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Novel Estrogen Receptor-Targeted Agents for Breast Cancer

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Opinion statement

It has become clear that patients whose cancers have progressed post-CDK4/6 inhibitor therapy (CDK4/6i) are not deriving the same magnitude of benefit to subsequent standard endocrine therapy as historical studies would suggest. For example, anticipated duration of benefit to fulvestrant prior to CDK4/6i historically was ~ 5–6 months, and data from the VERONICA and EMERALD trials report less than 2 months. This has magnified our need for novel endocrine agents. Some have argued that patients post-CDK4/6i may just have more endocrine-resistant tumors and perhaps should just receive chemotherapy. While this may be appropriate for some, we do not currently have an assay that reliably predicts whose cancers remain endocrine sensitive and whose are endocrine resistant. ESR1 mutations can enrich for patients whose tumors are more likely to be heavily dependent on estrogen, but this is certainly not the whole answer and many patients without ESR1 mutations continue to derive benefit from subsequent endocrine agents. Most patients would strongly prefer the side effect profile of endocrine agents compared to chemotherapy, and thus, premature use of cytotoxic agents when subsequent ER targeting can control disease is not preferred. These novel ER targeting agents (PROTAC, SERD, SERCA, CERAN) hold great promise to not only outperform standard agents like fulvestrant, but also offer the promise of agents with a different side effect profile that may be more advantageous when compared to menopausal symptoms, hot flashes, arthralgias, and sexual side effects so commonly seen with AIs. We also are likely to see these novel agents move to earlier lines, whether that be 1st line in combination with CDK4/6i or even adjuvant disease.

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Abbreviations

AE:

Adverse event

AI:

Aromatase inhibitor

BC:

Breast cancer

CBR:

Clinical benefit rate

CDK4/6i:

Cyclin-dependent kinase 4/6 inhibitor

CERAN:

Complete estrogen receptor antagonist

ctDNA:

Circulating tumor DNA

DLTs:

Dose-limiting toxicities

EBC:

Early-stage breast cancer

ER:

Estrogen receptor

ET:

Endocrine therapy

FIH:

First-in-human

G:

Grade

HR:

Hazard ratio

HR + :

Hormone receptor-positive

iDFS:

Invasive disease-free survival

1L:

1st line

2-3L:

2nd or 3rd line

MBC:

Metastatic breast cancer

ORR:

Overall response rate

OS:

Overall survival

PFS:

Progression-free survival

PROTAC:

Proteolysis targeting chimera

SERCA:

Selective estrogen receptor covalent antagonist

SERD:

Selective estrogen receptor degrader

SERM:

Selective estrogen receptor modulator

WT:

Wild type

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Authors and Affiliations

  1. Sarah Cannon Research Institute, Nashville, TN, USA

    Mythili Shastry PhD & Erika Hamilton MD

  2. Tennessee Oncology, 335 24th Ave North, Suite 300, Nashville, TN, 37203, USA

    Erika Hamilton MD

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Mythili Shastry reports no conflict of interest.

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Tolmar

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Torque Therapeutics

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Treadwell Therapeutics

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Verastem

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Vincerx Pharma

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Zenith Epigenetics

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Zymeworks

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Erika Hamilton’s institution has received consulting fees from multiple entities (see below).

Time frame: past 36 months

Arcus

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Astra Zeneca

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Daiichi Sankyo

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Ellipses Pharma

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Greenwich LifeSciences

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iTeos

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Janssen

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Lilly

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Loxo

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Mersana

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Novartis

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Olema Pharmaceuticals

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Orum Therapeutics

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Pfizer

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Relay Therapeutics

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Roche/Genentech

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Seagen

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Stemline Therapeutics

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Tubulis

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Shastry, M., Hamilton, E. Novel Estrogen Receptor-Targeted Agents for Breast Cancer. Curr. Treat. Options in Oncol. 24, 821–844 (2023). https://doi.org/10.1007/s11864-023-01079-y

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