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

The 2-year cumulative rate of invasive cancer in the same breast was 4.2% with active surveillance and 5.9% with standard treatment. The difference did not reach statistical significance, but fell within the statistical limits to demonstrate noninferiority of active surveillance to guideline-recommended treatment for DCIS, reported Shelley Hwang, MD, MPH , from the Duke University School of Medicine in Durham, North Carolina, at Breast Cancer Symposium in San Antonio.

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

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

The study was published simultaneously in JAMA.

Calling the findings provocative, news 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,” Hwang said. “So while the results are provocative, I don’t think they really change practice yet. What I think 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 surveillance.”

“For patients who have already decided, like many of my patients, to refuse surgery, I believe we have developed an active surveillance protocol that is safe and clearly detects invasive cancers at a very early stage “, she noted. . “We will have to wait for the analysis planned over 5 years, 7 years and 10 years to see if these results are sustainable. I then think that this will change practices.”

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

“So we would probably expect that the active surveillance group would probably have a similar rate in surgery?” » asked Kaklamani.

“I think that’s absolutely true,” Hwang said. “Even though 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 we detected indicates that we have delayed diagnosis in a way that was not possible. harmful to patients in the active surveillance group.

The findings conflict with a recent analysis showing that delaying surgery for DCIS could be detrimental to patients.

“This is a selected group of low-risk patients,” Hwang said. “This is not an approach for everyone with DCIS. It is also clear that there are many subgroups of DCIS, some of which likely have no propensity for invasive progression. Our team is currently working to develop of a biomarker that would help predict which patients are at the lowest risk of developing invasive progression, and I think that will really be an additional complement to combine with the clinical characteristics to help patients make decisions about their disease. care.

“I think these preliminary results at least start a reflection on DCIS and a very different presentation for patients and the clinicians who care for them,” she added.

Refusal of breast surgeons

THE authors of an editorial who accompanied the JAMA The article argues against the notion that the study supports active surveillance as a reasonable option for low-risk DCIS, especially after only 2 years of follow-up.

Only 52% of patients randomized to guideline 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. In the subset who underwent surgery, the 2-year rate of invasive cancer increased to 8.7%.

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

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

“A definitive conclusion regarding the safety of active surveillance can only be drawn with longer follow-up,” they added.

In support of their view, Morrow and Barrio cited recent studies of low-risk DCIS surgery. THE ECOG-ACRIN E1594 The trial showed 12-year rates of ipsilateral breast events and invasive events of 14.4% and 7.5%, respectively, with no plateau in either rate. In the RTOG 9804 In this trial, patients with DCIS were randomized to receive surgery alone or radiation therapy (RT). In the surgical only group, the 15-year recurrence and invasive recurrence rates were 15.1% and 9.5%.

A joint analysis of NSABP B-17 and B-24 and a separate analysis of EORTC 10853 showed that invasive recurrence after DCIS treatment was associated with an increased risk of breast cancer mortality compared to no recurrence.

“Given the clinically significant risk of invasive recurrence observed in low-risk DCIS patients treated with surgical excision during long-term follow-up, there is no reason to predict that with further follow-up, the risk of invasive recurrence in the context of long-term follow-up. The COMET trial monitoring group will be inferior unless the use of endocrine therapy differs significantly between studies,” Morrow and Barrio asserted.

Study results

DCIS has an annual incidence of approximately 50,000 people in the United States. Surgery remains the main treatment, often associated with RT and/or endocrine therapy. 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,” Hwang and co-authors noted.

The multicenter COMET trial was designed to compare guideline-compliant care and active surveillance, with surgery reserved only for progression to invasive cancer. The primary endpoint was the diagnosis of ipsilateral invasive cancer at 2 years. Investigators recruited women aged 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 surgical mastectomy. Patients who opted for lumpectomy were offered RT. Patients in both groups could opt for endocrine therapy. Follow-up mammograms took place at 12-month intervals.

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

The primary analysis included 957 patients with a median age of 64 years. A quarter of DCIS lesions were nuclear grade 1 and the rest were grade 2.

The 1.7% difference in the 2-year invasive cancer rate did not reach statistical significance but supported the conclusion that “active surveillance is not inferior to guideline-consistent care,” noted Hwang and his co-authors.

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