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Nature Medicine Nov 2021The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a...
The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 (HER2) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2-amplified mCRC, which might especially benefit patients in first-line treatment.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Circulating Tumor DNA; Colorectal Neoplasms; Female; Gene Dosage; Genotyping Techniques; Humans; Male; Middle Aged; Prospective Studies; Receptor, ErbB-2; Translational Research, Biomedical; Trastuzumab
PubMed: 34764486
DOI: 10.1038/s41591-021-01553-w -
Gastric Cancer : Official Journal of... Jan 2014Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and... (Review)
Review
Human epidermal growth factor receptor 2 (HER2) is involved in the pathogenesis and poor outcomes of several types of cancer, including advanced gastric and gastroesophageal junction cancer. Molecular-targeted drugs, such as trastuzumab, which prolong overall survival and progression-free survival in HER2-positive breast cancer, may also be beneficial in patients with HER2-positive gastric cancer. Several studies have examined this possibility, such as the Trastuzumab for Gastric Cancer trial. In this context, the first part of this review provides an update on our knowledge of HER2 in breast and gastric cancer, including the detection and prognostic relevance of HER2 in gastric cancer. The second part of the review discusses the results of pivotal clinical trials that examined the potential for using trastuzumab to treat this disease. This section also summarizes the trials that have been conducted or that are underway to determine the optimal uses of trastuzumab in gastric cancer, including its use as monotherapy and continuation beyond disease progression. The final section discusses the future prospects of other anti-HER2 drugs, including lapatinib, trastuzumab emtansine, and pertuzumab, for the treatment of HER2-positive gastric cancer. The introduction of trastuzumab led to the establishment of a new disease entity, "HER2-positive gastric cancer," similar to HER2-positive breast cancer. It is expected that more anti-HER2 drugs will be developed and introduced into clinical practice to treat HER2-positive cancers, including gastric cancer.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Female; Humans; Lapatinib; Maytansine; Molecular Targeted Therapy; Prognosis; Quinazolines; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab
PubMed: 23563986
DOI: 10.1007/s10120-013-0252-z -
Breast Cancer Research : BCR Jan 2023KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus... (Randomized Controlled Trial)
Randomized Controlled Trial
Tumor biomarkers and efficacy in patients treated with trastuzumab emtansine + pertuzumab versus standard of care in HER2-positive early breast cancer: an open-label, phase III study (KRISTINE).
BACKGROUND
KRISTINE is an open-label, phase III study of trastuzumab emtansine + pertuzumab (T-DM1 + P) versus docetaxel + carboplatin + trastuzumab + pertuzumab (TCH + P) in patients with HER2-positive, stage II-III breast cancer. We investigated the association of biomarkers with clinical outcomes in KRISTINE.
METHODS
Patients were randomized to receive neoadjuvant T-DM1 + P or TCH + P and assessed for pathologic complete response (pCR; ypT0/is, ypN0). HER2 status (per central assessment), hormone receptor status, PIK3CA mutation status, HER2/HER3 mRNA levels, tumor-infiltrating lymphocyte levels, PD-L1 status, and NanoString data were analyzed. pCR rates by treatment arm were compared across biomarker subgroups. Analyses were descriptive.
RESULTS
Biomarker analyses included data from all 444 patients (T-DM1 + P, n = 223; TCH + P, n = 221) enrolled in KRISTINE. Biomarker distribution was balanced across treatment arms. All subgroups with higher HER2 amplification/expression and immune marker levels showed numerically higher pCR rates in both arms. Mutated versus non-mutated PIK3CA tumors were associated with numerically lower pCR rates in the T-DM1 + P arm but not in the TCH + P arm. In a multivariate analysis, Prediction Analysis of Microarray with the 50-gene classifier (PAM50) HER2-enriched subtype, HER2 gene ratio ≥ 4, and PD-L1-positive status positively influenced the pCR rate. Biomarkers associated with lower pCR rates (e.g., low HER2 levels, positive hormone receptor status, mutated PIK3CA) were more likely to co-occur. Dynamic on-treatment biomarker changes were observed. Differences in the treatment effects for T-DM1 + P versus TCH + P were similar to those observed in the intent-to-treat population for the majority of the biomarker subgroups.
CONCLUSIONS
Although our biomarker analysis did not identify a subgroup of patients that benefited from neoadjuvant T-DM1 + P versus TCH + P, the data revealed that patients with higher HER2 amplification/expression and immune marker levels had improved response irrespective of treatment arm. These analyses confirm the role of HER2 tumor biology and the immune microenvironment in influencing pCR in the neoadjuvant setting and reaffirm the molecular diversity of HER2-positive breast cancer.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02131064. Registered 06 May 2014.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Neoadjuvant Therapy; Receptor, ErbB-2; Standard of Care; Trastuzumab; Tumor Microenvironment
PubMed: 36631725
DOI: 10.1186/s13058-022-01587-z -
JAMA Oncology Sep 2022Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant... (Clinical Trial)
Clinical Trial
Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial.
IMPORTANCE
Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects.
OBJECTIVE
To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase.
DESIGN, SETTING, AND PARTICIPANTS
This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III.
INTERVENTIONS
Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks.
MAIN OUTCOMES AND MEASURES
The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes.
RESULTS
A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase.
CONCLUSIONS AND RELEVANCE
In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03881878.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Hormones; Humans; Immune Checkpoint Inhibitors; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Trastuzumab
PubMed: 35797012
DOI: 10.1001/jamaoncol.2022.2310 -
European Journal of Cancer (Oxford,... May 2022The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive... (Clinical Trial)
Clinical Trial
Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial.
AIM
The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations.
METHODS
Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention.
RESULTS
The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking.
CONCLUSIONS
STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score.
TRIAL REGISTRATION
clinicaltrials.gov Identifier NCT01358877.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 35313167
DOI: 10.1016/j.ejca.2022.01.031 -
International Journal of Molecular... Dec 2023The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to...
The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Proteomics; Neoplasm Recurrence, Local; Cell Line; Antibodies, Monoclonal, Humanized
PubMed: 38203378
DOI: 10.3390/ijms25010207 -
Medicine May 2017The development of targeted therapies benefits patients with certain markers in the treatment of breast cancer. Pertuzumab is a novel humanized monoclonal antibody that... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The development of targeted therapies benefits patients with certain markers in the treatment of breast cancer. Pertuzumab is a novel humanized monoclonal antibody that blocks human epidermal growth factor receptor 2 (HER2) dimerization. The Food and Drug Administration has approved pertuzumab in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer.
METHODS
To assess the safety and efficacy profile of pertuzumab, we searched PubMed and Embase (articles from January 1966 to January 2015) using the keyword "pertuzumab".
RESULTS
Fourteen eligible studies were included in our final analysis. From the results of our analysis, diarrhea (56.9%, 95% confidence interval [CI] 49.6%-63.9%), nausea (34.0%, 95% CI 27.7%-40.8%), and rash (25.6%, 95% CI 20.8%-31.0%) were the most common adverse effects in pertuzumab alone and pertuzumab-based therapies. Based on randomized controlled clinical trials, diarrhea (odds ratio [OR] 2.310, 95% CI 1.818-2.936), rash (OR 1.848, 95% CI 1.094-3.122), and febrile neutropenia (OR 1.672, 95% CI 1.130-2.474) were of statistical significance, which meant that pertuzumab played a prominent role in the incidence of diarrhea. Meanwhile, pertuzumab showed its effective role in cancer control and lifetime prolongation.
CONCLUSION
In conclusion, considering that the common adverse effects for pertuzumab are gastrointestinal and skin toxicities, which are easier to handle than other toxicities, pertuzumab is a safe and effective drug for patients with solid tumors.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Humans; Neoplasms; Randomized Controlled Trials as Topic
PubMed: 28514302
DOI: 10.1097/MD.0000000000006870 -
Anais Da Academia Brasileira de Ciencias 2016It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast... (Review)
Review
It has now been 15 years since the HER2-targeted monoclonal antibody trastuzumab was introduced in clinical and revolutionized the treatment of HER2-positive breast cancer patients. Despite this achievement, most patients with HER2-positive metastatic breast cancer still show progression of their disease, highlighting the need for new therapies. The continuous interest in novel targeted agents led to the development of pertuzumab, the first in a new class of agents, the HER dimerization inhibitors. Pertuzumab is a novel recombinant humanized antibody directed against extracellular domain II of HER2 protein that is required for the heterodimerization of HER2 with other HER receptors, leading to the activation of downstream signalling pathways. Pertuzumab combined with trastuzumab plus docetaxel was approved for the first-line treatment of patients with HER2-positive metastatic breast cancer and is currently used as a standard of care in this indication. In the neoadjuvant setting, the drug was granted FDA-accelerated approval in 2013. Pertuzumab is also being evaluated in the adjuvant setting. The potential of pertuzumab relies in the dual complete blockade of the HER2/3 axis when administered with trastuzumab. This paper synthetises preclinical and clinical data on pertuzumab and highlights the mechanisms underlying the synergistic activity of the combination pertuzumab-trastuzumab which are essentially due to their complementary mode of action.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Female; Humans; Receptor, ErbB-2; Taxoids; Trastuzumab
PubMed: 27275646
DOI: 10.1590/0001-3765201620150178