Response and Resistance to ER-Directed Therapy in Metastatic Breast Cancer

Despite the reduction in cancer recurrence and mortality provided by hormonal therapy, estrogen receptor positive (ER+) metastatic breast cancer (MBC) remains the most common cause of breast cancer death, resulting in more than 20,000 deaths in the U.S each year. Although several therapeutic options exist to target the estrogen receptor, resistance to these therapies invariably occurs. Genetic mechanisms of acquired resistance to targeted therapies in ER+ MBC are not well understood. To address this, we developed a prospective biopsy protocol where multiple research biopsies are collected from metastatic samples and used for pathology, ER/PR/HER2, OncoPanel (a CLIA 300 gene sequencing panel), whole exome sequencing (WES), transcriptome sequencing (RNA-Seq), and single-cell RNA-seq (scRNA-seq). In some cases, tissue is used for cell line and xenograft generation. Archival primary biopsies are also obtained when possible for parallel genomic studies. Patients are followed and serial metastatic biopsies are obtained. This data will be used to determine the landscape of genomic alterations in treatment-resistant ER+ MBC, and compared to data generated by TCGA for treatment-naive ER+ primary breast cancer. Comparison of genomic studies from resistant, metastatic specimens with corresponding pre-treatment primary samples will allow us to identify genomic association with resistance to specific therapies. Analysis of the serial metastatic biopsies collected over the course of multiple treatments will also shed light on tumor evolution under selective therapeutic pressure.

Please note that a subset of the MBC blood biopsies that are included in our study can be accessed and downloaded from the phs001977 accession.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
  • Cohort
  • Longitudinal
• Total number of consented subjects: 78
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria:

• Cohort 1 and 2: Patients must have histologically or cytologically confirmed invasive breast cancer.
• Cohort 3: Patients with a lesion suspicious of primary breast cancer.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky ≥ 60%)
• Ability to understand and the willingness to sign an informed consent document.
• If receiving therapeutic anticoagulation, then able to temporarily discontinue in peri-procedural window, as per standard clinical practice.
• Breast cancer lesion that is accessible for biopsy under either local anesthesia or intravenous conscious sedation. Biopsies that would require general anesthesia are allowed only in patients enrolled in Cohort 1 (biopsies done for clinical purposes with additional tissue taken for research purposes). Patients enrolled in Cohort 2 (biopsies solely done for research purposes) and Cohort 3 (biopsies of lesions suspicious for breast cancer) may not undergo general anesthesia as part of this protocol.

Exclusion Criteria:

• Concurrent disease or condition that would make the patient inappropriate for study participation, or any serious medical or psychiatric disorder that would interfere with the subject's safety.
• Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
• History of serious or life-threatening allergic reaction to local anesthetics (i.e. lidocaine, xylocaine)
• Pregnant women are excluded from participating in Cohort 2 because there may be an increased risk to both mother and fetus in the setting of conscious sedation, which is required for biopsies of certain anatomic sites (e.g. liver, lung, bone). Also, ionizing radiation from CT-guided biopsies may pose a risk to the unborn fetus.
• Active cardiac disease, defined as:
• History of uncontrolled or symptomatic angina
• History of arrhythmias requiring medications, or clinically significant
• Myocardial infarction < 6 months from study entry
• Uncontrolled or symptomatic congestive heart failure
• Any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.
• Any other condition, which in the opinion of the patient's treating oncologist, or the physician performing the biopsy procedure, would make participation in this protocol unreasonably hazardous for the patient.
• Patients receiving bevacizumab or other angiogenesis inhibitors (or less than 6 weeks from last dose of an angiogenesis inhibitor) should not undergo a research liver biopsy on this protocol because of the concern for the possibility of increased bleeding risk. Patients may undergo other research biopsies, up to the discretion of the treating physician, but physicians should take the potential increased bleeding and/or delayed wound healing issues into consideration.

This protocol was activated in 2005. To date over 500 subjects have been enrolled, a large cohort of which have had serial blood biopsies and tissue biopsies prospectively collected for diagnostics, sequencing, and other studies as applicable.

• Primary Phenotype: Breast Neoplasms
• Receptors, Estrogen

• Principal Investigator
  • Nikhil Wagle, MD. Broad Institute, Cambridge, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA.
• Funding Source
  • U54HG003067. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.