Safety and efficacy of pyrotinib for HER­2­positive breast cancer in the neoadjuvant setting: A systematic review and meta­analysis.

As a novel tyrosine kinase inhibitor (TKI), pyrotinib can irreversibly block dual pan-ErbB receptors and has been used in the treatment of advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, there are limited data on the use of pyrotinib in early breast cancer. Therefore, the present meta-analysis was conducted to evaluate the safety and efficacy of pyrotinib in the neoadjuvant setting for patients with early-stage or locally advanced HER2-positive breast cancer. Online databases (Pubmed, Web of Science, Embase and Cochrane Library) were comprehensively searched for eligible prospective clinical trials on August 17, 2023. The primary endpoint was the treatment-related adverse events (TRAEs), and the secondary endpoint was pathological complete response (pCR) rate. In total, seven trials with a total enrolment of 407 patients were included. A total of seven studies evaluated pyrotinib in combination with trastuzumab and chemotherapy in the neoadjuvant setting. The median age ranged from 47-50 years. The most common TRAEs were diarrhea [98% of patients; 95% confidence interval (CI): 92-100%], followed by anemia (71%; 95% CI: 55-89%), vomiting (69%; 95% CI: 55-82%), and leucopenia (66%; 95% CI: 35-91%). No treatment-related deaths occurred. The pooled pCR rate was 57% (95% CI: 47-68%). It was concluded that pyrotinib-containing neoadjuvant therapy could be an effective treatment strategy in patients with early-stage or locally advanced HER2-positive breast cancer; however, the management of adverse events should be a key consideration. The management of adverse events should be paid great attention to, during pyrotinib therapy, although pyrotinib-contained neoadjuvant therapy could be an effective treatment for patients with early-stage or locally advanced HER2-positive breast cancer. Head-to-head randomized clinical trials are warranted to further confirm the benefits and risks associated with pyrotinib therapy in patients with breast cancer.

Survival outcomes of Zo-NAnTAx: a five-year analysis of zoledronic acid added to a neoadjuvant regimen for HER2-positive breast cancer.

Background: Zoledronic acid (ZA) improved outcomes in breast cancer. In pre-clinical studies, ZA increased tumour regression in combination chemotherapy and anti-human epidermal growth factor receptor 2 (HER2) target therapy. The Zo-NAnTax study, a clinical trial combining ZA with neoadjuvant therapy for HER2-positive tumours met the primary endpoint, showing a higher pathological complete response (pCR) rate than predicted in patients receiving surgery. Here, we report the exploratory relapse-free survival (RFS) and overall survival (OS) analysis after five years of follow-up. Methods: Adult women with HER2-positive breast cancer amendable to curative surgery who consented to the study received four cycles of ZA at 4 mg + doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of ZA at 4 mg + docetaxel 100 mg/m2 + trastuzumab 6 mg/kg (8 mg/kg as a loading dose), all in a 21 days-cycle, totalizing 8 cycles before surgery. To achieve the primary endpoint of pCR rate between 22% and 35%, 56 patients were needed. The secondary endpoints included safety, gene expression according to treatment response, prediction of pCR rate by an interim breast magnetic resonance imaging (bMRI). Results: Beyond the overall pCR rate of 42%, alongside a good safety profile, we showed similar pCR rates in both hormonal receptor (HR) positive (40%) and HR-negative (44%). RFS and OS at five years were evaluated in 58 subjects, and the overall rate was 79.3% and 86.2%, respectively. Numerically higher values of both RFS and OS were observed in patients achieving pCR vs. non-achieving, respectively 83.3% vs. non-pCR 76.5% (P=0.57) and 95.8% vs. non-pCR 79.4% (P=0.08). Although not statistically significant, OS was numerically equivalent according to HR status, respectively 85.7% vs. 87.5% for HR-positive and HR-negative (P=0.91), which contrasted with RFS, HR-positive 81% vs. HR-negative 75% (P=0.58). None of the assessed clinicopathological biomarkers significantly correlated with survival. Conclusions: ZA plus neoadjuvant therapy in HER2-positive breast cancer shows provoking survival outcomes. Clinical and pre-clinical investigation with dual anti-HER2 blockage is warranted.

Complete response after treatment of breast cancer with isolated liver metastasis: a case report.

Background: Breast cancer has a high incidence and is prone to metastasis, while isolated liver metastasis is rare. A growing body of evidence supports the effectiveness of treating breast cancer with anti-human epidermal growth factor receptor-2 (HER2) therapy in combination with chemotherapy. However, little is known about its impact on metastatic liver disease. There is also a lack of consensus on managing liver metastases from breast cancer, and no studies have been conducted on managing the disappearance of liver metastases after treatment. Case Description: In May 2021, a 51-year-old female patient with HER2-positive breast cancer with isolated liver metastases had immunohistochemistry of estrogen receptor (ER) (-), progesterone receptor (PR) (-), and HER2 (3+) for both her primary lesion and liver metastases. After undergoing 17 cycles of anti-HER2 therapy and chemotherapy, the patient expressed a desire for surgery. Then a preoperative examination was performed, which revealed the disappearance of both the primary breast lesion and the liver metastases. Immediately afterwards, a left mastectomy was performed, and postoperative pathology showed a complete response to the breast tumor. As for the liver, where the metastatic lesions disappeared, no relevant study has reported how to deal with this situation. Finally, after a hospital-wide discussion, the patient was given trastuzumab maintenance therapy. Until now, no obvious signs of recurrence or metastasis have been observed during regular follow-ups. Conclusions: This case suggests that maintenance therapy may be the best option for patients with breast cancer whose liver metastases disappear by medication. Also, it can be inferred that in HER2-positive metastatic breast cancer (MBC), patients with isolated liver metastases may be more likely to achieve a cure-like outcome. Nevertheless, more cases and follow-up information are needed to support these views.

Primary results of ELAINA: a randomized, multicenter, open-label, phase III study of the efficacy and safety of trastuzumab emtansine vs. lapatinib plus capecitabine in Chinese patients with HER2-positive locally advanced or metastatic breast cancer who have received prior trastuzumab-based therapy.

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.

Efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients with pretreated HER2-positive advanced metastatic breast cancer: results from a randomized, open-label, multicenter, phase II bridging study.

Background: Trastuzumab is the recommended first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in China, but therapeutic resistance to trastuzumab and other early-line treatments is common and late-line treatment options are limited. Derived from the same murine precursor antibody, margetuximab has enhanced anti-tumor activity compared with trastuzumab and may be an effective late-line treatment. However, data regarding the use of margetuximab in pre-treated Chinese patients are scarce. This study aimed to evaluate the efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients, and to determine whether the results are consistent with the clinical benefit of margetuximab observed in the pivotal global phase III study. Methods: In this randomized, open-label, multicenter, phase II bridging study, eligible Chinese patients pretreated with ≥2 lines of anti-HER2 therapies were randomized 1:1 by stratified block randomization to margetuximab (15 mg/kg over at least 120 minutes) or trastuzumab (6 mg/kg over at least 30 minutes), each administered intravenously once every 21-day cycle and plus chemotherapy. Disease assessment was conducted once every two treatment cycles (6 weeks ± 7 days). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and the incidence and severity of treatment-emergent adverse events (TEAEs). Results: Between February 4, 2020 and February 23, 2021, 123 patients were randomized to the margetuximab (n=62) and trastuzumab (n=61) arms. Among them, 15 and 7 patients, respectively, were still on study treatment as of data cut-off (September 3, 2021). Overall, 99.2% were female, median age was 53 years old. All patients were pretreated with trastuzumab, and 83.7% and 25.2%, respectively, were pretreated with tyrosine kinase inhibitors (TKIs) and pertuzumab. Baseline characteristics were numerically balanced between arms. BICR-assessed median PFS (mPFS) was 5.5 months in the margetuximab arm and 4.1 months in the trastuzumab arm, with a hazard ratio (HR) of 0.69 [95% confidence interval (CI): 0.43-1.12], which met the consistency criterion (HR <0.88) for bridging success. Median investigator-assessed PFS was 5.5 months in the margetuximab arm and 4.0 months in the trastuzumab arm (HR =0.63; 95% CI: 0.41-0.96). Median OS (mOS) was not yet reached. Both ORR and CBR were greater in the margetuximab arm (25.5% vs. 12.5%; 32.7% vs. 14.3%). Safety results were numerically comparable between the two arms. Anti-HER2 treatment-related infusion-related reactions (IRRs) were more common in the margetuximab arm than in the trastuzumab arm (12.9% vs. 1.7%). All IRRs could be resolved. Conclusions: Margetuximab was effective and well-tolerated in this study, supporting its clinical use in pretreated HER2-positive MBC patients in China. Trial Registration: ClinicalTrials.gov Identifier: NCT04262804.

An economic evaluation of trastuzumab as adjuvant treatment of early HER2-positive breast cancer patients in Colombia / Evaluación económica del trastuzumab como tratamiento adyuvante en cáncer de mama HER2- positivo en Colombia

Objective: Trastuzumab (Herceptin®), a recombinant, humanized, monoclonal antibody targeting HER2 is well established as an effective treatment for HER2-positive breast cancer. Evidence from developed countries showed that trastuzumab was cost-effective; but there are few evidences in developing countries. This study assesses the cost-effectiveness of adjuvant trastuzumab treatment in Colombia. Methods: A Markov health-state transition model was built to estimate clinical and economic outcomes in HER2-positive breast cancer with or without 12 months trastuzumab adjuvant chemotherapy over a lifetime perspective with annual transition cycles. The model incorporated five health states (diseasefree, local recurrence, distant recurrence, cardiac failure, and death). Baseline event rates and 3-year hazard ratio (HR=0.51, IC 95% 0.44-0.59; p<0.0001) were derived from 4-year follow up of the N9831 and NSABP B-31 trial. Costs and utility weights were obtained from the literature and were discounted by 5% annually. Results: The model showed that the utilization of adjuvant trastuzumab treatment in early breast cancer can prolong 0.80 quality-adjusted life-years (QALY), compared with standard chemotherapy, an incremental cost-effectiveness ratio (ICER) of US$ 71,491 per QALY gained. Conclusion: The results suggest that 1-year adjuvant Trastuzumab treatment is not cost-effective in Colombia, using the definition of WHO cost-effectiveness threshold of 3 times GDP per capita.

Introducción. El trastuzumab es un anticuerpo monoclonal de reconocida efectividad para el tratamiento en mujeres con cáncer de mama positivo para HER2. Sin embargo, la mayoría de estudios de costo-efectividad se han llevado a cabo en países desarrollados. Objetivo. Determinar el costo-efectividad del tratamiento adyuvante con trastuzumab en mujeres con cáncer de mama HER2+ en Colombia. Materiales y métodos. Se construyó un modelo de Markov, con ciclos de transición anuales y desde la perspectiva del pagador, para estimar los resultados clínicos y económicos derivados de la administración de trastuzumab en mujeres con HER2 positivo. El modelo incorpora cinco estados de transición: libre de enfermedad, recurrencia local, metástasis, falla cardiaca y muerte. La tasa de eventos y la razón de tazas instantáneas (0,51; IC 95% 0,44-0,59; p<0,0001) se derivaron del reporte a cuatro años de los ensayos clínicos controlados N9831 y NSABP B-31. Los costos y las utilidades se estimados a partir de la literatura científica, utilizando una tasa de descuento del 5 % anual. Resultados. El modelo revela que la utilización de trastuzumab como tratamiento adyuvante prolonga la expectativa de vida ajustada por calidad en 0,8 años, en comparación con la quimioterapia sin trastuzumab; a una razón de costo efectividad incremental (sic.) de US$ 71.491 por año de vida ganado ajustado por calidad de vida. Conclusión. El tratamiento con trastuzumab durante un año no es costo-efectivo en Colombia, utilizando la definición de costo-efectividad de la OMS de menos de dos a tres veces el PIB per cápita por año de vida ganado ajustado por calidad de vida.