At the 112th American Association of Cancer Research (AACR) annual meeting, held virtually in April, more than 13,500 attendees joined to hear their colleagues present and share information on cutting-edge advances in basic, clinical, and translational cancer research. Several BCRF researchers were among this year’s presenters, and BCRF investigator Dr. Charles Swanton notably served as the event’s program chair.
Here, we highlight BCRF-supported projects and researchers who presented on the therapeutic vulnerabilities and resistance mechanisms in estrogen receptor (ER)–positive breast cancer.
Understanding the problem of resistance in ER-positive breast cancer
ER-positive breast cancer, the most commonly diagnosed form of the disease, responds well to anti-estrogen therapies such as tamoxifen, aromatase inhibitors, and fulvestrant. While there are many excellent treatments—including hormonal and targeted treatment combinations (i.e., those with CDK4/6 inhibitors)—resistance remains a problem, particularly in metastatic disease. Researchers are studying resistance mechanisms in ER-positive breast cancer in the hopes of identifying novel biomarkers that may unlock new targeted treatments and strategies.
New research on therapeutic vulnerabilities and resistance mechanisms
To gain a better understanding of how resistance develops, Dr. Nikhil Wagle discussed comparing patient samples of matched primary and metastatic ER-positive breast cancer cells. In these samples, his team found that after ER-directed therapy, 63 percent of the primary breast cancer tumors they analyzed acquired specific genetic alterations in the ER, HER2, and FGFR genes as they evolved to become resistant or metastatic. His team also examined resistance to CDK4/6 inhibitors and showed distinct differences between primary and resistant or metastatic tumors. Specifically, they found that in 66 percent of the resistant samples analyzed, eight mechanisms were amplified compared to the primary tumors. These genetic alterations and mechanisms provide potential targets for various combinations of drugs.
Dr. Carlos Arteaga presented results of research utilizing presurgical and neoadjuvant trials as a platform to uncover the mechanisms involved in endocrine resistance. Researchers have previously observed that the growth factor receptor FGFR will increase as endocrine resistance develops. These trials revealed that this process could be overcome by adding an FGFR inhibitor to treatment. They also showed that FGFR1 alterations/amplification conferred resistance and promoted tumor progression following anti-endocrine plus CDK4/6inhibitor treatment. In addition, the mechanism of resistance or escape from treatment correlates with an increased expression of the mRNA required for cyclin CCNE1 protein production.
Dr. Arteaga also highlighted findings examining HER2 mutations and the role they play in endocrine resistance. Specific mutations in the HER2 kinase gene are associated with resistance to endocrine treatment, and Dr. Arteaga and his team showed that this occurs through a cascade of interactions: The HER2 protein binds to HER3 protein causing HER3 dimerization, a process that subsequently activates a key pathway in tumor growth, P13K. In addition, co-occurring HER2 and HER3 mutations cooperate to increase breast cancer growth and decrease the effectiveness of the anti-HER2 drug neratinib. These results suggest that tumors with co-occurring HER2/HER3 mutations are prime candidates for the combination anti-HER2 plus P13Kα treatment to decrease the activation of the P13K pathway thereby potentially decreasing tumor growth.
Dr. Maurizio Scaltriti, a former BCRF investigator, discussed his BCRF-funded work to identify novel targets associated with ER-positive breast cancer’s resistance to endocrine therapy. He showed that the gene ARID1A is the most frequently mutated gene observed in tumor cells that develop resistance. Moreover, the loss of ARID1A occurs as cells are reprogrammed and evolve to become endocrine resistant. In addition, he detailed how a mutation in the FOXA1 gene facilitates resistance to endocrine therapy by providing several growth advantages in estrogen-low conditions. Together, the loss of ARID1A and the presence of FOXA1 mutations promote ER-positive tumor cell resistance and provide actionable targets to prevent resistance.
Looking forward
These results provide valuable clues on the processes that occur as primary breast cancers become resistant to treatment and metastasize. In addition, these results have potentially significant clinical implications for ER-positive breast cancer patients: Combination treatments to target the multiple genes or signaling pathways that are altered could be utilized to combat different causes of resistance and decrease incidence of metastasis. Based on these presentations and others, more of these strategies will be developed in the next few years.
MORE HIGHLIGHTS FROM AACR 2021:
Digging Deeper into the Breast Cancer-Obesity Connection
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