Genetic alterations may predict everolimus efficacy

SAN FRANCISCO – Among postmenopausal women with advanced hormone receptor–positive breast cancer, everolimus appeared to be more effective in the patients with one or no alterations in four key genes.

In a secondary analysis of data from the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2) study, one or no alterations in the PIK3CA; CCND1; FGFR1 and FGFR2 genes were seen in 76% of 227 tumor samples from women who took everolimus. These patients had significantly better progression-free survival than did patients with two or more alterations in these genes, Dr. Hope S. Rugo reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The number of patients with multiple gene alterations was admittedly small, but "potentially we have identified a population of patients who are less likely to benefit from everolimus," Dr. Rugo said.

She and her associates performed next-generation sequencing on DNA extracted tumor samples taken at diagnosis in BOLERO-2. Point mutations, short insertions or deletions, copy number alterations, or gene rearrangements were assessed in 219 tumors. Each tumor averaged 4 somatic mutations, with a range of 0-15 somatic mutations. Of the 182 genes sequenced, 104 had at least one known somatic mutation.

In the primary data analysis, all patients on everolimus had a 55% improvement in progression-free survival. In the secondary analysis of patients with minimal or no genetic alterations, 73% had an improvement in progression-free survival, reported Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco.

The genetic analysis found alterations in PIK3CA in 48% of samples, altered CCND1 in 31% of samples, altered P53 in 23%, and altered FGFR1 in 18%, so the researchers used these common alterations to seek predictors of treatment response. The four most commonly altered genes and the overall "tumor genetic landscape" in the current analysis were similar to those seen in previous large analyses such as The Cancer Genome Atlas Network (Nature 2012;490:61-70).

There was a hint that patients with alterations of FGFR1 or FGFR2 might be less likely to benefit from everolimus therapy. These numbers were small, however, and so the finding is only a hypothesis-generating observation, she said.

The sample group comprised approximately one-third of the cohort in BOLERO-2, the trial data that was the basis for the approval of everolimus. Baseline characteristics and outcomes were similar between the subgroup in the secondary analysis and the overall cohort.

The BOLERO-2 study comprised 724 postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that had recurred or progressed despite nonsteroidal aromatase inhibitor therapy. The women were randomized to treatment with exemestane plus everolimus or placebo. At 18 months of follow-up, median progression-free survival was 11 months in the patients in the exemestane-plus-everolimus group, significantly longer than the 4-month median progression-free survival seen in the exemestane-plus-placebo group (N. Engl. J. Med. 2012;366:520-29).

As in other recent trials, most of the tumor samples for the genetic analysis were archived from the time of initial diagnosis rather than after metastasis. "Although the impact on the results shown here is unknown, we do know that additional mutations in these pathways are acquired with metastatic progression," Dr. Rugo said. "I think it’s important for all of us to try to obtain metastatic tumor tissue for these analyses moving forward."

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Novartis Pharmaceuticals Corp., which markets everolimus (Afinitor), funded the study. Dr. Rugo reported having financial associations with Novartis, Merck, and Pfizer.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Among postmenopausal women with advanced hormone receptor–positive breast cancer, everolimus appeared to be more effective in the patients with one or no alterations in four key genes.

In a secondary analysis of data from the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2) study, one or no alterations in the PIK3CA; CCND1; FGFR1 and FGFR2 genes were seen in 76% of 227 tumor samples from women who took everolimus. These patients had significantly better progression-free survival than did patients with two or more alterations in these genes, Dr. Hope S. Rugo reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The number of patients with multiple gene alterations was admittedly small, but "potentially we have identified a population of patients who are less likely to benefit from everolimus," Dr. Rugo said.

She and her associates performed next-generation sequencing on DNA extracted tumor samples taken at diagnosis in BOLERO-2. Point mutations, short insertions or deletions, copy number alterations, or gene rearrangements were assessed in 219 tumors. Each tumor averaged 4 somatic mutations, with a range of 0-15 somatic mutations. Of the 182 genes sequenced, 104 had at least one known somatic mutation.

In the primary data analysis, all patients on everolimus had a 55% improvement in progression-free survival. In the secondary analysis of patients with minimal or no genetic alterations, 73% had an improvement in progression-free survival, reported Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco.

The genetic analysis found alterations in PIK3CA in 48% of samples, altered CCND1 in 31% of samples, altered P53 in 23%, and altered FGFR1 in 18%, so the researchers used these common alterations to seek predictors of treatment response. The four most commonly altered genes and the overall "tumor genetic landscape" in the current analysis were similar to those seen in previous large analyses such as The Cancer Genome Atlas Network (Nature 2012;490:61-70).

There was a hint that patients with alterations of FGFR1 or FGFR2 might be less likely to benefit from everolimus therapy. These numbers were small, however, and so the finding is only a hypothesis-generating observation, she said.

The sample group comprised approximately one-third of the cohort in BOLERO-2, the trial data that was the basis for the approval of everolimus. Baseline characteristics and outcomes were similar between the subgroup in the secondary analysis and the overall cohort.

The BOLERO-2 study comprised 724 postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that had recurred or progressed despite nonsteroidal aromatase inhibitor therapy. The women were randomized to treatment with exemestane plus everolimus or placebo. At 18 months of follow-up, median progression-free survival was 11 months in the patients in the exemestane-plus-everolimus group, significantly longer than the 4-month median progression-free survival seen in the exemestane-plus-placebo group (N. Engl. J. Med. 2012;366:520-29).

As in other recent trials, most of the tumor samples for the genetic analysis were archived from the time of initial diagnosis rather than after metastasis. "Although the impact on the results shown here is unknown, we do know that additional mutations in these pathways are acquired with metastatic progression," Dr. Rugo said. "I think it’s important for all of us to try to obtain metastatic tumor tissue for these analyses moving forward."

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Novartis Pharmaceuticals Corp., which markets everolimus (Afinitor), funded the study. Dr. Rugo reported having financial associations with Novartis, Merck, and Pfizer.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Among postmenopausal women with advanced hormone receptor–positive breast cancer, everolimus appeared to be more effective in the patients with one or no alterations in four key genes.

In a secondary analysis of data from the Breast Cancer Trials of Oral Everolimus–2 (BOLERO-2) study, one or no alterations in the PIK3CA; CCND1; FGFR1 and FGFR2 genes were seen in 76% of 227 tumor samples from women who took everolimus. These patients had significantly better progression-free survival than did patients with two or more alterations in these genes, Dr. Hope S. Rugo reported at a breast cancer symposium sponsored by the American Society of Clinical Oncology.

The number of patients with multiple gene alterations was admittedly small, but "potentially we have identified a population of patients who are less likely to benefit from everolimus," Dr. Rugo said.

She and her associates performed next-generation sequencing on DNA extracted tumor samples taken at diagnosis in BOLERO-2. Point mutations, short insertions or deletions, copy number alterations, or gene rearrangements were assessed in 219 tumors. Each tumor averaged 4 somatic mutations, with a range of 0-15 somatic mutations. Of the 182 genes sequenced, 104 had at least one known somatic mutation.

In the primary data analysis, all patients on everolimus had a 55% improvement in progression-free survival. In the secondary analysis of patients with minimal or no genetic alterations, 73% had an improvement in progression-free survival, reported Dr. Rugo, director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco.

The genetic analysis found alterations in PIK3CA in 48% of samples, altered CCND1 in 31% of samples, altered P53 in 23%, and altered FGFR1 in 18%, so the researchers used these common alterations to seek predictors of treatment response. The four most commonly altered genes and the overall "tumor genetic landscape" in the current analysis were similar to those seen in previous large analyses such as The Cancer Genome Atlas Network (Nature 2012;490:61-70).

There was a hint that patients with alterations of FGFR1 or FGFR2 might be less likely to benefit from everolimus therapy. These numbers were small, however, and so the finding is only a hypothesis-generating observation, she said.

The sample group comprised approximately one-third of the cohort in BOLERO-2, the trial data that was the basis for the approval of everolimus. Baseline characteristics and outcomes were similar between the subgroup in the secondary analysis and the overall cohort.

The BOLERO-2 study comprised 724 postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that had recurred or progressed despite nonsteroidal aromatase inhibitor therapy. The women were randomized to treatment with exemestane plus everolimus or placebo. At 18 months of follow-up, median progression-free survival was 11 months in the patients in the exemestane-plus-everolimus group, significantly longer than the 4-month median progression-free survival seen in the exemestane-plus-placebo group (N. Engl. J. Med. 2012;366:520-29).

As in other recent trials, most of the tumor samples for the genetic analysis were archived from the time of initial diagnosis rather than after metastasis. "Although the impact on the results shown here is unknown, we do know that additional mutations in these pathways are acquired with metastatic progression," Dr. Rugo said. "I think it’s important for all of us to try to obtain metastatic tumor tissue for these analyses moving forward."

The symposium was cosponsored by the American Society of Breast Disease, the American Society of Breast Surgeons, the National Consortium of Breast Centers, the Society of Surgical Oncology, and the American Society for Radiation Oncology.

Novartis Pharmaceuticals Corp., which markets everolimus (Afinitor), funded the study. Dr. Rugo reported having financial associations with Novartis, Merck, and Pfizer.

[email protected]

On Twitter @sherryboschert