One Adverse Event During the Neoadjuvant Period [ Time Frame: From first dose of any study drug prior to surgery through the day before the first dose of study drug after surgery (up to 25 weeks) ]
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.

  6. Overview of the Number of Participants With at Least One Adverse Event During the Adjuvant Period [ Time Frame: From the first dose of any study drug after surgery through 42 days after the last dose of any study drug (during the adjuvant treatment period; up to approximately 39 weeks) ]
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous with respect to an AE. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), whereas a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness needed to be independently assessed for each AE that was recorded. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as an AE with the term of ejection fraction decreased). In the results table, multiple occurrences of the same AE in one individual were counted only once. Any AE includes all serious and non-serious AEs.

  7. Overview of the Number of Participants With at Least One Adverse Event During the Treatment-Free Follow-Up Period [ Time Frame: From 42 days after the last dose of study treatment until the end of treatment-free follow-up (TFFU; up to 5 years) ]
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal attribution. The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (rated according to NCI-CTCAE v4.0 criteria or, if not listed, the following scale: Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to AE), and a serious AE (SAE) is a significant medical event (per standard criteria). Severity and seriousness were independently assessed for each AE. Selected AEs for reporting included heart failure (NYHA Class II/III/IV) and asymptomatic declines in LVEF (reported as ejection fraction decreased). During TFFU, only heart failure, pregnancies, and non-breast-related second primary malignancies, irrespective of causal relationship with study treatment, and drug-related SAEs were reported. Multiple occurrences of the same AE in 1 subject were counted only once.

  8. Percentage of Participants Positive for Anti-Therapeutic Antibodies (ATAs) to Pertuzumab at Baseline and Anytime Post-Baseline [ Time Frame: Screening (baseline) then prior to pertuzumab infusion (Hour 0) in Cycles 5, 14, 18 thereafter anytime between Cycle 8 Day 21 and surgery, up to treatment completion visit (cycle length=2-3 weeks; up to approximately 1 year, 3 months) ]
    ATAs to pertuzumab in serum samples were detected using a validated bridging enzyme-linked immunosorbent assay (ELISA) method. This analysis only included participants with an ATA assay result from a baseline sample and/or at least one post-baseline sample.

  9. Percentage of Participants With Total Pathologic Complete Response (tpCR), Evaluated After Surgery [ Time Frame: After completion of neoadjuvant treatment and surgery (up to 25 weeks) ]
    Total pathologic complete response (tpCR) was the pCR based on tumor and nodal staging (i.e., histological confirmation of pCR in breast and nodes at surgery) and was defined as the absence of any residual invasive cancer in the breast and the absence of any metastatic cells in the regional lymph nodes (i.e., ypT0/is ypN0 tpCR). Participants who did not undergo surgery or did not have a valid pCR assessment were considered non-responders in the analysis. The 95% CIs were calculated using the Clopper-Pearson method.

  10. Percentage of Participants With Clinical Response as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 During the Neoadjuvant Treatment Period [ Time Frame: From Baseline until disease progression or death due to any cause up to 24 weeks (during the neoadjuvant treatment period; assessed on Day 1 of Cycles 1-8 [cycle length=2-3 weeks]) ]
    The clinical response rate was defined as the percentage of participants in the ITT population who achieved a complete response (CR) or partial response (PR) prior to surgery, according to RECIST v1.1. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of the longest diameter compared to Baseline. Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient (20%) increase to qualify for disease progression, in addition to no new target lesions. Progressive Disease (PD): at least a 20% increase in the sum of the longest diameter, taking as reference the smallest sum of the longest diameter observed at previous tumor assessment, or the appearance of any new lesions. Participants were classified as missing or unevaluable if no assessments were measured prior to surgery on the ipsilateral breast. The 95% CIs were calculated using the Clopper-Pearson method; they were only calculated for responses (not for missing or unevaluable data).

  11. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Event-Free Survival (EFS) at 1 to 5 Years, Determined by the Investigator According to RECIST v1.1 [ Time Frame: At 1, 2, 3, 4, and 5 years ]
    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Event-free survival (EFS) was defined as the time from enrollment to the first occurrence of progressive disease (PD), relapse, or death from any cause, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be free from progressive disease or relapse. Participants with no tumor evaluations after baseline were censored at the date of enrollment plus 1 day.

  12. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Invasive Disease-Free Survival (iDFS) at 1 to 4 Years, Determined by the Investigator According to RECIST v1.1 [ Time Frame: At 1, 2, 3, and 4 years ]
    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Invasive disease-free survival (iDFS) was defined as the time from the first date of no disease (the date of surgery) to the first documentation of progressive invasive disease, relapse, or death, with tumor evaluations performed by the investigator according to RECIST v1.1. Ipsilateral or contralateral in situ disease and second primary non-breast cancers (including in situ carcinomas and non-melanoma skin cancers) were not counted as progressive disease or relapse. Participants who withdrew from the study without documented progression or relapse and for whom there existed evidence that evaluations had been made, were censored at the date of the last assessment at which the participant was known to be alive and disease-free. Participants with no postbaseline information and participants who did not undergo surgery were excluded from the analysis.

  13. Kaplan-Meier Estimate of the Percentage of Participants Event-Free for Overall Survival (OS) at 1 to 5 Years [ Time Frame: At 1, 2, 3, 4, and 5 years ]
    The Kaplan-Meier method was used to estimate the percentage of participants who were event-free at landmark timepoints. Overall survival (OS) was defined as the time from enrollment to death from any cause. Participants who were alive or lost to follow-up were censored at their last known date in the study. Participants with no post-baseline assessments were censored at the date of enrollment plus 1 day.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male and female participants with locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer. Participants with inflammatory breast cancer must be able to have a core needle biopsy
  • Primary tumor greater than (>) 2 centimeters (cm) in diameter, or > 5 millimeters (mm) in diameter and node-positive
  • HER2-positive breast cancer confirmed by a central laboratory
  • Availability of tumor tissue specimen
  • Baseline LVEF greater than or equal to (>/=) 55%
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (</=) 1
  • At least 4 weeks since major unrelated surgery, with full recovery
  • Women of childbearing potential and male participants with partners of childbearing potential must agree to use a "highly effective" non-hormonal form of contraception or two "effective" forms of non-hormonal contraception by the patient and/or partner. Contraception must continue for the duration of study treatment and for at least 7 months after the last dose of study treatment

Exclusion Criteria:

  • Metastatic disease (Stage IV) or bilateral breast cancer
  • Participants who have had an incisional biopsy of the primary tumor or the primary tumor excised
  • Prior breast or non-breast malignancy within 5 years prior to study entry, except for carcinoma in situ and basal cell and squamous cell carcinoma of the skin. Participants with malignancies occurring more than 5 years prior to study entry are permitted if curatively treated
  • Any previous systemic therapy (including chemotherapy, immunotherapy, HER2 targeted agents, and antitumor vaccines) for cancer, or radiation therapy for cancer
  • Participants with a past history of ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) are not allowed to enter the study if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast (they are allowed to enter the study if treated with surgery alone)
  • High-risk participants who have received chemopreventive drugs in the past are not allowed to enter the study
  • Inadequate bone marrow, renal, or liver function
  • History or evidence of cardiovascular condition
  • Dyspnea at rest or other diseases that require continuous oxygen therapy
  • Severe, uncontrolled systemic disease
  • Participants with poorly controlled diabetes or with evidence of clinically significant diabetic vascular complications
  • Pregnancy or breast-feeding women
  • Participants who received any investigational treatment within 4 weeks of study start
  • Participants with known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus
  • Current chronic daily treatment with corticosteroids (dose >10 mg methylprednisolone or equivalent [excluding inhaled steroids])
  • Known hypersensitivity to any of the study drugs or excipients

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02132949


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02132949    
Other Study ID Numbers: WO29217
2014-000156-28 ( EudraCT Number )
First Posted: May 7, 2014    Key Record Dates
Results First Posted: April 13, 2017
Last Update Posted: September 17, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Docetaxel
Cyclophosphamide
Doxorubicin
Fluorouracil
Trastuzumab
Epirubicin
Pertuzumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors