Researchers working on whole-exome and transciptome sequencing of endocrine-resistant estrogen receptor–positive metastatic breast cancer have shown that the mutational landscape differs from that of estrogen receptor–positive primary breast cancer, and these differences have the potential to inform treatment decisions for metastatic breast cancer.
Abnormalities in genes such as ESR1, ERBB2, PIK3CA, AKT1, and RBI can be acquired in the metastatic setting, and they appear to represent resistance mechanisms to endocrine therapy. This work, although still relatively early, may pave the way for improved therapies, since there are available and experimental therapies that can target these genes.
Even if you know alterations in the primary setting, this may not be sufficient to guide treatment in the metastatic setting. Knowledge about acquired genes may give you a handle on how to treat metastatic disease.— Ofir Cohen, MD
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“Although we know a lot about the molecular and genomic landscape of primary estrogen receptor–positive breast cancer, this landscape is underexplored in the metastatic setting,” said Ofir Cohen, MD, of Dana-Farber Cancer Institute, Boston, who presented his work in progress at the 2016 San Antonio Breast Cancer Symposium (SABCS).1 “Even if you know alterations in the primary setting, this may not be sufficient to guide treatment in the metastatic setting. Knowledge about acquired genes may give you a handle on how to treat metastatic disease.”
Metastatic breast cancer is a leading cause of death in women. Although endocrine therapy is effective for estrogen receptor–positive metastatic breast cancer, endocrine resistance frequently develops. Resistant tumors are the most common cause of death, yet resistance mechanisms are poorly understood, he explained. The goal of the research at Dana-Farber is to use next-generation sequencing technology to tease out resistance genes from tumor samples of patients with resistant estrogen receptor–positive metastatic breast cancer.
Study Details and Results
The study Dr. Cohen presented was based on 149 biopsies from metastatic estrogen receptor–positive breast cancer matched with 44 primary tumor biopsies collected between 2006 and 2015. Nearly all patients whose biopsy samples were used had received at least one estrogen receptor–directed therapy, including tamoxifen, an aromatase inhibitor, and fulvestrant (Faslodex) prior to biopsy. The biopsies (149 metastatic and 44 primary tumors) underwent whole-exome sequencing of tumor and germline, and transcriptome sequencing (RNA sequencing) of tumor was performed on 128 metastatic biopsies.
The researchers found significant alterations in specific genes in metastatic breast cancer: TP53, GATA3, PIK3CA, ERBB2, AKT 1, KRAS, and RBI. Some of these genes are altered primary breast cancer tumors, such as TP53, KRAS, and ERBB2, Dr. Cohen noted.
“The selection pressure is different as the cancer metastasizes. We highlight genes that increase the metastatic potential and the endocrine therapy resistance. We wanted to take a head-to-head comparison of how tumors evolve from primary to metastatic,” he explained.
“You can think about it as a family tree, with two siblings [primary and metastatic] arising from a common parent—the primary tumor and the metastatic tumor. They can have some shared mutations and some acquired ones,” he continued.
“We acknowledge that tumors may develop resistance through other mechanisms. If those mechanisms leave a footprint in the transcriptome, sequencing of the exome may reveal those mechanisms,” Dr. Cohen added.
Clinical Implications in Selecting Treatment
The implication of this work for patients is that sequencing defined multiple clinically relevant mutations in metastatic breast cancer, which can inform the choice of next therapy after endocrine resistance develops, help select patients for clinical trials of drugs that target those mutations, and identify novel drug targets. “This study highlights the value of genomic profiling of metastatic biopsies or blood biopsies [ie, liquid biopsies],” Dr. Cohen stated.
At a press conference where these data were discussed, Dr. Cohen said the researchers are continuing to gather biopsies and study them in an ongoing effort. Although the initial insights presented at SABCS 2016 may provide some guidelines, “we are still at baseline trying to get insights.” They are using functional assays to identify functional pathways in all lines of samples.
Dr. Cohen provided two examples of how his research is potentially applicable in selecting second-line treatment for patients who develop resistance to endocrine therapy. Inactivation of RBI predicts resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors and to phosphatidylinositol 3-kinase (PIK3CA) inhibitors, so these drugs would not be good choices for second-line therapy. Inactivation of ESR1 predicts resistance to letrozole, so fulvestrant would be a better choice for that patient.
Additional Comments
Steven E. Vogl, MD
Steven E. Vogl, MD, of Montefiore Medical Center, Bronx, New York, pointed out that these data provide only partial knowledge of the entire burden of disease in a given patient. The “genomic landscape” might be strongly influenced by the exact nature of prior treatment, he suggested. What mutations occur at relapse from standard adjuvant hormonal therapy would be of most interest, Dr. Vogl indicated, since by targeting them before clinical relapse, time to relapse may be prolonged.
Virginia Kaklamani, MD, of the University of Texas Health Science Center at San Antonio, said that the effort to sequence the genome and transcriptome is valuable. “This work will move us forward from shooting in the dark when we select second-line therapy. We currently don’t have a good indication as to whether a therapy will be successful or not. We don’t know now what the chances of working are for a given therapy. But if I know what is feeding the tumor, I can use a drug to target that mutation. For example, patients with RBI mutation may not respond to palbociclib [Ibrance]. I could avoid that drug and use other treatments, such as a PIK3CA inhibitor instead,” she revealed.
Data on the genomic landscape of metastatic breast cancer can also inform the design of clinical trials. “This work will enable smaller studies with multiple treatment arms using drugs that have the potential to work on identified mutations,” concluded Dr. Kaklamani. ■
Disclosure: Dra. Cohen, Vogl, and Kaklamani reported no potential conflicts of interest.
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