NEW YORK (GenomeWeb News) – Using whole-genome sequencing in a clinical trial of aromatase-inhibitor therapy for estrogen-positive breast cancer patients, researchers from the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and the Genome Institute at Washington University in St. Louis have found genomic signatures that correlate with drug response and resistance.
The study's results were published online Sunday in Nature.
"This is one of the first cancer genomics studies to move beyond cataloging mutations involved in cancer to finding those linked to treatment response and other clinical features," senior author and Co-director of the Genome Institute, Elaine Mardis, said in a statement.
In ER-positive breast cancer, estrogen stimulates the growth of tumors, and aromatase inhibitors are designed to lower estrogen in the body in order to stop and shrink tumor growth. Only about half of women respond to the drugs, yet there currently is not any way to tell those women apart.
The goal of incorporating sequencing into the trial was to try and identify genomic markers to better predict which women will respond.
The researchers sequenced the whole genomes of 46 patients and the whole exomes of 31 patients with stage 2 or 3 estrogen-positive breast cancer who were receiving aromatase inhibitors to try and reduce the tumor mass prior to surgery.
The tumor samples came from women enrolled in one of two clinical trials sponsored by the American College of Surgeons Oncology Group. Detailed information about the women's tumors and whether they responded to a four-month course of treatment were collected. Of the 77 patients, 29 were resistant to therapy and 48 responded.
Sequencing identified 18 significantly mutated genes, many of which were previously known like PIK3CA and TP53, but three of which had not previously been implicated in cancer —LDLRAP1, AGTR2, and STMN2.
Overall, the tumors of the women who responded tended to have fewer total mutations than those of the women who were resistant, which "makes sense in hindsight, but it's not something we would have predicted," Mardis said.
The researchers then extended their analysis of select genes to another 240 patients, incorporating clinical features, like levels of a tumor proliferation marker known as Ki67 and whether the tumor was considered luminal A or luminal, to identify genomic changes that seemed to be linked to response.
Mutations to the tumor suppressor gene TP53 were associated with poor prognosis, resistance to therapy, and fast-growing tumors that are more likely to metastasize. Mutations to that gene were seen in 131 out of 317 tumors, or 42 percent of patients.
Additionally, after conducting a pathway analysis, researchers found that 11 of the 29 resistant tumors, or 38 percent, had mutations in the TP53 signaling pathway, with three having double or triple hits involving TP53, ATR, APAF1, or THBS1, while in the group that responded to therapy, 17 percent, or eight out of 48 tumors, had mutations to that pathway, none with more than a single hit to either TP53, ATR, CCNE2, or IGF1.
On the other hand, a little less than 16 percent of patients had mutations to the genes MAP3K1 and MAP2K4, which were linked to a good response to aromatase inhibitors. Mutations to GATA3 also appeared to be associated with a good response to aromatase inhibitors.
The researchers now plan to follow up on these initial results using a $4 million grant from the Susan G. Komen for the Cure foundation to test whether using genomic information from whole-genome sequencing to guide treatment can lead to better clinical outcomes.
Women with ER-positive breast cancer will have their whole genomes sequenced after initial diagnosis and prior to receiving any therapy. Women whose mutational profile indicates a good response to aromatase inhibitors will be given those drugs, while women whose genomic profile indicates resistance to therapy will be given other treatment options — likely surgery to remove the tumor followed by chemotherapy or a targeted agent.