SABCS 2016: Genomic Sequencing of Treatment-Resistant Metastatic Breast Cancer Reveals Clinically Relevant Genetic Alterations
Genomic sequencing of estrogen receptor–positive metastatic breast cancer that had become resistant to therapies revealed multiple genomic and molecular alterations that were not present in the primary tumor samples, with implications for choice of next therapy, clinical trial eligibility, and novel drug targets, according to data presented at the 2016 San Antonio Breast Cancer Symposium, held December 6 to 10 (Abstract S1-01).
“In spite of tremendous advances in the treatment of estrogen receptor–positive breast cancer using therapies directed against the estrogen receptor, patients frequently develop resistance to these therapies,” said senior investigator of the study Nikhil Wagle, MD, Deputy Director of the Center for Cancer Precision Medicine at Dana-Farber Cancer Institute (DFCI), Assistant Professor of Medicine at Harvard Medical School, and an Associate Member of the Broad Institute of MIT and Harvard.
“These resistant tumors remain the most common cause of breast cancer death, yet mechanisms by which this resistance develops are poorly understood,” Dr. Wagle added.
In contrast to the published studies of primary, treatment-naive breast tumors, this research focuses on metastatic tumor samples from patients with resistant disease, explained lead author of the study Ofir Cohen, PhD, a postdoctoral researcher and computational biologist at the Broad Institute and DFCI. This represents a clinically important population of patients that is largely uncharacterized by comprehensive exome and transcriptome sequencing, he added.
“Our current research is part of a growing effort by many researchers to start closing the gap by better understanding the genomic underpinning of the metastatic and resistance states,” Dr. Cohen said.
Study Findings
Drs. Wagle and Cohen and colleagues analyzed treatment-resistant metastatic breast tumor samples collected from 130 patients who were treated at the Susan F. Smith Center for Women’s Cancers at DFCI. Pretreatment samples of the primary tumors were analyzed from 34 of these patients. The investigators performed massively parallel sequencing (also known as next-generation sequencing) to sequence the whole exome and transcriptome of these breast cancer samples.
“We found that the genomic landscape of drug-resistant estrogen receptor–positive metastatic breast cancer is significantly different from that of primary estrogen receptor–positive breast cancer. Moreover, we were able to identify multiple clinically relevant genomic and molecular alterations in the metastatic biopsies with implications for choice of next therapy, clinical trial eligibility, and novel drug targets,” said Dr. Cohen.
Briefly, whole exome sequencing showed metastatic breast cancer samples to have more frequent alterations in the genes ESR1, ERBB2, PIK3CA, PTEN, RB1, and AKT1, among others. Transcriptomic sequencing helped identify several types of resistance that are likely to be clinically relevant.
“With increasing numbers of patients from whom we were able to obtain and sequence the original primary tumor, we have been able to distinguish between preexisting events [found in both the primary and the metastatic samples] and evolutionary, acquired events [found only in the metastatic sample],” said Dr. Cohen.
“Preexisting events may highlight events that predispose to metastasis, supporting the idea that comprehensive characterization of primary tumors might help predict metastatic potential, while acquired events may suggest novel therapeutic approaches to overcome or prevent resistance, and highlight the idea of periodic monitoring with technologies such as cell-free DNA from blood [liquid biopsies],” Dr. Cohen added.
Clinically relevant results that are identified by next-generation sequencing in these tumors have been returned to the clinicians and patients and are being used for clinical decision making, Dr. Wagle noted.
Ultimately, the goal of this collaborative effort is to integrate the functional and clinical findings into a unified “Resistance Atlas” for estrogen receptor–positive metastatic breast cancer, which should help inform treatment decisions for individual patients as well as propel the development of new combination treatment strategies for estrogen receptor–positive metastatic breast cancer, Dr. Wagle said.
A limitation of the study is that most of the samples were both metastatic and treatment-resistant and therefore, potential “drivers” of metastasis were interwoven with that of drug resistance. The investigators are using several functional assays to help untangle metastasis-driving events from resistance-conferring events, Dr. Cohen explained.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
