Comparison of Operative to Monitoring and Endocrine Therapy (COMET) Trial For Low Risk DCIS

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
surveillance (AS) approach does not yield inferior cancer or quality of life outcomes
compared to guideline concordant care (GCC).

Inclusion Criteria:

- New diagnosis of DCIS without invasive cancer; date of diagnosis defined as the date
of the first pathology report that diagnosed the patient with DCIS

- Unilateral, bilateral, unifocal, or multifocal DCIS

- ADH/borderline DCIS

- A patient who has had a lumpectomy with positive margins as part of their treatment
for a current DCIS diagnosis is eligible (post-excision mammogram required at
enrollment to establish a new baseline)

- No previous history of breast cancer (DCIS or invasive cancer) in either breast 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:

- 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)

- Pathologic criteria:

- Any grade I DCIS (irrespective of necrosis/comedonecrosis)

- Any grade II DCIS (irrespective of necrosis/comedonecrosis)

- Absence of invasion or microinvasion

- Diagnosis confirmed on core needle, vacuum-assisted or surgery ≤ 120 days of
registration

- ER(+) and/or PR(+) by IHC (≥ 10% staining or Allred score ≥ 4)

- 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 mammographic extent of
calcifications exceeds 4 cm, with second biopsy benign or both sites fulfilling
pathology eligibility criteria

- 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 imaging at site of DCIS prior to biopsy yielding
diagnosis of DCIS, with exception of fibroadenoma at a distinct/separate site from
site of DCIS (or diagnosis of mass as a cyst). 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

- Bloody nipple discharge (ipsilateral breast)

- Mammographic finding of BIRADS 4 or greater within 6 months of registration at site
other than that of known DCIS, without pathologic assessment

- Use of investigational cancer agents within 6 weeks prior to diagnosis

- 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; however, a pregnancy test for all women of
child-bearing potential is not mandatory

- Documented history of prior tamoxifen, aromatase inhibitor, or raloxifene in last 6
months