Combining Blood Tests Improves Prediction of Breast Cancer Treatment Response

3D rendered medically accurate illustration of a breast cancer: © SciePro - stock.adobe.com

The TBCRC041 trial (NCT02860000) investigated the effectiveness of alisertib (MLN8237), an aurora A kinase inhibitor, combined withfulvestrant for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer.

The trial suggested promising results for alisertib, and researchers aimed to identify biomarkers associated with response to the treatment using blood tests. 

Researchers analyzed patients' blood samples collected before treatment and after the first cycle, looking specifically for genetic mutations in genes like ESR1 and PIK3CA in circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs).They also measured the amount of methylated tumor fraction (mTF) in ctDNA, which indicates the presence of tumor cells.

Mutations were identified in various genes, with PIK3CA being the most common (42%). Patients with a PIK3CA mutation had a significantly shorter progression-free survival (PFS; HR, 1.8; 95%CI, 1.1-2.9, P =.014) compared with those without the mutation, including in those with an ESR1 mutation (P =.583). mTF levels measured after the first cycle were more informative than baseline levels (PreC1-mTF), and patients with higher EOC1-mTF had a worse PFS (HR, 3.0; 95% CI, 1.6-5.2; P <.001). Similarly, having at least 5 CTCs before treatment was associated with shorter PFS (HR, 1.8; 95% CI, 1.1-3.0; P =.018). However, EOC1-CTC counts were not significantly associated with PFS (P =.065).

This study suggests that PIK3CA mutations may predict response to alisertib treatment for HR+/HER2–metastatic breast cancer. Combining ctDNA and CTC analysis at baseline and after the first cycle provided valuable information about treatment response.

In an interview with Targeted Oncology^TM, Karthik Giridhar, MD, breast medical oncologist at Mayo Clinic and first author of the study, discussed the results and implications of this trial.

Karthik Giridhar, MD

Targeted Oncology: What previous research has been done with alisertib?

Giridhar: What know about aurora A kinase activity is that in breast cancer, estrogen receptor-positive, elevated aurora A kinase activity is associated with endocrine resistance, with more of a mesenchymal phenotype, and less responsive to endocrine therapy.

What are the unmet needs in the patient population this study focused on?

In this patient population, as of now, we are working on developing specific compounds that target the aurora A kinase pathway. We are delighted that my colleague, [Tufia C. Haddad, MD, breast medical oncologist at Mayo Clinic] was involved leading the phase 2 study that has been previously reportedwhere they showed that in CDK4/6-resistant, heavily pretreated populations naive to with or without fulvestrant showed a meaningful improvement in progression-free survival.

What were the goals of this study?

The key question here is [to determine] who benefits the most from alisertib, and [to see], can we identify looking at dynamic biomarkers collected during therapy to better understand who is gaining the most benefit from this treatment?

Could you summarize the findings?

The [patients] in this study gave blood samples before treatment started and at the end of cycle 1. We looked at genetic and epigenetic variants, tumor methylated fraction, and we looked at circulating tumor cells. First, what we wanted to better understand is the genetic landscape of the patients at baseline that were on this study, and it was typical of what we might expect. We see a lot of ESR1 mutations, PIK3CA mutations. We focused initially on looking at outcomes in those that harbor those variants at baseline. What we observed, which has been reported by others,is that in the endocrine resistance setting, if there is a PIK3CA mutation, less benefit was observed from alisertib.

Next, what we wanted to look at is these dynamic biomarkers and how they changed with treatments. We started by looking at circulating tumor cells. As we expected, when we saw baseline elevation in circulating tumor cells before treatment, that was an adverse prognostic biomarker. What we were intrigued by was looking at the methylated, tumor fraction percentage. Here, there is less definition of what are the appropriate thresholds we should use. We saw a significant reduction in methylated tumor fraction during treatment. If that value was 1% or less, those [patients] were clearly gaining a better duration of a longer duration of benefit with alisertib.

What do you consider to be the major implications of these findings for clinicians?

I think the takeaway is we are now at the early steps of this analysis. We need to do more to understand which variants help us understand who may benefit the most from alisertib. We are going to gain that as we dive deeper into the existing pathways that are associated with aurora A kinase activity. We are going to learn more by looking at the progression samples to understand which emerging mutations confer resistance to alisertib therapy. I think this is a little bit premature for us to say, deriving any definitive conclusions about who gains treatment, but there is so much more to come from this robust sample set. We are very excited that alisertib is continuing to move forward in development, and that my colleague, Dr. Haddad, is involved in leading the next dose finding optimization study that is hopefully going to be starting soon.

REFERENCE:

Giridhar K, Suman VJ, Tan X, et al. Molecular profiling of serial liquid biopsy specimens utilizing cell free DNA (cfDNA) and circulating tumor cells (CTCs) in TBCRC041: A phase II study of alisertib in endocrine resistant metastatic breast cancer (MBC).J Clin Oncol.2024;42(suppl 16)abstr 1037. doi:10.1200/JCO.2024.42.16_suppl.1037