SAN ANTONIO – An investigational genetic test may not only be able to differentiate women likely to have early recurrence of estrogen receptor–positive breast cancer but also could lead to novel combinations of existing drugs to treat these patients earlier in the disease process, according to Dr. Minetta C. Liu.
Researchers developed a 91-gene classifier "that essentially separated those patients who were going to recur early [within 3 years] vs. those who were going to recur late [beyond 10 years]," Dr. Liu announced at a press briefing held during the San Antonio Breast Cancer Symposium.
"Our work is very much hypothesis generating. To be able to identify early vs. late recurrences at the time of diagnosis would be useful, but we actually need to be able to know what to do about it once we identify it," said Dr. Liu, director of translational breast cancer research at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.
The ability to reliably predict early treatment failure may help to identify patients who require agents beyond endocrine therapy to prevent the early onset of distant metastases, she said. "We hope to exploit these molecular differences of early vs. later recurrences to help us guide novel drug combinations in ER–positive early-stage disease," Dr. Liu added.
Dr. Minetta C. Liu
Session moderator Dr. Jennifer A. Ligibel of Dana-Farber Cancer Institute, Boston, agreed: This type of analysis "will help us to give chemotherapy to fewer patients potentially, if they do not have tumors that are consistent with early relapse and to know which patients really require extended therapy beyond the initial 5 years of treatment of endocrine therapy for patients who are potentially destined for late relapse."
The researchers acquired snap-frozen, pretreatment tumor biopsies collected at the Edinburgh Breakthrough Research Unit in Scotland between 1982 and 1990. The samples were from patients with stages I-III estrogen receptor–positive breast cancer, starting tamoxifen-alone adjuvant treatment. These patients had to have at least a 10-year follow-up in the absence of distant release.
A histology review was performed of the samples and those that contained at least 50% tumor were cleared for RNA extraction for gene expression profiling.
This training data set included 111 samples, with 57 relapses. Tumors from patients with relapse were subdivided into early recurrence (within 3 years of diagnosis) and late recurrence (more than 10 years). A total of 25 patients had early recurrences and 22 had late recurrences. Median follow-up was 13 years.
The investigators selected a validation data set from the literature that met certain criteria, such as quality of data and follow-up (BMC Genomics 2008;9:239). This previously published data set included 255 samples from patients with stages I-II estrogen receptor–positive breast cancer with tamoxifen-alone adjuvant treatment. Of these, 67 had distant relapse – 25 patients had early recurrences and 7 had late recurrences. The median follow-up was 9 years.
Using this training data set, the researchers developed a 91-gene classifier "that essentially separated those patients, who were going to recur early vs. those who were going to recur late," Dr. Liu said. They optimized the classifier and applied it to a validation data set.
"We had very high accuracy, sensitivity, specificity, positive predictive value, and negative predictive value," said Dr. Liu. However, "we didn’t stop at developing a classifier. We wanted to understand what these genes are trying to tell us within the classifier. ... A novel computational method allowed us to look at [estrogen receptor]network topology – to create a map basically."
The investigators identified several genes that were overexpressed in patients with early recurrences: CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1. They also identified genes that had increased expression in patients with late recurrences: ESR1, ESR2, EGFR, BCL2, and AR.
"Clearly there are robust molecular differences between those tumors that recur early versus those that recur much later despite adjuvant tamoxifen. The majority of the genes in our classifier relate to apoptosis and proliferation," said Dr. Liu.
"I want to emphasize that we’re not just about developing a score and identifying these patients. We actually want to do something about it and understand what the underlying mechanisms are behind these genetic differences."
Dr. Liu reported that she has no relevant financial disclosures.