RESUMEN
BACKGROUND: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. METHODS: Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. RESULTS: The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09-0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). CONCLUSIONS: The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.
Asunto(s)
Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Quinolinas , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/uso terapéutico , Persona de Mediana Edad , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Anciano , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Biomarcadores de Tumor/genética , Mutación , Anciano de 80 o más Años , Trastuzumab/uso terapéutico , Trastuzumab/administración & dosificación , Resultado del Tratamiento , Metástasis de la NeoplasiaRESUMEN
T-DM1 (Trastuzumab Emtansine) belongs to class of Antibody-Drug Conjugates (ADC), where cytotoxic drugs are conjugated with the antibody Trastuzumab to specifically target HER2-positive cancer cells. Platelets, as vital components of the blood system, intricately influence the immune response to tumors through complex mechanisms. In our study, we examined platelet surface proteins in the plasma of patients before and after T-DM1 treatment, categorizing them based on treatment response. We identified a subgroup of platelets with elevated expression of CD63 and CD9 exclusively in patients with favorable treatment responses, while this subgroup was absent in patients with poor responses. Another noteworthy discovery was the elevated expression of CD36 in the platelet subgroups of patients exhibiting inadequate responses to treatment. These findings suggest that the expression of these platelet surface proteins may be correlated with the prognosis of T-DM1 treatment. These indicators offer valuable insights for predicting the therapeutic response to T-DM1 and may become important references in future clinical practice, contributing to a better understanding of the impact of ADC therapies and optimizing personalized cancer treatment strategies.
Asunto(s)
Ado-Trastuzumab Emtansina , Plaquetas , Neoplasias de la Mama , Humanos , Femenino , Plaquetas/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/sangre , Ado-Trastuzumab Emtansina/uso terapéutico , Persona de Mediana Edad , Trastuzumab/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Anciano , Maitansina/uso terapéutico , Maitansina/análogos & derivadosRESUMEN
BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.
RESUMEN
PURPOSE OF REVIEW: To summarize the treatment strategies for patients with human epidermal growth factor receptor 2 (HER2)-positive disease and triple-negative breast cancer (TNBC) who have residual disease after preoperative systemic therapy. RECENT FINDINGS: There has been a shift towards neoadjuvant systemic therapy for selected patients with HER2-positive and TNBC. Assessing the tumor's response to therapy provides prognostic information and allows individualization of the postoperative treatment for these patients based on the tumor response to neoadjuvant therapy. Patients with TNBC with residual disease after neoadjuvant therapy can be treated with pembrolizumab, capecitabine, or olaparib. Those with HER2-positive disease are treated with adjuvant trastuzumab emtansine. The treatment of early breast cancer has evolved significantly, and patient outcomes continue to improve. As better treatments are developed, we will need biomarkers to determine which patients may benefit from certain therapies to continue to improve outcomes by right-sizing treatments and limiting toxicities.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Ado-Trastuzumab Emtansina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
OBJECTIVES: To investigate the potential relationship between trastuzumab emtansine (T-DM1) treatment and radionecrosis induced by brain stereotactic radiosurgery (SRS) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. MATERIALS AND METHODS: Patients with HER2-positive breast cancer who were diagnosed with brain metastasis and received both SRS and HER2-targeted agents between 2012 and 2022 were retrospectively analyzed. Patients who received T-DM1 within 1 year (either before or after) of SRS were considered as 'T-DM1 exposure (+)'. T-DM1 exposure (-) group had other HER2-targeted agents or received T-DM1 more than 1 year before or after SRS. Symptomatic radionecrosis was defined as Common Terminology Criteria for Adverse Events grade 2 or greater. RESULTS: A total of 103 patients with 535 treatment sessions were included from seven tertiary medical centers in Korea and Italy. The median follow-up duration was 15.5 months (range 1.1-101.9). By per-patient analysis, T-DM1 exposure (+) group had an increased risk of overall radionecrosis after multivariate analysis (HR 2.71, p = 0.020). Additionally, T-DM1 exposure (+) group was associated with a higher risk of symptomatic radionecrosis compared to T-DM1 exposure (-) patients (HR 4.34, p = 0.030). In per-treatment analysis, T-DM1 exposure (+) was linked to higher incidences of overall (HR 3.13, p = 0.036) and symptomatic radionecrosis (HR 10.4, p = 0.013) after multivariate analysis. A higher prevalence of radionecrosis was observed with T-DM1 exposure (+) and a previous history of whole brain radiotherapy. CONCLUSION: An increased risk of radionecrosis was observed in patients receiving T-DM1 with brain SRS. Further research is needed to better understand the optimal sequence and interval for administering T-DM1 and SRS.
RESUMEN
Background: Trastuzumab emtansine (T-DM1) has been approved worldwide for treating metastatic breast cancer (mBC) in patients who have received first-line therapy, shown disease progression, and are human epidermal growth factor receptor 2 (HER2)-positive. T-DM1 received approval in China to treat early-stage breast cancer (BC) in 2020 and for mBC in 2021. In March 2023, T-DM1 was included in medical insurance coverage, significantly expanding the eligible population. Materials and methods: This post-marketing observational study aimed to assess the safety and effectiveness of T-DM1 in real-world clinical practice in China. This study enrolled 31 individuals with HER2-positive early-stage BC and 70 individuals with HER2-positive advanced BC from 8 study centers in Shandong Province, China. The T-DM1 dosage was 3.6 mg/kg injected intravenously every 3 weeks until the disease advanced or the drug toxicity became uncontrollable, whichever occurred earlier. Additionally, efficacy and safety information on T-DM1 were collected. Results: During the 7-month follow-up period, no recurrence or metastases were observed in patients who had early-stage BC. The disease control rate was 31.43% (22/70) in patients with advanced BC. The most common adverse effect of T-DM1 was thrombocytopenia, with an incidence of 69.31% (70/101), and the probability of Grade ≥ 3 thrombocytopenia was 11.88% (12/101). Conclusion: This real-world study demonstrated that T-DM1 had good efficacy and was well tolerated by both HER2-positive early-stage BC and mBC patients.
RESUMEN
Purpose: This study aimed to investigate clinical practices and factors related to the outcomes of T-DM1 use in patients with HER2-positive metastatic breast cancer (mBC). Methods: We included patients with HER2-positive mBC who received T-DM1 as a palliative therapy between August 2017 and December 2018. The safety and outcomes of T-DM1, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), were evaluated. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) for mortality or progression to HER2-positive mBC. Results: In total, 824 patients were enrolled during the study period. The mean age of patients was 58 years, and 516 (62.6%) patients relapsed after curative treatment. Excluding a history of endocrine therapy, 341 (41.4%) patients previously received none or first-line chemotherapy, 179 (21.7%) received second-line therapy, and 303 (36.9%) received third-or later-line chemotherapy before T-DM1 therapy. During a median follow-up of 16.8 months, the ORR was 35%, the median PFS was 6.6 months, and the median OS was not reached. The clinical factors associated with the hazard of progression were age (<65 years), poor performance status (⩾2), advanced line of palliative chemotherapy (⩾2), prior pertuzumab use, and treatment duration of palliative trastuzumab (<10 months). Common grade 3-4 adverse events were thrombocytopenia (n = 107, 13.2%), neutropenia (n = 23, 2.8%), anemia (n = 21, 2.6%), and elevated liver enzyme (n = 20, 2.5%). Hypokalemia (⩽3.0 mmol/L) and any-grade bleeding events occurred in 25 (3.1%) and 94 (22.6%) patients, respectively. Conclusion: This is the first nationwide real-world study of T-DM1 use in patients with HER2-positive mBC in Korea. The effectiveness and toxicity profiles of T-DM1 in real-world practice were comparable to those in randomized trials. Moreover, patient factors and previous anti-HER2 therapy could predict the outcomes of T-DM1 therapy.
RESUMEN
Breast cancer remains the most common cancer in women worldwide. Among women with breast cancer, brain metastases are very prevalent among HER2-positive and affect those in the advanced stages of the disease. Various factors, including molecular subtypes, performance status, extracranial disease status, leptomeningeal metastasis, and the number of lesions, significantly influence the prognosis of patients with brain metastases from breast cancer (BCBrM). Understanding and addressing the specific risks associated with different breast cancer subtypes is crucial for developing tailored and effective medical treatments. This report presents a case of a breast cancer patient with recurrent disease and brain metastases who achieved long-term survival following a treatment regimen that included radiotherapy and a T-DM1 biosimilar.
RESUMEN
Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.
Asunto(s)
Ado-Trastuzumab Emtansina , Enfermedades de los Perros , Trastuzumab , Animales , Perros , Enfermedades de los Perros/tratamiento farmacológico , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Línea Celular Tumoral , Ado-Trastuzumab Emtansina/farmacología , Ado-Trastuzumab Emtansina/uso terapéutico , Ratones , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Maitansina/farmacología , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Receptor ErbB-2/metabolismo , Ratones Desnudos , Femenino , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Human epidermal growth factor receptor 2 (HER2) serves as both a prognostic indicator and a therapeutic target for breast cancer. Therefore, anti-HER2 therapy plays a crucial role in the treatment of HER2-positive cancer. Antibody-drug conjugates (ADCs) are composed of a monoclonal antibody, a chemical linker and a payload, wherein their aim is to reduce the toxicity associated with chemotherapy drugs by utilizing specific antibodies. Among the anti-HER2 ADCs currently approved for clinical use, trastuzumab emtansine(T-DM1) and trastuzumab deruxtecan (T-Dxd) have demonstrated remarkable efficacy in treating HER2-positive breast cancer. However, it is essential to emphasize the occurrence of lung toxicity during the treatment process, which can be life-threatening. In this review, we provide an overview of the new epidemiological features associated with interstitial lung disease (ILD) related to anti-HER2 ADCs in breast cancer. We also summarize the potential pathogenesis and explore the diagnosis and treatment strategies within this field.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Inmunoconjugados , Enfermedades Pulmonares Intersticiales , Femenino , Humanos , Ado-Trastuzumab Emtansina/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Receptor ErbB-2/metabolismo , Trastuzumab/efectos adversos , Enfermedades Pulmonares Intersticiales/inducido químicamenteRESUMEN
PURPOSE: This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. METHODS: An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. RESULTS: The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. CONCLUSION: In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.
Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , España , Receptor ErbB-2/metabolismo , Encuestas y Cuestionarios , Pautas de la Práctica en Medicina/estadística & datos numéricos , Trastuzumab/uso terapéutico , Actitud del Personal de Salud , Toma de Decisiones Clínicas , Estadificación de Neoplasias , Persona de Mediana Edad , Quimioterapia Adyuvante , Antineoplásicos Inmunológicos/uso terapéutico , Ado-Trastuzumab Emtansina/uso terapéutico , AdultoRESUMEN
Trastuzumab emtansine (T-DM1) is a mainstay therapy for HER2-positive metastatic breast cancer (mBC). However, identifying patients who will benefit most remains a challenge due to the lack of reliable biomarkers. The recently developed pan-immune-inflammation value (PIV), a novel immune-inflammation marker, could aid in this regard, considering the immunomodulatory effects of T-DM1. Therefore, we aimed to evaluate the association between the PIV and the efficacy of T-DM1 in patients with HER2-positive mBC. A total of 122 HER2-positive mBC patients treated with T-DM1 were included. Receiver operating characteristic (ROC) curve analyses were conducted to determine the optimal PIV threshold value for survival prediction. Kaplan-Meier survival curves and Cox regression analyses were used for univariable and multivariable survival analyses, respectively. The median age was 51 years, and 95.1% of the patients had ECOG PS 0-1. The optimal PIV cutoff value was identified as 338 in ROC analyses (AUC: 0.667, 95% CI: 0.569-0.765, p = 0.002). The multivariate analysis revealed that patients in the high-PIV group had significantly shorter OS (HR: 2.332; 95% CI: 1.408-3.861; p = 0.001) and PFS (HR: 2.423; 95% CI: 1.585-3.702; p < 0.001) than patients in the low-PIV group. Additionally, both ORR and DCR were significantly lower in the high-PIV group (36.6% vs. 61.3%, p = 0.011; 56.1% vs. 76.0%, p = 0.027). Our findings suggest that pre-treatment PIV may be a novel prognostic biomarker for HER2-positive mBC patients receiving T-DM1. A low PIV level is associated with more favorable outcomes. Future prospective studies are warranted to validate these findings and explore the potential utility of PIV in aiding treatment decisions.
RESUMEN
Background: Breast cancer (BC) is one of the most common cancers worldwide. The inevitability of drug resistance to initial anti-HER-2 therapy necessitates the emergence of second-line anti-HER-2 drugs which exhibit a promising outlook. Consequently, it is imperative to appraise their efficacy through network meta-analysis and ascertain their comparative cost-effectiveness. Methods: The data used in our analysis were acquired from patients enrolled in the EMILIA, DESTINY-Breast03, and PHOEBE phase III randomized clinical trials. A partitioned survival model was used for patients diagnosed with HER-2-positive metastatic Breast cancer. The model was crafted with a time horizon of 10 years, operating on a 21-day cycle and incorporating a 5% discount rate for both costs and outcomes. The willingness-to-pay threshold was set at $36,058.06 per quality-adjusted life year (QALY). The impact of parameter uncertainty on the findings was assessed using a one-way deterministic sensitivity analysis and probability sensitivity analysis. Findings: Within the model encompassing 1782 patients, the utilization of pyrotinib plus capecitabine (PC) treatment yielded an additional 0.70 QALY in comparison to T-DM1, resulting in an incremental cost-effectiveness ratio (ICER) of $31,121.53 per QALY gained. Similarly, the administration of T-DXd treatment led to an additional 0.80 QALY compared to T-DM1, resulting in an ICER of $153,950.19 per QALY gained. The PC strategies are considered more cost-effective than T-DXd when the WTP threshold is set at $36,058.06 per QALY. However, this method is not cost effective for T-DXd. The probability of the PC strategies being cost-effective was 62%, whereas the probability of T-DXd was 0% when compared to T-DM1. Conclusion: PC is a cost-effective therapy for patients afflicted with HER-2-positive metastatic BC compared to T-DM1 from the perspective of China at a WTP threshold of $36,058.06 per QALY. Nevertheless, T-DXd is not as cost-effective as T-DM1, considering its current medication pricing. Therefore, reducing the cost of T-DXd could improve its overall cost-effectiveness.
RESUMEN
Background: Coronavirus disease 19 (COVID-19) has played a pivotal role in changing medical care around the world. During the pandemic, the operating rooms (ORs) were closed to elective surgery. Since breast cancer surgery is not regarded as an emergent procedure, there was an adoption of treatment regimen modification due to delays in treatment. Therefore, a decision was made to bridge early-stage HER2-positive breast cancer patients with neoadjuvant treatment to postpone surgery. Consequently, to reduce the frequency of dosing and the number of visits, as well as avoid steroid premedication, these patients were treated with ado-trastuzumab emtansine (T-DM1) every three weeks as opposed to weekly taxol and herceptin (TH). Case Description: Five patients with early-stage HER2-positive cancer were treated with neoadjuvant T-DM1 3.6 mg/kg IV every three weeks. Three of the five patients developed cancer progression identified by their physical exam and/or imaging. T-DM1 was discontinued, and all three patients underwent immediate surgery. The remaining two patients, 4 and 5, had a complete and partial pathological response, respectively. All five patients received adjuvant therapy after surgery, and currently, none of these patients show evidence of disease on follow-up. Conclusions: Our findings underscore the obstacles and treatment challenges encountered during the COVID-19 pandemic while preventing the spread of the virus and cancer progression. Furthermore, the use of T-DM1 for neoadjuvant treatment remains controversial, particularly when T-DM1 is used as a bridge to surgery during critical times. Perhaps better patient selection or a different drug regimen could have resulted in a better outcome in our study.
RESUMEN
BACKGROUND: During targeted treatment, HER2-positive breast cancers invariably lose HER2 DNA amplification. In contrast, and interestingly, HER2 proteins may be either lost or gained. To longitudinally and systematically appreciate complex/discordant changes in HER2 DNA/protein stoichiometry, HER2 DNA copy numbers and soluble blood proteins (aHER2/sHER2) were tested in parallel, non-invasively (by liquid biopsy), and in two-dimensions, hence HER2-2D. METHODS: aHER2 and sHER2 were assessed by digital PCR and ELISA before and after standard-of-care treatment of advanced HER2-positive breast cancer patients (n=37) with the antibody-drug conjugate (ADC) Trastuzumab-emtansine (T-DM1). RESULTS: As expected, aHER2 was invariably suppressed by T-DM1, but this loss was surprisingly mirrored by sHER2 gain, sometimes of considerable entity, in most (30/37; 81%) patients. This unorthodox split in HER2 oncogenic dosage was supported by reciprocal aHER2/sHER2 kinetics in two representative cases, and an immunohistochemistry-high status despite copy-number-neutrality in 4/5 available post-T-DM1 tumor re-biopsies from sHER2-gain patients. Moreover, sHER2 was preferentially released by dying breast cancer cell lines treated in vitro by T-DM1. Finally, sHER2 gain was associated with a longer PFS than sHER2 loss (mean PFS 282 vs 133 days, 95% CI [210-354] vs [56-209], log-rank test p=0.047), particularly when cases (n=11) developing circulating HER2-bypass alterations during T-DM1 treatment were excluded (mean PFS 349 vs 139 days, 95% CI [255-444] vs [45-232], log-rank test p=0.009). CONCLUSIONS: HER2 gain is adaptively selected in tumor tissues and recapitulated in blood by sHER2 gain. Possibly, an increased oncogenic dosage is beneficial to the tumor during anti-HER2 treatment with naked antibodies, but favorable to the host during treatment with a strongly cytotoxic ADC such as T-DM1. In the latter case, HER2-gain tumors may be kept transiently in check until alternative oncogenic drivers, revealed by liquid biopsy, bypass HER2. Whichever the interpretation, HER2-2D might help to tailor/prioritize anti-HER2 treatments, particularly ADCs active on aHER2-low/sHER2-low tumors. TRIAL REGISTRATION: NCT05735392 retrospectively registered on January 31, 2023 https://www. CLINICALTRIALS: gov/search?term=NCT05735392.
Asunto(s)
Neoplasias de la Mama , Receptor ErbB-2 , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Biopsia Líquida/métodos , Persona de Mediana Edad , Ado-Trastuzumab Emtansina/uso terapéutico , Anciano , Trastuzumab/uso terapéutico , Trastuzumab/farmacología , Adulto , Biomarcadores de TumorRESUMEN
Breast cancer continues to have a high incidence rate among female malignancies. Despite significant advancements in treatment modalities, the heterogeneous nature of breast cancer and its resistance to various therapeutic approaches pose considerable challenges. Antibody-drug conjugates (ADCs) effectively merge the specificity of antibodies with the cytotoxicity of chemotherapeutic agents, offering a novel strategy for precision treatment of breast cancer. Notably, trastuzumab emtansine (T-DM1) has provided a new therapeutic option for HER2-positive breast cancer patients globally, especially those resistant to conventional treatments. The development of trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) has further broadened the applicability of ADCs in breast cancer therapy, presenting new hopes for patients with low HER2 expression and triple-negative breast cancer. However, the application of ADCs presents certain challenges. For instance, their treatment may lead to adverse reactions such as interstitial lung disease, thrombocytopenia, and diarrhea. Moreover, prolonged treatment could result in ADCs resistance, complicating the therapeutic process. Economically, the high costs of ADCs might hinder their accessibility in low-income regions. This article reviews the structure, mechanism of action, and clinical trials of commercially available ADCs for breast cancer treatment, with a focus on the clinical trials of the three drugs, aiming to provide insights for clinical applications and future research.
RESUMEN
Background: The antibody-drug conjugate (ADCs) trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. The phase III ELAINA trial aimed to determine the clinical utility of T-DM1 in Chinese patients. Methods: ELAINA was a randomized, multicenter, open-label bridging study of Chinese patients with HER2-positive locally advanced breast cancer (LABC) or mBC previously treated with trastuzumab and a taxane. Using an interactive voice/internet response system, patients were randomized 3:1 to receive T-DM1 or lapatinib plus capecitabine. Patents were stratified by number of prior therapies in this disease setting and by presence of visceral disease using a permuted block randomization scheme. Patients received treatment until disease progression, unmanageable toxicity, or study termination. After that, data on survival and subsequent cancer therapies were collected at approximately 3-month intervals. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall response rate, duration of response, overall survival (OS), safety, patient-reported quality of life, and pharmacokinetics (PKs). Results: ELAINA was fully enrolled with 200 patients randomized to T-DM1 (n=151) or lapatinib plus capecitabine (n=49). Median treatment duration was approximately 6 months in each study arm. Median follow-up time was approximately 9 months for all analyses except for OS. T-DM1 was associated with a 15% reduction in risk of disease progression or death compared with lapatinib plus capecitabine [stratified hazard ratio (HR) =0.85; 95% confidence interval (CI): 0.56-1.29] in the intent-to-treat (ITT) population. The objective response rate (ORR) was similar with T-DM1 (50.4%) and lapatinib plus capecitabine (55.8%); median duration of response was 8.4 months for both treatments. At a median follow-up time of approximately 30 months, OS was similar in each treatment arm. Incidence of grade ≥3 adverse events (AEs) was similar with T-DM1 (54.3%) and lapatinib plus capecitabine (57.1%). Grade ≥3 thrombocytopenia was greater with T-DM1 (40.4%) than with lapatinib plus capecitabine (4.1%); there was no grade ≥3 hemorrhage with either treatment. Conclusions: T-DM1 demonstrated an acceptable benefit-risk profile in Chinese patients with HER2-positive LABC/mBC previously treated with trastuzumab and a taxane. T-DM1 therefore provides a chemotherapy-free option in this setting. Trial Registration: ClinicalTrials.gov identifier: NCT03084939.