Breast Cancer Recurrent
Conditions
Brief summary
This is a prospective phase 2 study to use Functional Precision Oncology (FPO) to predict, prevent and treat early metastatic recurrence in subjects with HR-low/Her2 negative or triple negative breast cancer.
Detailed description
The aim of this clinical trial is to extend the findings of the investigators' first observational clinical study titled "Towards personalized medicine: patient derived breast tumor grafts as predictors of relapse and response to therapy" (TOWARDS-I). In TOWARDS-II, the investigators will develop patient derived models (PDMs), comprising patient derived xenografts (PDXs) and organoids (PDO and PDxO), from patients newly diagnosed with local or locally advanced hormone receptor-low/Her2 negative or triple negative breast cancer. The investigators will prospectively evaluate the correlation between PDX engraftment with recurrence. Using PDMs, the investigators will perform genomic studies and functional drug screens (FPO). Upon distant disease recurrence, the investigators will return the results to the physician with the intent to inform treatment selection.
Interventions
OTHERFunctional Precision Oncology
Patient derived models (PDMs), comprising patient derived xenografts (PDXs) and organoids (PDO and PDxO),
Sponsors
University of Utah
United States Department of Defense
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Registration: Pre-tumor Collection Eligibility Participant Inclusion Criteria * Subject aged ≥ 18 years. * Subject has Stage I-III disease. * Histologically or cytologically confirmed invasive breast carcinoma that is triple negative (TNBC) or hormone receptor (HR)-low/Her2 negative --TNBC is defined as: * HER2 expression 0 or 1+ on immunohistochemistry (IHC) or non-amplified (defined as HER2/CEP17 ratio \<2 or copy number \<6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, non-amplified HER2 expression must be confirmed by FISH. Pathologic diagnosis of TNBC (negative HER2 status by cytogenetics, \<1% of cells stained positive for estrogen receptor (ER) by IHC, and \<1% of cells stained positive for progesterone receptor (PR) by IHC). --HR-low/Her2(-) is defined as: * HER2 expression 0 or 1+ on IHC or non-amplified (defined as HER2/CEP17 ratio \<2 or copy number \<6) on fluorescence in situ hybridization (FISH). If HER2 expression is 2+ on IHC, non-amplified HER2 expression must be confirmed by FISH.1-10% of cells stained positive for ER by IHC, and/or 1-10% of cells stained positive for PR by IHC). * Primary tumor OR local lymph node metastasis that is ≥ 1.5 cm. Patients with inflammatory breast cancer are eligible, regardless of tumor size. Patients with multifocal or multicentric breast cancer are eligible so long as ALL tumors biopsied per standard of care guidelines and/or investigator discretion meet receptor status criteria, and at least one tumor measures ≥ 1.5 cm. * Patient is considered for preoperative cytotoxic chemotherapy per standard of care or in the context of a separate, ongoing clinical trial. * Patient has not received any prior therapy for thier breast cancer. * Willing and capable (per treating investigator's assessment) to undergo baseline tumor material collection from the primary tumor or lymph node metastasis. * Patient can safely undergo tumor collection: * The tumor is reasonably accessible to tumor collection * The tumor is amenable to tumor collection (e.g. does not abut neurovascular structures) * If the patient receives anticoagulation, anticoagulation can be safely withheld to accommodate for tumor material acquisition * The patient does not have a medical condition that would render tumor acquisition a high-risk procedure (e.g. tumor material acquisition from lung metastases in a patient with emphysema) * Life expectancy of ≥ 12 months as assessed by the treating investigator. * ECOG Performance Status ≤ 2. * Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have estradiol and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). * Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). * Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines. * No prior history of local or locally advanced hormone receptor positive (ER and/or PR expression \>10% on immunohistochemistry) breast cancer, unless the following conditions are met: * All treatment with curative intent has been completed, except adjuvant medical non-chemotherapy treatments (e.g. adjuvant endocrine therapy with any hormonal agent and/or CDK4/6 inhibitors), AND * An interval of ≥6 months has elapsed between completion of these treatments and histologic diagnosis of eligible breast cancer. Physician Inclusion Criteria * Physician is the treating medical oncologist for a patient who meets all of the inclusion criteria and none of the
Exclusion criteria
. If care has been transferred to a new physician while the patient is on-study, physician is the treating medical oncologist for the patient who met all of the inclusion criteria and none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Compare the distant recurrence rates between patients whose tumors successfully engrafted in mice (PDX+) vs. not (PDX-) | Data will be assessed at 1-year and 3-year endpoints from the time of definitive surgery. | Confirm that tumor engraftment as a PDX predicts early metastatic recurrence |
| Compare the recurrence rates between patients whose tumors successfully engrafted in mice (PDX+) vs. not (PDX-) | Data will be assessed at 3-years from the time of definitive surgery. | Confirm that tumor engraftment as a PDX predicts early metastatic recurrence |
| Proportion of cases where clinically actionable therapies were identified by FPO. | up to 3 years | Assess the feasibility and utility of Functional Precision Oncology (FPO) testing to identify therapies for patients with TNBC or HR-low/HER2- breast cancer who are at high risk of early recurrence |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation between tumor engraftment (PDX+/-) and relapse-free survival, overall survival, and response to preoperative chemotherapy and treatment response as assessed on the Residual Cancer Burden scale | up to 3 years | assess the correlation between PDX establishment and other clinical outcomes |
| Proportion of cases where any type of patient derived models are successfully generated and clinically actionable therapies are identified by functional precision oncology. | up to 3 years | assess additional measures of feasibility and utility of Functional Precision Oncology |
| determine the feasibility of returning FPO results to inform the selection of 2nd line therapy after recurrence | up to 3 years | The proportion of cases where clinically actionable therapies are identified by FPO within 12 weeks of initiating 1st line therapy after distant recurrence. This endpoint is restricted to the subset of patients where clinically actionable therapies were not identified prior to time of distant recurrence |
| Correlation between MHCII Immune Activation Score (high vs. low and as a continuous variable) and tumor engraftment (PDX+/-) and clinical outcomes (relapse-free and overall survival). | up to 3 years | determine the correlation between MHCII immune activation score and PDX engraftment |
| Calculate PFS ratios of 2nd line FPO-informed: 1st line "uninformed" therapy as a preliminary measure of efficacy | up to 3 years | assess the clinical efficacy of treatment decisions informed by FPO compared with treatment decisions not informed by FPO |
| Correlation between methylated ctDNA measurements as assessed using the MethylPatch assay pretreatment, pre- and post surgery, with PDX engraftment data (+/-) and clinical outcomes (relapse-free and overall survival) | up to 3 years | determine if measurement of methylated ctDNA can strengthen predictions of recurrence when combined with PDX engraftment data |
| frequency with which therapeutic responses in PDX, PDxO, and/or PDO align with the clinical, radiographic, and pathologic responses observed in the matched patient | up to 3 years | determine the concordance between therapeutic responses in PDX, PDxO, and/or PDO and matched patient tumors |
Countries
United States
Contacts
CONTACTJanna Espinosa
PRINCIPAL_INVESTIGATORChristos Vaklavas, MD
Huntsman Cancer Institute
Outcome results
None listed