Envision this possible future clinical scenario: a breast cancer patient and her physicians are deciding on the best possible treatment. Their decision is informed by a comprehensive molecular profile of the patient's cancer samples that predicts the most likely response of the cancer to treatment. If the profile predicts a high likelihood of a complete positive response and long-term freedom from relapse, then this treatment would be the preferred choice. But if the profile predicts that the tumor would likely be resistant to treatment, alternative treatments must be implemented.
Although this situation is not yet a reality, a team led by researchers at Baylor College of Medicine and the Broad Institute of Massachusetts Institute of Technology and Harvard has taken significant steps in that direction. They report in Cell Reports Medicine that conducting an integrated proteogenomic profiling of cancer cells, which combines the analysis of DNA, RNA, protein and phosphoprotein data, revealed two novel indicators of tumor response to treatment and alternative therapeutic targets for treatment-resistant HER2+ breast cancer.
"Proteogenomics provides a powerful approach to refine biomarker discovery and reveal critical mechanisms underlying drug resistance or novel vulnerabilities in HER2+ breast cancer," said co-corresponding author Dr. Meenakshi Anurag, assistant professor of medicine at Baylor. "By incorporating proteomics, this study enhances our understanding of protein expression and signaling pathways that drive treatment response and resistance and potentially improve precision medicine strategies."
"Being able to predict the response of cancer to treatment by analyzing a tumor sample before therapy is given would significantly impact clinical outcomes," said first author Dr. Eric Jaehnig, staff computational biologist in the lab of co-author Dr. Bing Zhang, professor of molecular and human genetics and the Lester and Sue Smith Breast Center at Baylor. Zhang also is a member of the Dan L Duncan Comprehensive Cancer Center and a McNair Scholar.
From 2008 to 2012, the CALGB 40601 clinical trial tested the response of HER2+ breast cancers to the drugs trastuzumab, lapatinib or their combination. There were 305 patients in the trial. The frequencies of complete response to treatment were 57% for the group that received the combination treatment, 45% for the trastuzumab group and 30% for the lapatinib group.
Research biopsies were obtained from all participants before therapy began. Prior studies using these biopsies focused on RNA and DNA analyses and found, among other findings, that PIK3CA gene mutation and immune gene expression signatures were associated with treatment response.
In the current study, the researchers expanded the original RNA and DNA analyses in a subset of 54 CALGB 40601 frozen pretreatment biopsies by incorporating protein and phosphoprotein data analysis. Their goal was to offer additional insights into biomarkers and pathways associated with treatment response, as well as candidate therapeutic targets for resistant cases.
Pathway analysis identified elevated EMT and WNT-beta catenin signaling and absence of ERBB2 gene amplification and HER2 protein overexpression associated with cases not responding to treatment. Biomarker analysis suggested that a number of protein candidates were associated with response.
"A key challenge in studying underpowered clinical cohorts like this one is distinguishing true biomarkers from study-specific associations," Jaehnig said. "To identify the most reproducible biomarkers for clinical application, we conducted a meta-analysis including our dataset and other similar datasets. We identified GPRC5A and TPBG as potential biomarkers for a poor response to anti-HER2 therapy."
"Our proteogenomic analysis of CALGB 40601 revealed likely false-positives among patients diagnosed with HER2+ breast cancer, underscoring the need for enhanced diagnostic accuracy. GPRC5A and TPBG, the two cell surface proteins we identified as key biomarkers associated with treatment resistance, present new opportunities for targeted therapies," said Drs. Shankha Satpathy, Michael Gillette and Steve Carr, co-authors from the Broad Institute. "Cell surface proteins hold significant therapeutic potential. To help realize this opportunity, the Broad Institute Proteomics Platform continues to refine technologies to advance the identification of such proteins in relevant clinical samples, including patient-derived tissues acquired in the context of clinical trials."
"This study exemplifies the importance of a long-term vision in translational research," says Dr. Matthew J Ellis, formerly at Baylor, now at Guardant Health and one of the senior authors of this paper. "The CALGB 40601 trial was approved in 2001, and the proteogenomic technologies applied in this paper were not even conceived at the time of patient accrual. Yet, many years later, the ability of frozen samples to preserve cancer biology is vividly demonstrated, enabling the discovery of new plasma membrane targets in trastuzumab-resistant HER2+ breast cancer."
Other contributors to this work include Aranzazu Fernandez-Martinez, Tanmayi D. Vashist, Matthew V. Holt, LaTerrica Williams, Jonathan T. Lei, Chang In Moon, Beom-Jun Kim, Yongchao Duo, Haoquan Zhao, Viktoriya Korchina, Richard A. Gibbs, Donna Marie Muzny, Harshavardhan Doddapaneni, Charles M. Perou, Lisa A. Carey, Ana I. Robles, Terry Hyslop, Yujia Wen, Linda McCart, Azra Krek, Francesca Petralia, George Miles, Shyam M. Kavuri and D. R. Mani. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of North Carolina at Chapel Hill, Broad Institute of Massachusetts Institute of Technology and Harvard, National Cancer Institute and Thomas Jefferson University Hospital.
For a complete list of financial sources for this work, see the publication.
