Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3

André, Fabrice; Hurvitz, Sara A.; Fasolo, Angelica; Tseng, Ling‐Ming; Jérusalem, Guy; Wilks, Sharon; O’Regan, Ruth; Isaacs, Claudine; Toi, Masakazu; Burris, Howard A.; He, Wei; Robinson, Douglas; Riester, Markus; Taran, Tetiana; Chen, David; Slamon, Dennis J.

doi:10.1200/jco.2015.63.9161

Cited by 150 publications

(111 citation statements)

References 26 publications

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“…Biomarker analysis of two phase III trials (BOLERO-1 and BOLERO-3) that randomized Her2-positive breast cancer patients to receiving a chemotherapy with and without everolimus revealed that participants with an altered PI3K pathway had a statistically improved PFS with an everolimus-containing regimen (hazard ratio [HR]: 0.67; 95% confidence interval [CI], 0.48–0.93), while there was no benefit from everolimus among patients with wild-type PI3K pathway (HR: 1.19; 95% CI, 0.87–1.62) (46). Janku et al have also reported that, among diverse malignancies, PIK3CA or PTEN alterations were the independent factor predicting response to inhibitors targeting PI3K pathway, including mTor inhibitors, albeit when used in combination therapy rather than as single agents (47).…”

Section: Discussionmentioning

confidence: 99%

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.

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Section: Discussionmentioning

confidence: 99%

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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“…In this trial, amplification of cyclin D1 had no impact on everolimus efficacy, whereas mutation or amplification of FGFR1 or FGFR2 resulted in less benefit from everolimus treatment, though the trial was not sufficiently powered to deliver definitive conclusions in this regard. A meta-analysis of the BOLERO-1 and BOLERO-3 phase 3 trials of everolimus or placebo in combination with trastuzumab and chemotherapy (paclitaxel or vinorelbine, respectively) in patients with HER2+ advanced breast cancer revealed a significant PFS benefit from everolimus in patients with either PIK3CA mutation or low PTEN expression (by IHC), whereas patients with neither of these alterations experienced no PFS benefit from the addition of everolimus (André et al, 2016). …”

Section: Therapeutic Targeting Of the Pi3k Pathway In Cancermentioning

confidence: 99%

The PI3K Pathway in Human Disease

Fruman

Chiu

Hopkins

et al. 2017

Cell

1,883

1,658

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Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers, and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

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“…In vitro studies showed that mTOR activation was related to HER2 overexpression and responsible for HER2-positive breast cancer progression. A recent randomized phase 3 study (BOLERO 3) was designed to compare the efficacy of everolimus plus trastuzumab and vinorelbine with trastuzumab and vinorelbine combination in trastuzumab-resistant HER2-positive MBC patients [26]. In this study, 100% of patients were previously treated with taxanes plus trastuzumab and 28% of patients were previously treated with lapatinib.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

Wang

Liu²,

Jia³

et al. 2016

Chemotherapy

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Background: The aim of this study was to evaluate the efficacy of vinorelbine-based regimens as first-, second- and more-line therapies in advanced breast cancer (ABC) and to analyze the best timing of vinorelbine treatment. Methods: A total of 71 ABC patients were retrospectively reviewed. Of these, 35 patients were treated with vinorelbine-based regimens as first-line chemotherapy, and 36 patients were treated with vinorelbine-based regimens as second-line or more-line therapy. The primary end point of the study was progression-free survival (PFS). Results: No difference was found in baseline characteristics between the two groups (p > 0.1 for all comparisons). There was a significant difference in the objective response rate (ORR; p = 0.006) and clinical benefit rate (CBR; p = 0.013) between the first-line group and the second- or more-line groups. In the vinorelbine first-line group, the ORR was 68.6% (24 patients), and in the second-line or more-line groups the ORR was 36.1% (13 patients). A significant difference in PFS between the first-line group and the second-line or more-line groups was also observed (p = 0.030). The median PFS in the overall population was 6.3 ± 1.32 months (95% CI 3.69-8.90). The median PFS was 11.1 ± 3.76 months (95% CI 3.73-18.47) in the first-line group compared with 5.2 ± 1.35 months (95% CI 2.54-7.85) in the second-line or more-line groups. In patients treated with vinorelbine-trastuzumab combination as the first-line therapy, a complete response was observed in 1 patient (12.5%) and partial response in 5 patients (62.5%), giving an ORR of 75.0%. Progressive disease was observed in 1 patient (12.5%), and stable disease in 1 patient (12.5%), leading to a CBR of 87.5%. The median PFS was 13.8 ± 2.75 months (95% CI 8.42-19.18), and median OS was 37.0 ± 11.6 months (95% CI 14.18-59.82). No significant difference was found in overall survival (OS) between the groups (p = 0.612). Conclusion: For ABC patients, no significant difference in median OS was found between the early use and delayed use of vinorelbine-based regimens, but the short-term efficacy and PFS of vinorelbine-based regimens were significantly better in the early use group than in the delayed use group.

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Molecular Alterations and Everolimus Efficacy in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancers: Combined Exploratory Biomarker Analysis From BOLERO-1 and BOLERO-3

Abstract: This analysis, although exploratory, suggests that patients with human epidermal growth factor receptor 2-positive advanced breast cancer having tumors with PIK3CA mutations, PTEN loss, or hyperactive PI3K pathway could derive PFS benefit from everolimus.

Cited by 150 publications

References 26 publications

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

The PI3K Pathway in Human Disease

Comparison of the Therapeutic Efficacy of the Early and the Delayed Use of Vinorelbine-Based Regimens for Patients with Advanced Breast Cancer

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