Purpose: Prognostic and predictive biomarkers to CDK4/6 inhibitors are lacking. Circulating tumour DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy. Experimental Design: Correlative blood samples were collected at baseline (C1D1) and prior to treatment (C1D15). Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A pre-specified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model. Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse PFS/OS. Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n=120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms. Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with HR+/HER2- MBC harbouring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted.

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Supplementary data

Supplementary Figure S1

Supplementary Figure 1. Survival analysis in baseline population (C1D1).

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Supplementary Figure S2

Supplementary Figure 2. PFS analysis in baseline population (C1D1) on TP53 mutations, by treatment arms.

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Supplementary Figure S3

Supplementary Figure 3. Survival analysis in baseline population (C1D1) on TP53 mutations, within the population with any detectable mutation (n=146).

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Supplementary Figure S4

Supplementary Figure 4. OS analysis in baseline population (C1D1) on ESR1 and PIK3CA mutations, within the population with any detectable mutation (N=146).

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Supplementary Figure S5

Supplementary Figure 5. CDR and clinical benefit rate within the longitudinal predictive ctDNA analysis.

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Supplementary Table S1

Supplementary Table 1. List of the 21 genes included in the breast cancer panel used for sequencing, and the targeted coding regions in each case.

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Supplementary Table S2

Supplementary Table 2. Complete table results for all patients (n=201) involved in baseline (C1D1) analysis.

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Supplementary Table S3

Supplementary Table 3. Complete table results for all patients (n=120) involved in C1D15 analysis.

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Supplementary Table S4

Supplementary Table 4. Baseline characteristics comparison between our selected study population and the overall PEARL population.

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Supplementary Table S5

Supplementary Table 5. Baseline characteristics comparison between treatment arms in the selected study population

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Supplementary Table S6

Supplementary Table 6. Summary of all baseline mutations identified for the 146 patients with ctDNA detection.

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Supplementary Table S7

Supplementary Table 7. Baseline genomic landscape of mutations distribution in population, by number of mutations or presence/absence, across treatment arms.

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Supplementary Table S8

Supplementary Table 8. Summary of baseline ESR1 and PIK3CA mutations, with number of affected patients and mean VAF.

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Supplementary Table S9

Supplementary Table 9. Summary of PFS results for ESR1 and PIK3CA mutations. Cox regression univariate and multivariate analysis.

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Supplementary Table S10

Supplementary Table 10. Summary of OS results for ESR1 and PIK3CA mutations. Cox regression univariate and multivariate analysis.

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Supplementary Table S11

Supplementary Table 11. Baseline characteristics comparison between population with CDR calculation (n=120) vs non-CDR population (n=81).

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Supplementary Table S12

Supplementary Table 12. Baseline genomic landscape of mutations distribution for the CDR population (n=120), by number of mutations or presence/absence, across treatment arms.

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Supplementary Table S13

Supplementary Table 13. Alternative methodologies used for the calculation of CDR and PFS predictions.

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