A new clinical trial will compare treatment vs. active surveillance for stage zero breast cancer. Doctors say it’s a lot more complicated than that.

Women with stage zero breast cancer may be getting more treatment than they need.

Researchers are concerned about the effects of potential overtreatment, and are launching a study to learn more.

The prospective randomized clinical trial is called COMET. Its purpose is to compare active surveillance with usual care for this level of breast cancer, known as ductal carcinoma in situ (DCIS).

DCIS is noninvasive and not life-threatening.

But it can eventually become invasive.

Every year, about 50,000 women in the United States are diagnosed with DCIS. For many of them, it will never become a problem, even without treatment.

For others, it will become life-threatening.

Doctors have no way of knowing the difference.

The researchers say there’s a risk of persistent pain from lumpectomy or mastectomy, which can also lead to disability and psychological distress.

They hypothesize that managing low-risk DCIS with active surveillance doesn’t result in poorer outcomes.

COMET is currently recruiting participants. The estimated completion date is July 2021.

Dr. Sandy D. Kotiah, medical oncologist at Mercy Medical Center in Maryland, said there’s a 35 to 50 percent chance that DCIS will eventually become invasive.

And a biopsy can miss cancerous cells.

“It is possible to miss the diagnosis of invasive breast cancer, depending on the sample,” Kotiah told Healthline.

“It has happened in our institution that it is found at surgery and was not found on breast biopsy. This is not a common occurrence, however,” she explained.

Dr. Jane Kakkis, medical director of breast surgery at MemorialCare Breast Center at Orange Coast Memorial Medical Center in California, pointed out that staging isn’t complete until after surgery.

What a biopsy gives you is a “working stage zero,” she said.

“It’s hard for people to understand that in many cases a biopsy won’t tell you definitively that it’s DCIS. You’ve only sampled a small portion of the lesion. I let my patients know it’s stage zero only after surgery,” said Kakkis.

Kotiah said active surveillance would likely require diagnostic mammograms.

Younger patients with dense breasts might also need MRIs.

“I don’t think our breast surgeons recommend active surveillance often, given the lack of data that we currently have,” she said. “Most patients are anxious when they find out that they have a pre-cancer lesion, as they are more concerned about the potential of developing cancer, in my opinion.”

Dr. Dennis Holmes is a breast cancer surgeon, researcher, and interim director of the Margie Petersen Breast Center at John Wayne Cancer Institute at Providence Saint John’s Health Center in California.

Holmes told Healthline that active surveillance typically involves semiannual mammograms and breast examinations. Without surgery or radiation, it would also include anti-estrogen medication for estrogen-sensitive DCIS.

It doesn’t mean you can avoid mammograms or needle biopsies.

“They must first undergo breast cancer screening followed by a needle biopsy of any suspicious finding. It is from the needle biopsy that we determine if a DCIS lesion is suitable for active surveillance,” he said.

He explained that there’s no clear guidance on the rate of progression of various types of DCIS.

“What we can say is that high-grade DCIS is more likely to progress to invasive cancer more quickly [i.e., over a few years]. Low-grade DCIS is less likely to do so [i.e., over a decade or more],” he continued.

Holmes said ideal candidates are women with low- or intermediate-grade estrogen-sensitive DCIS measuring one centimeter or less. They must be willing to remain compliant with anti-estrogen medication and a follow-up schedule.

He generally doesn’t recommend active surveillance.

“I prefer to offer other alternatives, like excision alone or excision plus intraoperative radiotherapy. In my experience, women expressing a strong preference for active surveillance were generally averse to conventional therapy like surgery and radiotherapy, and have not expressed much anxiety about active surveillance,” said Holmes.

Kakkis said that when it comes to doing a study like COMET, it’s more complicated than many people realize.

“As a practitioner in the field, the biggest problem for me with the study is what they’re calling active surveillance is treatment with expensive drugs that need to be taken every day, with substantial side effects. These are the exact drugs we use to treat breast cancer. It’s a bit of a misnomer to say ‘active surveillance’ when you’re treating with a cancer drug,” she explained.

Side effects associated with anti-estrogen medication include hot flashes, sleep disturbance, vaginal dryness, mood changes, and muscle and joint aches, according to Holmes.

“That’s why noncompliance is such a problem with anti-estrogen medications. Many women commit to a five-year course of medication. But it is well-documented that the two-year compliance rate is only about 60 to 70 percent,” he explained.

“Surgical excision might be the more practical solution, with optional radiation, depending on the patient’s age and surgical pathology results,” said Holmes.

“The use of intraoperative radiotherapy for DCIS has not been widely adopted, but I have been offering this treatment to women with DCIS for over 10 years with excellent long-term results,” he said.

“For many women, surgery and intraoperative radiotherapy are the perfect one-stop solution that quickly gets them back to their normal lives with less anxiety about not doing enough vs. doing too much,” said Holmes.

Kotiah said it would likely be inadvisable for hormone receptor-negative or high-grade DCIS patients to do active surveillance.

“They are more likely to have aggressive invasive cancer at progression. Also patients with genetic mutations,” she said.

“I did have three patients who had surgery for DCIS and did not take hormonal blocking [medications], and went on to develop metastatic breast cancer in the last seven years,” she continued.

Kotiah said the breast surgeons she works with offer lumpectomy to all patients with DCIS. They recommend a mastectomy if the abnormal cells are extensive, but that’s rare.

She explained that the surgeons discuss the risks and benefits of surgery vs. no surgery. The majority of patients choose surgery.

“We are also hoping to cut down on chemotherapy regimens and radiation where we can for earlier-stage invasive breast cancer. We give less chemotherapy to stage 1 high-risk invasive breast cancer that is hormone receptor-negative or HER2-positive than we used to just in the last few years,” she explained.

“We are hoping to maintain good long-term survival, avoid or minimize treatment toxicity, and decrease unnecessary cost in general for our cancer patients,” said Kotiah.

All three doctors who spoke with Healthline agreed on the need for more DCIS research.

Kakkis observed that COMET is designed with a lot of specific criteria, different end points, and intermediate points.

Even so, she doesn’t think it will show anything different from what she sees in her practice.

“Most women have a small surgery, a small scar, and go home and be fine, vs. five to 10 years of drugs with significant side effects,” said Kakkis.

“They [COMET] discuss pain of surgery as life-altering pain. I don’t see that kind of pain. But in my practice, 50 percent of patients who take the pills are miserable and can’t continue. I’m just baffled with the way they describe active surveillance,” she said.

“It would be overtreatment for DCIS if instead of a little lumpectomy you removed the whole breast when it’s not necessary,” said Kakkis. “Or after surgery, do you really need to treat with radiation or endocrine therapy? That to me is overtreatment. It’s way more caustic to the body. It’s more expensive, and you need longer lengths of treatment. In no way would it be considered less therapy. Surgery is so safe compared to every other treatment we do.”

Kakkis emphasized that each patient with DCIS has a completely different risk profile.

“Even if we had five patients with the exact same tumor size and grading, they may not all behave the same. It’s extremely complicated. You don’t really know what’s there until you surgically remove it,” she said.

“We recommend the least aggressive surgery that would effectively handle the problem. You try not to allow fear and anxiety with the initial diagnosis take over,” said Kakkis.