CHICAGO — Tumor heterogeneity in luminal-type breast cancer was observed to be driven by specific patterns of somatic mutations, yet most targetable or prospective prognostic mutations appeared infrequently.
In comparing clinical features of ER-positive breast cancer with somatic mutations, Matthew James Ellis, MD, PhD, FRCP, head of the section of breast oncology and Anheuser Busch endowed chair of medical oncology at Washington University in St. Louis, and colleagues applied massively parallel sequencing to tumor and normal DNAs accumulated from patients treated with neoadjuvant aromatase inhibitors.
“The question would be: Is it clinically significant to identify the low-frequency patterns of mutation in a relatively rare disease? Or what does a rare drug mutation really mean in the context of the common malignancy?” Ellis said at a press conference. “To put it in context, just 2% of breast cancer produces a population similar to the annual instance of chronic myeloid leukemia, and no one would tell the leukemia doctor and patient that this disease is not significant.”
In the study, massively parallel sequencing was applied to 77 baseline tumor biopsy samples from the preoperative letrozole trial and the Z1031 trial, followed by targeted sequencing in another 240 trial samples. Standard statistical approaches were used to compare mutation status and clinical parameters, and pathway-based correlation was used to assess interactions between signaling perturbations induced by gene mutations and response to neoadjuvant aromatase inhibitors.
According to the study results, 18 genes were observed to be significantly mutated above background. Aside from PIK3CA mutations, the list is populated by loss-of-function mutations in tumor suppressor genes. Five genes — including RUNX1, CBFP, MYH9, MLL3 and SF3B1 — have been previously associated with benign and malignant hematopoietic disorders.
Researchers said TP53 mutation was associated with PAM50 LumB status, high-grade histology and high proliferation rates, whereas loss-of-function mutations in MAP3K1 associate with PAM50 lumA status, low proliferation rates and low-grade histology.
“You can look at this data through the lens of the clinical phenotypes and mutations, which provide dichotomies in order to compare these integrated pathway activities between tumors of different genotype and phenotype and then correlate the findings,” Ellis said.
Mutations in GATA3 were linked to significant inhibition of proliferation upon aromatase inhibitors treatment, which suggested that the mutant GATA3 could predict endocrine response. Pathway analysis demonstrated that rare MAP2K4 mutations produce similar pathway perturbations as MAP3K1 mutation. Signaling network patterns driven by IncRNA MALAT1 mutations were also associated with multiple poor clinical outcome features.
“Despite enormous complexity, we were able to find frequently mutant genes with significant effects on the clinical phenotype of the disease,” Ellis said. “Bioinformatic analysis identified a number of functional hubs or pathways consistent with luminal-type resistant tumors. We also identified multiple new types of mutations, in particular low-frequency mutations, which I believe are certainly likely to represent a challenge to investigation, but not impossible.”
For more information:
Ellis MJ. #503. Presented at: the 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.
Disclosure: Dr. Ellis reports no relevant financial disclosures.