DCIS, Ductal Carcinoma in Situ
Conditions
Keywords
Ductal Carcinoma
Brief summary
This study looks at the risks and benefits of active monitoring (AM) compared to surgery in the setting of a pragmatic prospective randomized trial for low risk DCIS. Our overarching hypothesis is that management of low-risk Ductal Carcinoma in Situ (DCIS) using an AM approach does not yield inferior cancer or quality of life outcomes compared to surgery.
Detailed description
Overdiagnosis and overtreatment resulting from mammographic screening have been estimated to be as high as 1 in 4 patients diagnosed with breast cancer although the absence of standard definitions for measuring overdiagnosis has led to much uncertainty around this estimate. The national health care expenditure resulting from false positive mammograms and breast cancer overdiagnosis has been estimated to approach $4 billion annually. There is general consensus that much of this burden derives from the treatment of DCIS; for those estimated 40,000 women per year whose DCIS may never have progressed even without treatment, medical intervention can only harm. In those women who undergo surgical management of DCIS, there is risk of developing persistent pain at the surgical site, with estimates ranging from 25-68%. Importantly, persistent pain after lumpectomy may be as prevalent as that after total mastectomy. Persistent postsurgical pain is rated by patients as the most troubling symptom, leading to disability and psychological distress, and is often resistant to management. Although prospective population-based data have demonstrated significant patient and surgical focus on pain with remarkably high levels of chronic pain 4 and 9 months after breast surgery, much of these data have been collected in women with invasive cancer, with little data directly relevant to patients with DCIS. The overarching hypothesis of the study is that management of low-risk DCIS using an active monitoring (AM) approach does not yield inferior cancer or quality of life outcomes compared to surgery.
Interventions
OTHERSurgery
Surgery +/- radiation choice for endocrine therapy
OTHERActive Monitoring
Choice for endocrine therapy
Sponsors
Alliance Foundation Trials, LLC.
Duke University
Dana-Farber Cancer Institute
New York University
Washington University School of Medicine
Patient-Centered Outcomes Research Institute
M.D. Anderson Cancer Center
Rising Tide Foundation
Breast Cancer Research Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS without invasive breast cancer (date of diagnosis defined as the date of the first pathology report that diagnosed the patient with DCIS) OR: atypia verging on DCIS OR: DCIS + LCIS (mix and/or separate locations in the same breast) * A patient who has had a lumpectomy or partial mastectomy with margins positive for DCIS (i.e. \<2mm/ink on tumor) as part of their treatment for a current DCIS diagnosis is also eligible (post-excision bilateral mammogram required at enrollment to establish a new baseline) * No previous DCIS or invasive breast cancer in ipsilateral breast 5 years prior to current DCIS diagnosis * 40 years of age or older at time of DCIS diagnosis * ECOG performance status 0 or 1 * No contraindication for surgery * Baseline imaging (must include dimensions): * Unilateral DCIS: contralateral normal mammogram ≤ 6 months of registration and ipsilateral breast imaging ≤ 120 days of registration (must include ipsilateral mammogram; can also include ultrasound or breast MRI) * Bilateral DCIS: bilateral breast imaging ≤ 120 days of registration (must include bilateral mammogram; can also include ultrasound or breast MRI) * DCIS s/p lumpectomy: post excision mammogram on side of excision ≤ 60 days of registration * Pathologic criteria: * Any grade I DCIS (irrespective of necrosis/comedonecrosis) * Any grade II DCIS (irrespective of necrosis/comedonecrosis) * Absence of invasion or microinvasion * Diagnosis of DCIS confirmed on core needle biopsy, vacuum-assisted or surgery ≤ 120 days of registration * ER(+) and/or PR(+) by IHC (≥ 10% staining or Allred score ≥ 4) unless atypia verging on DCIS in which case biomarker criterion does not apply * HER2 0, 1+, or 2+ by IHC if HER2 testing is performed * Histology slides reviewed and agreement between two clinical pathologists (not required to be at same institution) that pathology fulfills COMET eligibility criteria. In cases of disagreement between the two pathology reviews about whether or not a case fulfills the eligibility criteria, a third pathology review will be required. * At least two sites of biopsy for those cases where individual mammographic extent of calcifications exceeds 4 cm, with second biopsy benign or both sites fulfilling pathology eligibility criteria (ER/PR testing required for second biopsy) * Amenable to follow up examinations * Ability to read, understand and evaluate study materials and willingness to sign a written informed consent document * Reads and speaks Spanish or English
Exclusion criteria
* Male DCIS * Grade III DCIS * Concurrent diagnosis of invasive or microinvasive breast cancer in either breast * Documented mass on examination or mass/hypoechoic area on imaging at site of DCIS prior to biopsy yielding diagnosis of DCIS, with exception of: subsequent lumpectomy or partial mastectomy (with positive DCIS margins i.e. \<2mm/ink on tumor) followed by a post-surgery MMG; fibroadenoma at a distinct/separate site from site of DCIS; or diagnosis of mass/hypoechoic area as a cyst or a papilloma. In cases of uncertainty about whether the mass was present on physical examination prior to biopsy, the following criteria should be applied: if mammogram noting abnormal findings is diagnostic MMG = symptomatic/if mammogram noting abnormal findings is screening MMG = asymptomatic. If a patient has a mass on imaging that is biopsied (worked-up) and does not show invasive breast cancer, they are eligible. If a patient has a mass on initial MMG that is not seen on subsequent MMG, they are eligible (if initial mass occurred due to additional work-up). * Any color/bloody nipple discharge (ipsilateral breast) * Mammographic finding of BIRADS 4 or greater within 6 months prior to registration at site of breast other than that of known DCIS, without pathologic assessment * Use of investigational cancer agents within 6 weeks prior to diagnosis of DCIS * Any serious and/or unstable pre-existing medical, psychiatric, or other existing condition that would prevent compliance with the trial or consent process * Pregnancy. If a woman has been confirmed as pregnant, she will not be eligible to take part in the trial. If she suspects there is a chance that she may be pregnant, a pregnancy test should be undertaken, although a pregnancy test for all women of child-bearing potential is not mandatory. In addition, if a woman becomes pregnant once registered to the trial, she can continue to be followed (endocrine therapy is not a mandatory requirement of the study) * Documented history of prior tamoxifen, aromatase inhibitor, or raloxifene use in the 6 months prior to registration * Current use of exogenous hormones (i.e. oral progesterone)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of New Diagnoses of Ipsilateral Invasive Cancer in Surgery and AM Arms at 2 Years of Follow up | At 2 years follow-up | To compare the number of patients that develop ipsilateral invasive cancer that received surgery to the number of patients that were placed on active monitoring after 2 years of follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life (QOL) | Baseline, 6 months, 1 year, and once a year (years 2 through 5) | Measured by Short Form (SF)-36 |
| Psychological Outcomes | Baseline, 6 months, 1 year, and once a year (years 2 through 5) | Measured by five dimensions questionnaire (EQ-5D) |
| Generalized Anxiety | Baseline, 6 months, 1 year, and once a year (years 2 through 5) | Measured by the State Trait Anxiety Inventory (STAI) scale |
| Generalized Depression | Baseline, 6 months, 1 year, and once a year (years 2 through 5) | Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) 10 |
| Coping | Baseline | Coping evaluated using the Brief COPE, a shortened form of the COPE Inventory, inclusive of 28 items (14 subscales). |
| Intolerance of Uncertainty | Baseline and at 2 years | Assessment of feelings of uncertainty using the Intolerance of Uncertainty Scale (Short-form), which has been used in studies of active monitoring in the prostate cancer setting. |
| Mastectomy Rate | 2, 5, and 7 year follow-up | To compare the impact of surgery vs. AM on the number of mastectomies performed in patients with DCIS |
| Breast Conservation Rate | 2, 5, and 7 year follow-up | To compare the impact of surgery vs. AM on the number of breast conservation surgeries performed in patients with DCIS |
| Contralateral Invasive Cancer Rate | 2, 5, and 7 year follow-up | To compare the impact of surgery vs. AM on the rate of development of contralateral invasive cancer in patients with DCIS |
| Overall Survival Rate | 2, 5, and 7 year follow-up | To compare the impact of surgery vs. AM on the overall survival rate in patients with DCIS |
| Breast Cancer Specific Survival Rate | 2, 5, and 7 year follow-up | To compare the impact of surgery vs. AM on the breast cancer specific survival rate in patients with DCIS |
| Ipsilateral Invasive Cancer Rate in Surgery Arm at 5 and 7 Year Follow-up | 5 and 7 year follow-up | To determine the number of DCIS patients in the surgery arm that develop ipsilateral invasive cancer |
| Ipsilateral Invasive Cancer Rate in AM Arm | 5 and 7 year follow-up | To determine the number of DCIS patients in the AM arm that develop ipsilateral invasive cancer |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORShelley Hwang, MD, MPH
Duke University
STUDY_CHAIRAnn Partridge, MD, MPH
Dana-Farber Cancer Institute
STUDY_CHAIRAlastair Thompson, MD
Baylor College of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Monitoring DCIS - Choice for endocrine therapy (MMG q 6 months x 5 years GCC for invasive progression)\>
\> Active Monitoring: Choice for endocrine therapy | 484 |
| Surgery DCIS - Surgery +/- radiation choice for endocrine therapy (MMG q 12 months x 5 years usual care for recurrent disease)\>
\> Surgery: Surgery +/- radiation choice for endocrine therapy | 473 |
| Total | 957 |
Baseline characteristics
| Characteristic | Surgery | Active Monitoring | Total |
|---|---|---|---|
| Age, Customized <55 | 114 Participants | 112 Participants | 226 Participants |
| Age, Customized 55-65 | 164 Participants | 164 Participants | 328 Participants |
| Age, Customized >65 | 195 Participants | 208 Participants | 403 Participants |
| Comorbidities | 256 Participants | 284 Participants | 540 Participants |
| DCIS ERBB2 status at diagnosis 0 | 3 Participants | 1 Participants | 4 Participants |
| DCIS ERBB2 status at diagnosis 1+ | 5 Participants | 3 Participants | 8 Participants |
| DCIS estrogen receptor positive at diagnosis | 467 Participants | 473 Participants | 940 Participants |
| DCIS grade at diagnosis 1 | 127 Participants | 125 Participants | 252 Participants |
| DCIS grade at diagnosis 2 | 346 Participants | 359 Participants | 705 Participants |
| DCIS laterality at diagnosis Bilateral | 2 Participants | 4 Participants | 6 Participants |
| DCIS laterality at diagnosis Left | 235 Participants | 247 Participants | 482 Participants |
| DCIS laterality at diagnosis Right | 236 Participants | 233 Participants | 469 Participants |
| DCIS progesterone receptor status at diagnosis Negative | 52 Participants | 41 Participants | 93 Participants |
| DCIS progesterone receptor status at diagnosis Positive | 359 Participants | 364 Participants | 723 Participants |
| ECOG performance status score 0 | 410 Participants | 431 Participants | 841 Participants |
| ECOG performance status score 1 | 63 Participants | 53 Participants | 116 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 34 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 440 Participants | 438 Participants | 878 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 12 Participants | 28 Participants |
| Premenopausal/perimenopausal | 92 Participants | 90 Participants | 182 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 23 Participants | 23 Participants | 46 Participants |
| Race (NIH/OMB) Black or African American | 70 Participants | 80 Participants | 150 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants | 18 Participants | 33 Participants |
| Race (NIH/OMB) White | 359 Participants | 359 Participants | 718 Participants |
| Sex: Female, Male Female | 473 Participants | 484 Participants | 957 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Total No. of comorbidities 0 | 175 Participants | 148 Participants | 323 Participants |
| Total No. of comorbidities 1 | 124 Participants | 137 Participants | 261 Participants |
| Total No. of comorbidities 2 | 55 Participants | 58 Participants | 113 Participants |
| Total No. of comorbidities 3 | 27 Participants | 34 Participants | 61 Participants |
| Total No. of comorbidities 4 | 11 Participants | 14 Participants | 25 Participants |
| Total No. of comorbidities 5+ | 39 Participants | 41 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 11 / 484 | 8 / 473 |
| other Total, other adverse events | 378 / 484 | 351 / 473 |
| serious Total, serious adverse events | 11 / 484 | 8 / 473 |
Outcome results
Primary
Proportion of New Diagnoses of Ipsilateral Invasive Cancer in Surgery and AM Arms at 2 Years of Follow up
To compare the number of patients that develop ipsilateral invasive cancer that received surgery to the number of patients that were placed on active monitoring after 2 years of follow-up
Time frame: At 2 years follow-up
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Monitoring | Proportion of New Diagnoses of Ipsilateral Invasive Cancer in Surgery and AM Arms at 2 Years of Follow up | 4.2 percentage of participants |
| Surgery | Proportion of New Diagnoses of Ipsilateral Invasive Cancer in Surgery and AM Arms at 2 Years of Follow up | 5.9 percentage of participants |
Secondary
Breast Cancer Specific Survival Rate
To compare the impact of surgery vs. AM on the breast cancer specific survival rate in patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Secondary
Breast Conservation Rate
To compare the impact of surgery vs. AM on the number of breast conservation surgeries performed in patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Secondary
Contralateral Invasive Cancer Rate
To compare the impact of surgery vs. AM on the rate of development of contralateral invasive cancer in patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Secondary
Coping
Coping evaluated using the Brief COPE, a shortened form of the COPE Inventory, inclusive of 28 items (14 subscales).
Time frame: Baseline
Secondary
Generalized Anxiety
Measured by the State Trait Anxiety Inventory (STAI) scale
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Secondary
Generalized Depression
Measured by the Center for Epidemiologic Studies Depression Scale (CES-D) 10
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Secondary
Intolerance of Uncertainty
Assessment of feelings of uncertainty using the Intolerance of Uncertainty Scale (Short-form), which has been used in studies of active monitoring in the prostate cancer setting.
Time frame: Baseline and at 2 years
Secondary
Ipsilateral Invasive Cancer Rate in AM Arm
To determine the number of DCIS patients in the AM arm that develop ipsilateral invasive cancer
Time frame: 5 and 7 year follow-up
Secondary
Ipsilateral Invasive Cancer Rate in Surgery Arm at 5 and 7 Year Follow-up
To determine the number of DCIS patients in the surgery arm that develop ipsilateral invasive cancer
Time frame: 5 and 7 year follow-up
Secondary
Mastectomy Rate
To compare the impact of surgery vs. AM on the number of mastectomies performed in patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Secondary
Overall Survival Rate
To compare the impact of surgery vs. AM on the overall survival rate in patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Secondary
Psychological Outcomes
Measured by five dimensions questionnaire (EQ-5D)
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Secondary
Quality of Life (QOL)
Measured by Short Form (SF)-36
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Adherence to Hormonal Therapy
Evaluated with a drug diary
Time frame: 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Body Image
Body image will be evaluated by the Breast-Questionnaire, a validated instrument to evaluate outcomes following surgery, will be used to evaluate satisfaction with body image
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Breast Biopsy Rate
Determine the rate of biopsies performed during follow-up of patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Other Pre-specified
Breast MRI Utilization Rate
Determine the rate of use of breast MRI imaging compared to use of other breast imaging techniques
Time frame: 2, 5, and 7 year follow-up
Other Pre-specified
Breast Specific Pain
Breast specific pain will be measured by the Breast Cancer Pain Questionnaire (BCPQ); the BCPQ includes assessment of pain severity, pain frequency (how many days/week), and pain location (breast, arm, side, axilla), from which a Pain Burden Index (PBI) can be calculated
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Chemotherapy Rate
Determine the rate of the use of chemotherapy on patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Other Pre-specified
Communication With Physicians
To assess communication with physicians about DCIS management options, the investigators will adapt items used in a prior study of surgical decision-making, including the extent to which their physician talked to them about AM vs. surgery. Additionally the investigators will ask about sources of information for the management of their DCIS
Time frame: Baseline
Other Pre-specified
Concerns About Future Breast Events
Four items from the Quality of Life in Adult Cancer Survivors (QLACS) scale will be adapted to evaluate frequency (1=never; 7=always) of worries about DCIS, including concerns about future breast events and death from DCIS
Time frame: Baseline and 2 years
Other Pre-specified
Decisional Regret
The Decision Regret Scale will measure how women perceived their DCIS treatment decision. The SURE scale, which is composed of four items from the Decisional Conflict Scale will be used to measure patients' uncertainty about which treatment to choose and factors contributing to uncertainty (feeling uninformed, unclear values, and unsupported in decision-making).
Time frame: Years 1 through 5
Other Pre-specified
Employment Status
Employment status will be assessed using a measure that is being added to the Alliance Patient Questionnaire as it has been tested and validated in breast cancer populations.
Time frame: Baseline, 6 months, year 1, and once a year (years 1 through 5)
Other Pre-specified
Financial Burden
The investigators will adapt items from the National Health Interview Survey and the Cancer Outcomes Research and Surveillance (CanCORS) Study to assess financial burden. The investigators will also ask women to Cancer Care estimate out of pocket expenses attributed to their DCIS diagnosis.
Time frame: 6 months
Other Pre-specified
General Pain
Evaluated with the Brief Pain Inventory, a well-validated general measure of pain and disability worst pain, least pain, and interference
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Knowledge
DCIS and breast cancer knowledge will be measured with items adapted from the Breast Cancer Surgery Decision Quality Instrument (BCS-DQI) as well as questions developed specifically for a study that assessed DCIS knowledge and risk perceptions. The investigators will assess risk perceptions in women with DCIS using questions developed by Lerman and Croyle that will measure risk perceptions in relation to psychosocial outcomes in women with DCIS
Time frame: Baseline and 2 years
Other Pre-specified
Radiation Rate
Determine the rate of the performance of radiation therapy on patients with DCIS
Time frame: 2, 5, and 7 year follow-up
Other Pre-specified
Risk Perceptions
Measured by the Breast Cancer Surgery Decision Quality Instrument (BCS-DQI)
Time frame: Baseline and 2 years
Other Pre-specified
Self-reported Co-morbidity
Self-reported diary
Time frame: 6 months, 1 year, and once a year (years 2 through 5)
Other Pre-specified
Symptoms
A modified 19-item version of the Breast Cancer Prevention Trial (BCPT) Symptom Checklist will evaluate commonly reported menopausal symptoms
Time frame: Baseline, 6 months, 1 year, and once a year (years 2 through 5)