Genetic alterations affect everolimus benefit in breast cancer

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.

CHICAGO – The benefit of everolimus in hormone receptor–positive, HER2-negative advanced breast cancer appears to be greater for women who have little or no genetic alteration in this cancer’s most commonly altered molecular signaling pathways, based on data presented at the annual meeting of the American Society of Clinical Oncology.

A team led by Dr. Gabriel N. Hortobagyi performed next-generation sequencing on archival tumor tissue from patients enrolled in the randomized BOLERO-2 trial, which tested the addition to exemestane of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

Among all 227 patients whose tumors were tested, adding everolimus reduced the risk of progression or death by 60% as compared with adding placebo.

Patients having alterations in any of the four genes that were most commonly altered in the tumors or that were part of their respective signaling pathways derived similar benefit from everolimus as patients who had wild-type (normal) genes.

Thus, "no predictive marker of everolimus efficacy was identified in individual analysis of the four pathways," commented Dr. Hortobagyi, who chairs the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston.

However, there was differential benefit when patients were broadly grouped according to the extent of alterations – either minimal or multiple.

Three-fourths had minimal (none or one) alteration of these genes or another gene lying on the same pathway: the PIK3CA gene or the PTEN gene (PI3 kinase pathway), the CCND1 gene (cell cycle pathway), or the FGFR1 gene (FGFR1/2 pathway).

This group had a 73% reduction in the risk of progression or death if given everolimus as compared with placebo. In contrast, the group having multiple (two or more) alterations of these genes had a much smaller 22% reduction in risk.

"Further delineation of the interaction of these genetic events might help us to understand how the oncogenic signal cascades work and find better options to attenuate disease progression," Dr. Hortobagyi proposed. "These results are hypothesis generating only and should be validated in independent patient cohorts. But if confirmed, they could lead to new hypotheses for development of novel and more effective combination targeted therapies in hormone receptor–positive, HER2-negative breast cancer."

Session attendee Dr. Larry Norton of the Memorial Sloan-Kettering Cancer Center in New York, asked, "How many of these biopsies came from metastatic lesions and how many came from the primary? And if you just looked at the ones from the metastatic sites, do you see any differences there, because as we know, there is clonal evolution in the metastatic sites."

"About 20% came from metastatic disease, and about 80% from the primary. There are a number of individual differences between the two groups, but unfortunately, the numbers in the metastatic group are so small that you can’t really derive patterns," Dr. Hortobagyi replied. "Now all of the samples, both the primary and the metastatic ones, were from before the study, so it would not really directly reflect on the study itself. But that’s a very important question that we eventually have to address."

Attendee Dr. Ian Krop of the Dana-Farber Cancer Institute in Boston, commented, "It was interesting that those tumors that had multiple alterations in one of those four genes had what appeared to be decreased benefit from everolimus. Could that represent just genomic instability? In other words, if you look at random alterations in your data set, did that also correlate with lack of benefit?"

"We looked at that, and the genetic background for the two groups is very similar," Dr. Hortobagyi replied. "So my a priori thinking was exactly as you mentioned, that those would be associated with instability and therefore multiple driver pathways. But we did not see that."

Women in the BOLERO-2 trial were postmenopausal and had locally advanced or metastatic breast cancer that was refractory to a nonsteroidal aromatase inhibitor. They were assigned 2:1 to exemestane (brand name Aromasin) plus either everolimus (Afinitor) or placebo.

Everolimus is currently approved by the Food and Drug Administration for use in combination with exemestane to treat advanced hormone receptor–positive breast cancer in postmenopausal women. It is also approved for selected indications in other cancers.

In the new retrospective exploratory analysis, Dr. Hortobagyi’s team collected formalin-fixed, paraffin-embedded archival tumor tissue in a subset of patients and performed sequencing for 3,230 exons in 182 oncogenes and tumor suppressor genes.

Results showed that the four most commonly altered genes were PIK3CA (altered in 48% of patients), CCND1 (31%), TP53 (23%), and FGFR1 (18%).

In the patient subset as a whole, addition of everolimus was associated with a significant reduction in the risk of progression or death (hazard ratio, 0.40) similar to that previously reported in the entire trial population (HR, 0.45).

Neither alteration of any one of these four genes nor alteration of any one gene in their respective pathways predicted everolimus benefit. "Basically, the treatment effect was independent of the genetic status of these genes and pathways," Dr. Hortobagyi commented.

But when the pathways were considered simultaneously, patients having minimal genetic alteration derived a progression-free survival benefit from everolimus that exceeded that in the whole subset (HR, 0.27), whereas their counterparts having multiple alterations derived a benefit much less than that in the whole subset (HR, 0.78).

Dr. Hortobagyi disclosed that he is a consultant to Allergan, AstraZeneca, Galena Biopharma, Genentech, Myriad Genetics, Novartis, and Sanofi; receives research funding from Novartis; and has other affiliations with Genentech, Novartis, and Sanofi. The BOLERO-2 trial was sponsored by Novartis.