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Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer.

ABSTRACT: This study explored the clinical implications of tumor mutational burden (TMB) in a well-defined HER2-positive metastatic breast cancer (MBC) patient population who had been previously treated but had subsequent disease progression. Whole exome sequencing was performed on formalin-fixed paraffin-embedded tumor samples and matched normal tissue. Among the 46 patients, 13 (28.3%) were estrogen receptor-positive and nine (19.6%) were progesterone receptor-positive by immunohistochemistry analysis. Twenty patients (43.5%) had recurrent MBC compared with de novo MBC (n = 26, 56.5%). Sixteen patients (34.6%) demonstrated more than 100 somatic non-synonymous SNV mutations, which was predefined as a high TMB. The median follow-up duration was 57.5 months. The median overall survival (mOS) differed significantly between low and high TMB status (44.9 months vs. 85.8 months, respectively, p = 0.016). In a multivariate Cox regression analysis, TMB was the only independent prognostic factor for good metastatic overall survival after adjusting for age and recurrence (Hazard ratio [HR] = 0.32, 95% confidence interval [CI], 0.103-0.998, p = 0.049). These data suggest that high TMB may be a prognostic marker for predicting good overall survival for patients undergoing conventional HER2-directed treatments and chemotherapy. Further, future clinical trials harnessing TMB may benefit by identifying an appropriate population who may have a favorable response to immunotherapy after recurrence following HER2-directed treatments.

SUBMITTER: Park SE

PROVIDER: S-EPMC6136852 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer.

Park Song Ee SE Park Kyunghee K Lee Eunjin E Kim Ji-Yeon JY Ahn Jin Seok JS Im Young-Hyuck YH Lee Choonghoon C Jung Hun H Cho Soo Youn SY Park Woong-Yang WY Cristescu Razvan R Park Yeon Hee YH

Oncoimmunology 20180524 8

This study explored the clinical implications of tumor mutational burden (TMB) in a well-defined HER2-positive metastatic breast cancer (MBC) patient population who had been previously treated but had subsequent disease progression. Whole exome sequencing was performed on formalin-fixed paraffin-embedded tumor samples and matched normal tissue. Among the 46 patients, 13 (28.3%) were estrogen receptor-positive and nine (19.6%) were progesterone receptor-positive by immunohistochemistry analysis. ...[more]

PMID: 30221068

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Project description:BackgroundIn patients with metastatic breast cancer that is positive for human epidermal growth factor receptor 2 (HER2), progression-free survival was significantly improved after first-line therapy with pertuzumab, trastuzumab, and docetaxel, as compared with placebo, trastuzumab, and docetaxel. Overall survival was significantly improved with pertuzumab in an interim analysis without the median being reached. We report final prespecified overall survival results with a median follow-up of 50 months.MethodsWe randomly assigned patients with metastatic breast cancer who had not received previous chemotherapy or anti-HER2 therapy for their metastatic disease to receive the pertuzumab combination or the placebo combination. The secondary end points of overall survival, investigator-assessed progression-free survival, independently assessed duration of response, and safety are reported. Sensitivity analyses were adjusted for patients who crossed over from placebo to pertuzumab after the interim analysis.ResultsThe median overall survival was 56.5 months (95% confidence interval [CI], 49.3 to not reached) in the group receiving the pertuzumab combination, as compared with 40.8 months (95% CI, 35.8 to 48.3) in the group receiving the placebo combination (hazard ratio favoring the pertuzumab group, 0.68; 95% CI, 0.56 to 0.84; P<0.001), a difference of 15.7 months. This analysis was not adjusted for crossover to the pertuzumab group and is therefore conservative. Results of sensitivity analyses after adjustment for crossover were consistent. Median progression-free survival as assessed by investigators improved by 6.3 months in the pertuzumab group (hazard ratio, 0.68; 95% CI, 0.58 to 0.80). Pertuzumab extended the median duration of response by 7.7 months, as independently assessed. Most adverse events occurred during the administration of docetaxel in the two groups, with long-term cardiac safety maintained.ConclusionsIn patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel, as compared with the addition of placebo, significantly improved the median overall survival to 56.5 months and extended the results of previous analyses showing the efficacy of this drug combination. (Funded by F. Hoffmann-La Roche and Genentech; CLEOPATRA ClinicalTrials.gov number, NCT00567190.).

Dataset Information

Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer.

Publications

Clinical implication of tumor mutational burden in patients with HER2-positive refractory metastatic breast cancer.

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