Clinical and Molecular Landscape of ESR1 and PIK3CA Co-Mutated Hormone Receptor-Positive Metastatic Breast Cancer (HR+ MBC): Insights from 8,626 Patients Including Polyclonality and TP53 Alterations
SABCS 2025
A. Sivapiragasam; A. Dugan; S. Fragkogianni; M. Ciampricotti; E. Williams
Background: Patients with HR+ MBC are treated with first-line endocrine therapy plus CDK4/6 inhibitors, but resistance often emerges through ESR1 or PIK3CA mutations (MUT). Co-mutations (co-MUT), present in ∼10-15% of patients, remain poorly understood. Here, we compare molecular features and Real-world overall survival (rwOS) among patients with co-MUT vs. those with single or no mutations (no-MUT).
Methods: We used Tempus Lens (Tempus AI, Inc., Chicago, IL) to identify patients with a primary diagnosis of MBC who had Tempus xF or xT testing from the Tempus multi-modal database (N = 8,626). Patients with tumor purity of at least 30% were assessed and all pathogenic or likely pathogenic (P/LP) somatic SNVs/indels for PIK3CA, ESR1, and TP53 were extracted. Polyclonal ESR1 and PIK3CA were defined as more than one distinct P/LP somatic SNV/indel. Tumor mutational burden (TMB) (mt/mB) was analyzed by DNA-sequencing. rwOS analyses were run for all samples collected in the year preceding any line of therapy using risk-set adjusted Cox models with the start of therapy as the index date, the later date of sequencing and treatment start as the study entry time, and a maximum follow up of 5 years.
Results: Of the total cohort, 53% of patients had no-MUTs, 32% were _PIK3CA-_MUT, 9% were ESR1-MUT, and 6% were co-MUT. As shown in the table, age and hormone receptor status were significantly different between the groups, but not race. The co-MUT group exhibited a higher prevalence of bone metastases, while ESR1-only patients had increased liver and lung involvement. TP53 P/LP MUT were present in 33% (N=903) of the PIK3CA-only patients and 24% (N=131) of the co-MUT patients. High TMB rate was significantly different between all groups and was highest in the co-MUT and PIK3CA patients (15% vs 14%). Polyclonal changes in both genes were also more frequent in the co-MUT group. The most common ESR1 mutation was p.D538G (6.4%), while p.His1047Arg was the predominant PIK3CA mutation (14%, n=1,187). Liquid biopsy identified 40% of co-MUT, while tissue sequencing detected 61%. Co-MUT patients had significantly worse rwOS compared to no-MUT (HR=1.75, p<0.001), though evidence of non-proportionality was observed.
Conclusions: Herein, we characterized the largest real-world cohort of co-MUT HR+ MBC patients, identifying distinct clinical and molecular features such as enriched bone metastasis, higher TMB, and increased polyclonality. The lower overall frequency of ESR1 MUT and co-MUT likely reflects that only 25% of patients had late molecular testing, suggesting these mutations often arise after prolonged endocrine therapy. In this subgroup, the ESR1 MUT rate was 24% and the co-MUT rate was 15%, as expected. Limitations include the retrospective design; future studies will address these and examine PTEN/AKT alterations.
Table 1
Cohort demographic and clinical characteristics.
| No-MUT (N=4,561) | PIK3CA-only (N=2,747) | ESR1-only (N=779) | Co-MUT (N= 539) | P-value | |
|---|---|---|---|---|---|
| ER and PR Status | <0.001 | ||||
| ER-, PR+ | 136 (3.1%) | 44 (1.7%) | 0 (0%) | 2 (0.4%) | |
| ER+, PR- | 1,793 (41%) | 968 (37%) | 152 (21%) | 95 (18%) | |
| ER+, PR+ | 2,460 (56%) | 1,615 (61%) | 579 (79%) | 417 (81%) | |
| Missing Obs. | N=172 | N=120 | N=48 | N=25 | |
| Age at biopsy (IQR) | 62 (51, 70) | 64 (56, 72) | 62 (54, 70) | 65 (58, 73) | <0.001 |
| Missing Obs. | N=39 | N=38 | N=3 | N=5 | |
| Race, N (%) | 0.069 | ||||
| White | 2,375 (75%) | 1,495 (79%) | 424 (76%) | 301 (80%) | |
| Black or African American | 404 (13%) | 193 (10%) | 70 (12%) | 37 (9.8%) | |
| Asian | 142 (4.5%) | 80 (4.2%) | 25 (4.5%) | 10 (2.6%) | |
| Other Race | 257 (8.1%) | 132 (6.9%) | 42 (7.5%) | 30 (7.9%) | |
| Missing Obs. | N=1,383 | N=847 | N=218 | N=161 | |
| Bone metastasis N (%) | 2,245 (49%) | 1,449 (53%) | 455 (58%) | 323 (60%) | <0.001 |
| Liver metastasis N (%) | 1,187 (26%) | 713 (26%) | 434 (56%) | 246 (46%) | <0.001 |
| Lung metastasis N (%) | 952 (21%) | 495 (18%) | 177 (23%) | 72 (13%) | <0.001 |
| Polyclonal PIK3CA, N (%) | 0 (0%) | 354 (13%) | 0 (0%) | 99 (18%) | <0.001 |
| Polyclonal ESR1, N (%) | 0 (0%) | 0 (0%) | 66 (8.5%) | 63 (12%) | <0.001 |
| TP53 P/LP MUT | 1,457 (32%) | 903 (33%) | 170 (22%) | 131 (24%) | <0.001 |
| TMB, N (%) | <0.001 | ||||
| High | 164 (6.3%) | 277 (14%) | 30 (5.7%) | 48 (15%) | |
| Low | 2,433 (94%) | 1,720 (86%) | 500 (94%) | 278 (85%) | |
| Missing Obs. | N=1,964 | N=750 | N=249 | N=213 |
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