Search for Biomarkers of mTOR Inhibitor Benefit in Breast Cancer Fails to Pan Out 


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The search for a biomarker of benefit from mTOR inhibitors in breast cancer fell flat in an exploratory genetic analysis of the ­BOLERO-2 trial, presented at the 2013 ASCO Annual Meeting by Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston.1

The biomarker analysis involved 3,230 exons of 182 oncogenes and tumor-suppressor genes that were sequenced using next-generation sequencing on 309 tissue samples. Kaplan-Meier curves and summary descriptive statistics were calculated for each genetic alteration.

BOLERO-2 Outcomes

In BOLERO-2, median progression-free survival was 7.8 months with everolimus (Afinitor) and 3.2 months with placebo—a 55% reduction in risk.2 Clinical outcomes for the next-generation sequencing population were similar, confirming that the sample was representative of the study population.

Next-generation sequencing identified almost 1,500 sequence alterations, 24 rearrangements, and about 550 copy number variations. The average tumor sample contained 4.1 genetic alterations, and at least one known somatic alteration was identified in 219 patients. The genetic pathways harboring the most genetic alterations were PIK3CA (48%), CCND1 (31%), TP53 (23%), and FGFR1 (18%), Dr. Hortobagyi reported.

As background, activating mutations in the catalytic domain of PI3K have been identified in about one-third of estrogen receptor–positive tumors. Up to one-third of patients with breast cancer show reduced expression of PTEN, and this has been associated with poor response to tamoxifen.

Equivalent Benefit across Subgroups

There was a positive treatment effect in favor of everolimus across the various key genetic marker subgroups, pointing to the inability to identify subsets of patients most likely to benefit from the drug.

“This retrospective exploratory analysis found no predictive marker of everolimus efficacy in subgroups defined by each of the four most frequently altered genes and pathways, when assessed individually,” Dr. Hortobagyi reported.

A greater benefit from everolimus treatment was derived in patients with minimal genetic alterations in PIK3CA/PTEN/CCND1 or FGFR1/2 genes combined, which represented 76% of the next-generation sequencing population. Patients with a single alteration in one of these pathways had a median progression-free survival of 214 days with everolimus, compared to 77 days with placebo (hazard ratio [HR] = .26). For those with multiple alterations, median progression-free survival was 138 and 128 days, respectively (HR = .28).

Dr. Hortobagyi suggested that the results, if validated, “may help to generate new hypotheses for combinations of novel targeted therapies as treatment for hormone receptor–positive/HER2-negative breast cancer.” ■

Disclosure: Dr. Hortobagyi serves as a consultant to and receives research support (via his institution) from Novartis.

References

1. Hortobagyi GN, Piccart-Gebhart MJ, Rugo HS, et al: Correlation of molecular alterations with efficacy of everolimus in hormone receptor-positive, HER2-negative advanced breast cancer: Results from BOLERO-2. 2013 ASCO Annual Meeting. Abstract LBA509. Presnted June 3, 2013.

2. Hortobagyi GN, Piccart M, Rugo H, et al: Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. 2011 San Antonio Breast Cancer Symposium. Abstract S3-7. Presented December 8, 2011


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