Sequencing Reveals MAP3K1 Mutation in Luminal-Type Breast Cancer

ORLANDO – Massively parallel sequencing of DNA from tumor samples in 50 patients with luminal-type breast cancer revealed a novel mutation in the breast cancer tumor suppressor gene MAP3K1, which normally controls programmed cell death.

Presumably, the knockout mutation – which affected about 10% of estrogen receptor–positive breast cancers in the study and which "unequivocally destroys the function of the gene" – allows cells to survive when they would normally die, Dr. Matthew J. Ellis said at the annual meeting of the American Association for Cancer Research.

This finding, along with others from the sequencing of more than 10 trillion chemical bases of DNA in this extensive genomics investigation (one of the largest to date), marks an important early step toward personalized therapy for breast cancer patients who fail to respond to estrogen-lowering therapy prior to surgery, said Dr. Ellis, professor of medicine and chief of breast oncology at the Washington University in St. Louis.

Luminal-type breast cancer is the most common form of the disease, accounting for 70%-80% of hormone receptor–positive breast cancers. Many patients have a good prognosis, but a subset has this very aggressive type of disease. Indeed, more patients die of aggressive luminal-type breast cancer than do all other breast cancer subtypes combined, he said.

"So we set out to find a molecular basis for poor outcome in receptor-positive disease," he said.

DNA from tumor samples of patients who were enrolled in ongoing neoadjuvant endocrine clinical trials – 24 of whom were resistant to estrogen receptor–targeted therapy – was used for the supercomputer-conducted analysis. The whole genomes of the tumors were compared with the matched DNA of the same patients’ healthy cells, allowing identification of mutations occurring only in the cancer cells.

In all, 1,700 mutations were identified, and most of these were unique to individuals. In addition to two previously identified, relatively common mutations (PIK3CA and TP53), Dr. Ellis and his colleagues found only three others – including MAP3K1 – that recurred at a frequency of at least 10%; the other two were ATR and MYST3.

PIK3CA and TP53 were the most frequently mutated genes in estrogen receptor–positive breast cancer in this study, occurring in about 50% and 20% of tumors, respectively. MAP3K1 was the third most commonly mutated gene.

Considering the large number of mutations found, it was "a rather shocking result" to find only three new gene mutations at the 10% recurrence level, Dr. Ellis said. "What it says is that breast cancer is highly complex, that the genetic make-up involves a large number of mutations that averages about 20 tier-1 [or coding region] mutations in each tumor, and there’s a wide range," he added.

But the findings do offer a glimpse into how therapy can be personalized.

Using a "very, very simple model" produced by this analysis, Dr. Ellis illustrated how a constellation of mutations could be used to predict response or resistance patterns: The three-gene cluster of mutated MAP3K1, mutated PIK3CA, and wild type TP53, which occurred in a small subset of patients, was shown to be significantly associated with "luminal A status [indicative of good prognosis], suppressed proliferation, and favorable small tumors at the end of neoadjuvant treatment," he said.

Although there remains "a great sea of unknown," the findings – when considered in the context of the growing list of "druggable mutations" and treatments approved for other diseases – allow for a vision of therapy that involves obtaining the genetic information in advance of treatment to allow for the design of individually appropriate therapy to address the problem of resistance.

"Very clearly, this is a big problem clinically ... and only a tailored approach will lead to a solution to the problem," he said.

Dr. Ellis disclosed that he has received grant or research support from and/or served on the speakers bureau for Novartis, AstraZeneca, and Bioclassifier LLC.

ORLANDO – Massively parallel sequencing of DNA from tumor samples in 50 patients with luminal-type breast cancer revealed a novel mutation in the breast cancer tumor suppressor gene MAP3K1, which normally controls programmed cell death.

Presumably, the knockout mutation – which affected about 10% of estrogen receptor–positive breast cancers in the study and which "unequivocally destroys the function of the gene" – allows cells to survive when they would normally die, Dr. Matthew J. Ellis said at the annual meeting of the American Association for Cancer Research.

This finding, along with others from the sequencing of more than 10 trillion chemical bases of DNA in this extensive genomics investigation (one of the largest to date), marks an important early step toward personalized therapy for breast cancer patients who fail to respond to estrogen-lowering therapy prior to surgery, said Dr. Ellis, professor of medicine and chief of breast oncology at the Washington University in St. Louis.

Luminal-type breast cancer is the most common form of the disease, accounting for 70%-80% of hormone receptor–positive breast cancers. Many patients have a good prognosis, but a subset has this very aggressive type of disease. Indeed, more patients die of aggressive luminal-type breast cancer than do all other breast cancer subtypes combined, he said.

"So we set out to find a molecular basis for poor outcome in receptor-positive disease," he said.

DNA from tumor samples of patients who were enrolled in ongoing neoadjuvant endocrine clinical trials – 24 of whom were resistant to estrogen receptor–targeted therapy – was used for the supercomputer-conducted analysis. The whole genomes of the tumors were compared with the matched DNA of the same patients’ healthy cells, allowing identification of mutations occurring only in the cancer cells.

In all, 1,700 mutations were identified, and most of these were unique to individuals. In addition to two previously identified, relatively common mutations (PIK3CA and TP53), Dr. Ellis and his colleagues found only three others – including MAP3K1 – that recurred at a frequency of at least 10%; the other two were ATR and MYST3.

PIK3CA and TP53 were the most frequently mutated genes in estrogen receptor–positive breast cancer in this study, occurring in about 50% and 20% of tumors, respectively. MAP3K1 was the third most commonly mutated gene.

Considering the large number of mutations found, it was "a rather shocking result" to find only three new gene mutations at the 10% recurrence level, Dr. Ellis said. "What it says is that breast cancer is highly complex, that the genetic make-up involves a large number of mutations that averages about 20 tier-1 [or coding region] mutations in each tumor, and there’s a wide range," he added.

But the findings do offer a glimpse into how therapy can be personalized.

Using a "very, very simple model" produced by this analysis, Dr. Ellis illustrated how a constellation of mutations could be used to predict response or resistance patterns: The three-gene cluster of mutated MAP3K1, mutated PIK3CA, and wild type TP53, which occurred in a small subset of patients, was shown to be significantly associated with "luminal A status [indicative of good prognosis], suppressed proliferation, and favorable small tumors at the end of neoadjuvant treatment," he said.

Although there remains "a great sea of unknown," the findings – when considered in the context of the growing list of "druggable mutations" and treatments approved for other diseases – allow for a vision of therapy that involves obtaining the genetic information in advance of treatment to allow for the design of individually appropriate therapy to address the problem of resistance.

"Very clearly, this is a big problem clinically ... and only a tailored approach will lead to a solution to the problem," he said.

Dr. Ellis disclosed that he has received grant or research support from and/or served on the speakers bureau for Novartis, AstraZeneca, and Bioclassifier LLC.

ORLANDO – Massively parallel sequencing of DNA from tumor samples in 50 patients with luminal-type breast cancer revealed a novel mutation in the breast cancer tumor suppressor gene MAP3K1, which normally controls programmed cell death.

Presumably, the knockout mutation – which affected about 10% of estrogen receptor–positive breast cancers in the study and which "unequivocally destroys the function of the gene" – allows cells to survive when they would normally die, Dr. Matthew J. Ellis said at the annual meeting of the American Association for Cancer Research.

This finding, along with others from the sequencing of more than 10 trillion chemical bases of DNA in this extensive genomics investigation (one of the largest to date), marks an important early step toward personalized therapy for breast cancer patients who fail to respond to estrogen-lowering therapy prior to surgery, said Dr. Ellis, professor of medicine and chief of breast oncology at the Washington University in St. Louis.

Luminal-type breast cancer is the most common form of the disease, accounting for 70%-80% of hormone receptor–positive breast cancers. Many patients have a good prognosis, but a subset has this very aggressive type of disease. Indeed, more patients die of aggressive luminal-type breast cancer than do all other breast cancer subtypes combined, he said.

"So we set out to find a molecular basis for poor outcome in receptor-positive disease," he said.

DNA from tumor samples of patients who were enrolled in ongoing neoadjuvant endocrine clinical trials – 24 of whom were resistant to estrogen receptor–targeted therapy – was used for the supercomputer-conducted analysis. The whole genomes of the tumors were compared with the matched DNA of the same patients’ healthy cells, allowing identification of mutations occurring only in the cancer cells.

In all, 1,700 mutations were identified, and most of these were unique to individuals. In addition to two previously identified, relatively common mutations (PIK3CA and TP53), Dr. Ellis and his colleagues found only three others – including MAP3K1 – that recurred at a frequency of at least 10%; the other two were ATR and MYST3.

PIK3CA and TP53 were the most frequently mutated genes in estrogen receptor–positive breast cancer in this study, occurring in about 50% and 20% of tumors, respectively. MAP3K1 was the third most commonly mutated gene.

Considering the large number of mutations found, it was "a rather shocking result" to find only three new gene mutations at the 10% recurrence level, Dr. Ellis said. "What it says is that breast cancer is highly complex, that the genetic make-up involves a large number of mutations that averages about 20 tier-1 [or coding region] mutations in each tumor, and there’s a wide range," he added.

But the findings do offer a glimpse into how therapy can be personalized.

Using a "very, very simple model" produced by this analysis, Dr. Ellis illustrated how a constellation of mutations could be used to predict response or resistance patterns: The three-gene cluster of mutated MAP3K1, mutated PIK3CA, and wild type TP53, which occurred in a small subset of patients, was shown to be significantly associated with "luminal A status [indicative of good prognosis], suppressed proliferation, and favorable small tumors at the end of neoadjuvant treatment," he said.

Although there remains "a great sea of unknown," the findings – when considered in the context of the growing list of "druggable mutations" and treatments approved for other diseases – allow for a vision of therapy that involves obtaining the genetic information in advance of treatment to allow for the design of individually appropriate therapy to address the problem of resistance.

"Very clearly, this is a big problem clinically ... and only a tailored approach will lead to a solution to the problem," he said.

Dr. Ellis disclosed that he has received grant or research support from and/or served on the speakers bureau for Novartis, AstraZeneca, and Bioclassifier LLC.