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Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer.

ABSTRACT: Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a prospectively-collected database that included prospective clinical trials at Yonsei Cancer Center, Republic of Korea. TIC was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10 percentage points from the baseline to a value less than 55%, as identified by a multiple-gated acquisition scan or an echocardiogram. Among the 115 patients, 70 patients (60.9%) received trastuzumab combined with chemotherapy, and 45 patients (39.1%) received chemotherapy alone as a first-line therapy. Symptomatic heart failure was not observed in either group, but a significant asymptomatic drop in LVEF was noted in five (7.1%) of the trastuzumab combined-group patients and in one (2.2%) chemotherapy-only group patient [hazard ratio (HR), 3.47; 95% confidence interval (CI), 0.40-29.8; P=0.257]. TIC was observed more frequently in elderly patients than in younger patients (HR, per age in year, 1.16; 95% CI, 1.02-1.31; P=0.019). Similar to prior observations in breast cancer, TIC in gastric cancer patients is not frequent or reversible. However, the asymptomatic drop in LVEF should be monitored continually in HER2-positive gastric cancer patients treated with trastuzumab, especially in elderly patients.

SUBMITTER: Soo Park J

PROVIDER: S-EPMC5617468 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer.

Soo Park Ji J Youn Jong-Chan JC Shim Chi Young CY Hong Geu-Ru GR Lee Choong-Kun CK Kim Jee Hyung JH Park Hyung Soon HS Heo Su Jin SJ Beom Seung Hoon SH Kim Hyo Song HS Rha Sun Young SY Chung Hyun Cheol HC Kang Seok-Min SM Jung Minkyu M

Oncotarget 20170627 37

Trastuzumab-induced cardiotoxicity (TIC) is the primary adverse event that limits the use of trastuzumab in HER2-positive breast cancer patients. However, the incidence and risk factors of TIC in HER2-positive gastric cancer are not known. Therefore, we evaluated the incidence and predictive factors of TIC in gastric cancer patients treated with trastuzumab in clinical practice. We reviewed cardiac dysfunction in HER2-positive gastric cancer patients between December 2005 and April 2015 in a pro ...[more]

PMID: 28977908

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Project description:BackgroundTrastuzumab (Herceptin® [H]) is the standard of care for HER2-positive locally advanced/metastatic breast cancer and gastric/gastroesophageal junction (GEJ) cancer. However, there is a paucity of data available on long-term H treatment of patients. The Rollover Protocol (ROP) Study was conducted to report safety data for patients with HER2-positive locally advanced/metastatic breast and gastric/GEJ cancer who have received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively).MethodsThe ROP Study was a single-arm, multicenter, international continuation trial of H in patients who had previously completed a global Roche-sponsored trial with H therapy, had stable disease, and were receiving H at the end of the lead-in trial. Patients with chronic heart failure during the lead-in trial could be included following a risk-benefit analysis. The primary objectives were to provide H therapy to patients with HER2-overexpressing locally advanced/metastatic breast or gastric/GEJ cancer at the end of the lead-in study, and to follow the long-term outcomes and long-term overall safety in these patients.ResultsTwenty-five of 69 patients enrolled in the ROP Study received long-term H therapy (19 breast cancer and 6 gastric/GEJ cancer). The median duration of H treatment for patients with breast cancer was 8 years 7 months, and 5 years 2 months for patients with gastric/GEJ cancer. The cardiac status of the patients remained stable over time, with no serious cardiac adverse events or marked changes in left ventricular ejection fraction (LVEF). The median overall worst LVEF measurement was 57.0%, and no patients experienced an LVEF of < 45% (range 47-63%). There were no serious adverse events related to study treatment.ConclusionsThese results suggest that H has an acceptable safety profile and was well tolerated in patients who received long-term H therapy (≥ 5 years and ≥ 3 years for breast and gastric/GEJ cancer, respectively). Further investigation and reporting of long-term H therapy would be valuable.Trial registrationThis study was retrospectively registered on March 24, 2016 with Clinicaltrials.gov, number NCT02721641 .

Project description:BACKGROUND:HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS:Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS:Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION:Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE:This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.

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Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer.

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Cardiotoxicity of trastuzumab in patients with HER2-positive gastric cancer.

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