Evaluating the Addition of Adjuvant Chemotherapy to Ovarian Function Suppression Plus Endocrine Therapy in Premenopausal Patients With pN0-1, ER-Positive/HER2-Negative Breast Cancer and an Oncotype Recurrence Score Less Than or Equal to 25

Study Overview
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Brief Summary
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This Phase III Trial will determine whether adjuvant chemotherapy (ACT) added to ovarian function suppression (OFS) plus endocrine therapy (ET) is superior to OFS plus ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early- stage breast cancer (EBC) patients with estrogen receptor (ER)-positive, HER2-negative tumors and 21-gene recurrence score (RS) between 16-25 (for pN0 patients) and 0-25 (for pN1 patients).

Detailed Description
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Younger age at diagnosis is an adverse prognostic factor in early breast cancer: women who are less than 35 years of age at diagnosis are more likely to die from their disease than their older counterparts following standard treatments. There remains a pressing need for advancements in therapeutic options for this patient population. One increasingly utilized option is ovarian suppression, which was first reported as treatment for advanced breast cancer in 1896 and has been examined in a multitude of clinical trials over the past century. As chemotherapeutic options became more commonplace for breast cancer therapy, however, the role of ovarian suppression became uncertain. In the pre-genomic era, several studies evaluated the role of ovarian suppression compared to chemotherapy, with conflicting results. These studies either looked at ovarian suppression alone or at tamoxifen compared to chemotherapy. A meta-analysis examining LHRH-agonists (luteinizing hormone-releasing hormone) in the Early Breast Cancer Overview group (LHRH-agonists in Early Breast Cancer Overview group 2007) showed that when LHRH-agonists were added to tamoxifen, chemotherapy, or both, there was a 12.7% reduction in the risk of recurrence and a 15.1% reduction in the risk of death. When compared to chemotherapy, LHRH-agonists appeared to be equally as effective, especially if patients were less than 40 years of age. These older studies, conducted in the pre-taxane/anthracycline era, typically used CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy, and were designed prior to the use of genomic assays .

Official Title
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A Phase III Adjuvant Trial Evaluating the Addition of Adjuvant Chemotherapy to Ovarian Function Suppression Plus Endocrine Therapy in Premenopausal Patients With pN0-1, ER-Positive/HER2-Negative Breast Cancer and an Oncotype Recurrence Score Less Than or Equal to 25 (OFSET)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ovarian Function Suppression + Aromatase Inhibitor
* Drug: Adjuvant Chemotherapy + Ovarian Function Suppression


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A patient cannot be considered eligible for this study unless ALL of the following conditions are met. The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information. Female patients must be greater than or equal to 18 years of age. Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as: Age 50 years or under with spontaneous menses within 12 months; or Age greater than 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range. The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 60%). Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy. Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy. Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy. For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS (ductal carcinoma in situ) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS (lobular carcinoma in situ) are eligible without additional resection.) For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT (radiation therapy) of the chest wall will be administered.) Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND). The following staging criteria must be met postoperatively according to AJCC 8th edition criteria: By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.) By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c). Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes. Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1. Oncotype DX RS (recurrence score) requirements*: If node-negative: Oncotype DX RS must be RS 21-25, or Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size greater than 3 cm, intermediate histologic grade with primary tumor size greater than 2 cm, or high histologic grade with primary tumor size greater than 1 cm. If 1-3 nodes involved: Oncotype DX RS must be less than 26. * Patients with a Low Risk or MP1 MammaPrint (a genomic test that analyzes the activity of certain genes in early-stage breast cancer) result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible. The tumor must be ER and/or PgR-positive (progesterone receptor) by current ASCO/CAP guidelines based on local testing results. Patients with greater than or equal to 1% ER and/or PgR staining by IHC will be classified as positive. The tumor must be HER2-negative by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines based on local testing results. The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks. Short course of endocrine therapy of less than 6 weeks duration before pre-entry is acceptable either as neoadjuvant or adjuvant therapy. An Oncotype DX RS must be performed on core biopsy specimen obtained prior to initiation of neoadjuvant endocrine therapy if received. Patients with a prior or concurrent non-breast malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. This would include prior cancers treated with curative intent. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry. Exclusion Criteria: • Definitive clinical or radiologic evidence of metastatic disease. pT4 (pathological state) tumors, including inflammatory breast cancer. History of ipsilateral or contralateral invasive breast cancer. (Patients with synchronous and/or previous DCIS or LCIS are eligible.) If prior ipsilateral DCIS was treated with lumpectomy and XRT (ionizing radiation therapy), a mastectomy must have been performed for the current cancer. Life expectancy of less than 10 years due to co-morbid conditions in the opinion of the investigator. Known results from most recent lab studies obtained as part of routine care prior to study entry showing ANY of the following values: ANC (absolute neutrophil count) less than 1200/mm3; Platelet count less than 100,000/mm3; Hemoglobin less than 10 g/dL; Total bilirubin greater than ULN (upper limit of normal) for the lab or greater than 1.5 x ULN for patients who have a bilirubin elevation due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; AST(aspartate aminotransferase)(SGOT)/ALT (alanine transminase)(SGPT): greater than 3 × institutional ULN; Renal function of GFR (glomular filtration rate) less than 30 mL/min/1.73m2. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Non-epithelial breast malignancies such as sarcoma or lymphoma. Any treatment with radiation therapy, chemotherapy, or biotherapy administered for the currently diagnosed breast cancer prior to pre-entry. (Patients with prior ET of more than 6 weeks duration for treatment of this cancer are not eligible.) Prior tamoxifen given for breast cancer prevention is allowed. Prior AI or GnRH for fertility preservation is allowed. Hormonally based contraceptive measures must be discontinued prior to pre-entry (including progestin/progesterone IUDs). Patients with evidence of chronic hepatitis B virus (HBV) infection are ineligible unless the HBV viral load is undetectable on suppressive therapy. Patients with a history of hepatitis C virus (HCV) infection are ineligible unless they have been treated and cured or have an undetectable HCV viral load if still on active therapy. Pregnancy or lactation at the time of pre-entry. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to pre-entry.) Other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1: Ovarian Function Suppression + Aromatase Inhibitor<br>Aromatase inhibitor co-administered with a GnRH agonist (gonadotropin releasing hormone) for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired. | Drug: Ovarian Function Suppression + Aromatase Inhibitor<br>* Aromatase inhibitor co-administered with a GnRH agonist for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired.<br>|
| Active Comparator: Arm 2 Adjuvant Chemotherapy + Ovarian Function Suppression + Aromatase Inhibitor<br>Adjuvant chemotherapy of investigator's choice followed by an aromatase inhibitor (AI) co-administered with an GnRH agonist for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired. | Drug: Ovarian Function Suppression + Aromatase Inhibitor<br>* Aromatase inhibitor co-administered with a GnRH agonist for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired.<br>Drug: Adjuvant Chemotherapy + Ovarian Function Suppression<br>* Adjuvant chemotherapy of investigator's choice followed by an aromatase inhibitor (AI) co-administered with an GnRH agonist for 5 years. The choice of AI is per investigator discretion. The choice of GnRH agonist and dosing schedule is per investigator's discretion. Options commonly include goserelin, leuprolide, or triptorelin given monthly or every-three-months. The dose and schedule of AI should be consistent with the drug package insert. Endocrine treatment beyond 5 years is at the investigator's discretion. Bilateral oophorectomy may substitute for ovarian suppression if desired.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive breast cancer-free survival (IBCFS) | Time from randomization to the first diagnosis of local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause prior to recurrence or contralateral breast cancer. | Time from randomization for duration of trial, 11 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive disease-free survival (IDFS) | Time from randomization to the first diagnosis of local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distant recurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause prior to recurrence or second primary cancer. | Time from randomization for duration of trial, 11 years | 
| Overall survival | Time from randomization to death from any cause | Time from randomization for duration of trial, 11 years | 
| Distant recurrence-free interval (DRFI) | Time from randomization until the first diagnosis of distant metastasis or death from breast cancer, regardless of occurrence of any intervening local or regional recurrences, contralateral breast cancers, or non-breast second primary cancers. This endpoint is censored at the time of death from causes other than breast cancer. | Time from randomization for duration of trial, 11 years | 
| Breast cancer-free interval (BCFI) | Time from randomization until the first diagnosis of local invasive recurrence, regional recurrence, distant recurrence, contralateral breast cancer or death from breast cancer. | Time from randomization for duration of trial, 11 years | 
| Menopausal symptoms measured by the FACT ESS-19 score | The FACT-ES 19 Item Endocrine Symptom Subscale (ESS-19) score. The score is calculated as a sum of 19 endocrine symptom items. The score range is 0-76 and a higher score indicates better QOL. | Measured at one year after randomization | 
| Pain during aromatase inhibitor (AI) therapy | The pain severity question from the PROMIS-29 Profile. Pain will be measured on a 0-10 scale using the pain questions from the PROMIS-29 profile. | Measured at one year after randomization |