Background:
Breast cancer is the most common cancer in US women. There are different types of breast cancers; some are aggressive and difficult to treat. Researchers want to know if an algorithm (ENLIGHT) can help choose approved drugs that will treat these cancers more effectively.
Objective:
To test whether ENLIGHT can find better treatments for aggressive breast cancers.
Eligibility:
People aged 18 years and older with triple-negative or endocrine therapy resistant breast cancer; the cancer must have either failed to respond to treatment or come back after treatment.
Design:
Participants will be screened. A sample of tissue taken from the tumor will be tested using ENLIGHT as well as another method (TruSight Oncology 500).
Participants will be assigned to 1 of 3 groups based on the algorithm search results:
Group 1: No drug option was recommended. Participants will continue with their standard treatment with their local doctors.
Group 2: A drug already approved for the participant's disease was recommended, but the participant has not yet received it. These results will be sent to the participant's local doctors. Participants may return to the NIH if their disease gets worse after using the suggested drugs.
Group 3: A drug approved for other uses was recommended. Participants will be treated with the recommended drugs at the NIH; their care will be managed by an NIH doctor. They will continue to receive treatment as long as the drugs are helping them. They will have follow-up visits for 2 years after treatment ends.
Participants who are not treated at the NIH will be contacted for a check on their health every 3 months for 2 years.
Participants must have a histologically confirmed diagnosis of metastatic breast cancer. Note: Pathology testing outside NIH will be accepted for eligibility purposes.
TNBC Cohort: TNBC will be defined as ER < 10% or PR < 10% by immunohistochemistry (IHC).
Endocrine-Refractory Cohort: HR+ (ER+ and/or PR+) will be defined as ER >= 10% or PR >= 10% by IHC.
For both cohorts, HER2 will be considered negative if not amplified as per ASCOCAP guidelines per IHC/FISH. Note: HER2-low status will be regarded in accordance with NCCN guidelines (in which this designation serves as a predictive marker for trastuzumab deruxtecan, but participants are otherwise not considered eligible for other HER2-directed therapies).
Participants in active visceral crisis, symptomatic brain metastases requiring local therapy, or active leptomeningeal disease given the time required for testing and therapy selection.
Participants with uncontrolled intercurrent illness evaluated by physical exam and chemistries or situations that would limit compliance with study requirements, interpretation of results or that could increase risk to the participant.
Participants with the following active cardiac conditions: symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia (per medical record).
Participants with lung disease requiring continuous oxygen supplementation.
Parallel
Expression Networks for highLIGHting Tumor vulnerabilities (ENLIGHT)
DeviceThis is a computational algorithm that takes RNA-seq data from tumor FFPE blocks and, given a list of pre-specified treatments, generates as output the predicted responses to those treatments.
TruSight(R) Oncology 500
DeviceTSO500 uses formalin-fixed, paraffin-embedded (FFPE) tumor blocks to generate a 523-gene DNA panel (with tumor mutational burden and microsatellite instability) to assess for biomarkers linked to FDA-approved, on-label therapies as well as whole-exome RNA-seq that can be used with the ENLIGHT algorithm.
TruSeq Matched Tumor Normal Whole Exome Sequencing Assay
DeviceThe TruSeq Matched Tumor-Normal Whole Exome Sequencing assay is a next-generation sequencing assay that uses tumor DNA from formalin-fixed, paraffin-embedded (FFPE) tumor blocks and germline DNA drawn from blood to provide extended sequencing information on the tumor as well as any pathogenic variants, likely pathogenic variants, and variants of uncertain significance in 156 genes from the normal blood sample.
Part A: To assess the feasibility of using the ENLIGHT algorithm to match heavily pretreated participants with metastatic breast cancer to off-label therapies
The number of participants of the first 20 enrolled overall having a match via ENLIGHT and being assigned to Arm 3.
Part B: (If feasibility lead-in met) To assess the objective response rate (ORR) of participants with advanced breast cancer using treatment recommended by the ENLIGHT algorithm
ORR is reported as a single endpoint measure (percentage) at time of interim analysis and at time of study completion and will be accompanied by a 95% confidence interval.
To determine the overall frequency of the ENLIGHT algorithm in recommending matches of targeted therapy or immunotherapy for participants who would otherwise be ineligible per existing biomarkers associated with FDA-approved, on-label treatments
Fraction of the eligible participants who match with a treatment by ENLIGHT along with a 95% confidence interval on the fraction, separately by cohort
To assess the duration of clinical benefit for treatments recommended by the ENLIGHT algorithm
Reported using the Kaplan-Meier method along with the median duration of clinical benefit and its 95% confidence interval, separately by cohort
To determine the specific agents for which ENLIGHT demonstrates the best predictive performance in the context of breast cancer
Frequency of patients matched to therapeutic options on study (Count of participants per unique therapy in Arm 3)
To determine extent of therapy associated toxicity burden and related outcomes for participants who are matched to a therapy through the ENLIGHT algorithm
Frequency of adverse events (AE) per CTCAE v5.0, by type and grade of toxicity
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