Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Recurrence

Carcinoma

Breast Neoplasms

Carcinoma in Situ

Carcinoma, Ductal

Carcinoma, Intraductal, Noninfiltrating

Carcinoma, Ductal, Breast

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Breast Diseases

Skin Diseases

Adenocarcinoma

Breast Carcinoma In Situ

Bone Density Conservation Agents

Antineoplastic Agents

All Drugs and Chemicals

Anticoagulants

Other Dietary Supplements

Tamoxifen

Hormones

Exemestane

Letrozole

Citric Acid

Sodium Citrate

Anastrozole

Aromatase Inhibitors

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Citrate

Patients receive a protocol-approved chemotherapy regimen based on the patient and/or physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Systemic Chemotherapy

Tamoxifen Citrate

Kevin M Kalinsky

This randomized phase III clinical trial studies how well tamoxifen citrate, anastrozole, letrozole, or exemestane with or without chemotherapy work in treating patients with breast cancer that has spread from where it began in the breast to surrounding normal tissue (invasive). Estrogen can cause the growth of breast cancer cells. Hormone therapy, using tamoxifen citrate, may fight breast cancer by blocking the use of estrogen by the tumor cells. Aromatase inhibitors, such as anastrozole, letrozole, and exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving tamoxifen citrate, anastrozole, letrozole, or exemestane is more effective with combination chemotherapy in treating patients with breast cancer.

PRIMARY OBJECTIVE:

I. To determine the effect of chemotherapy in patients with node positive breast cancer who do not have high recurrence scores (RS) by Oncotype DX.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS), distant disease-free survival (DDFS) and local disease-free interval (LDFI) by receipt of chemotherapy or not and its interaction with RS.

II. To compare the toxicity across the treatment arms. III. To perform other molecular assays or test other signatures that measure prognosis and potential benefit of chemotherapy and compare them to Oncotype DX.

IV. To determine the impact of management with Oncotype DX on patient-reported anxiety (co-primary Health-Related Quality of Life \[HRQL\] outcome) prior to screening, after disclosure of test results, and during the randomized trial.

V. To determine the impact of Oncotype DX on the initial management cost of node-positive, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

VI. To compare patient-reported utilities (e.g., quality of life \[QOL\]) for those randomized to chemotherapy versus no chemotherapy.

VII. Using modeling and DFS information from the trial, to estimate the cost-effectiveness of management with Oncotype DX vs usual care.

VIII. To determine the role of other assays as predictors of DFS, DDFS, and LDFI for patients randomized to chemotherapy versus no chemotherapy.

IX. To determine the impact of treatment with chemotherapy versus no chemotherapy on patient-reported fatigue and cognitive concerns (secondary HRQL outcomes).

X. To determine the impact of management with Oncotype DX on patient-reported decision conflict, perceptions regarding Oncotype DX testing, and survivor concerns prior to screening, after disclosure of test results, and during the randomized trial (secondary HRQL outcomes).

XI. The presence of circulating tumor cells (CTC+) using two CTC platforms will be assessed at up to two time points to assess late recurrence in those still at risk for the primary outcome.

XII. To compare clinically reported menopausal status with status categorized by serum hormone levels determined from baseline serum in women under age 55 years and to assess subsequent association with outcomes.

BANKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive a protocol-approved chemotherapy regimen based on the patient and/or physician preference. Patients then receive a protocol-approved adjuvant endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive a protocol-approved endocrine therapy comprising tamoxifen citrate, an aromatase inhibitor (anastrozole, letrozole, or exemestane), or both for 5-10 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 4 years, and then yearly for 15 years.

Tamoxifen Citrate, Letrozole, Anastrozole, or Exemestane With or Without Chemotherapy in Treating Patients With Invasive RxPONDER Breast Cancer

A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients With 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less. RxPONDER: A Clinical Trial Rx for Positive Node, Endocrine Responsive Breast Cancer

From date of randomization (2nd Registration) to date of first invasive recurrence (local, regional or distant), second invasive primary cancer (breast or not), or death due to any cause. Patients last known to be alive who have not experienced recurrence or second primary cancer are censored at their last contact date. This is the STEEP definition of invasive disease-free survival. Kaplan-Meier estimates were calculated for the 5-year IDFS rate.

Due to the results of the third prespecified interim analysis, prespecified separate analyses were conducted for all outcomes by menopausal status (see Statistical Analysis 2). The NCI and data and safety monitoring committee recommended early reporting of the data. After the primary analysis, changes in eligibility status were identified for three participants, making the population of eligible and evaluable participants different between the reporting of this outcome and both the Participant Flow section and the Adverse Events section.

Only adverse events that are possibly, probably, or definitely related to study drug are reported. Assessed at 6, 12, 24, and 36 months after randomization.

Time from date of randomization (2nd Registration) to date of death due to any cause. Participants last known to be alive are censored at their last contact date.

Time from date of randomization (2nd Registration) to date of invasive distant disease recurrence, second invasive primary cancer (breast or not) or death due to any cause. Participants last known to be alive who have not experienced distant recurrence, or second primary cancer are censored at their last contact date. This secondary outcome requires continuing to follow the patient after local recurrence in order to ascertain subsequent distant recurrence.

Invasive recurrence is defined as: appearance of any new invasive lesion(s) during or after protocol treatment. Whenever possible, recurrences should be documented histologically. Invasive recurrence includes local, regional, or distant recurrence with an invasive component. A new diagnosis of ipsilateral or contralateral DCIS without an invasive component is not considered to be a recurrence.

Time from date of randomization (2nd Registration) to date of invasive local or regional recurrence. Participants last known to be alive without recurrence are censored at their last contact date. Participants with distant recurrence, second primary cancer or death are censored at the time of that event.

Invasive recurrence is defined as: appearance of any new invasive lesion(s) during or after protocol treatment. Whenever possible, recurrences should be documented histologically. Invasive recurrence includes local, regional, or distant recurrence with an invasive component. A new diagnosis of ipsilateral or contralateral DCIS without an invasive component is not considered to be a recurrence.

Anxiety is evaluated with the Patient-Reported Outcomes Measurement Information System (PROMIS) Emotional Distress-Anxiety Short Form. Raw PROMIS scores can be re-scaled into T-scores based on a reference population with a mean score of 50 and a standard deviation of 10. Higher scores reflect greater anxiety.

PROMIS Anxiety scores at the 6 month timepoint will be compared between the two randomized study arms separately by menopausal status.

Assessed using the EuroQol-5D (EQ-5D), in which participants rate their health status in five different health-related domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The raw scores can be converted to index scores on a scale of 0 to 1, where a higher index score represents better health.

EQ-5D index scores at the 6-month timepoint will be compared between the two randomized study arms separately by menopausal status.

National Cancer Institute (NCI)

Only participants who received protocol treatment and assessed for adverse event were included in the adverse event result: 2062 in the Chemo and Endocrine Therapy arm and 2342 in the Endocrine Therapy Alone arm.

All-Cause mortality is reported for all eligible and evaluable participants (2487 in the Chemo and Endocrine arm and 2497 in the endocrine therapy arm). Due to eligibility changes found after the primary analysis, the number at risk differs from the Outcomes Section.

Participants receive a protocol-approved chemotherapy regimen based on the participant and/or physician preference. Participants then receive a protocol-approved adjuvant endocrine therapy for 5-10 years in the absence of disease progression or unacceptable toxicity.

Chemo and Endocrine Therapy

Participants receive a protocol-approved endocrine therapy for 5-10 years in the absence of disease progression or unacceptable toxicity.

Endocrine Therapy Alone

Total

Age, Continuous

Age, Customized

This trial only included female participants.

Sex: Female, Male

Ethnicity (NIH/OMB)

Race/Ethnicity, Customized

Premenopausal was defined as: \< 6 months since last menstrual period and no prior bilateral oophorectomy and not on estrogen replacement.

Postmenopausal was defined as: prior bilateral oophorectomy, or \> 12 months since last menstrual period with no prior hysterectomy.

If these categories did not apply, premenopausal was defined as age \< 50 and postmenopausal was defined as age \>= 50.

Menopausal Status

The Oncotype DX® Recurrence Score is based on a 21-gene breast cancer assay. The score ranges from 0-100, with higher scores indicating a worse prognosis. This study included participants with a score of 0-25.

Recurrence Score

Axillary Surgery

Positive Nodes

Randomized participants who were eligible for the study.

Breast Committee Statistician

This test describes the interaction of the treatment arm with the recurrence score in the analysis of invasive disease-free survival in the overall study population, to determine whether chemotherapy benefit depends on the recurrence score. If the interaction was statistically significant, the interaction term was planned to be included in the Cox model to evaluate the invasive disease-free survival outcome.

This test describes the interaction of the treatment arm with menopausal status (one of the study stratification factors) in the analysis of invasive disease-free survival in the overall study population, to determine whether chemotherapy benefit depends on menopausal status. If the interaction was statistically significant, separate analyses of IDFS were planned to be conducted by menopausal status.

This analysis includes only premenopausal participants.

This analysis includes only postmenopausal participants.

Premenopausal

Postmenopausal

For the participants flow and baseline characteristics summary, 5018 eligible participants were included. However, among them, there were 34 participants (10 in the chemo and endocrine arm, and 24 in the endocrine alone arm) that withdrew consent immediately after randomization; thus these participants were excluded from the survival analyses.

Invasive Disease-Free Survival (IDFS)

Abdominal infection

Abdominal pain

Acute kidney injury

Alanine aminotransferase increased

Alkaline phosphatase increased

Allergic reaction

Anemia

Anorexia

Anxiety

Arthralgia

Aspartate aminotransferase increased

Atrial fibrillation

Back pain

Blood and lymphatic system disorders - Other

Bone marrow hypocellular

Bone pain

Breast infection

Bronchial infection

CD4 lymphocytes decreased

Cardiac arrest

Cataract

Catheter related infection

Chest pain - cardiac

Chest wall pain

Colitis

Constipation

Death NOS

Dehydration

Depression

Dermatitis radiation

Device related infection

Diarrhea

Dizziness

Dry mouth

Dry skin

Dyspareunia

Dyspepsia

Dyspnea

Ear pain

Edema limbs

Ejection fraction decreased

Erythema multiforme

Erythroderma

Esophagitis

Fatigue

Febrile neutropenia

Fever

Flank pain

Flu like symptoms

GGT increased

Gastric hemorrhage

Gastric ulcer

Gastrointestinal disorders - Other, specify

Gastrointestinal pain

General disorders and admin site conditions - Other

Generalized muscle weakness

Headache

Heart failure

Hematuria

Hemorrhoids

Hot flashes

Hyperglycemia

Hyperhidrosis

Hypertension

Hypokalemia

Hyponatremia

Hypotension

INR increased

Infections and infestations - Other, specify

Injection site reaction

Insomnia

Irregular menstruation

Joint range of motion decreased

Kidney infection

Left ventricular systolic dysfunction

Leukemia secondary to oncology chemotherapy

Leukocytosis

Lipase increased

Localized edema

Lung infection

Lymphedema

Lymphocyte count decreased

Menorrhagia

Mucositis oral

Muscle weakness lower limb

Musculoskeletal and connective tiss disorder - Other

Myalgia

Myelitis

Myocardial infarction

Nausea

Neck pain

Neoplasms benign, malignant and unspecified - Other

Nervous system disorders - Other, specify

Neutrophil count decreased

Osteoporosis

Pain

Pain in extremity

Palmar-plantar erythrodysesthesia syndrome

Paresthesia

Peripheral ischemia

Eligible participants who received at least one dose of protocol treatment and assessed for Adverse Event.

Number of Participants With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs

Overall Survival (OS)

Distant Disease-Free Survival (DDFS)

Local Disease-Free Interval (LDFI)

Participant-Reported Anxiety

Participant-Reported Health Status

To compare DRFS between the Chemo and Endocrine Therapy arm and the Endocrine Therapy Alone arm, a Cox model was used with adjustment for the continuous recurrence score.

Premenopausal participants

Postmenopausal participants

Time from date of randomization (2nd Registration) to date of invasive distant disease recurrence or death due to any cause. Participants last known to be alive who have not experienced distant recurrence are censored at their last contact date. This outcome requires continuing to follow the patient after local recurrence in order to ascertain subsequent distant recurrence. Kaplan-Meier estimates were calculated for the 5-year DRFS rate.

Due to the results of the third prespecified interim analysis, prespecified separate analyses were conducted for all outcomes by menopausal status. The NCI and the data and safety monitoring committee recommended early reporting of the data. Due to subsequent data collection and data cleaning, the population of eligible and evaluable participants differs slightly between the reporting of this outcome and the Participant Flow section.

Distant Relapse-Free Survival (DRFS)

Overall Study

Spots Global Cancer Trial Database for multicentric breast carcinoma