Comparison of Operative to Monitoring and Endocrine Therapy (COMET) Trial for Low Risk DCIS: A Phase III Prospective Randomized Trial

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.

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)