Despite the ongoing challenges of COVID-19 over the past year, researchers in 2021 reported important progress and major discoveries in breast cancer. A panel of experts discussed some of the latest advances in early and advanced breast cancer, basic science, and translational research during the special session Year in Review on Friday, December 10 at SABCS 2021.
In a review of basic science papers published over the past year, important findings related to the genetic heterogeneity of breast cancer and the role of metabolism in tumor progression were among the topics that stood out in 2021, according to Xiang Zhang, PhD, Professor of Molecular and Cellular Biology and William T. Butler, M.D., Endowed Chair for Distinguished Faculty at Baylor College of Medicine.
“We learned this year that the genetic heterogeneity of breast cancer is dynamic and maintained throughout tumor evolution, and that the ability to change the phenotype, or plasticity, is an important feature of cancer cells that seeds metastasis and drives resistance,” Dr. Zhang said. “This opens important new questions, including how to integrate genetic and phenotypic heterogeneity together to better understand metastasis and therapeutic resistance.”
Other studies reported in 2021, he said, showed how tumor metabolism may play multiple roles in tumor progression and therapeutic responses.
“Importantly, we learned that metabolic features contribute to define tumor heterogeneity, and that metabolic adaptation of cancer cells to a foreign metastatic microenvironment may confer unexpected therapeutic vulnerability. Additionally, important biological processes, such as migration and invasion, may actually be regulated by metabolism, which has been underappreciated,” Dr. Zhang said. “Going forward, we still need to think about how to integrate this information into our precision medicine research.”
Studies looking at resistance mechanisms, anti-tumor immunity, and biomarkers in hormone receptor-positive (HR+) breast cancer were among the highlights of translational research published in 2021 discussed by Christina Curtis, PhD, MSc, Associate Professor in the Departments of Medicine and Genetics and Director of Breast Cancer Translational Research at Stanford University.
Findings reported over the past year, she said, have advanced the understanding of the mechanisms of resistance to endocrine therapy, including somatic alterations in HER2, FGFR, and other RTKs, as well as epigenetic changes, and are paving the way for future research.
“Elucidating the molecular features of sensitivity and resistance to CDK4/6 inhibitors may ultimately lead to the identification of predictive biomarkers and new therapeutic strategies,” Dr. Curtis said.
Moving forward, she said, there are important opportunities for further advances in understanding metastatic evolution, immune evasion, as well as therapeutic adaptation and resistance.
“This will be supported by longitudinal profiling efforts, and clearly also by trial-embedded molecular correlates, and real-world data,” Dr. Curtis said. “Another exciting area is in the development of biomarkers to enable therapy de-escalation. This is most advanced in the HER2+ setting, but we really hope to see these opportunities move forward for other subgroups of disease so that we can spare patients unnecessary toxicity. There is so much exciting work in the field and yet, there is much more to be done.”
Early Breast Cancer
Foluso Olabisi Ademuyiwa, MD, MPH, MSCI, Associate Professor of Medicine, Division of Oncology, Section of Breast Oncology at Washington University School of Medicine, provided an overview of key studies in early breast cancer over the past year, including important findings related to both therapy escalation in high-risk patients and de-escalation in lower-risk patients.
“Despite these challenging times, we’ve continued to make strides in early breast cancer with the approval of pembrolizumab plus chemotherapy in early triple negative breast cancer, and abemaciclib with endocrine therapy for high-risk ER-positive breast cancer patients,” Dr. Ademuyiwa said.
With regard to de-escalating therapy in lower-risk HER2+ early breast cancer patients, she said early results from ongoing studies are promising and have provided important insight for further investigation.
In future de-escalation studies, she said, it will be important to identify those patients who do well with a chemotherapy-free approach.
“Going forward, we need to think about how we might use other biomarkers to guide patient selection for further chemotherapy-free trials in HER2-positive disease, while maintaining or increasing pCR rates and survival and minimizing toxicities,” Dr. Ademuyiwa said. “In early breast cancer, most patients are cured and go on to live full and long lives; therefore, trying to balance the long-term treatment-related toxicities, as well as the financial burden, through the expected disease course with the magnitude of benefit from adding on more therapies is critical.”
Advanced Breast Cancer
Peter Schmid, MD, PhD, Lead of the Centre for Experimental Cancer Medicine at Barts Cancer Institute, Queen Mary University of London, concluded the session with a review of several important advances related to the management of metastatic breast cancer.
Regarding HER2-positive metastatic disease, he said, key highlights of the year included data from studies looking at new antibody drug conjugates (ADCs), such as sacituzumab, as well findings from a study that looked at trastuzumab deruxtecan (T-DXd) vs. trastuzumab emtansine (T-DM1) in metastatic breast cancer.
“We see increasing data in triple negative breast cancer with different ADCs, sacituzumab being the frontrunner at the moment, but encouraging data with T-DXd and Dato-DXd alone and in combination with immune therapy are emerging,” Dr. Schmid said. “Additionally, new ADCs and TKIs (tyrosine kinase inhibitors) are emerging, but we need to see what value they have post-T-DXd.”
In ER+ metastatic disease, he said, evidence continues to demonstrate that CDK4/6 inhibitors can substantially improve outcome and overall survival in a first-line setting.
“We are increasingly understanding the mutational profiles of tumors that are developing resistance to CDK4/6 inhibitors,” Dr. Schmid said. “There remains a high need for new targets to overcome endocrine resistance. HDAC (histone deacetylase) inhibitors are being investigated, and CDK7 inhibitors show early promising results.”
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