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SAN ANTONIO -- Active monitoring for low-risk ductal carcinoma in situ (DCIS) did not lead to a higher rate of ipsilateral invasive cancer versus guideline-recommended treatment, the randomized COMET trial showed.

The 2-year cumulative rate of invasive cancer in the same breast was 4.2% with active monitoring and 5.9% with standard-of-care treatment. The difference did not achieve statistical significance but did fall within the statistical boundaries for demonstrating noninferiority for active monitoring versus guideline-recommended treatment for DCIS, reported Shelley Hwang, MD, MPH, of Duke University School of Medicine in Durham, North Carolina, at the San Antonio Breast Cancer Symposium.

"At 2 years, women with low-risk DCIS randomized to active monitoring had a noninferior rate of invasive cancer in the ipsilateral breast compared to those randomized to guideline-concordant care," Hwang said during a press briefing. "There were no significant differences between groups in invasive tumor size, node status, or tumor grade, and we found no obvious imbalance in patient characteristics between groups, but we cannot exclude the introduction of bias."

"We feel these short-term results are encouraging, and additional follow-up will determine the long-term outcomes and feasibility of this approach for women with low-risk DCIS," she added.

The study was published simultaneously in .

Calling the results provocative, press briefing moderator Virginia Kaklamani, MD, of UT Health San Antonio and Mays Cancer Center, asked how Hwang would discuss the findings with patients.

Conclusions with Caveats

"The important point to make here is that these are early results," said Hwang. "So, while the results are provocative, I don't think they're quite practice changing yet. I think the way that this will change the way we interact with patients is that we can tell them that their risk of developing invasive cancer is low, even with active monitoring."

"For those patients who have already decided, as many of my patients have, to refuse to have surgery, I think we've come up with an active monitoring protocol that's safe and clearly detects invasive cancers at a very early stage," she noted. "We'll have to wait for the planned analysis of 5 years, 7 years, and 10 years to see whether these results are durable. Then I believe this will be practice changing."

Responding to another question from Kaklamani, Hwang said the higher rate of invasive cancer in the surgery arm resulted from intraoperative discovery that the breast lesion was not DCIS but instead was cancer. "The majority of the invasive cancers detected in the patients who had surgery were detected at the time of staging, with the exception of four or five patients."

"So we would probably expect that the active monitoring group would probably have a similar rate at surgery?" Kaklamani asked.

"I think that's exactly right," said Hwang. "While the results are short, at 2 years, we have now followed 40% of this patient population for more than 5 years, and the small size of the tumors that we have detected indicates that we had delayed diagnosis in a way that was not harmful to the patients in the active monitoring group."

The findings are at odds with a recent analysis showing that delayed surgery for DCIS might be detrimental to patients.

"This is a select group of patients who are at low risk," said Hwang. "This is not an approach for everyone with DCIS. It's also clear that there are many subgroups of DCIS, some of which probably have no propensity for invasive progression. Our team is currently working on developing a biomarker that would help to predict which patients are at lowest risk for developing invasive progression, and I think that will really be an additional adjunct to combine with clinical characteristics to help patients make decisions about their care."

"I think these preliminary results at least start the conversation of thinking about DCIS and casting it in a very different way for both patients and clinicians who are taking care of them," she added.

Pushback From Breast Surgeons

The that accompanied the JAMA article pushed back against the notion that the study supports active monitoring as a reasonable option for low-risk DCIS, especially after only 2 years of follow-up.

Only 52% of patients randomized to guideline-concordant surgery had undergone surgery at 24 months, noted Monica Morrow, MD, and Andrea V. Barrio, MD, of Memorial Sloan Kettering Cancer Center in New York City. In the subset who actually had surgery, the 2-year rate of invasive cancer increased to 8.7%.

In the active monitoring arm, 86% had initiated active monitoring at 6 months, and the 2-year rate of invasive breast cancer was 3.1% in that subgroup.

"The authors concluded that the results support the short-term safety of active monitoring in a low-risk DCIS cohort," Morrow and Barrio wrote. "However, based on what is known about the natural history of DCIS treated surgically, the only conclusion that can be drawn from the initial study results is that the incidence of undersampled invasive cancer present in patients with low-risk DCIS at surgical excision is not negligible."

"A definitive conclusion regarding the safety of active monitoring can be addressed only with longer follow-up," they added.

In support of their viewpoint, Morrow and Barrio cited recent studies of surgery for low-risk DCIS. The trial showed 12-year rates of any ipsilateral breast events and invasive events of 14.4% and 7.5%, respectively, with no plateau in either rate. In the trial, patients with DCIS were randomized to surgery alone or with radiotherapy (RT). In the surgery-alone group, the 15-year rates of any recurrence and invasive recurrence were 15.1% and 9.5%.

A joint analysis of and a separate analysis of showed that invasive recurrence after treatment for DCIS was associated with an increased risk of breast cancer mortality compared with no recurrence.

"Given the clinically meaningful risk of invasive recurrence observed in patients with low-risk DCIS treated with surgical excision at long-term follow-up, there is no reason to anticipate that with further follow-up, the risk of invasive recurrence in the active monitoring group of the COMET trial will be lower unless endocrine therapy use differed substantially between the studies," Morrow and Barrio asserted.

Study Results

DCIS has an annual incidence in the U.S. of about 50,000. Surgery remains the primary treatment, often in combination with RT and/or endocrine therapy. The treatment is the same as for low- and intermediate-risk invasive breast cancer.

"Because not all DCIS progresses to invasive cancer, there is a potential opportunity to de-escalate surgery in the management of DCIS," noted Hwang and co-authors.

The multicenter was designed to compare guideline-concordant care and active monitoring, with surgery reserved only for progression to invasive cancer. The primary outcome was ipsilateral invasive cancer diagnosis at 2 years. The investigators enrolled women ages 40 and older with newly diagnosed, grade 1/2, hormone receptor-positive, HER2-negative DCIS without evidence of invasive disease.

Patients randomized to guideline-concordant care could choose either lumpectomy or mastectomy for surgery. Patients who opted for lumpectomy were offered RT. Patients in both groups could opt for endocrine therapy. Follow-up mammograms occurred at 12-month intervals.

In the active monitoring arm, patients had diagnostic mammograms every 6 months for the affected breast and every 12 months for the unaffected breast. If a new lesion developed or imaging detected concerning changes in breast tissue, a core needle biopsy was recommended. Surgery was required if the biopsy revealed invasive cancer.

The primary analysis included 957 patients who had a median age of 64. A fourth of DCIS lesions were nuclear grade 1 and the rest were grade 2.

The 1.7% difference in the rate of invasive cancer at 2 years did not achieve statistical significance but did support the conclusion that "active monitoring is not inferior to guideline-concordant care," Hwang and co-authors noted.

They also performed a prespecified analysis of 673 patients who actually received assigned treatment. The analysis showed a 5.6% absolute difference in the rate of invasive breast cancer at 2 years, "supporting a conclusion that active monitoring is superior to guideline-concordant care."