Dr. Dixon’s study is currently too small to alter clinical practice. His four-gene signature, while promising, needs to be taken into rigorous assay development, and much larger studies are needed.
—Matthew J. Ellis, MB, BChir, PhD
Matthew J. Ellis, MB, BChir, PhD, Director of the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston, commented on endocrine resistance and the potential of the four-gene panel for assessing resistance for The ASCO Post. Endocrine response and resistance is a research focus of Dr. Ellis’.
“Dr. Dixon’s presentation highlights some very important principles that are emerging regarding the use of endocrine agents in breast cancer,” he said. First, is the key idea of profiling tumors not just at baseline, which is routine, but after endocrine treatment has been started. Estrogen receptor–positive tumors that do not demonstrate a dramatic decline in gene-expression patterns associated with cell growth are clearly resistant to endocrine intervention, and multiple groups have shown that persistent proliferation despite an aromatase inhibitor or tamoxifen portends a poor outcome, even when chemotherapy is administered, he noted.
Second, neoadjuvant endocrine therapy can be used to discern mutations that drive resistance, according to Dr. Ellis. “As we shift to genome-driven oncology, treatment with an aromatase inhibitor may become a way to detect the presence of uncommon clones harboring resistance mutations that were not detectable at baseline. Equally, mutant allele dropout might signal the presence of mutations/clones that are highly sensitive to therapy and help identify mutations that are not associated with resistance,” he continued.
Finally, biomarker models can be developed to predict outcomes based on the presence or absence of a gene signature in treated samples, he said. When fully developed, these tests could drive change in the neoadjuvant approach, rather than leave patients on inadequately effective neoadjuvant endocrine therapy when other options are readily available.
“In the final analysis, Dr. Dixon’s study is currently too small to alter clinical practice. His four-gene signature, while promising, needs to be taken into rigorous assay development, and validation efforts and much larger studies are needed,” according to Dr. Ellis.
The ALTERNATE trial is one such ongoing example in the United States, where patients with high levels of proliferation (based on Ki67) despite neoadjuvant endocrine therapy (anastrozole, fulvestrant [Faslodex], or the combination) are taken off neoadjuvant endocrine therapy after just 1 month and offered a switch to neoadjuvant chemotherapy (NCT01953588). ■
Disclosure: Dr. Ellis has received royalties from patents related to Nanostring’s Prosigna Breast Cancer Prognostic Test.
At the 2014 San Antonio Breast Cancer Symposium, a research team led by Michael Dixon, MD, of Western General Hospital in Edinburgh, shed light on the development of endocrine resistance and presented a four-gene messenger RNA (mRNA) profile that can predict response to letrozole with a high degree ...