The use of next-generation sequencing (NGS) for patients with metastatic HR+/HER2- breast cancer is expanding, with applications for identifying actionable mutations, assessing prognosis, and monitoring treatment response. Researchers at the 2024 ASCO Annual Meeting presented data from several studies using NGS in patients with both early-stage and advanced HR+/HER2- breast cancer.

Following these proceedings, featured expert William J. Gradishar, MD, FACP, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Gradishar’s clinical perspectives on these findings are presented here.

NGS is a tool that can be used on tissue or circulating tumor DNA (ctDNA) to detect mutations that may arise as a result of the cancer. ctDNA is thought to be representative of everything that is going on in the body. In patients with metastatic disease, it gives a more holistic view of what is happening with the tumor at any given time point compared with what is detected from tissue samples from different sites of metastases. Occasionally, you may miss a few things with 1 test vs the other, but I think that, in general, most people would accept that these tests are pretty good.

At first diagnosis of metastatic breast cancer, we want to perform a tissue biopsy as much to confirm the diagnosis as to ensure that the markers are the same, and it affords us the opportunity to do NGS testing. If a patient has a lesion in their bone or lung, you want to be sure that you are actually dealing with breast cancer. However, from that point forward, we largely rely on blood for information about what is going on in the tumor at a molecular level. There have been reports suggesting imperfect concordance between tissue and ctDNA NGS, but concordance can be high, as shown in a retrospective analysis presented at ASCO 2024 (abstract e15033).

Clinical guidelines suggest that NGS should be performed at initial diagnosis in patients with metastatic disease, but the question is whether the information obtained from NGS is immediately actionable. The current standard of care for first-line therapy is the use of an endocrine therapy plus a CDK4/6 inhibitor. At this time, there is nothing that you can learn from NGS testing that will deter you from giving that regimen as the first therapy because endocrine therapy plus CDK4/6 inhibitors significantly improve progression-free survival, and some trials show prolonged survival.

However, results of NGS can certainly have some impact on what you do thereafter, and it can guide whether you use targeted treatment. Although NGS can assess hundreds of genes, the reality is that we have a limited number of drugs that we know target clinically useful pathways, including somatic mutations in ESR1, PIK3CA, AKT1, PTEN, and both germline and somatic mutations in BRCA1/2. PARP inhibitors could be considered before chemotherapy in patients with a BRCA1/2 mutation and early-stage, high-risk disease or metastatic disease after endocrine therapy. At ASCO 2024, data from the TBCRC 048 trial suggested that PARP inhibitors can work in patients with germline PALB2 mutations and somatic BRCA1/2 mutations (abstract 1021).

There was an intriguing study presented at the meeting by Morganti et al about the epigenomic profiling of liquid biopsies to try to predict estrogen receptor status and signaling (abstract 1066). One day, this may be a tool that we could use to determine if a patient is still sensitive to endocrine therapy.

Data from the monarchE trial, which was also presented at ASCO 2024, suggest that, in the adjuvant setting, patients who become ctDNA positive have a median lead time of 9 months until the disease recurs (abstract LBA507). At first blush, this sounds like it would be really good to know, but without having something that we can do about it, all that we have done is create anxiety and concern. So, at least from a patient standpoint, that could be a step backward rather than a step forward. The information needs to be actionable with an impact on outcome to be truly useful.

Over the last several years, the molecular understanding of tumors has advanced faster than the clinical development of drugs that can target specific pathways. I am hopeful and optimistic that, with time, we will have genetic and epigenetic signatures based on NGS tools that will be able to dictate which therapy is best for a patient.