Molecular Subtyping for Metastatic Breast Cancer

(HARMONY Trial)

Recruiting at 1 trial location

Overseen By Lori Stravers

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: UNC Lineberger Comprehensive Cancer Center

Disqualifiers: Dementia, Altered mental status, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how detailed information about breast cancer tumors can assist doctors in selecting treatments for metastatic breast cancer (MBC). Researchers aim to determine if identifying the molecular subtype of a tumor through PAM50 testing provides more insight than the current method, which relies on clinical subtypes like hormone receptor status. The study involves doctors using this molecular information to assess changes in treatment plans and collect their feedback. Individuals with metastatic breast cancer, who have the necessary tumor samples and are receiving treatment, might be suitable candidates for this trial. As an unphased trial, this study offers a unique opportunity to contribute to research that could personalize and enhance future treatment strategies for metastatic breast cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. It is best to discuss this with your doctor.

What prior data suggests that this method is safe for determining treatment options in metastatic breast cancer?

Research has shown that analyzing the specific type of breast cancer is generally safe and well-tolerated. This process examines the tumor to understand its unique features. Studies indicate that this analysis provides important insights into cancer behavior, aiding in treatment selection. Although researchers have not directly tested the safety of this analysis, it uses existing tissue samples, posing no additional risks for participants. The goal is to guide treatment decisions without introducing new drugs or procedures. Therefore, participants should not experience negative effects from the analysis itself. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the molecular subtyping for metastatic breast cancer because it offers a more personalized approach to treatment. Unlike traditional treatments that generally target all breast cancer types similarly, this method identifies the specific subtype of breast cancer present in the patient, allowing for more tailored therapies. By understanding the intrinsic subtype of the primary breast cancer tissue, doctors can better predict how the cancer will respond to different treatments, potentially leading to more effective and less toxic treatment plans. This approach could revolutionize how metastatic breast cancer is managed, making it more precise and individualized.

What evidence suggests that intrinsic subtyping is effective for metastatic breast cancer?

Research has shown that identifying the specific type of breast cancer aids doctors in selecting the best treatment, particularly when the cancer has spread. Breast cancer divides into types such as Luminal A, Luminal B, HER2-enriched, and Basal-like, each responding differently to treatments. For example, Luminal types typically respond well to hormone therapies. Although much research has focused on early-stage breast cancer, these findings may also assist in treating metastatic cancer, potentially improving survival rates. This trial will concentrate on the intrinsic subtyping of primary breast cancer tissue from patients with metastatic breast cancer. Identifying the specific type of breast cancer enables doctors to create personalized treatment plans, tailoring them for better patient outcomes. ^{1 3 6 7 8}

Who Is on the Research Team?

Lisa Carey

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Are You a Good Fit for This Trial?

The HARMONY trial is for men and women over 18 with metastatic breast cancer, who are well enough for standard treatments like chemo. They must have measurable cancer with known hormone receptor status, accessible medical records, and be in or starting their first line of treatment. Participants need to provide blood samples and a tumor biopsy if no suitable sample exists.

Inclusion Criteria

I am in or before my first treatment for metastatic breast cancer, with no more than one prior therapy.

I can provide a sample of my original tumor for research, or I am willing to have a biopsy.

My doctor thinks I'm fit for standard cancer treatments like chemotherapy.

Exclusion Criteria

I cannot or do not want to provide tissue for research.

Has dementia, altered mental status, or any psychiatric or co-morbid condition prohibiting the understanding or rending of informed consent

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Consent and Tissue Collection

Subjects consent to the trial and archival tissue from the primary tumor and metastatic sites is obtained

1-2 weeks

Molecular Subtyping and Physician Survey

PAM50 testing is conducted to determine molecular subtypes, and physicians are surveyed on treatment preferences before and after receiving subtype information

4 weeks

Follow-up

Participants are monitored for changes in treatment plans and progression-free survival (PFS) over a 4-year period

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Intrinsic Subtyping of Primary Breast Cancer

Trial Overview This study tests whether knowing the molecular subtype of a breast tumor (using PAM50 testing) helps doctors choose better treatments for metastatic breast cancer. It compares current clinical subtyping methods against additional molecular information to see if it changes treatment decisions.

How Is the Trial Designed?

Group I: Intrinsic subtyping of Primary Breast Cancer Experimental Treatment 1 Intervention

Intrinsic subtype of primary breast tissue from metastatic breast cancer subject will be determined

Who Is Running the Clinical Trial?

UNC Lineberger Comprehensive Cancer Center

Lead Sponsor

Trials

377

Recruited

95,900+

Breast Cancer Research Foundation

Collaborator

Trials

79

Recruited

40,500+

Veracyte, Inc.

Industry Sponsor

Trials

5

Recruited

1,004,000+

Published Research Related to This Trial

In a study of 123 paired primary and metastatic breast cancer tissues, it was found that luminal A tumors frequently converted to luminal B or HER2-enriched subtypes during metastatic progression, indicating significant tumor evolution.

Metastatic tumors showed increased expression of proliferation and migration-related genes, which were better predictors of overall survival in metastatic disease compared to primary tumors, highlighting the importance of analyzing gene expression in the context of tumor progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer. Cejalvo, JM., Martínez de Dueñas, E., Galván, P., et al.[2022]

Patients with metastatic breast cancer (MBC) who experienced intrinsic subtype conversion from primary tumors (PT) to metastatic tumors (MT) had significantly decreased overall survival (OS), indicating that subtype changes can lead to worse outcomes.

The study highlights the importance of obtaining biopsies from metastatic lesions and using circulating tumor cell (CTC) analyses to identify patients at higher risk, suggesting that personalized treatment strategies may be necessary for those with aggressive subtype conversions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of mRNA-Assessed Molecular Subtype Conversion, Intact and Apoptotic Circulating Tumor Cells on Survival of Metastatic Breast Cancer Patients: Proof of Principle. Stefanovic, S., Deutsch, TM., Wirtz, R., et al.[2020]

The study highlights that many reported prognostic signatures in breast carcinoma (BC) may be misleading due to a lack of understanding of how patient subtypes and molecular factors interact, which can confound results.

By identifying a small group of patients (about 7% of BC cases) who appear to have a good prognosis at diagnosis but still experience distant metastasis within 5 years, the research emphasizes the need for further investigation into the complexities of tumor heterogeneity in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The prognostic ease and difficulty of invasive breast carcinoma. Tofigh, A., Suderman, M., Paquet, ER., et al.[2018]

The ADEStrata framework, previously used for breast cancer, was successfully applied to ovarian cancer patients treated with cisplatin, demonstrating its versatility in predicting adverse drug events (ADEs) and patient outcomes.

By analyzing 156 ovarian cancer patients, the study showed that understanding the molecular mechanisms of cisplatin-related ADEs can help identify tumor subtypes with varying clinical outcomes, potentially guiding personalized treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Drug Events-based Tumor Stratification for Ovarian Cancer Patients Receiving Platinum Therapy. Wang, C., Zimmermann, MT., Chute, CG., et al.[2020]

Breast cancer is not a single disease but consists of various subtypes with unique characteristics, which can be identified through gene expression profiling using DNA microarrays.

The intrinsic subtypes of breast cancer can predict important clinical outcomes such as patient relapse, overall survival, and responses to treatments, highlighting the significance of understanding a tumor's subtype for effective therapy planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systems biology and genomics of breast cancer. Perou, CM., Børresen-Dale, AL.[2022]

In a study of 57 paired primary and metastatic breast cancer samples, subtype conversion occurred in 24.6% of clinical subtypes and 36.9% of intrinsic subtypes, indicating significant changes as the disease progresses.

Metastatic tumors exhibited a higher mutation cell fraction (CCF) compared to primary tumors, particularly in cases of clinical subtype conversion, suggesting that changes in breast cancer subtypes are associated with clonal remodelling and tumor evolution.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. Lluch, A., González-Angulo, AM., Casadevall, D., et al.[2020]

Whole-genome sequencing of 442 patients with metastatic breast cancer revealed that the tumor mutational burden is twice as high compared to primary breast cancer, indicating a more complex genetic landscape in advanced stages.

The study identified specific mutational signatures associated with prior chemotherapy treatments, which could help in tailoring future therapies and improving patient management based on genomic features.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Angus, L., Smid, M., Wilting, SM., et al.[2022]

A new classification system called Breast Cancer Consensus Subtypes (BCCS) was developed, identifying seven distinct subtypes of breast cancer from a large dataset of 5950 samples, which can help in understanding prognosis and treatment responses.

The BCCS subtypes reveal important characteristics, such as the presence of good and poor prognosis groups among estrogen receptor-positive tumors, which can guide personalized treatment strategies for breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breast Cancer Consensus Subtypes: A system for subtyping breast cancer tumors based on gene expression. Horr, C., Buechler, SA.[2021]

The ADEStrata approach, developed in this study, allows for the stratification of tumor mutations based on adverse drug events (ADEs), specifically focusing on musculoskeletal adverse events in breast cancer patients treated with aromatase inhibitors, using data from 212 patients.

By prioritizing somatic variants linked to ADEs, the study found that this method can identify high-risk patients who may experience poor outcomes, suggesting that it could help tailor cancer therapies to improve patient safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Drug Event-based Stratification of Tumor Mutations: A Case Study of Breast Cancer Patients Receiving Aromatase Inhibitors. Wang, C., Zimmermann, MT., Prodduturi, N., et al.[2018]

Combining functional and genomic screening methods can identify important genetic factors that influence how well cancer treatments work.

These findings can lead to more personalized cancer therapies, improving treatment outcomes for patients by targeting specific genetic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional genomics for personalized cancer therapy. Tyner, JW.[2022]

A study involving 123 patients with untreated metastatic breast cancer revealed that luminal A tumors are more likely to undergo subtype switching, indicating significant heterogeneity in their genetic profiles.

The research found that metastases have a higher mutation load, particularly in late-stage cases, and identified several druggable genes, suggesting that profiling metastatic tumors can provide crucial insights for prognosis and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular features of untreated breast cancer and initial metastatic event inform clinical decision-making and predict outcome: long-term results of ESOPE, a single-arm prospective multicenter study. Callens, C., Driouch, K., Boulai, A., et al.[2022]

Breast cancer is now understood to have significant intertumour and intratumour heterogeneity, meaning that different patients and even different areas within the same tumor can have distinct genetic profiles, which complicates treatment.

To improve the development of targeted therapies for advanced breast cancer, new strategies such as molecular profiling of metastatic tumors, monitoring circulating tumor DNA, and innovative clinical trial designs are essential to address the complexities of this disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of targeted therapies in advanced breast cancer: the need for large-scale molecular screening and transformative clinical trial designs. Fadoukhair, Z., Zardavas, D., Chad, MA., et al.[2018]

Citations

1. aacrjournals.org aacrjournals.org/cancerres/article/77/9/2213/625048/Intrinsic-Subtypes-and-Gene-Expression-Profiles-in

Intrinsic Subtypes and Gene Expression Profiles in Primary ... In primary disease, the immunohistochemical analyses showed 73.17% (n = 90) of patients had HR-positive (HR+), 15.45% (n = 19) HER2-positive (HER2+), and 9.76% ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5423143/

Intrinsic subtypes and genomic signatures of primary breast ... Abstract. Molecular subtypes and gene expression signatures are widely used in early breast cancer but their role in metastatic disease is less explored.

3. academic.oup.com academic.oup.com/jnci/article/106/8/dju152/905915

Molecular Features and Survival Outcomes of the Intrinsic ... The likelihood of cHER2-positivity in HER2E, Luminal B, Basal-like and Luminal A subtypes was 64.6%, 20.0%, 14.4% and 7.3%, respectively. Within ...

4. esmoopen.com esmoopen.com/article/S2059-7029(23)00440-4/fulltext

Prognostic value of intrinsic subtypes in hormone-receptor- ... Metastatic breast cancer (MBC) is a major cause of cancer death with 5-year overall survival (OS) rates of ∼38%.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4656721/

Breast cancer intrinsic subtype classification, clinical use ... This review explores and summarizes the existing intrinsic subtypes, patient clinical features and management, commercial signature panels, as well as various ...

6. aacrjournals.org aacrjournals.org/cancerres/article/84/9_Supplement/PO5-24-03/743603/Abstract-PO5-24-03-Breast-cancer-intrinsic

Abstract PO5-24-03: Breast cancer intrinsic subtypes predict ... Breast cancer intrinsic subtypes predict outcomes in primary and metastatic samples [abstract]. In: Proceedings of the 2023 San Antonio ...

7. mdpi.com mdpi.com/2072-6694/13/7/1592

PAM50 Intrinsic Subtype Profiles in Primary and Metastatic ... Background: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear.

8. unclineberger.org unclineberger.org/peroulab/wp-content/uploads/sites/1008/2015/04/HER2E-subtype-Prat-JNCI-2014.pdf

HER2E-subtype-Prat-JNCI-2014.pdf Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer. Methods. We interrogated The Cancer Genome ...