The past 12 months brought a wide array of advances across breast cancer – from biomarkers and screening to novel therapy combinations and sequences. The Year in Review session at the 2024 San Antonio Breast Cancer Symposium® summarized key takeaways from journal articles and conference presentations throughout the year.

A recording of the session, held Friday, December 13, will be available on demand for registered 2024 SABCS® participants until March 31, 2025.

Basic science

Neil Vasan, MD, PhD, Assistant Professor of Medicine at the Columbia University Irving Medical Center, discussed new insights into old questions regarding tumorigenesis, senescence and dormancy, and new methods of target inhibition using established pathways.

“In breast cancer, it’s been very hard to understand the role of aneuploidy and copy number alterations due to technical limitations,” Dr. Vasan said.

He reviewed data suggesting that aneuploidy in normal cells increases with age, that sex chromosome alterations can alter certain phenotypes in cancer, and that there are other copy number alteration events necessary for tumorigenesis outside of those already understood.

Dr. Vasan noted research by 2024 American Association for Cancer Research (AACR) Outstanding Investigator Award for Breast Cancer Research recipient Christina Curtis, PhD, MSc, that explored how germline and somatic alterations interact. Through use of very large data sets of both normal and tumor sequencing data, Dr. Curtis and colleagues concluded that high germline epitope burden is potentially protective against invasive cancer in the pre-cancerous stages but may lead to worse prognosis once cancer has developed.

“This is a really interesting study. It’s very provocative, and I think [it] really changes how we think about germline-somatic interactions,” he said. “There are a lot of implications here, I think, in terms of biomarkers and also [for] vaccine strategies against some of these very peptides to prevent breast cancer.”

In discussing CDK4/6 inhibitor resistance, Dr. Vasan reviewed data showing that patients with estrogen receptor-positive (ER+) metastatic breast cancer harboring p53 mutations or loss had the poorest response to CDK4/6 inhibitors. Based on this, Dr. Vasan postulated that p53 loss could potentially be used to select patients for combination CDK2 and CDK4/6 inhibitors.

Translational science

Pedram Razavi, MD, PhD, discussed improvements in liquid biopsy technologies and use of artificial intelligence in translational research. Dr. Razavi is Director of the Breast Translational Program and Molecular Tumor Board at Memorial Sloan Kettering (MSK) Cancer Center and Scientific Director of the MSK Global Research Program.

Liquid biopsy is used routinely in the metastatic setting for cancer genotyping, as well as monitoring for therapeutic response. There is a concentration of research focused on improving the sensitivity and limits of detection for assays, such as expanding the number of mutations included or decreasing the amount of background noise. Higher sensitivity is necessary for detection of molecular residual disease in early-stage breast cancer, according to Dr. Razavi.

“We have to collect cfDNA in pre-treatment samples and encourage the patients to provide post-treatment samples,” Dr. Razavi said. “I cannot emphasize enough that translational work is based on going from clinic to lab and back.”

Artificial intelligence featured prominently in this year’s translational research discussions. Machine learning was used to enhance assay detection rates by decreasing the background noise for identifying single nucleotide and copy number variants in whole-genome sequencing using cfDNA. In addition, an algorithm was built using machine learning to detect signs of  cancer in healthy people, people with a high risk of cancer, and in patients with cancer. One large-language model was trained to interact with pathologists and provide input, while another large-language model was used to extract clinical data from more than 24,000 patient charts to create visualizations. In some of these examples, the model itself or the data it captured was made publicly available, empowering researchers and decreasing time for data collection.

“The use of these foundational models and democratizing them empowers many of the smaller centers,” Dr. Razavi noted. “Analysis of this large data is already transforming translational research and is here to stay [through incorporation of] the large language models into our EMRs.”

Early-stage disease

Janice Tsang, MBBS, MRCP, FRCP, Specialist in Medical Oncology at The University of Hong Kong, discussed how 2024 has bolstered confidence in immunotherapy and highlighted the possibility of discontinuing chemotherapy and/or anthracyclines for some patient populations with early-stage disease.

KEYNOTE-522 showed a five-year absolute overall survival gain of 4.9% in favor of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared to neoadjuvant chemotherapy alone. According to Dr. Tsang, this ranks pembrolizumab in the top five most impactful adjuvant treatments for breast cancer. She noted, however, that only a subset of the population benefited from this therapy and a certain percentage of women still show no response.

“The value of adjuvant [immunotherapy], especially pembrolizumab, I think is still not clear; especially, it’s not without immune-related toxicities and financial toxicities,” Dr. Tsang said.

Although the exploratory biomarker analysis from the same KEYNOTE-522 study showed a positive association between a T-cell inflammatory gene expression profile and complete pathological response and event-free survival in both treatment arms, Dr. Tsang referenced other studies in which it was unclear if the added benefit was because of the chemotherapy or the pembrolizumab. Questions remain, as these studies had different designs and included patients with varied nodal involvement and risk profiles.

Based on A-BRAVE data presented at this year’s American Society of Clinical Oncology Annual Meeting, one year of adjuvant immunotherapy without neoadjuvant immunotherapy was not found to improve disease-free survival for patients with high-risk triple-negative breast cancer. Dr. Tsang suggested that these patients should probably receive neoadjuvant immunotherapy plus chemotherapy followed by tailored adjuvant treatment.

When discussing whether chemotherapy can be replaced with immunotherapy alone, an antibody-drug conjugate alone, or both in combination, Dr. Tsang showed that 32% of patients in the I-SPY 2.2 trial who received datopotamab deruxtecan (Dato-DXd) were able to forgo traditional chemotherapy based on a favorable predicted residual cancer burden; these patients went on to receive four cycles of Dato-DXd and then surgery. In addition, a short course of Dato-DXd combined with durvalumab has been shown to lead to pathologic complete response in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer. In a separate trial, this population also was shown to benefit from letrozole plus HER3-DXd.

“HER3-DXd was associated with lower incidence of side effects and also achieving a comparable complete response rate and overall response rate. Probably, it may be a potential replacement [for] multiagent chemotherapy in the days to come,” Dr. Tsang said.

Regarding CDK4/6 inhibition in the adjuvant setting for high-risk women, Dr. Tsang said she feels there is still added benefit based on the updated results of the NATALEE trial. Further research is needed regarding circulating tumor DNA (ctDNA) use to predict response to aromatase inhibitors or CDK4/6 inhibitors so that decisions regarding therapeutic switches can be made more effectively.

Metastatic disease

Michael A. Danso, MD, Research Director at Virginia Oncology Associates, summarized progress in metastatic disease and noted that the addition of CDK4/6 inhibitors to endocrine therapy has been shown to double progression-free survival in the first-line setting.

Both the RIGHT Choice and ABIGAIL trials worked together to establish this combination as the appropriate treatment in patients with a high burden of disease or visceral crisis. However, the SONIA trial showed that first-line CDK4/6 therapy for treatment-naive patients with advanced ER+ disease was associated with higher total treatment costs and more grade 3 events; there was no statistically significant benefit of using CDK4/6 inhibitors in the first versus second line regarding progression-free survival.

“In the real world, in elderly patients with comorbidities and a low burden of disease, it is very reasonable to consider single-agent endocrine therapy as first-line therapy,” he said.

This year also saw the FDA approval of inavolisib as a first-line treatment option for patients with a PIK3CA mutation and endocrine-resistant disease, based on INAVO120.

In the second line and later, biomarker testing using tumor tissue or ctDNA is strongly recommended for patients with HR+/HER2- metastatic disease. Germline testing is also essential, Dr. Danso said.

Once testing has been performed, patients with PIK3CA alterations may receive endocrine therapy and fulvestrant (based on SOLAR-1) or fulvestrant and capivasertib (based on CAPItello-291). According to Dr. Danso, patients with an ESR1 mutation who have previously been on endocrine therapy and CDK4/6 therapy for 12 months or longer should be offered elacestrant based on the EMERALD trial. In addition, new research from EMBER-3 presented at this year’s SABCS looked at imlunestrant with or without abemaciclib after progression on prior CDK4/6 therapy for patients with ER+/HER2-negative advanced breast cancer.

“The combination of imlunestrant with or without abemaciclib based on EMBER-3 may become an alternative approach, particularly in patients who have more endocrine-resistant disease,” he said.

There is a potential new standard of care for patients with HR+/HER2+ metastatic disease based on the AFT-38 PATINA trial, which added palbociclib to anti-HER2 and endocrine therapy. Taken together with the MONARCH trial, these results establish the addition of CDK4/6 inhibitor therapy to maintenance trastuzumab, pertuzumab, and endocrine therapy as a very reasonable new standard, Dr. Danso said.

He noted that this approach is already being done in practice by some clinicians, but that a much lower dose of palbociclib is typically given in the real world. Therefore, he is interested to see if efficacy of palbociclib will be maintained at that lower real-world dose in future data.