Dataset Information

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

ABSTRACT:

Background

We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy.

Methods

Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tissue specimens were obtained from primary or metastatic lesion. Tissue specimens were examined for gene mutations or protein expression using a Foundation Medicine gene panel and immunohistochemistry.

Results

In the 32 tissue specimens collected, we detected 33 gene mutations, with the most frequent nonsynonymous mutations found in TP53. The objective response rates (ORRs) in patients with and without HRR-related gene mutation were 33.3% and 40%, respectively (P?=?.732), and the ORRs in patients with and without somatic BRCA mutations were 60% and 33.3%, respectively (P?=?.264), with the ORR numerically higher in the somatic BRCA-mutation group but not statistically significant. There was no correlation between immunohistochemistry status and response or between BRCA status or HRR-related gene mutation and survival. Immunohistochemical analysis indicated that EGFR-negative patients had a tendency for better progression-free survival (log-rank P?=?.059) and significantly better overall survival (log-rank P?=?.046); however, there was no correlation between the status of other immunohistochemistry markers and survival.

Conclusion

These findings suggested somatic BRCA mutation and EGFR-negativity as a potential biomarker for predicting the efficacy of eribulin/olaparib combination therapy. (UMIN000018721).

SUBMITTER: Shimomura A

PROVIDER: S-EPMC6698310 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

Shimomura Akihiko A Yonemori Kan K Yoshida Masayuki M Yoshida Teruhiko T Yasojima Hiroyuki H Masuda Norikazu N Aogi Kenjiro K Takahashi Masato M Naito Yoichi Y Shimizu Satoru S Nakamura Rikiya R Hamada Akinobu A Michimae Hirofumi H Hashimoto Jun J Yamamoto Harukaze H Kawachi Asuka A Shimizu Chikako C Fujiwara Yasuhiro Y Tamura Kenji K

Translational oncology 20190802 10

<h4>Background</h4>We conducted a phase I/II clinical trial to evaluate the efficacy of eribulin and olaparib in a tablet form (EO study) for triple-negative breast cancer (TNBC) patients. We hypothesized that somatic BRCA mutations and homologous recombination repair (HRR)-related gene alterations might affect efficacy.<h4>Methods</h4>Our analyses identified mutations in HRR-related genes and BRCA1/2, and we subsequently evaluated their association to response by the EO study participants. Tiss ...[more]

PMID: 31382135

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Project description:BACKGROUND:Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS:The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5?mg daily; eribulin 1.4?mg/m2?days 1 and 8 every 3 weeks), A2 (everolimus 7.5?mg daily; eribulin 1.4?mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5?mg daily; eribulin 1.1?mg/m2?days 1 and 8 every 3 weeks). RESULTS:Twenty-seven patients with median age 55?years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ??grade 3 toxicity, 44% had ??grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6?months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3?months (95% CI [5.5, undefined]). CONCLUSION:Eribulin 1.1?mg/m2?days 1 and 8 every 3 weeks with everolimus 5?mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.

Project description:PurposeEpidermal growth factor receptor (EGFR) is a targetable receptor frequently overexpressed in basal-like breast cancer, which comprises most triple-negative breast cancers (TNBCs), the only subtype without established targeted therapy.Patients and methodsIn this randomized phase II trial, patients with metastatic TNBC received anti-EGFR antibody cetuximab (400 mg/m(2) load then 250 mg/m(2) per week intravenously [IV]) alone, with carboplatin (area under the curve of 2, once per week IV) added after progression or as concomitant therapy from the beginning. Response rate (RR) was the primary end point; others included time to progression (TTP), overall survival (OS), and toxicity. Embedded correlative studies included molecular subtyping on archival tissue. Fresh tumor tissue before and after 7 to 14 days of therapy was used for microarray analyses exploring EGFR pathway activity and inhibition.ResultsIn 102 patients with TNBC, RRs were 6% (two of 31) to cetuximab and 16% (four of 25) to cetuximab plus carboplatin after progression. RR to those treated from the beginning with cetuximab plus carboplatin was 17% (12 of 71); 31% of patients responded or had prolonged disease stabilization. The cetuximab plus carboplatin regimen was well tolerated, but both TTP and OS were short at 2.1 months (95% CI, 1.8 to 5.5 months) and 10.4 months (95% CI, 7.7 to 13.1 months), respectively. Of 73 patients with archival tissue for analysis, 74% had basal-like molecular subtype. Sixteen patients had tumor biopsies before and 1 week after therapy; genomic patterns of the EGFR pathway showed activation in 13 and inhibition by therapy in five.ConclusionDespite strong preclinical data, combination cetuximab plus carboplatin in metastatic TNBC produced responses in fewer than 20% of patients. EGFR pathway analysis showed that most TNBCs involved activation. However, cetuximab blocked expression of the EGFR pathway in only a minority, suggesting that most had alternate mechanisms for pathway activation.

Dataset Information

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

Background

Methods

Results

Conclusion

Publications

Gene Alterations in Triple-Negative Breast Cancer Patients in a Phase I/II Study of Eribulin and Olaparib Combination Therapy.

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