Clinical and molecular characteristics of human epidermal growth factor receptor 2-positive and human epidermal growth factor receptor 2-negative breast cancer

Lead Investigator: Sheng Luo, Duke University
Title of Proposal Research: Clinical and molecular characteristics of human epidermal growth factor receptor 2-positive and human epidermal growth factor receptor 2-negative breast cancer
Vivli Data Request: 8180
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Background
Breast cancer is the most commonly diagnosed cancer in women worldwide, contributing about 11.7% of the total number of new cases diagnosed in 2020. Because of its high incidence, the clinical treatment of breast cancer is always an area of active investigation. According to the expression of human epidermal growth factor receptor 2 (HER2), breast cancer can be separated into HER2-positive and HER2-negative breast cancer. In particular, about 15-20% of all invasive breast cancers are HER2-positive. HER2-positive is defined as a tumor with HER2 overexpression as measured by ImmunoHistoChemistry (IHC) or in situ hybridization assay (ISH). IHC is a staining process performed on breast cancer tissue removed during biopsy and is used to show whether or not the cancer cells have HER2 receptors and/or hormone receptors on their surface. ISH is a technique used to identify specific genes within the tissue by a process called gene amplification. The overexpressed HER2 results in a more aggressive cancer with a worse prognosis and higher recurrence rate in the absence of therapy in breast cancer patients.

As the development of HER2 targeted agents, including antibody-drug, vaccine and small molecule drugs, the prognosis of the HER2-positive breast cancer has been improved to some extent. However, HER-2 positive patients with an IHC score of 3+ or 2+ and a positive ISH assay have responded to conventional anti-HER2 drugs, but the efficacy of conventional anti-HER2 drugs was not satisfactory. Furthermore, no HER-2-targeted therapy is recommended for clinical treatment for the majority of breast cancer patients either with an IHC score of 0 or 1+, or with an IHC score of 2+ with a negative ISH assay. It is very important to investigate clinical and molecular characteristics of HER2-positive and HER2-negative breast cancer to guide the clinical treatment in breast cancer patients. Hormone receptors (HR) and HER2 are both important markers in breast-cancer, and they have an effect on whether the cancer responds to treatment. Previous studies have found that most HER2-negative tumors are HR-positive, and low expression of HER2 was more common in HR-positive tumors versus tumors that are negative for HER2, HR and to ISH, both in primary and recurrent tumors. Therefore, there is a potential relationship between HR status and the efficacy of anti-HER2 treatment. The subgroup analysis of previous clinical trials demonstrated contradictory results on whether the efficacy of anti-HER2 treatment is independent of HR status, and no study has so far directly compared the outcome of anti-HER2 treatment between HR-positive and HR-negative breast cancer patients. It is imperative to address this important knowledge gap, which will help provide the evidence for the treatment guidance for breast cancer.

Clinical implications
It remains controversial whether HER2-positive and HER2-negative breast cancer patients with distinct HR expression patterns benefit differently from anti-HER2 agents. This study will provide more data to address this question and may guide treatment choices and trial design for these patients.

Statistical Analysis Plan:

Data extraction
Individual patient data on date of trial initiation, date of last follow-up, patient characteristics (e.g., sex, age, ER and PR status at initial diagnosis/metastatic disease, grade, stage, performance status, previous treatment, metastatic sites, number of metastatic sites, interventions, and study outcomes (including pCR rate, dDFS, OS) of each participant as well as the duration from the primary surgery to the disease recurrence/death or study ends in eligible trials will be extracted.

Data analysis
Analyses of all endpoints and subgroups are carried out on an intention-to-treat basis. Participants in each trial are first split into two subgroups (HR-positive and HR-negative), and a meta-analysis of effects in HR-positive patients is compared with a meta-analysis of effects in HR-negative patients for each endpoint separately. The times to event (distant relapse or death) for each individual are used within trials to calculate the hazard ratios, and pooled hazard ratios are calculated stratified by study. We will synthesize hazard ratios based on the random effect model. We will use Chi-square heterogeneity tests to assess statistical heterogeneity across trials and calculate the I2 statistics to measure any inconsistency between the trials. If there’s heterogeneity among studies, we will test for endpoints stratifies by the study and study will be include in the regression models. For the OS and dDFS, we will perform the adjusted Cox regression analysis by study to compare the OS or dDFS in HER2 negative vs. HER2 positive subgroups given the overall level or different HR status. Also, we will compare the pCR for the patients who received neoadjuvant therapy using multivariable logistic regression given the overall level and different HR status. Missing covariate data will be imputed using multiple imputation by chained equations (MICE). Missing outcome data will be treated as censored data and they will be accounted for in the survival models.

Requested Studies:

A Phase 1, Multicenter, Open-label, Single Sequence Crossover Study to Evaluate Drug-drug Interaction Potential of OATP1B/CYP3A Inhibitor on the Pharmacokinetics of DS-8201a in Subjects With HER2-expressing Advanced Solid Malignant Tumors
Data Contributor: Daiichi Sankyo
Study ID: NCT03383692
Sponsor ID: DS8201-A-A104

A Phase 2, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1 (DESTINY-Breast01)
Data Contributor: Daiichi Sankyo
Study ID: NCT03248492
Sponsor ID: DS8201-A-U201

A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab and Taxane Based Therapy
Data Contributor: Roche
Study ID: NCT02924883
Sponsor ID: WO30085

monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib Plus Trastuzumab With or Without Fulvestrant to Standard-of-Care Chemotherapy of Physician’s Choice Plus Trastuzumab in Women With HR+, HER2+ Locally Advanced or Metastatic Breast Cancer
Data Contributor: Lilly
Study ID: NCT02675231
Sponsor ID: 15804

A Phase III, Double-Blind, Placebo-Controlled, Randomized Study of Taselisib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women With Estrogen Receptor-Positive and HER2-Negative Locally Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy
Data Contributor: Roche
Study ID: NCT02340221
Sponsor ID: GO29058

A Multistage, Phase II Study Evaluating the Safety and Efficacy of Cobimetinib Plus Paclitaxel, Cobimetinib Plus Atezolizumab Plus Paclitaxel, or Cobimetinib Plus Atezolizumab Plus Nab-Paclitaxel as First-Line Treatment for Patients With Metastatic Triple-Negative Breast Cancer
Data Contributor: Roche
Study ID: NCT02322814
Sponsor ID: WO29479

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
Data Contributor: Roche
Study ID: NCT02132949
Sponsor ID: WO29217

A Randomized, Multicenter, Open-Label, Two-Arm, Phase III Neoadjuvant Study Evaluating Trastuzumab Emtansine Plus Pertuzumab Compared With Chemotherapy Plus Trastuzumab and Pertuzumab for Patients With HER2-Positive Breast Cancer
Data Contributor: Roche
Study ID: NCT02131064
Sponsor ID: BO28408

MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 3 TRIAL OF FULVESTRANT (FASLODEX (REGISTERED)). WITH OR WITHOUT PD-0332991 (PALBOCICLIB) +/- GOSERELIN IN WOMEN WITH HORMONE RECEPTOR-POSITIVE, HER2-NEGATIVE METASTATIC BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE THERAPY
Data Contributor: Pfizer
Study ID: NCT01942135
Sponsor ID: A5481023

A Randomized, Multicenter, Open-Label Phase III Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy for Patients With HER2-Positive Primary Breast Cancer Who Have Residual Tumor Present Pathologically in the Breast or Axillary Lymph Nodes Following Preoperative Therapy
Data Contributor: Roche
Study ID: NCT01772472
Sponsor ID: BO27938

A RANDOMIZED, MULTICENTER, DOUBLE-BLIND PHASE 3 STUDY OF PD-0332991 (ORAL CDK 4/6 INHIBITOR) PLUS LETROZOLE VERSUS PLACEBO PLUS LETROZOLE FOR THE TREATMENT OF POSTMENOPAUSAL WOMEN WITH ER (+), HER2 (-) BREAST CANCER WHO HAVE NOT RECEIVED ANY PRIOR SYSTEMIC ANTI CANCER TREATMENT FOR ADVANCED DISEASE
Data Contributor: Pfizer
Study ID: NCT01740427
Sponsor ID: A5481008

A Two-Cohort, Open-Label, Multicenter Study of Trastuzumab Emtansine (T-DM1) in HER2-Positive Locally Advanced or Metastatic Breast Cancer Patients Who Have Received Prior Anti-HER2 and Chemotherapy-Based Treatment
Data Contributor: Roche
Study ID: NCT01702571
Sponsor ID: MO28231

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT01663727
Sponsor ID: GO25632

A Randomized, Multicenter, Adaptive Phase II/III Study To Evaluate The Efficacy And Safety Of Trastuzumab Emtansine (T-DM1) Versus Taxane (Docetaxel Or Paclitaxel) In Patients With Previously Treated Locally Advanced Or Metastatic HER2-Positive Gastric Cancer, Including Adenocarcinoma Of The Gastroesophageal Junction
Data Contributor: Roche
Study ID: NCT01641939
Sponsor ID: BO27952

A Phase III Prospective, Two-Cohort Non-Randomized, Multi-Centre, Multinational, Open-Label Study to Assess the Safety of Assisted- and Self-Administered Subcutaneous Trastuzumab as Therapy in Patients With Operable HER2-Positive Early Breast Cancer
Data Contributor: Roche
Study ID: NCT01566721
Sponsor ID: MO28048

A Randomized, Two-Arm, Open-Label, Multicenter Phase II Trial Assessing the Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab Plus an Aromatase Inhibitor in First Line Patients With HER2-Positive and Hormone Receptor-Positive Advanced (Metastatic or Locally Advanced) Breast Cancer
Data Contributor: Roche
Study ID: NCT01491737
Sponsor ID: MO27775

A Phase III Randomized, Multicenter, Two Arm, Open-label Trial to Evaluate the Efficacy of Trastuzumab Emtansine Compared With Treatment of Physician’s Choice in Patients With HER2-positive Metastatic Breast Cancer Who Have Received at Least Two Prior Regimens of HER2 Directed Therapy
Data Contributor: Roche
Study ID: NCT01419197
Sponsor ID: BO25734

A Randomized, Multi-Center Cross-Over Study to Evaluate Patient Preference and Health Care Professional (HCP) Satisfaction With Subcutaneous (SC) Administration of Trastuzumab in HER2-Positive Early Breast Cancer (EBC)
Data Contributor: Roche
Study ID: NCT01401166
Sponsor ID: MO22982

A Randomized Multicenter, Double-Blind, Placebo-Controlled Comparison of Chemotherapy Plus Trastuzumab Plus Placebo Versus Chemotherapy Plus Trastuzumab Plus Pertuzumab as Adjuvant Therapy in Patients With Operable HER2-Positive Primary Breast Cancer
Data Contributor: Roche
Study ID: NCT01358877
Sponsor ID: BO25126

An Observational Study of Cardiac Events in Patients With HER2 Positive Early Breast Cancer Treated With Herceptin
Data Contributor: Roche
Study ID: NCT01152606
Sponsor ID: BO20652

A Randomized, 3 Arm, Multicenter, Phase III Study to Evaluate the Efficacy and the Safety of T-DM1 Combined With Pertuzumab or T-DM1 Combined With Pertuzumab-Placebo (Blinded for Pertuzumab), Versus the Combination of Trastuzumab Plus Taxane, as First Line Treatment in HER2 Positive Progressive or Recurrent Locally Advanced or Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT01120184
Sponsor ID: BO22589

A Multicenter Randomized Phase III Study to Compare the Combination Trastuzumab and Capecitabine, With or Without Pertuzumab, in Patients With HER2-Positive Metastatic Breast Cancer That Have Progressed After One Line of Trastuzumab-Based Therapy in the Metastatic Setting (PHEREXA)
Data Contributor: Roche
Study ID: NCT01026142
Sponsor ID: MO22324

A Randomised, Multicentre, Multinational Phase II Study to Evaluate Pertuzumab in Combination With Trastuzumab, Given Either Concomitantly or Sequentially With Standard Anthracycline-based Chemotherapy or Concomitantly With a Non-anthracycline-based Chemotherapy Regimen, as Neoadjuvant Therapy for Patients With Locally Advanced, Inflammatory or Early Stage HER2-positive Breast Cancer
Data Contributor: Roche
Study ID: NCT00976989
Sponsor ID: BO22280

A Phase III, Randomized Open-Label Study to Compare the Pharmacokinetics, Efficacy, and Safety of Subcutaneous (SC) Trastuzumab With Intravenous (IV) Trastuzumab Administered in Women With HER2-Positive Early Breast Cancer (EBC)
Data Contributor: Roche
Study ID: NCT00950300
Sponsor ID: BO22227

A Phase II, Open-Label Study to Evaluate Corrected QT Interval Effects of Trastuzumab-MCC-DM1 (T-DM1) in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer and to Evaluate the Safety and Tolerability of Combined T-DM1 and Pertuzumab in Patients With Early Disease Progression While Receiving T-DM1 Alone
Data Contributor: Roche
Study ID: NCT00943670
Sponsor ID: TDM4688g

An Open-Label, Multi-Center Phase I/II Study of the Safety and Tolerability of the Combination of Trastuzumab-MCC-DM1 (T-DM1) With Docetaxel, and Potentially Pertuzumab, for Treatment for Patients With Advanced Breast Cancer
Data Contributor: Roche
Study ID: NCT00934856
Sponsor ID: BP22572

A Randomized, Multicenter, Phase III Open-label Study of the Efficacy and Safety of Trastuzumab MCC-DM1 vs. Capecitabine + Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab-Based Therapy
Data Contributor: Roche
Study ID: NCT00829166
Sponsor ID: BO21977

PHASE 1/2, OPEN-LABEL, RANDOMIZED STUDY OF THE SAFETY, EFFICACY, AND PHARMACOKINETICS OF LETROZOLE PLUS PD 0332991 (ORAL CDK 4/6 INHIBITOR) AND LETROZOLE SINGLE AGENT FOR THE FIRST-LINE TREATMENT OF ER POSITIVE, HER2 NEGATIVE ADVANCED BREAST CANCER IN POSTMENOPAUSAL WOMEN
Data Contributor: Pfizer
Study ID: NCT00721409
Sponsor ID: A5481003

A Multicenter, Multinational, Randomized, Double-Blind, Phase III Study of IMC-1121B Plus Docetaxel Versus Placebo Plus Docetaxel in Previously Untreated Patients With HER2-Negative, Unresectable, Locally-Recurrent or Metastatic Breast Cancer
Data Contributor: Lilly
Study ID: NCT00703326
Sponsor ID: 13892

A Randomized, Multicenter, Phase ii Study of the Efficacy and Safety of Trastuzumab-MCC-DM1 vs. Trastuzumab (Herceptin®) and Docetaxel (Taxotere®) in Patients With Metastatic HER2-positive Breast Cancer Who Have Not Received Prior Chemotherapy for Metastatic Disease
Data Contributor: Roche
Study ID: NCT00679341
Sponsor ID: BO21976

A Phase II, Single-Arm, Open-Label Study of Trastuzumab-Mcc-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT00679211
Sponsor ID: TDM4374g

A Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Efficacy and Safety of Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated HER2-Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT00567190
Sponsor ID: TOC4129g

A Randomized, Open Label Study to Compare the Complete Pathological Response Rate Achieved With 4 Combinations of Herceptin, Docetaxel and Pertuzumab in Patients With Locally Advanced, Inflammatory or Early Stage HER2 Positive Breast Cancer
Data Contributor: Roche
Study ID: NCT00545688
Sponsor ID: WO20697

An International Multi-centre Open-label 2-arm Phase III Trial of Adjuvant Bevacizumab in “Triple Negative” Breast Cancer.
Data Contributor: Roche
Study ID: NCT00528567
Sponsor ID: BO20289

A Phase II, Single-arm, Open-label Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Progressed While Receiving HER2-Directed Therapy
Data Contributor: Roche
Study ID: NCT00509769
Sponsor ID: TDM4258g

A Randomized, Open-label Study to Compare the Effect of First-line Treatment With Avastin in Combination With Herceptin/Docetaxel and Herceptin/Docetaxel Alone on Progression-free Survival in Patients With HER2 Positive Locally Recurrent or Metastatic Breast Cancer.
Data Contributor: Roche
Study ID: NCT00391092
Sponsor ID: BO20231

A Randomised, Double Blind, Placebo Controlled, Multicentre Study to Evaluate the Efficacy and Safety of Bevacizumab in Combination With Docetaxel in Comparison With Docetaxel Plus Placebo, as First Line Treatment for Patients With HER2 Negative Metastatic and Locally Recurrent Breast Cancer.
Data Contributor: Roche
Study ID: NCT00333775
Sponsor ID: BO17708

A Randomized Three-Arm, Multicenter Comparison of 1 Year and 2 Years of Herceptin Versus No Herceptin in Women With HER2-Positive Primary Breast Cancer Who Have Completed Adjuvant Chemotherapy
Data Contributor: Roche
Study ID: NCT00045032
Sponsor ID: BO16348

A Randomized, Open-label Study of the Effect of Herceptin Plus Arimidex Compared With Arimidex Alone on Progression-free Survival in Patients With HER2-positive and Hormone-receptor Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: NCT00022672
Sponsor ID: BO16216

A Multicenter, Randomized Comparative Study on the Efficacy and Safety of Herceptin (Trastuzumab) Plus Docetaxel (Taxotere) Versus Docetaxel Alone as First Line Treatment in Patients with HER2-Positive Metastatic Breast Cancer
Data Contributor: Roche
Study ID: M77001
Sponsor ID: M77001

A multicenter, expanded access, open-label safety study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2 overexpression who relapsed following multiple cytotoxic chemotherapy regimens for metastatic breast cancer.
Data Contributor: Roche
Study ID: H0693G
Sponsor ID: H0693G

A multicenter, open-label, single-arm phase II study of safety and efficacy of a once three-weekly regimen of Herceptin monotherapy in patients with HER2-overexpressing metastatic breast cancer
Data Contributor: Roche
Study ID: WO16229
Sponsor ID: WO16229

An open-label, randomized phase II study of Herceptin (trastuzumab), Taxotere (docetaxel) and Xeloda (capecitabine) in combination, versus Herceptin (trastuzumab) plus Taxotere (docetaxel), in patients with advanced and/or metastatic breast cancers that overexpress HER2.
Data Contributor: Roche
Study ID: MO16419
Sponsor ID: MO16419

An open-label extension study with recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) for patients whose metastatic breast cancer progressed during treatment on protocol H0648g.
Data Contributor: Roche
Study ID: H0659G
Sponsor ID: H0659G

A multinational randomized single-blind study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2lneu overexpression who have not received prior cytotoxic chemotherapy for metastatic breast cancer.
Data Contributor: Roche
Study ID: H0650G
Sponsor ID: H0650G

A multinational open-label study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) in patients with HER2lneu overexpression who have relapsed following one or two cytotoxic chemotherapy regimens for metastatic breast cancer.
Data Contributor: Roche
Study ID: H0649G
Sponsor ID: H0649G

Chemotherapy and Antibody Response Evaluation (CARE): A phase III, multinational, randomized study of recombinant humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) combined with chemotherapy in patients with HER2 overexpression who have not received cytotoxic chemotherapy for metastatic breast cancer.
Data Contributor: Roche
Study ID: H0648G
Sponsor ID: H0648G

A randomized, open-label study of the effect of different doses of pertuzumab on treatment response in patients with metastatic breast cancer with low HER2 expression
Data Contributor: Roche
Study ID: BO16934
Sponsor ID: BO16934

Public Disclosures:

Li, H., Wu, Y., Zou, H., Koner, S., Plichta, J.K., Tolaney, S.M., Zhang, J., He, Y.W., Wei, Q., Tang, L. and Zhang, H., 2024. Clinical efficacy of CDK4/6 inhibitor plus endocrine therapy in HR-positive/HER2-0 and HER2-low-positive metastatic breast cancer: a secondary analysis of PALOMA-2 and PALOMA-3 trials. EBioMedicine, 105. Doi : 10.1016/j.ebiom.2024.105186

Summary of results:

We did not find enough information for Her 2 negative research by utilizing the data from Lilly, Daiichi Sankyo, and Roche under this research.