Biomarker-Directed Approach to Guide Hormonal Therapy before Surgery for Patients with Stage II/III ER-Positive, HER2-Negative Breast Cancer
This phase II trial tests how well a biomarker-directed approach to guide endocrine (hormonal) therapy, such as with anastrozole, before surgery works for patients with stage II/III estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Although endocrine therapy and surgery are standard treatment for this type of breast cancer, responses to this treatment have been mixed. Researchers are looking for better ways to predict how people’s tumors will respond to endocrine therapy so that alternative treatments (such as chemotherapy) can be started to shrink the tumor better. Some tumors shrink well with endocrine therapy, yet others do not, and may need chemotherapy to shrink them better before the tumor is removed. One of the ways of predicting tumor response to treatment is testing tumor samples to look at genetic activity and molecular characteristics of the tumors to try to better determine which treatment might be the best to shrink the tumor. Using tissue testing to guide the selection of pre-operative treatment (endocrine therapy/anastrozole or chemotherapy) may work better to treat patients with stage II/III ER-positive, HER2-negative breast cancer.
Inclusion Criteria
- Histologically or cytologically confirmed newly diagnosed clinical stage II or III (by American Joint Committee on Cancer [AJCC] 8th edition – at least T2, any N, M0 or if N1+ then any T) ER-positive (ER > 10%), any progesterone receptor (PR), and HER2-negative breast cancer with complete surgical excision of the breast cancer after neoadjuvant therapy as the treatment goal. * HER2 negative must be assessed by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) staining 0 or 1+ according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
- A palpable mass is not required; however, tumor size must be either: * ≥ 2 cm in one dimension by clinical or radiographic examination (World Health Organization [WHO] criteria), if clinically axillary lymph node negative. OR * Measurable (≥ 10 mm) by modified Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 for breast MRI, if histologically confirmed resectable locoregional nodal involvement
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
- Eligible to receive neoadjuvant aromatase inhibitor, as per treating physician.
- Eligible to receive neoadjuvant standard of care anthracycline- and/or taxane-based chemotherapy regimen, as per treating physician.
- Able to tolerate breast MRI with intravenous contrast administration. Must be able to complete the applicable MRI screening evaluation form.
- Adequate bone marrow and organ function, as determined by the treating physician.
- Known history of hepatitis C virus (HCV) infection is permissible provided the patient has been treated and cured.
- At least 18 years of age.
- Postmenopausal status, defined as one of the following: * Age >= 60 years. * Age < 60 with intact uterus and amenorrhea for 12 consecutive months or more. * Status post bilateral oophorectomy, total hysterectomy.
- Ability to understand and willingness to sign an Institutional Review Board (IRB) approved written informed consent document (or that of legally authorized representative, if applicable), and willing and able to comply with scheduled visits and treatment schedule.
Exclusion Criteria
- Inflammatory breast cancer (cT4d disease as per AJCC 8th edition).
- Locally recurrent or metastatic disease (cM1 disease as per AJCC 8th edition).
- Bilateral breast cancer.
- Prior systemic therapy for the indexed breast cancer.
- Pre-existing grade >= 2 neuropathy.
- Uncontrolled intercurrent illness that would limit compliance with study requirements.
- A history of other malignancy =< 5 years prior to the indexed breast cancer diagnosis with the following exceptions: * Basal cell or squamous cell carcinoma of the skin which were treated with local resection only. * Adequately treated carcinoma in situ of the cervix. * Prior or concurrent malignancy whose natural history or treatment will not interfere with the safety or efficacy assessments of the indexed breast cancer. In this event, review and approval by the study principal investigator (PI) is required
- Concurrent participation in any investigational therapeutic trial for treatment of breast cancer.
- Known human immunodeficiency virus (HIV) positivity that in the judgement of the treating physician would impact safety of chemotherapy receipt.
- A history of allergic reactions attributed to compounds of similar chemical or biologic composition to anastrozole, taxanes (paclitaxel or nab-paclitaxel), anthracyclines (doxorubicin or epirubicin) or cyclophosphamide.
- Evidence of uncontrolled ongoing or active infection, requiring parenteral anti-bacterial, anti-viral, or anti-fungal therapy =< 7 days prior to administration of study treatment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.
- Any uncontrolled medical condition that in the opinion of the Investigator would pose a risk to participant safety or interfere with study participation or interpretation of individual participant results.
Additional locations may be listed on ClinicalTrials.gov for NCT05837455.
Locations matching your search criteria
United States
Illinois
Shiloh
Missouri
Saint Louis
PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR) by breast magnetic resonance imaging (MRI) in the pooled protocol-defined low-risk group plus high-risk endocrine-sensitive group (high-risk patients with week 4 post-anastrozole Ki 67 =< 10%).
SECONDARY OBJECTIVES:
I. To determine the breast conservation surgery (BCS) rate and transition to BCS by cohort and treatment arm.
II. To evaluate the rate of change in need for oncoplastic breast reduction surgery at time of BCS based on cohort and treatment assignment.
III. To determine the ORR by breast MRI in the high-risk endocrine-sensitive group.
IV. To determine the ORR by breast MRI in the high-risk endocrine-resistant group (high-risk patients with week 4 Ki67 > 10% post anastrozole).
EXPLORATORY OBJECTIVES:
I. To report the proportion of patients with luminal A, luminal B and non-luminal prediction analysis of microarray 50 (PAM50) molecular intrinsic subtypes by race, specifically in Black patients.
II. To assess PAM50 molecular intrinsic subtypes distribution within Oncotype diagnosis (registered trademark) recurrence score (Oncotype DX RS) category (RS 0-10, 11-25, > 25), by race.
III. To report the distribution of week 4 Ki67 > 10% post-anastrozole in patients with breast cancers associated with Oncotype DX RS =< 25.
IV. To evaluate the proportion of patients with PAM50-derived risk of recurrence (ROR) class low (ROR-low) and intermediate (ROR-intermediate) in all groups, and by race.
V. To assess the ORR by breast MRI in patients with ROR-low and ROR-intermediate who completed 6 cycles of neoadjuvant anastrozole per protocol, by race.
VI. To evaluate the ORR by breast MRI and preoperative endocrine prognostic index (PEPI) score in patients with breast cancers associated with Oncotype DXR RS =< 25 who completed 6 cycles of neoadjuvant anastrozole.
VII. To determine the PEPI score in the high-risk endocrine-sensitive group.
VIII. To report the number of patients with breast cancers associated with Oncotype DXR RS =< 25 who are triaged to receive chemotherapy due to week 4 Ki 67 > 10%.
IX. To report the week 4 Ki67 =< 10% and > 10% rates post-anastrozole in patients with luminal B and non-luminal breast cancer subtype.
X. To report the incidence and grade of aromatase inhibitor-induced musculoskeletal syndrome (AIMSS) to neoadjuvant anastrozole, by race.
XI. To assess the incidence, severity and changes in AIMSS measures based on baseline and subsequent vitamin D levels.
XII. To report the incidence and differences in chemotherapy-induced adverse events of special interest by race.
XIII. To identify proteo-genomic biomarkers of neoadjuvant treatment response on baseline and on-treatment tumor tissue, and by race.
XIV. To compare treatment effect on ER and other signaling pathways in endocrine-sensitive versus endocrine-resistant tumors, and by race.
XV. To determine if changes in minimal residual disease (MRD) detection by circulating tumor deoxyribonucleic acid DNA (ctDNA) correlate with Ki67 changes from baseline to week 4 (high-risk endocrine-sensitive and endocrine-resistant groups only) and time of surgery.
XVI. To determine the complete cell cycle arrest (CCCA) rate at surgery by cohort and treatment assignment.
XVII. To determine pathologic complete response (pCR) rate differences in the high-risk group by treatment arm (both endocrine-sensitive and endocrine-resistant).
XVIII. To record neoadjuvant anastrozole treatment adherence rate based on pharmacy prescription refill history.
XIX. To assess the effect of treatment arm assignment on quality of life indices and patient reported outcomes (PROs).
XX. To assess vitamin D levels and report differences in baseline vitamin D levels by race.
XXI. To correlate patient-reported quality of life indices relative to vitamin D levels.
XXII. To report the 5-year invasive relapse-free survival (RFS) and overall survival (OS) by cohort and treatment arm.
OUTLINE:
Patients undergo blood sample collection, MRI and may undergo tissue collection at baseline. Patients receive standard of care (SOC) anastrozole orally (PO) for 1 28 day cycle. Patients' tissue samples undergo SOC genome signature assay testing (Oncotype DX RS), Ki67, and study-mandated PAM50 molecular intrinsic subtyping. At the end of cycle 1, patients are assigned to 1 of 2 groups, depending on results of testing performed during cycle 1.
GROUP I (LOW-RISK): Patients with baseline Ki67 =< 10% or luminal A molecular intrinsic subtype by PAM50 receive SOC anastrozole PO prior to SOC surgery. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the trial.
Patients with baseline non-luminal A molecular intrinsic subtype by PAM50 or non-diagnostic PAM50 molecular intrinsic subtype, undergo tissue biopsy at week 4 post cycle 1. Patients are then assigned to 1 of 2 groups, depending on tumor endocrine responsiveness based on Ki67 assay.
GROUP II (HIGH-RISK): Patients who are deemed to have endocrine-sensitive disease (defined as Ki67 =< 10% per SOC) at week 4 will receive anastrozole PO prior to SOC surgery. Treatment repeats every 28 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo tissue biopsy at time of SOC surgery.
GROUP III (HIGH-RISK): Patients who are deemed to have endocrine-resistant disease (defined as Ki67 > 10% per SOC) at week 4 will discontinue anastrozole PO and will receive 5-6 months of chemotherapy per physician choice. Patients also undergo tissue biopsy at time of SOC surgery.
After completion of study treatment, patients are followed up every 6 months for 5 years after surgery.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationSiteman Cancer Center at Washington University
Principal InvestigatorNusayba Bagegni
- Primary ID202305007
- Secondary IDsNCI-2023-05555
- ClinicalTrials.gov IDNCT05837455