Biomarker Consortium

Breast Cancer

HR+/HER2−

); encode tumor suppressor proteins central to homologous recombination repair (HRR) of DNA double-strand breaks

Gene Location: Chromosome 17 (17q21.31) for 

In an HRR-proficient cell, BRCA1 coordinates cell-cycle checkpoint control and DNA end resection, while BRCA2 loads RAD51 onto resected single-stranded DNA, enabling error-free repair of double-strand breaks.

Tumorigenesis follows a two-hit pattern: an inherited loss-of-function allele plus somatic loss of the remaining wild-type allele leaves the tumor, but not normal tissue, HRR-deficient. Cells are forced onto error-prone backup repair pathways, producing the genomic instability that creates the therapeutic window.

PARP inhibitors block PARP1 catalytic activity and trap PARP1 on DNA at single-strand break sites. The trapped complexes collapse replication forks into double-strand breaks that an HRR-deficient tumor cannot repair, producing synthetic lethality. The same deficiency underlies sensitivity to platinum chemotherapy.

 pathogenic variants are inherited and present from birth, not acquired under treatment pressure. Status is established once and does not require retesting at progression, in contrast to acquired markers such as 

-associated tumors are predominantly triple-negative and basal-like, whereas 

-associated tumors are more often hormone receptor-positive. Carriers are enriched among patients with young-onset disease, bilateral disease, and a suggestive family history.

Triple-negative breast cancer carries the highest carrier frequency of the major subtypes.

 from blood or saliva. Tumor-only next-generation sequencing cannot distinguish germline from somatic origin and does not establish eligibility for the germline-restricted PARP inhibitor indications; a 

 finding on a tumor panel requires germline confirmation.

 testing to all patients diagnosed with breast cancer at or below age 65. Above age 65, offer testing to patients who are candidates for PARP inhibitor therapy, have triple-negative disease, were assigned male sex at birth, or have a personal or family history suggestive of a pathogenic variant.

Offer testing regardless of age to any patient with local or metastatic recurrent breast cancer who is a candidate for PARP inhibitor therapy, and to patients with a second primary in the contralateral or ipsilateral breast.

Multigene panel next-generation sequencing on germline DNA, combining sequence analysis with large-rearrangement and copy-number analysis. Deletion and duplication testing matters, since large rearrangements are a meaningful minority of 

 pathogenic variants and are missed by sequencing alone.

BRACAnalysis CDx (Myriad Genetic Laboratories) is the FDA-approved companion diagnostic for both olaparib and talazoparib in breast cancer, covering the metastatic indications and the adjuvant olaparib indication.

Panels typically also report the high-penetrance genes 

. Moderate-penetrance findings inform second-primary and family risk but do not create an approved treatment option in breast cancer.

Variants of uncertain significance are common and are not actionable. A VUS should not be treated as a positive result in therapy selection or in risk-reducing surgical planning.

ASCO and the Society of Surgical Oncology published a joint germline testing guideline for breast cancer in 2024, which sets the age-65 threshold and directs additional predisposition-gene testing based on personal and family history.

 status in the workup of recurrent or stage IV HER2-negative disease and of high-risk early-stage disease where adjuvant olaparib is under consideration, with detailed testing criteria in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate.

Two oral PARP inhibitors are FDA-approved specifically for germline 

-mutated, HER2-negative breast cancer: olaparib (Lynparza) and talazoparib (Talzenna). Both require selection by an FDA-approved companion diagnostic performed on germline DNA.

On January 12, 2018, the FDA approved olaparib for germline 

-mutated, HER2-negative metastatic breast cancer based on the phase 3 OlympiAD trial, which demonstrated improved progression-free survival versus physician's choice chemotherapy. On March 11, 2022, the indication was extended to the adjuvant treatment of high-risk early breast cancer based on the phase 3 OlympiA trial.

On October 16, 2018, the FDA approved talazoparib for germline 

-mutated, HER2-negative locally advanced or metastatic breast cancer based on the phase 3 EMBRACA trial. Talazoparib has no adjuvant breast cancer indication.

Olaparib is the only PARP inhibitor with an early breast cancer indication, and the only one to have demonstrated an overall survival benefit in breast cancer, in the adjuvant OlympiA setting.

Adults with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor-positive disease should have received prior endocrine therapy or be considered inappropriate for it.

Adjuvant treatment of adults with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative high-risk early breast cancer previously treated with neoadjuvant or adjuvant chemotherapy.

Oral inhibitor of PARP1, PARP2, and PARP3 that blocks catalytic activity and traps PARP at sites of DNA damage.

Trapped PARP-DNA complexes collapse replication forks into double-strand breaks that HRR-deficient tumor cells cannot repair, producing synthetic lethality.

Adults with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer. Patients must be selected based on an FDA-approved companion diagnostic.

Oral PARP inhibitor with potent PARP-trapping activity, blocking PARP1 and PARP2 catalytic function and stabilizing PARP-DNA complexes.

The resulting replication-associated double-strand breaks cannot be repaired in HRR-deficient tumor cells.

HRR deficiency also predicts platinum sensitivity, and platinum agents remain a common comparator and sequencing consideration in germline 

-mutated disease. They are not biomarker-gated by label.

 germline pathogenic variants produce a comparable HRR-deficient phenotype, and small single-arm studies have shown high response rates to PARP inhibition. There is currently no FDA-approved PARP inhibitor indication for 

 in breast cancer; use in that setting is off-label.

1. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. 

2. BRCA1 and BRCA2: Cancer Risks and Management (PDQ). National Cancer Institute. Accessed July 2026.

3. LYNPARZA (olaparib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 2026.

4. TALZENNA (talazoparib) capsules. Prescribing information. Pfizer Inc. Accessed July 2026.

5. Merck & Co, Inc. LYNPARZA (olaparib) reduced risk of death by 32% in patients with germline BRCA-mutated, HER2-negative high-risk early breast cancer in the phase 3 OlympiA trial. News release. Accessed July 2026.

6. Bedrosian I, Somerfield MR, Achatz MI, et al. Germline testing in patients with breast cancer: ASCO-Society of Surgical Oncology guideline. 

. 2024;42(5):584-604. doi:10.1200/JCO.23.02225

7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026, and for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate V.3.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

8. US Food and Drug Administration. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. January 12, 2018. Accessed July 2026.

9. US Food and Drug Administration. FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. March 11, 2022. Accessed July 2026.

10. US Food and Drug Administration. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. October 16, 2018. Accessed July 2026.

BRCA1/2

Estrogen receptor alpha (ERα), encoded by 

; progesterone receptor (PR/PgR), encoded by 

Gene Location: Chromosome 6 (6q25.1) for 

ER and PR are ligand-activated nuclear hormone receptors; ERα is the principal driver of cell proliferation and survival in hormone receptor (HR)-positive breast cancer.

PR expression is induced by an intact ER signaling pathway and serves primarily as a marker of ER-pathway functionality and as a prognostic indicator.

Endocrine therapies target this axis at three points: selective estrogen receptor modulators (SERMs) modulate the receptor, aromatase inhibitors (AIs) deprive it of estrogen, and selective estrogen receptor degraders (SERDs) promote its degradation.

CDK4/6 inhibitors act downstream of ER signaling, blocking retinoblastoma protein phosphorylation and arresting cell-cycle progression from G1 to S phase. They are given with endocrine therapy rather than as monotherapy in this setting.

HR-positive (ER- and/or PR-positive) disease is the most common breast cancer subtype, accounting for roughly 70% to 80% of cases.

Under ASCO/CAP criteria, ER/PR positivity is defined as at least 1% of tumor cell nuclei staining by immunohistochemistry. Samples with 1% to 10% staining are reported as ER Low Positive, a category with more limited and less consistent benefit from endocrine therapy.

Unlike acquired resistance markers such as 

 mutations, ER and PR status is established at diagnosis and defines the treatment pathway from the outset.

ER and PR status should be determined on all newly diagnosed invasive breast cancers and, when tissue is available, on recurrences or metastases. ER testing of ductal carcinoma in situ (DCIS) is also recommended to guide endocrine risk reduction.

Immunohistochemistry is the standard validated assay. ASCO/CAP require standardized pre-analytic handling, with cold ischemia time under 1 hour and fixation of 6 to 72 hours, and appropriate external and internal controls.

PgR is used primarily for prognosis in the setting of an ER-positive cancer; the ER Low Positive reporting comment applies to ER, not PgR.

The ASCO/CAP Estrogen and Progesterone Receptor Testing in Breast Cancer guideline governs assay validation, scoring, the 1% threshold, and the ER Low Positive category.

NCCN recommends ER and PR testing by immunohistochemistry on all newly diagnosed invasive breast cancers and on accessible recurrences or metastases, using the ASCO/CAP 1% positivity threshold.

ER/PR status directs the largest treatment class in breast cancer. Endocrine therapy forms the backbone: SERMs (tamoxifen, toremifene), aromatase inhibitors (anastrozole, letrozole, exemestane), and the injectable SERD fulvestrant.

Three oral CDK4/6 inhibitors are approved in combination with endocrine therapy: palbociclib (2015), ribociclib (2017), and abemaciclib (2017). Ribociclib and abemaciclib also carry adjuvant early breast cancer indications; palbociclib does not.

-mutated disease (elacestrant, vepdegestrant) are covered on the 

 Mutation page. PI3K/AKT-directed agents for endocrine-resistant disease with pathway alterations (alpelisib, capivasertib, inavolisib) are covered on the relevant pathway biomarker page.

Selective Estrogen Receptor Modulators (SERMs)

Treatment of metastatic breast cancer in women and men; adjuvant treatment of breast cancer following primary surgery, including node-positive and node-negative disease.

Reduction in the incidence of contralateral breast cancer; treatment of DCIS following surgery and radiation; and reduction of breast cancer incidence in women at high risk.

Effective in both premenopausal and postmenopausal patients, and the only endocrine agent here that does not require ovarian suppression in premenopausal women.

Binds the estrogen receptor and acts as a competitive antagonist in breast tissue, blocking estrogen-driven transcription.

A prodrug activated by CYP2D6; avoid strong CYP2D6 inhibitors such as paroxetine and fluoxetine where an alternative exists.

https://www.cancer.gov/about-cancer/treatment/drugs/tamoxifencitrate

Treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown tumors.

A SERM structurally related to tamoxifen that competitively binds the estrogen receptor.

Carries a boxed warning for QTc prolongation and Torsade de Pointes; positioned as a tamoxifen alternative, with cross-resistance expected.

https://www.cancer.gov/about-cancer/treatment/drugs/toremifene

Aromatase Inhibitors (postmenopausal patients only)

Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

First-line treatment of postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer, and treatment of advanced disease progressing after tamoxifen.

A nonsteroidal aromatase inhibitor that reversibly binds the aromatase enzyme, blocking peripheral conversion of androgens to estrogens.

https://www.cancer.gov/about-cancer/treatment/drugs/anastrozole

Adjuvant and extended adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

First-line treatment of postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer, and treatment of advanced disease progressing after antiestrogen therapy.

A nonsteroidal aromatase inhibitor that reversibly binds the aromatase enzyme, suppressing circulating estrogen.

https://www.cancer.gov/about-cancer/treatment/drugs/letrozole

Adjuvant treatment of postmenopausal women with estrogen receptor-positive early breast cancer who have received two to three years of tamoxifen, to complete a total of five consecutive years of adjuvant endocrine therapy.

Treatment of advanced breast cancer in postmenopausal women whose disease has progressed following tamoxifen therapy.

A steroidal aromatase inactivator that binds irreversibly to the enzyme, distinguishing it from the nonsteroidal inhibitors.

Partial non-cross-resistance may allow activity after a nonsteroidal agent. Taken after a meal.

https://www.cancer.gov/about-cancer/treatment/drugs/exemestane

Selective Estrogen Receptor Degrader (SERD)

As monotherapy for HR-positive, HER2-negative advanced breast cancer in postmenopausal women not previously treated with endocrine therapy, and for HR-positive advanced disease progressing after endocrine therapy.

In combination with a CDK4/6 inhibitor for HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression after endocrine therapy.

Binds the estrogen receptor with high affinity and promotes its degradation, producing receptor downregulation rather than modulation.

The only parenteral agent in the endocrine backbone, administered as two intramuscular injections.

https://www.cancer.gov/about-cancer/treatment/drugs/fulvestrant

HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, or with fulvestrant following disease progression on endocrine therapy.

In combination with inavolisib and fulvestrant for endocrine-resistant, 

-mutated, HR-positive, HER2-negative locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.

Oral CDK4/6 inhibitor that blocks retinoblastoma protein phosphorylation and cell-cycle progression from G1 to S phase.

ER/PR

 encodes the p110α catalytic subunit of PI3K; 

 encodes the AKT1 serine/threonine kinase; 

 is a tumor-suppressor phosphatase that negatively regulates the pathway

The PI3K/AKT/mTOR pathway is a central regulator of cell growth, proliferation, and survival. In breast cancer it is the most frequently altered pathway and a key driver of endocrine-therapy resistance.

 by mutation or reduced protein expression, all converge to constitutively activate AKT signaling downstream, promoting tumor cell proliferation and survival.

Three drug classes intervene at different nodes: PI3Kα inhibitors (alpelisib), PI3Kα inhibitor-degraders (inavolisib), and pan-AKT inhibitors (capivasertib). All three are given with fulvestrant, and inavolisib additionally with palbociclib.

 is the most commonly altered gene in this pathway, mutated in approximately 40% of HR-positive/HER2-negative breast cancers. The dominant hotspots are H1047R in the kinase domain and E545K and E542K in the helical domain.

 mutations occur in roughly 3% to 4% of cases, with the E17K hotspot accounting for the large majority. 

 loss of function is present at a variable frequency.

Taken together, about half of HR-positive/HER2-negative metastatic breast cancers carry an alteration in at least one of these three genes, making this the largest biomarker-defined subgroup in the setting.

 alterations in HR-positive/HER2-negative advanced or metastatic disease to identify candidates for pathway-directed therapy. Because alterations can be acquired under treatment pressure, retesting at progression is reasonable.

Next-generation sequencing of tumor tissue or plasma (circulating tumor DNA) is standard. Each agent carries a distinct FDA-approved companion diagnostic, and they are not interchangeable.

Alpelisib: therascreen PIK3CA RGQ PCR, on tumor tissue or plasma. Capivasertib: FoundationOne CDx (tissue) or FoundationOne Liquid CDx (plasma), covering all three genes. Inavolisib: selection is based on one or more 

, with FoundationOne Liquid CDx used in INAVO120.

When an alteration is not detected in plasma, testing tumor tissue is recommended, since circulating tumor DNA sensitivity is imperfect and a negative plasma result does not exclude an alteration.

 mutations, and for capivasertib eligibility 

 alterations, in HR-positive/HER2-negative metastatic breast cancer to guide selection of pathway-directed therapy.

NCCN includes pathway testing in the workup of HR-positive/HER2-negative recurrent or stage IV disease, with the specific alteration determining which of the three agents applies.

Three oral pathway-directed agents are FDA-approved in HR-positive/HER2-negative advanced or metastatic breast cancer: alpelisib (2019), capivasertib (2023), and inavolisib (2024). Each requires a distinct companion diagnostic and each is given with fulvestrant.

The three differ in the alterations they target and in where they sit in the treatment pathway. Alpelisib and capivasertib are used after progression on an endocrine-based regimen; inavolisib is used in first-line endocrine-resistant disease, as a triplet with palbociclib and fulvestrant, in patients who relapsed on or within 12 months of completing adjuvant endocrine therapy.

Hyperglycemia is a class effect of PI3K/AKT pathway inhibition and the characteristic toxicity of all three agents, requiring baseline and on-treatment glucose monitoring.

In combination with fulvestrant for adults with HR-positive, HER2-negative, 

-mutated advanced or metastatic breast cancer, as detected by an FDA-approved test, following progression on or after an endocrine-based regimen.

Oral alpha-selective inhibitor of phosphatidylinositol 3-kinase (PI3Kα).

In combination with fulvestrant for adults with HR-positive, HER2-negative locally advanced or metastatic breast cancer with one or more 

 alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy.

First-in-class oral pan-AKT inhibitor, targeting all three AKT isoforms (AKT1, AKT2, and AKT3).

In combination with palbociclib and fulvestrant for adults with endocrine-resistant, 

Oral PI3K inhibitor with activity predominantly against PI3Kα that also induces degradation of the mutated p110α protein.

The only agent in this class given as a triplet with a CDK4/6 inhibitor, and the only one indicated in the first-line setting.

1. Anderson EJ, Mollon LE, Dean JL, et al. A systematic review of the prevalence and diagnostic workup of PIK3CA mutations in HR+/HER2- metastatic breast cancer. 

. 2020;2020:3759179. doi:10.1155/2020/3759179

2. Bhave MA, Quintanilha JCF, Tukachinsky H, et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(−) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real-world practice. Breast Cancer Res Treat. 2024;207(3):599-609. doi:10.1007/s10549-024-07376-w

3. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for HR-positive, HER2-negative metastatic breast cancer: ASCO guideline update. 

. 2021;39(35):3959-3977. doi:10.1200/JCO.21.01392

4. PIQRAY (alpelisib) tablets. Prescribing information. Novartis Pharmaceuticals Corporation. Accessed July 2026.

5. TRUQAP (capivasertib) tablets. Prescribing information. AstraZeneca Pharmaceuticals LP. Accessed July 2026.

6. ITOVEBI (inavolisib) tablets. Prescribing information. Genentech, Inc; revised 10/2024. Accessed July 2026.

7. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

PIK3CA/AKT1/PTEN

); encodes estrogen receptor alpha (ERα)

 encodes ERα, a ligand-activated nuclear hormone receptor that is a principal driver of cell growth, survival, and proliferation in estrogen receptor (ER)-positive breast cancer.

Under normal conditions, estrogen (estradiol) binds ERα, prompting receptor dimerization and recruitment of transcriptional coactivators that activate estrogen-responsive genes promoting tumor cell proliferation.

Endocrine therapies interrupt this axis by modulating the receptor (selective estrogen receptor modulators, SERMs), degrading it (selective estrogen receptor degraders, SERDs), or depriving it of estrogen (aromatase inhibitors, AIs).

Hotspot mutations in the ligand-binding domain confer constitutive, ligand-independent ERα activity, driving resistance to standard endocrine therapy. Y537S in particular is associated with the highest degree of endocrine resistance.

 mutations are rare in treatment-naive primary tumors and emerge under the selective pressure of prolonged endocrine therapy, most notably aromatase inhibitors, as an acquired mechanism of resistance.

 mutations are present in up to approximately 40% of ER-positive/HER2-negative advanced or metastatic breast cancers previously treated with endocrine therapy.

The hotspot ligand-binding domain mutations Y537S and D538G together account for the majority of 

 mutations are typically subclonal and polyclonal, and their prevalence rises with successive lines of endocrine therapy.

 mutations is recommended at disease recurrence or progression on endocrine therapy in HR-positive/HER2-negative disease, rather than at initial diagnosis, because these mutations are typically acquired.

 mutations are subclonal and acquired, retesting at each progression is advised to capture newly emergent alterations.

Circulating tumor DNA (ctDNA) liquid biopsy is the preferred and most sensitive approach given the temporal and spatial heterogeneity of 

 mutations; tissue-based next-generation sequencing (NGS) is an acceptable alternative.

Guardant360 CDx is the companion diagnostic used to identify 

 mutations for both agents, performed on a plasma specimen (ctDNA). Note the labels differ in wording: ORSERDU directs selection using an 

. Reproduce each verbatim rather than harmonizing them.

 mutation testing, with blood-based ctDNA preferred over tissue, at recurrence or progression on endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

 mutation testing in ER-positive/HER2-negative advanced or metastatic disease, performed on blood-based ctDNA at progression on endocrine therapy.

Two oral agents are FDA-approved specifically for 

-mutated, ER-positive/HER2-negative advanced or metastatic breast cancer: elacestrant (Orserdu) and vepdegestrant (Veppanu).

On January 27, 2023, the US Food and Drug Administration approved elacestrant, the first oral SERD in this setting, based on the phase 3 EMERALD trial (NCT03778931), which demonstrated improved progression-free survival versus standard-of-care endocrine monotherapy in patients with 

On May 1, 2026, the FDA approved vepdegestrant based on the phase 3 VERITAC-2 trial (NCT05654623). Vepdegestrant is the first PROTAC protein degrader approved for any indication. Guardant360 CDx was approved concurrently as a companion diagnostic.

In VERITAC-2, progression-free survival was assessed both in patients whose tumors carried an 

 mutation and in the overall population; a statistically significant benefit was demonstrated 

, which is the basis for the biomarker-restricted indication. Overall survival was immature at the time of the analysis.

Postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, 

-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

Elacestrant is an oral selective estrogen receptor degrader (SERD) that binds ERα and promotes its degradation.

Degradation of ERα inhibits estrogen-dependent signaling and tumor cell proliferation, including in cells harboring 

Adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (

)-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.

Vepdegestrant is a heterobifunctional protein degrader (PROTAC): a small molecule comprising an estrogen receptor binding domain joined by a linker to an E3 ligase binding domain.

It binds ER and the E3 ligase cereblon (CRBN), triggering CRBN-mediated polyubiquitination and proteasomal degradation of ER, reducing ER protein levels in breast cancer cells.

Vepdegestrant induces degradation of both wild-type and mutant ER and has demonstrated antitumor activity in wild-type and 

1. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations as a mechanism for acquired endocrine resistance in breast cancer. 

. 2015;12(10):573-583. doi:10.1038/nrclinonc.2015.117

2. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. 

. 2013;45(12):1439-1445. doi:10.1038/ng.2822

3. Fanning SW, Mayne CG, Dharmarajan V, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. 

4. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. 

. 2021;23(1):85. doi:10.1186/s13058-021-01462-3

5. Burstein HJ, DeMichele A, Somerfield MR, et al. Testing for ESR1 mutations to guide therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: ASCO guideline rapid recommendation update. 

6. ORSERDU (elacestrant). Prescribing information. Stemline Therapeutics, Inc, a Menarini Group Company; 2023. Accessed July 2026.

7. VEPPANU (vepdegestrant). Prescribing information. Rigel Pharmaceuticals, Inc; revised 6/2026. Accessed July 2026. 

https://veppanu.com/downloads/pdf/VEPPANU-Full-Prescribing-Information.pdf

8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

9. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. 

. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

10. US Food and Drug Administration. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. May 1, 2026. Accessed July 2026.