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HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis.

ABSTRACT: Background: Intracranial metastatic disease (IMD) is a serious and known complication of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The role of targeted therapy for patients with HER2-positive breast cancer and IMD remains unclear. In this study, we sought to evaluate the effect of HER2-targeted therapy on IMD from HER2-positive breast cancer.

Methods: We searched MEDLINE, EMBASE, CENTRAL, and gray literature sources for interventional and observational studies reporting survival, response, and safety outcomes for patients with IMD receiving HER2-targeted therapy. We pooled outcomes through meta-analysis and examined confounder effects through forest plot stratification and meta-regression. Evidence quality was evaluated using GRADE (PROSPERO CRD42020161209).

Results: A total of 97 studies (37 interventional and 60 observational) were included. HER2-targeted therapy was associated with prolonged overall survival (hazard ratio [HR] 0.47; 95% confidence interval [CI], 0.39-0.56) without significantly prolonged progression-free survival (HR 0.52; 95% CI, 0.27-1.02) versus non-targeted therapy; the intracranial objective response rate was 19% (95% CI, 12-27%), intracranial disease control rate 62% (95% CI, 55-69%), intracranial complete response rate 0% (95% CI, 0-0.01%), and grade 3+ adverse event rate 26% (95% CI, 11-45%). Risk of bias was high in 40% (39/97) of studies.

Conclusion: These findings support a potential role for systemic HER2-targeted therapy in the treatment of patients with IMD from HER2-positive metastatic breast cancer.

SUBMITTER: Erickson AW

PROVIDER: S-EPMC7720818 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis.

Erickson Anders W AW Ghodrati Farinaz F Habbous Steven S Jerzak Katarzyna J KJ Sahgal Arjun A Ahluwalia Manmeet S MS Das Sunit S

Neuro-oncology advances 20200101 1

<h4>Background</h4>Intracranial metastatic disease (IMD) is a serious and known complication of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The role of targeted therapy for patients with HER2-positive breast cancer and IMD remains unclear. In this study, we sought to evaluate the effect of HER2-targeted therapy on IMD from HER2-positive breast cancer.<h4>Methods</h4>We searched MEDLINE, EMBASE, CENTRAL, and gray literature sources for interventional and observational ...[more]

PMID: 33305268

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Project description:Survival of patients with human epidermal growth receptor 2 (HER2)-positive metastatic breast cancer (MBC) has improved dramatically since trastuzumab has become available, although the disease eventually progresses in most patients. This study investigates the outcome (overall survival [OS] and time to next treatment [TNT]) in MBC patients pretreated with trastuzumab in the adjuvant setting (TP-group) compared with trastuzumab-naïve patients (TN-group) in order to investigate the possibility of trastuzumab resistance.Patients treated with first-line HER2-targeted-containing chemotherapy were eligible for the study. A power analysis was performed to estimate the minimum size of the TP-group. OS and TNT were estimated using Kaplan-Meier curves and multivariable Cox proportional hazards models.Between January 1, 2000, and June 1, 2014, 469 patients were included, of whom 82 were in the TP-group and 387 were in the TN-group. Median OS and TNT were significantly worse in the TP-group compared with the TN-group (17 vs. 30 months, adjusted hazard ratio [HR] 1.84 [1.15-2.96], p = .01 and 7 vs. 13 months, adjusted HR 1.65 [1.06-2.58], p = .03) after adjustment for age, year of diagnosis, disease-free interval, hormone receptor status, metastatic site, and cytotoxic regimens.First-line trastuzumab-containing treatment regimens are less effective in patients with failure of adjuvant trastuzumab compared with trastuzumab-naïve patients and might be due to trastuzumab resistance. The impact of trastuzumab resistance on the response on dual HER2 blockade with trastuzumab and pertuzumab and how resistance mechanisms can be used in the optimization of HER2-targeted treatment lines need further investigation.Evidence on the efficacy of palliative trastuzumab-based therapy after failure of trastuzumab in the adjuvant setting is limited because of a minority of patients treated with adjuvant trastuzumab in clinical trials. In this study, less clinical benefit of palliative trastuzumab-based therapy was observed in patients relapsing after adjuvant trastuzumab compared with no adjuvant trastuzumab treatment. Subgroup analyses and multivariable analyses revealed that this was independent of possible confounding factors, including adjuvant taxane-treatment. This might suggest a clinically meaningful impaired efficacy of trastuzumab after previous, in this case adjuvant, trastuzumab therapy. These results could have implications for treatment decision-making after short progression-free intervals on trastuzumab-containing regimens in the palliative setting.

Project description:BACKGROUND:An increasing proportion of human epidermal growth receptor 2 (HER2) positive (HER2+) metastatic breast cancer (MBC) is diagnosed as de novo stage IV disease. We hypothesize that a subset of these patients who achieve no evidence of disease (NED) status after multimodality HER2-targeted treatments may have prolonged progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS:Patients with de novo stage IV, HER2+ MBC (n = 483) diagnosed between 1998 and 2015 were identified at two institutions (Yale and MD Anderson Cancer Centers). Clinical variables, treatment details, and survival outcomes were compared between those who achieved NED and those who did not. RESULTS:All patients received trastuzumab, and 20% also received pertuzumab as first-line therapy. The median OS was 5.5 years (95% confidence interval [Cl]: 4.8-6.2). Sixty-three patients (13.0%) achieved NED; their PFS and OS rates were 100% and 98% (95% CI: 94.6%-100%), respectively, at 5 years and remained the same at 10 years. For patients with no NED (n = 420), the PFS and OS rates were 12% (95% CI: 4.5%-30.4%) and 45% (95% CI: 38.4%-52.0%) at 5 years and 0% and 4% (95% CI, 1.3%-13.2%) at 10 years, respectively. NED patients more frequently had solitary metastasis (79% vs. 51%, p = .005) and surgery to resect cancer (59% vs. 22%, p ≤ .001). In multivariate analysis, NED status (hazard ratio [HR]: 0.014, p = .0002) and estrogen receptor positive status (HR: 0.72; p = .04) were associated with prolonged OS. CONCLUSION:Among patients with de novo stage IV, HER2+ MBC, those who achieve NED status have a very high PFS and OS. Further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes. IMPLICATIONS FOR PRACTICE:In this retrospective review at two institutions, it was demonstrated that 13% of patients with de novo stage IV, human epidermal growth receptor 2 positive metastatic breast cancer achieved no evidence of disease (NED) status with trastuzumab-based therapy plus/minus local therapies, and these patients had a very high progression-free survival (100%) and overall survival (98%) at both the 5- and 10-year time points. Achieving NED status may be an important therapeutic goal. However, further randomized studies are required to fully understand the impact of systemic or locoregional therapy on achieving these excellent long-term outcomes.

Dataset Information

HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis.

Publications

HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis.

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