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Mutations in the ESR1 gene found in circulating tumor DNA (ctDNA) predicted outcomes in a subset of patients from the TREnd trial, meaning, the researchers said, that it may eventually be possible to identify a circulating prognostic biomarker for patients with metastatic breast cancer treated with CDK4/6 inhibitors.

In the new study, published in , Luca Malorni, MD, PhD, of the Hospital of Prato in Italy, and colleagues, analyzed ctDNA from 46 patients in the trial, which randomly assigned patients with ER+ HER- cancer to receive palbociclib (Ibrance) alone or with the endocrine therapy they had received in the previous line of treatment.

The researchers collected and analyzed ctDNA at three time points: before therapy, after the first cycle of chemotherapy, and at the time of progression. Having ESR1 mutations before treatment was associated with three times the risk of progression (HR 3.06, P=0.02). The risk was four times greater in the patients treated with palbociclib and endocrine therapy (HR 4.0, P=0.36).

Malorni and colleagues were not available for an interview, and the responses in this Q&A are taken from the paper.

Why did you undertake the study?

CDK4/6 inhibitors represent a standard option for first- and second-line treatment of patients with estrogen receptor–positive and human epidermal growth factor receptor 2–negative metastatic breast cancer. However, not all patients benefit from CDK4/6 inhibitors, showing that there is intrinsic or acquired resistance.

Studies have investigated the determinants of resistance, but to date, to our knowledge, no biomarker has been approved to direct CDK4/6 inhibition treatment in ER1/HER2– breast cancer. Also, there is uncertainty about how patients should be treated after progression on CDK4/6 inhibitors.

Analysis of ctDNA allows the identification of prognostic biomarkers that might be helpful for patients' stratification and monitoring. Through a mutational analysis of a subgroup of patients receiving the CDK4/6 inhibitor palbociclib within the TREnd trial, we aimed to identify mutations that might serve as prognostic circulating biomarkers.

What were the main findings and implications?

We identified mutations not previously described in patients treated with CDK4/6 inhibitors, and showed the feasibility of using a targeted gene panel to detect acquired mutations.

Our results confirm a worse prognosis for patients with ESR1-mutant tumors receiving palbociclib. However, an increased risk of progression was observed mainly in patients receiving palbociclib with endocrine therapy, supporting the hypothesis that ESR1 mutations confer particular resistance to endocrine therapy. Further studies are needed to fully understand the associations between these mutations and CDK4/6 inhibitor treatment.

We also identified mutations in additional genes that were likely acquired, not being present before starting treatment.

At the time of disease progression, we found the emergence of nine mutations in seven genes (ESR1, AKT1, ARID1A, BRIP1, CCNE1, MTOR, and TP53), confirmed by droplet digital polymerase chain reaction [ddPCR]. Of note, in all cases these were not detectable at earlier time points, suggesting they might be acquired during treatment.

We observed that patients with newly acquired mutations at T2 [the time of progression] tended to have a shorter TTF [time to treatment failure] after palbociclib progression. Indeed, 3 of 15 patients (20%) with TTF below the median of the entire population had acquired mutations compared with only 1 of 15 (7%) with TTF above the median.

Our preliminary observations suggest that the emergence of new mutations during treatment with palbociclib might be associated with worse outcome on the post-progression treatment. However, stronger evidence is needed from larger studies.

What did you find in terms of androgen receptor (AR) mutations?

Patients with AR mutant tumors tended to have lower, albeit not statistically significant, risk of progression (HR 0.53, P=0.30). Interestingly, AR and ESR1 mutations appeared to be mutually exclusive, and patients with AR mutations had a significantly longer progression-free survival compared with those with mutations in ESR1 (P=0.009).

However, the number of patients with AR mutations in our study is very limited, so larger studies are needed to assess the prognostic role of AR mutations in metastatic breast cancer.

What were the strengths and limitations of this study?

The major limitations are the limited number of patients, the lack of matched germline samples, and the exploratory nature of the analyses.

Strengths include the randomized nature of the trial, the availability of samples collected across multiple time points during treatment, the validation of the acquired mutations by ddPCR, and the unique availability for this study of a palbociclib monotherapy arm.

Read the study here and expert commentary about it here.