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JAMA Oncology Jul 2023Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy of Endocrine Therapy Plus Trastuzumab and Pertuzumab vs De-escalated Chemotherapy in Patients with Hormone Receptor-Positive/ERBB2-Positive Early Breast Cancer: The Neoadjuvant WSG-TP-II Randomized Clinical Trial.
IMPORTANCE
Combination of chemotherapy with (dual) ERBB2 blockade is considered standard in hormone receptor (HR)-positive/ERBB2-positive early breast cancer (EBC). Despite some promising data on endocrine therapy (ET) combination with dual ERBB2 blockade in HR-positive/ERBB2-positive BC, to our knowledge, no prospective comparison of neoadjuvant chemotherapy vs ET plus ERBB2 blockade in particular with focus on molecular markers has yet been performed.
OBJECTIVE
To determine whether neoadjuvant de-escalated chemotherapy is superior to endocrine therapy, both in combination with pertuzumab and trastuzumab, in a highly heterogeneous HR-positive/ERBB2-positive EBC.
DESIGN, SETTING, AND PARTICIPANTS
This prospective, multicenter, neoadjuvant randomized clinical trial allocated 207 patients with centrally confirmed estrogen receptor-positive and/or progesterone receptor-positive (>1%) HR-positive/ERBB2-positive EBC to 12 weeks of standard ET (n = 100) vs paclitaxel (n = 107) plus trastuzumab and pertuzumab. A total of 186 patients were required to detect a statistically significant difference in pathological complete response (pCR) (assumptions: 19% absolute difference in pCR; power, ≥80%; 1-sided Fisher exact test, 2.5% significance level).
INTERVENTIONS
Standard ET (aromatase inhibitor or tamoxifen) or paclitaxel, 80 mg/m2, weekly plus trastuzumab and pertuzumab every 21 days.
MAIN OUTCOMES AND MEASURES
The primary end point was pCR (ypT0/is, ypN0). Secondary end points included safety, translational research, and health-related quality of life. Omission of further chemotherapy was allowed in patients with pCR. PAM50 analysis was performed on baseline tumor biopsies.
RESULTS
Of the 207 patients included (median [range] age, 53 [25-83] years), 121 (58%) had cT2 to cT4 tumors, and 58 (28%) had clinically node-positive EBC. The pCR rate in the ET plus trastuzumab and pertuzumab arm was 23.7% (95% CI, 15.7%-33.4%) vs 56.4% (95% CI, 46.2%-66.3%) in the paclitaxel plus trastuzumab and pertuzumab arm (odds ratio, 0.24; 95% CI, 0.12-0.46; P < .001). Both immunohistochemical ERBB2 score of 3 or higher and ERBB2-enriched subtype were independent predictors for pCR in both arms. Paclitaxel was superior to ET only in the first through third quartiles but not in the highest ERBB2 quartile by messenger RNA. In contrast with the paclitaxel plus trastuzumab and pertuzumab arm, no decrease in health-related quality of life after 12 weeks was observed in the ET plus trastuzumab and pertuzumab arm.
CONCLUSIONS AND RELEVANCE
The WSG-TP-II randomized clinical trial is, to our knowledge, the first prospective trial comparing 2 neoadjuvant de-escalation treatments in HR-positive/ERBB2-positive EBC and demonstrated an excellent pCR rate after 12 weeks of paclitaxel plus trastuzumab and pertuzumab that was clearly superior to the pCR rate after ET plus trastuzumab and pertuzumab.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03272477.
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Neoadjuvant Therapy; Paclitaxel; Quality of Life; Receptor, ErbB-2; Trastuzumab
PubMed: 37166817
DOI: 10.1001/jamaoncol.2023.0646 -
Annals of Oncology : Official Journal... Sep 2023The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the...
BACKGROUND
The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status.
MATERIALS AND METHODS
Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status.
RESULTS
HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk.
CONCLUSIONS
HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Treatment Outcome; Trastuzumab; Taxoids; Neoadjuvant Therapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37302750
DOI: 10.1016/j.annonc.2023.05.012 -
Nature Communications Mar 2024The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.
Topics: Female; Humans; Adjuvants, Immunologic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Trastuzumab
PubMed: 38461323
DOI: 10.1038/s41467-024-45591-7 -
The Journal of Clinical Investigation Feb 2024BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical... (Clinical Trial)
Clinical Trial
BACKGROUNDHER2-targeting therapies have great efficacy in HER2-positive breast cancer, but resistance, in part due to HER2 heterogeneity (HET), is a significant clinical challenge. We previously described that in a phase II neoadjuvant trastuzumab emtansine (T-DM1) and pertuzumab (P) clinical trial in early-stage HER2-positive breast cancer, none of the patients with HER2-HET tumors had pathologic complete response (pCR).METHODSTo investigate cellular and molecular differences among tumors according to HER2 heterogeneity and pCR, we performed RNA sequencing and ERBB2 FISH of 285 pretreatment and posttreatment tumors from 129 patients in this T-DM1+P neoadjuvant trial. A subset of cases was also subject to NanoString spatial digital profiling.RESULTSPretreatment tumors from patients with pCR had the highest level of ERBB2 mRNA and ERBB signaling. HER2 heterogeneity was associated with no pCR, basal-like features, and low ERBB2 expression yet high ERBB signaling sustained by activation of downstream pathway components. Residual tumors showed decreased HER2 protein levels and ERBB2 copy number heterogeneity and increased PI3K pathway enrichment and luminal features. HET tumors showed minimal treatment-induced transcriptomic changes compared with non-HET tumors. Immune infiltration correlated with pCR and HER2-HET status.CONCLUSIONResistance mechanisms in HET and non-HET tumors are distinct. HER2-targeting antibodies have limited efficacy in HET tumors. Our results support the stratification of patients based on HET status and the use of agents that target downstream components of the ERBB signaling pathway in patients with HET tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT02326974.FUNDINGThis study was funded by Roche and the National Cancer Institute.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Receptor, ErbB-2; Trastuzumab
PubMed: 38300710
DOI: 10.1172/JCI176454 -
Bladder (San Francisco, Calif.) 2023Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC)... (Review)
Review
Urothelial carcinoma (UC) represents a common malignancy of the urinary system that can involve the kidneys, ureter, bladder, and urethra. Advanced/metastatic UC (mUC) tends to have a poor prognosis. UC ranks third in terms of human epidermal growth factor receptor 2 (HER2) overexpression among all tumors. However, multiple studies found that, unlike breast cancer, variable degrees of HER2 positivity and poor consistency between HER2 protein overexpression and gene amplification have been found. Trials involving trastuzumab, pertuzumab, lapatinib, afatinib, and neratinib have failed to prove their beneficial effect in patients with HER2-positive mUC, and a clinical trial on T-DM1 (trastuzumab emtansine) was terminated prematurely because of the adverse reactions. However, a phase II trial showed that RC48-ADC was effective. In this review, we provided an in-depth overview of the advances in the research regarding HER2-targeted therapy and the role of HER2 in mUC. Furthermore, we also discussed the prospects of potential strategies aimed at overcoming anti-HER2 resistance, and summarize the novel anti-HER2 approaches for the management of mUC used in recent clinical trials.
PubMed: 38155921
DOI: 10.14440/bladder.2023.871 -
Cureus Jul 2023Trastuzumab is a recombinant immunoglobulin G1 monoclonal antibody used to treat human epidermal growth factor receptor 2 (HER2) cancers. Trastuzumab-induced...
Trastuzumab is a recombinant immunoglobulin G1 monoclonal antibody used to treat human epidermal growth factor receptor 2 (HER2) cancers. Trastuzumab-induced interstitial pneumonitis is a rare adverse effect reported in a few patients. Interstitial pneumonitis presents as symptoms of dyspnea, hypoxia, cough, and fever. If the patient is treated early, corticosteroids can slow or reverse the disease progression. A 41-year-old woman presented with dyspnea and a dry cough three weeks after her third cycle of trastuzumab therapy for breast cancer. A diagnosis of trastuzumab-induced interstitial pneumonitis was made after multiple other disease processes were ruled out. The patient was started on methylprednisolone while inpatient and transitioned to prednisone for outpatient therapy. The patient was maintained on 2-3L of oxygen throughout her hospital stay and was discharged on 3L of oxygen through nasal cannula. Trastuzumab was never restarted after discharge. There have been many trials evaluating the safety, efficacy, and optimal treatment regimen of trastuzumab, but there are only a few reports of interstitial pneumonitis adverse reaction. The lack of correlation and limited cases make this adverse effect very difficult to diagnose and monitor. New trials and case reports can bring an insight into contributing factors, symptoms at onset, and treatment for future patients. With the increase in use of trastuzumab therapy, physicians should be aware of how to diagnose and treat the rare adverse reaction of trastuzumab-induced interstitial pneumonitis.
PubMed: 37602136
DOI: 10.7759/cureus.42116 -
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 -
Cancers Dec 2023Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately... (Review)
Review
Despite recent advances, HER2-positive advanced breast cancer (ABC) remains a largely incurable disease, with resistance to conventional anti-HER2 drugs ultimately unavoidable for all but a small minority of patients who achieve an enduring remission and possibly cure. Over the past two decades, significant advances in our understanding of the underlying molecular mechanisms of HER2-driven oncogenesis have translated into pharmaceutical advances, with the developing of increasingly sophisticated therapies directed against HER2. These include novel, more potent selective HER2 tyrosine kinase inhibitors (TKIs); new anti-HER2 antibody-drug conjugates; and dual epitope targeting antibodies, with more advanced pharmacological properties and higher affinity. With the introduction of adjuvant T-DM1 for incomplete responders to neoadjuvant therapy, fewer patients are relapsing, but for those who do relapse, disease that may be resistant to standard first- and second-line therapies requires new approaches. Furthermore, the risk of CNS relapse has not been abrogated by current (neo)adjuvant strategies; therefore, current research efforts are being directed towards this challenging site of metastatic disease. In this article, we review the currently available clinical data informing the effective management of HER2-positive breast cancer beyond standard first-line therapy with pertuzumab, trastuzumab, and taxanes, and the management of relapse in patients who have already been exposed to both these agents and T-DM1 for early breast cancer (EBC). We additionally discuss novel anti-HER2 targeted agents and combinations in clinical trials, which may be integrated into standard treatment paradigms in the future.
PubMed: 38201451
DOI: 10.3390/cancers16010023 -
Current Treatment Options in Oncology Nov 2023Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was... (Review)
Review
Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients' survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Lapatinib
PubMed: 37878202
DOI: 10.1007/s11864-023-01137-5