Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer
Simple Summary
Abstract
1. Introduction
2. The Molecular Landscape of Advanced ER-Positive Breast Cancer
3. Molecular Profiling in Advanced ER-Positive Breast Cancer
4. Therapies Targeting Genomic Aberrations in Advanced ER-Positive Breast Cancer
4.1. ESR1 Mutations
4.2. Alterations in PIK3CA, AKT and PTEN
4.3. BRCA1/2 and PALB2 Mutations
4.4. HER2 Mutations
5. Current Limitations and Future Directions of a Molecular Phenotypic Approach to Treating ER-Positive Breast Cancer
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
95% CI | 95% confidence interval |
ADC | Antibody–drug conjugate |
AIs | Aromatase inhibitors |
AKT1 | Protein kinase B |
ASCO | American Society of Clinical Oncology |
BRCA1/2 | Breast cancer gene 1 and 2 |
CDK4/6 | Cyclin-dependent kinase 4/6 |
cfDNA | Cell-free DNA |
ChT | Chemotherapy |
ctDNA | Circulating tumour DNA |
Dato-DXd | Datopotamab deruxtecan |
ddPCR | digital droplet polymerase chain reaction |
E2 | Oestradiol |
ER | Oestrogen receptor |
ERα | Oestrogen receptor alpha |
ERβ | Oestrogen receptor beta |
ESCAT | ESMO Scale for Clinical Actionability of Molecular Targets |
ESMO | European Society for Medical Oncology |
ESR1 | Oestrogen receptor 1 |
ET | Endocrine therapy |
FDA | Food and Drug Administration |
Fulv | Fulvestrant |
GNRH | Gonadotropin releasing hormone |
HER2 | Human epidermal growth factor 2 |
HR | Hazard ratio |
IHC | Immunohistochemistry |
MBC | Metastatic breast cancer |
Mo | Months |
MTOR | Mammalian target of rapamycin |
NA | Not applicable |
NGS | Next-generation sequencing |
NR | Not reported |
NTRK | Neurotrophic tyrosine receptor kinase |
OS | Overall survival |
PALB2 | Partner and localiser of BRCA2 |
PARP | Poly (ADP-ribose) polymerase |
PDK1 | 3-phosphoinositide-dependant kinase 1 |
PIK3CA | phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha |
PIP2 | Phosphatidylinositol (4,5)-bisphosphonate |
PIP3 | Phosphatidylinositol (3,4,5)-Triphosphonate |
PFS | Progression-free survival |
PR | Progesterone receptor |
PTEN | Phosphatase and tensin homolog |
Rb | Retinoblastoma |
SERD | Selective oestrogen receptor degrader |
SERM | Selective oestrogen receptor modulator |
SG | Sacituzumab Govitecan |
T | Testosterone |
T-DXd | Trastuzumab Deruxtecan |
TFI | Treatment-free interval |
TKI | Tyrosine kinase inhibitor |
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Molecular Aberration | Estimated Prevalence in ER-Positive Breast Cancer | ESCAT Scale Classification | Drug Class Matched | Key Clinical Trial |
---|---|---|---|---|
PIK3CAmut | 30–40% [17] | IA |
| |
PTENdel | 7% [17] | I/II | ||
AKT1mut | 7% [17] | I/II | ||
ESR1mut | Primary breast cancer: < 1% [15] Post adjuvant AI: 5% [16,17] Progression on AI for metastatic disease: 30–40% [16,17] | IA |
| |
Germline BRCA1/2mut | 4% [15] | IA |
| |
Somatic BRCA1/2mut | 3% [15] | IIB |
| |
HER2mut | 3–4% [15] | IIB |
| |
NTRKfusions | <1% [26] | IC |
|
|
Germline PALB2mut | 1% [26] | IIB |
|
|
ESR1 | Prevalence | Median OS (Months) [38] |
---|---|---|
ESR1wt | NA | 32.1 (95% CI 28.1–36.4) |
ESR1mut (all) | Primary breast cancer: <1% [15] Post adjuvant AI: 5% [16,17] Progression on AI for metastatic disease: 30–40% [16,17] | 20.7 (HR 1.6, 95% CI 17.7–28.1, p < 0.001) |
ESR1mut D538G | 21.1% [38]–41.2% [39] | 26.0 (HR 1.4, 95% CI 19.2–32.4, p = 0.03) |
ESR1mut Y537S | 13.3% [38]–22.1% [39] | 20.0 (HR 1.8, 95% CI 13.0–29.3, p = 0.003) |
Dual mutations | 3.8% [39]–5.5% [38] | 15.2 (HR 2.23, 95% CI 10.9–27.4, p < 0.001) |
Trial | Novel Drug and Mechanism | Phase | Line | Population | Treatment Arms | Prior CDK4/6i (%) | ESR1mut (%) | Efficacy ESR1 mut | Efficacy ESR1wt | Efficacy Overall Population |
---|---|---|---|---|---|---|---|---|---|---|
EMERALD [28] | Elacestrant (PO SERD) | 3 | 2–3 | ER+/HER2− MBC, post-ET+ CDK4/6i | Elacestrant vs. PCET | 100 | 48 | PFS 3.8 vs. 1.9 mo; HR 0.55, 95% CI 0.39–0.77, p = 0.0005 | NR | PFS 2.8 vs. 1.9 mo; HR 0.70, 95% CI 0.55–0.88, p = 0.002 |
SERENA-2 [60] | Camizestrant (PO SERD + ER antagonist) | 2 | 2 | ER+/HER2− MBC, post-ET | Camizestrant (75 mg, 100 mg, and 300 mg) vs. Fulvestrant | 51 | 38 | PFS 6.3 (75 mg) vs. 2.2 mo; HR 0.33, 90% CI 0.18–0.58 | PFS 7.2 (75 mg) vs. 7.2 mo; HR 0.80, 90% CI 0.51–1.27 | PFS 7.2 (75 mg) vs. 3.7 mo; HR 0.59, 90% CI 0.42–0.82, p = 0.017 |
EMBER-3 [61] | Imlunestrant (PO SERD) | 3 | 1–2 | ER+/HER2− MBC, post-ET ± CDK4/6i | Imlunestrant vs. Imlunestrant + Abemaciclib vs. PCET | 58 | 38 | Imlunestrant vs. PCET: PFS 5.5 vs. 3.8 mo; HR 0.76, p <0.001 Imlunestrant + Abemaciclib vs. Imlunestrant: PFS 9.4 vs. 5.5 mo; HR 0.57, 95% CI 0.44–0.73, p < 0.001 | NR | Imlunestrant vs. PCET: PFS 5.6 vs. 5.5 mo; HR 0.87, 95% CI 0.72–1.04, p = 0.12 |
* AMEERA-3 [64] | Amcenestrant (PO SERD) | 2 | 2–3 | ER+/HER2− MBC, post-ET | Amcenestrant vs. PCET | 79 | 44 | PFS 3.7 vs. 2.0, HR 0.9, 95% CI 0.57–1.5 | PFS 3.5 vs. 3.9 mo; HR 1.3, 95% CI 0.88–1.9 | PFS 3.6 vs. 3.7 mo; HR 1.05 (95% CI: 0.79–1.40), p = 0.64 |
* AMEERA-5 [65] | Amcenestrant (PO SERD) | 3 | 1 | ER+/HER2− MBC without prior therapy | Amcenestrant + Palbociclib vs. Letrozole + Palbociclib | 0 | NR | NR | NR | Stopped for futility; mPFS estimates not robust. HR 1.2, 95% CI 0.93–1.55, p = 0.93 |
acelERA [62] | Giredestrant (PO SERD) | 2 | 2–3 | ER+/HER2− MBC, post-ET ± CDK4/6i | Giredestrant vs. PCET | 42 | 38 | PFS 5.3 vs. 3.5 mo; HR 0.60, 95% CI 0.35–1.03 | PFS 7.2 vs. 6.6 months, HR 1.01, 95% CI 0.64–1.60 | PFS 5.6 vs. 5.4 mo; HR 0.81, 95% 0.60–1.1, p = 0.17 |
VERITAC-2 [63] | Vepdegestrant (PROTAC ER degrader) | 3 | 2–3 | ER+/HER2− MBC, post-ET ± CDK4/6i | Vepdegestrant vs. Fulvestrant | 100 | 43 | PFS 5.0 vs. 2.1 mo; HR 0.58, 955 CI 0.43–0.78, p < 0.001 | NR | PFS 3.8 vs. 3.6 mo; HR 0.83, 95% CI 0.69–1.01), p = 0.07 |
ELAINE-1 [66] | Lasofoxifene (SERM) | 2 | 2 | ER+/HER2− MBC, post-ET+ CDK4/6i, ESR1mut | Lasofoxifene vs. Fulvestrant | 100 | 100 | PFS 5.5 vs. 3.7 mo; HR 0.69, 95% CI 0.43–1.1, p = 0.138 | NA | PFS 5.5 vs. 3.7 mo; HR 0.69, 95% CI 0.43–1.1, p = 0.138 |
ELAINE-2 [67] | Lasofoxifene (SERM) | 2 | 2–3 | ER+/HER2− MBC, post-ET ± CDK4/6i, ESR1mut | Lasofoxifene + Abemaciclib (single arm) | 96 | 100 | ORR 55.6% (95% CI 33.7–75.4) | NA | ORR 55.6% (95% CI 33.7–75.4) |
PADA-1 [68] | Fulvestrant (IM SERD) | 3 | 1.5 (rising ESR1mut on 1L) | ER+/HER2− MBC on ET + Palbociclib | Continue ET + Palbociclib vs. Fulvestrant + Palbociclib | 100 | 100 | PFS 11.9 vs. 5.7 mo; HR 0.61, 95% CI 0.43–0.86, p = 0.004 | NA | PFS 11.9 vs. 5.7 mo; HR 0.61, 95% CI 0.43–0.86, p = 0.0040 |
SERENA-6 [29] | Camizestrant (PO SERD + ER antagonist) | 3 | 1.5 (rising ESR1mut on 1L) | ER+/HER2− MBC on ET + CDK4/6i | Continue ET + CDK4/6i vs. Camizestrant + CDK4/6i | 100 | 100 | PFS 16 vs. 9.2 mo; HR 0.44, 95% CI 0.31–0.60, p < 0.00001 | NA | PFS 16 vs. 9.2 mo; HR 0.44, 95% CI 0.31–0.60, p < 0.00001 |
SERENA-4 [69] | Camizestrant (PO SERD + ER antagonist) | 3 | 1 | ER+/HER2− MBC without prior therapy | Camizestrant + Palbociclib vs. Anastrazole + Palbociclib | 0 | NR | Results awaited | ||
persevERA [70] | Giredestrant (PO SERD) | 3 | 1 | ER+/HER2− MBC without prior therapy | Giredestrant + Palbociclib vs. Letrozole + Palbociclib | 0 | NR | Results awaited | ||
ELAINE-3 [71] | Lasofoxifene (SERM) | 3 | 2–3 | ER+/HER2− MBC, post-ET ± CDK4/6i (Ribociclib or Palbociclib), ESR1mut | Lasofoxifene + Abemaciclib vs. Fulvestrant + Abemaciclib | 100 | 100 | Results awaited |
Trial | Novel Drug and Mechanism | Phase | Line | Population | Treatment Arms | Prior CDK4/6i (%) | Mutant Population (%) | Detection Method for Genomic Profiling | Efficacy in Mutant Cohort | Efficacy in Non-Mutant Cohort | Efficacy Overall Population |
---|---|---|---|---|---|---|---|---|---|---|---|
SOLAR-1 [18] | Alpelisib (PIK3CA inhibitor) | 3 | 2 | ER+/HER2− MBC, post-ET | Alpelisib + Fulvestrant vs. placebo + Fulvestrant | 6 | 29 (PIK3CA) | Tissue | PFS 11.0 vs. 5.7 mo; HR 0.65, 95% CI 0.50–0.85, p < 0.001 | PFS 7.4 vs. 5.6 mo; HR 0.85, 95% CI 0.58–1.25 | NR |
BYLieve [19] | Alpelisib (PIK3CA inhibitor) | 2–single arm | 2 | ER+/HER2− MBC, post-ET + CDK4/6i | Alpelisib + Fulvestrant | 100 | 100 (PIK3CA) | Tissue or ctDNA | PFS 8.0 mo (95% CI 5.6–8.6) | NA | PFS 8.0 mo (95% CI 5.6–8.6) |
SANDPIPER [77] | Taselisib (PIK3CA inhibitor) | 3 | 2 | ER+ MBC, post-ET | Taselisib + Fulvestrant vs. placebo + Fulvestrant | 3 | 100 (PIK3CA) | Tissue | PFS 7.4 vs. 5.4 mo; HR 0.70, 95% CI 0.56–0.89, p = 0.0037 | NA | PFS 7.4 vs. 5.4 mo; HR 0.70, 95% CI 0.56–0.89, p = 0.0037 |
* FERGI [78] | Pictilisib (PIK3CA inhibitor) | 2 | 2 | ER+/HER2− MBC, post-ET | Pictilisib + Fulvestrant vs. Fulvestrant + placebo | U | 41 (PIK3CA) | Tissue | PFS 6.5 vs. 5.1 mo; HR 0.73, 95% CI 0.42–1.28, p = 0.268 | PFS 5.8 vs. 3.6 mo; HR 0.72, 95% CI 0.42–1.23, p = 0.23 | PFS 6.6 vs. 5.1 mo; HR 0.74, 95% CI 0.52–1.06, p = 0.096 |
CAPItello-291 [21] | Capivasertib (Pan-AKT inhibitor) | 3 | 2 | ER+ /HER2− MBC, post-ET± CDK4/6i | Capivasertib + Fulvestrant vs. Fulvestrant + placebo | 70 | 41 (PIK3CA, AKT1 or PTEN) | Tissue | PFS 7.3 vs. 3.1 mo; HR 0.50, 95% CI 0.38–0.65, p < 0.001 | PFS 7.2 vs. 3.7 mo; HR 0.70, 95% CI 0.56–0.88 (post-hoc) | PFS 7.2 vs. 3.6 mo; HR 0.60, 95% CI 0.51–0.71, p <0.001 |
FINER [76] | Ipatasertib (Pan-AKT inhibitor) | 3 | 2 | ER+/HER2− MBC, post-ET+ CDK4/6i | Ipatasertib + Fulvestrant vs. Fulvestrant + placebo | 100 | 44 (PIK3CA, AKT1 or PTEN) | ctDNA | PFS 5.45 vs. 1.91 mo; HR 0.47, 95% CI 0.31–0.72, p = 0.0005 | NR | PFS 5.32 vs. 1.94 mo; HR 0.61, 95% CI 0.46–0.81, p = 0.0007 |
INAVO120 [20] | Inavolisib (PIK3CA inhibitor) | 3 | 1 | ER+/HER2− MBC, PIK3CA-mutant, relapsed during or within 12 months of adjuvant ET | Inavolisib + Fulvestrant + Palbociclib vs. placebo + Fulvestrant + Palbociclib | 1 | 100 (PIK3CA) | Tissue or ctDNA | PFS 15.0 vs. 7.3 mo; HR 0.43, 95% CI 0.32–0.59, p < 0.001 | NA | PFS 15.0 vs. 7.3 mo; HR 0.43, 95% CI 0.32–0.59, p < 0.001 |
CAPItello-292 [27] | Capivasertib (Pan-AKT inhibitor) | 3 | 1 | ER+/HER2− MBC, relapsed during or within 12 months of adjuvant ET | Capivasertib + Fulvestrant + CDK4/6i (Ribociclib or palbociclib) vs. Fulvestrant + CDK4/6i (Ribociclib or palbociclib) | Results awaited |
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Childs, S.; Semba, R.; Haggstrom, L.; Lim, E. Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer. Cancers 2025, 17, 3174. https://doi.org/10.3390/cancers17193174
Childs S, Semba R, Haggstrom L, Lim E. Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer. Cancers. 2025; 17(19):3174. https://doi.org/10.3390/cancers17193174
Chicago/Turabian StyleChilds, Sarah, Ryoko Semba, Lucy Haggstrom, and Elgene Lim. 2025. "Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer" Cancers 17, no. 19: 3174. https://doi.org/10.3390/cancers17193174
APA StyleChilds, S., Semba, R., Haggstrom, L., & Lim, E. (2025). Integrating Molecular Phenotyping into Treatment Algorithms for Advanced Oestrogen Receptor-Positive Breast Cancer. Cancers, 17(19), 3174. https://doi.org/10.3390/cancers17193174