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

Trial Summary

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 data supports the effectiveness of the treatment Intrinsic Subtyping of Primary Breast Cancer for metastatic breast cancer?

Research shows that identifying the intrinsic subtypes of breast cancer can predict patient relapse, overall survival, and response to treatments like chemotherapy. This suggests that understanding these subtypes can help tailor treatments for better outcomes in metastatic breast cancer. ^{1 2 3 4 5}

Is molecular subtyping for metastatic breast cancer safe?

The research does not provide specific safety data for molecular subtyping of metastatic breast cancer, but it does explore adverse drug events in related cancer treatments, which may help identify high-risk patients. ^{1 6 7 8 9}

How does the treatment for metastatic breast cancer using molecular subtyping differ from other treatments?

This treatment is unique because it uses molecular subtyping to identify specific tumor types based on their gene expression profiles, allowing for more personalized and potentially effective treatment strategies compared to traditional methods that do not consider these molecular differences. ^{2 4 10 11 12}

What is the purpose of this trial?

The HARMONY trial is an interventional trial enrolling metastatic breast cancer (MBC). Current treatment of breast cancer uses clinical subtype information (e.g. hormone receptor-positive (HR+)) to help guide treatment options. Breast cancer can also be characterized by molecular subtype, but it is not known if this information is helpful in determining treatment when breast cancer has become metastatic. HARMONY will give the treating physician of each participant the molecular subtype of the tumor based on PAM50 testing. The usefulness of this information will be determined through the physician survey. Finding out the molecular subtype of each tumor also allows the investigators to determine if the molecular subtype is different from what is expected based on the clinical subtype. This study will help determine how new types of information about tumors can help choose treatments for MBC

Research Team

Lisa Carey

Principal Investigator

UNC Lineberger Comprehensive Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

The prognostic ease and difficulty of invasive breast carcinoma. [2018]

3. England 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. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Systems biology and genomics of breast cancer. [2022]

5. England 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. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. United States pubmed.ncbi.nlm.nih.gov

Adverse Drug Event-based Stratification of Tumor Mutations: A Case Study of Breast Cancer Patients Receiving Aromatase Inhibitors. [2018]

8. United States pubmed.ncbi.nlm.nih.gov

Adverse Drug Events-based Tumor Stratification for Ovarian Cancer Patients Receiving Platinum Therapy. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Functional genomics for personalized cancer therapy. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Intrinsic Subtypes and Gene Expression Profiles in Primary and Metastatic Breast Cancer. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Dynamic clonal remodelling in breast cancer metastases is associated with subtype conversion. [2020]

12. Switzerland 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. [2020]