Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine
Abstract
1. Background on Breast Cancer
Biomarkers and Precision Medicine
2. Personalization Based on Histopathological and Clinical Parameters
2.1. Personalization in Endocrine-Positive Breast Cancer
2.1.1. Endocrine Resistance
2.1.2. Overcoming the Resistance to Endocrine Therapy
- a.
- Elacestrant.
- b.
- Camizestrant.
- c.
- Imlumestrant.
- d.
- Lasofoxifene.
- e.
- Rintodestrant.
- f.
- SERDS and other novel agents in ESR1 mutant breast cancers.
Agent | Class | Clinical Trials | Patient Population | Endpoints | Salient Results | Status |
---|---|---|---|---|---|---|
Elacestrant [43,44] | Oral SERM/ SERD | EMERALD (NCT03778931) Randomized P-III | Patients with ESR1 mut. and ESTwt | PFS | ESR1 mut. = mPFS 3.8 vs. 1.9 months [HR = 0.55, 95% CI: 0.39–0.77] ESR1wt HR 0.86 (95% CI: 0.63–1.19) | Yes, only in patients with ESR1 mutation |
Elacestrant + Abemaciclib [46] | Oral SERM/ SERD + CDK 4/6i | NCT04791384 (P-Ib and II) | Breast cancer with brain metastasis | Safety and tolerability ORR CBR | Ongoing | |
Elacestrant + Samuraciclib [47] | Oral SERM/ SERD + CDK7 | NCT05963997 (P-Ib/2) | Locally advanced or metastatic patients HR-positive, HER2-unamplified | Safety and Tolerability, PFS, ORR, CBR, DOR | Ongoing | |
Elacestrant + everolimus, alpelisib, palbociclib and ribociclib [48] | Oral SERM/ SERD + CDK 4/6i or mTOR inhibitor or PIK3CAi | NCT05563220 (P-Ib/2) | Locally advanced or metastatic patients HR-positive, HER2-unamplified | Safety and tolerability, PFS, ORR, CBR, DOR, OS | Ongoing | |
Elacestrant [49] | Oral SERM/SERD | NCT05596409 (early P-II) | Locally advanced or metastatic patients HR-positive, HER2-unamplified (CDK 4/6i naïve) | PFS, OS, CBR, DOR | Ongoing | |
Camizestrant | SERD | SERENA-1 (NCT03616586) P-1 | Heavily pre-treated patients with ESR-1 mut. | ORR, CBR, PFS | ORR 10% CBR 35.3% across all dose levels. CBR 53.3% a dmPFS for 11.1 months at 75 mg dose | Ongoing |
Camizestrant + Palbociclib [51] | SERD + CDK 4/6i | SERENA-1 (NCT03616586) Dose expansion cohort | Heavily pre-treated patients with ESR-1 mut. | ORR CBR | ORR 6.3% CBR 50% | Ongoing |
Camizestrant vs. Fulvestrant [52] | SERD | SERENA-2 (NCT04214288) P-II | Heavily pre-treated patients | PFS, ORR, DOR, CBR | Ongoing | |
Camizestrant + Palbociclib vs. AI + Palbociclib [53] | SERD + CDK 4/6 i | SERENA-4 (NCT04711252) P-III | Denovo stage IV or locally advanced early-stage breast cancer | PFS, OS, CBR, secondary PFS | Ongoing | |
AI + CDK 4/6i vs. AI + CDK 4/6i + Camizestrant [54] | SERD + CDK 4/6 i | SERENA-6 (NCT04964934) | Metastatic or locally advanced Ca breast with ESR1 mut. emergence before radiographic progression | PFS1, PFS2, OS, ORR, CBR, QOL | Ongoing | |
Imlunestrant + alpelisib, abemaciclib, everolimus, trastuzumab +/− abemaciclib [56] | SERD + CDK 4/6i, anti-HER2 mAb, mTORi | EMBER-I P-I/II (NCT04647487) | Metastatic breast and endometrial cancer | Safety and tolerability, ESR-1 clearance, mPFS | 73% clearance or ctDNA with ESR-1 mutation, mPFS 6.5 vs. 4.3 months. | Ongoing |
Imlunestrant vs. Imlunestrant + abemaciclib [57] | SERD + CDK 4/6i, | EMBER-3 3 (NCT04975308), P-III | Previously treated endocrine-positive tumors | PFS, OS, ORR, CBR | Ongoing | |
Lasofoxifene vs. Fulvestrant [59] | SERM | ELAINE-I trial (NCT03781063), P-II | Previously treated endocrine-positive tumors with ESR-1 mut. | PFS; safety and tolerability | mPFS 5.6 vs. 3.7 months, p = 0.138, CBR 36.5% vs. 21.6%; p = 0.117, ORR 13.2% vs. 2.9%; p = 0.124 | Ongoing |
Lasofoxifene + Abemaciclib [58] | SERM + CDK 4/6i | ELAINE-II (NCT04432454), P-II | Previously treated endocrine-positive tumors with ESR-1 mut. | Safety and tolerability, PFS, CBR, ORR, DOR | Ongoing | |
Rintodestrant + Palbociclib [60,61] | SERD + CDK 4/6i | P-1/P-II | Previously treated endocrine-positive tumors with ESR-1 mut. (without prior CDK 4/6 exposure) | Safety and tolerability, ORR, CBR | ORR 5%, CBR 60% | Ongoing |
Borestrant (monotherapy) Or Borestrant + Palbociclib [62] | SERD/SERD + CDK4/6i | P-I and P-II (NCT04669587) | Metastatic or locally advanced Ca Breast | Recommended dose, response as monotherapy, response in combination, ORR, CBR | Ongoing | |
D-0502 (monotherapy) Or D-0502 + Palbociclib [63] | SERD/SERD + CDK4/6i | P-I (NCT03471663) | Metastatic or locally advanced breast cancer | MTD, DLT, ORR, PFS | Combination was better | Ongoing |
ZN-c5 Or ZN-c5 + Palbociclib [64,65] | SERD/SERD + CDK 4/6i | P-I/II (NCT03560531) | Pre- and postmenopausal women with advanced ER-positive breast cancer | MTD, RP2D; safety and tolerability. ORR, CBR | Monotherapy showed ORR of 5% and CBR of 38% | P-II is still ongoing |
H3B-6545 | SERCA | P-I/II | Pre- and postmenopausal women with advanced ER-positive breast cancer (patient received at least 3 previous lines of therapy), including CDK 4/6i | MTD, ORR, CBR, PFS | ORR = 16.6% CBR 39.7% mPFS = 3.8 months | |
H3B-6545 + Palbociclib [67,68] | SERCA + CDK 4/6i | P-I (NCT04288089) | Pre- and postmenopausal women with advanced ER-positive breast cancer (patient received at least 3 previous lines of therapy) | MTD, ORR, CBR, DOR | Ongoing | |
OP-1250 [70] | CERAN | P-I and P-II (NCT04505826) | Pre- and postmenopausal women with advanced ER-positive breast cancer with ESR-1 mut | DLT, MTD, ORR, CBR | P-I “ORR = 18%, CBR 38%” P-II ORR = 18%, CBR 38% |
3. Personalization in Human Epidermal Growth Factor Receptos-2 (HER2)-Amplified Breast Cancer
3.1. Level of HER2 and HER3 Expression
3.2. DNA and Gene-Based Biomarkers in HER2-Positive Tumors
3.3. Biomarkers for Predicting Pathological Response to HER2-Directed Therapy
4. Triple-Negative Breast Cancer
4.1. Molecular Basis of TNBC Heterogenicity
4.2. Programmed Death-Ligand 1 (PD-L1) Protein Expression as a Biomarker
4.3. Microsatellite Instability and Tumor Mutation Burden
4.4. Tumor Infiltrating Lymphocytes
4.5. Immune Gene Expression in TNBC
5. Circulating Tumor DNA as a Predictive and Prognostic Biomarker
5.1. Role of ctDNA in Locally Advanced Early-Stage Breast Cancer
5.2. Role of ctDNA in Metastatic Breast Cancer
Gene Mutation | Clinical Utility |
---|---|
ESR1 Hotspots: Y537C, Y537N, Y537C, S463P, D538G | Resistance to the endocrine therapy. Therapeutic agents: elacestrant, camizestrant, imlunestrant, lasofoxifene, rintodestrant [47,48,49,50,51,52,53,54,55,56,57,58,59,60,61], |
AKT Hotspots: E17K | Therapeutic agent: capivasertib, ipatasertib (AKT kinase) [227,231]. |
HER2 Hotspots: V777L, L755S | Increased sensitivity to HER2 targeted therapies. Therapeutic targets: neratinib, lapatinib (bind to kinase domains) [232,233,234] |
PTEN Hotspots: R130Q, R130G, R130*, R130P, R130Qfs*4 | Confers resistance to PI3Ki (loss of PTEN) and confers sensitivity to AKT inhibitors. Therapeutic targets: capivasertib, ipatasertib (AKT kinase) [227] |
PIK3CA Hotspots: H1047R, H1047L, N345K, E545K, E524K, E726K | Truncal mutation confers resistance to endocrine therapy. Therapeutic agents: alpelisib, taselisib, buparlisib, copanlisib, capivasertib [227,228,229] |
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Afzal, M.Z.; Vahdat, L.T. Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine. J. Pers. Med. 2024, 14, 719. https://doi.org/10.3390/jpm14070719
Afzal MZ, Vahdat LT. Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine. Journal of Personalized Medicine. 2024; 14(7):719. https://doi.org/10.3390/jpm14070719
Chicago/Turabian StyleAfzal, Muhammad Zubair, and Linda T. Vahdat. 2024. "Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine" Journal of Personalized Medicine 14, no. 7: 719. https://doi.org/10.3390/jpm14070719
APA StyleAfzal, M. Z., & Vahdat, L. T. (2024). Evolving Management of Breast Cancer in the Era of Predictive Biomarkers and Precision Medicine. Journal of Personalized Medicine, 14(7), 719. https://doi.org/10.3390/jpm14070719