By Monica Heger
A study to test whether next-generation sequencing can guide treatment for triple-negative breast cancer patients has led to the initiation of a phase I clinical trial of combination MEK/AKT inhibitors, which had previously not been tested for this indication.
The sequencing study, supported in part by Life Technologies and led by researchers from Baylor Health Care, the Translational Genomics Research Institute, and US Oncology, kicked off in March 2010 (IS 6/8/2010). Initial results were presented last week at the San Antonio Breast Cancer Symposium.
The team, which is using Life Tech's SOLiD, has completed the sequencing of 12 patients, including whole-genome sequencing of the tumor and matched normal sample and transcriptome sequencing of the tumor for all patients. They plan to do the same for two more patients.
Of the 12 sequenced patients, two have been matched to therapies based on their genomic profiles. Four others were put on treatment before the analysis was complete and their response or lack of response was then interpreted in the context of their genomic data. Analysis of the remaining patients is ongoing.
The study shows that "we can identify drivers that match patients to the appropriate therapy," said John Carpten, head of TGen's Cancer Gene Discovery and Molecular Validation Unit, whose lab conducted the sequencing.
All patients in the study had metastatic triple-negative breast cancer. Sequencing was done when the disease was stable with the goal of identifying a potential next course of treatment. All the patients had advanced forms of cancer, and some saw benefit from the treatments chosen. "If we can identify the [actionable mutations] even earlier, we could see even more dramatic responses," Carpten said.
After sequencing and initial analysis, each patient's results were discussed among a tumor board that included physicians, cancer biologists, as well as a researcher who had analyzed the sequence data.
Rather than look for specific genes that were mutated, the board sought to figure out which pathways appeared to be the most heavily mutated — including with gene amplifications or deletions — and then looked for drugs that would act within those pathways.
Any mutation deemed actionable was then validated in a CLIA setting. Turnaround time from biopsy to a clinical decision was two to three months.
While the patients each exhibited a diverse range of mutations, one of the more striking findings from the study is that all the patients had mutations to the MAPK pathway, although through different means, including amplification and overexpression of the known oncogene BRAF and overexpression of IQGAP3, which regulates cell proliferation.
All patients also had mutations that would activate the PI3-kinase pathway and the AKT pathway, including deletion of the tumor suppressor PTEN; a homozygous deletion to the gene FBXW7, mutations to which have been previously found in ovarian and breast cancer cell lines; and overexpression of ERAS, which is involved in cell proliferation.
The results suggested that a combination therapy of MEK and AKT inhibitors might be effective in triple-negative breast patients harboring these mutations.
Prior to this study, this drug combination had never been tried in breast cancer, only for lung cancer. Since the initial findings, a phase I clinical trial has begun of the combination therapy for metastatic triple-negative breast cancer. All women enrolled in the sequencing study have the option of joining the trial, said Joyce O'Shaughnessy, associate director of clinical research for US Oncology and co-director of the breast cancer research program at the Baylor Charles A. Sammons Cancer Center.
The first woman recommended for MEK/AKT combination therapy showed a "dramatic response," said Carpten. Her tumor nearly disappeared.
Despite this response, the woman ended up developing metastasis in her brain, from which she has since passed away. The metastatic brain tumor was driven by a different pathway, so did not respond to the targeted treatment.
The initial response does suggest, however, that if a targeted treatment can be identified sooner, patients may see longer-lasting results.
Another patient had a homozygous deletion to the FBXW7 gene, a tumor suppressor that binds to mTOR. She was put on a regimen that included mTOR inhibitors and has since "stabilized," said Carpten. While her personalized treatment did not elicit as dramatic a response, disease progression was slowed and the patient is currently still alive, said Carpten.
O'Shaughnessy said that the sequencing has helped both to identify treatments that may not have otherwise been tried and also to explain why a patient responds or doesn't respond to a given therapy.
For several of the patients, O'Shaughnessy recommended treatment before the sequencing and analysis was completed and has since used the analysis to try and figure out why they did or did not respond to treatment.
For instance, she found that two women who showed no response to their initial chemotherapy responded well to irinotecan, marketed by Pfizer as Camptosar. Both of those women had amplifications to genes in the RAS pathway, which "raises the hypothesis that patients who are refractory to standard chemotherapy and who have activation of the RAS pathway may benefit from irinotecan," O'Shaughnessy said.
The initial results also demonstrated that sequencing can point to treatments that may not have otherwise been tried. For instance, triple-negative breast cancer was not thought to be a candidate for MEK/AKT inhibitors.
While researchers have looked for activating mutations to genes that would respond to those inhibitors, they have never been identified in the case of triple-negative breast cancer, said O'Shaughnessy. However, the women who responded to the treatment did not have activating point mutations, but rather amplifications or deletions of those genes, said O'Shaughnessy.
The initial findings of the study also point to the importance of including transcriptome sequencing data and illustrate potential limitations of targeted sequencing approaches.
"A lot of events we identified that led to a [treatment] decision may not have been identified in a targeted panel," said David Craig, whose lab at TGen led the analysis portion of the sequencing.
The next step, said Carpten, is to determine whether sequencing-guided treatment leads to better results than "physician's choice."
For this study, Carpten said they hope to enroll around 200 women in a randomized phase II clinical trial. Half the women will enter into the sequencing protocol and genomic information will be used to help guide the next course of treatment. Outcomes from those patients will be compared to patients whose next course of treatment is determined by her physician without the genomic information.
"That will help us determine the true benefit," Carpten said.
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