Large DCIS Study Is 'Compelling Case' for Change

Nick Mulcahy

August 20, 2015

New results from an observational study of more than 100,000 women with ductal carcinoma in situ (DCIS) provides a "compelling case" that it is "time for a change" in the management of the disease, according to a pair of experts.

The study further fuels "a growing concern that we should rethink our strategy for the detection and treatment of DCIS," write Laura Esserman, MD, MBA, and Christina Yau, PhD, from the University of California, San Francisco, in an editorial that accompanies the study published online today in JAMA Oncology.

Given the low rate of breast cancer death (3.3% at 20 years) among women in the study — who underwent a variety of treatments for their DCIS — the editorialists believe radiologists and surgeons need to, at the very least, slow down.

"We should stop telling women that DCIS is an emergency and that they should schedule definitive surgery within 2 weeks of diagnosis," they write.

Treatment with "today's aggressive standards" is appropriate in about 20% of cases (identified by young age at diagnosis, African/American ethnicity, and/or specific tumor characteristics), but for the remaining large majority, other approaches should be considered, the editorialists note. These include endocrine therapy and, for the women with the lowest-risk lesions, observation and prevention interventions alone should be tested, they add.

Lead investigator Steven Narod, MD, from the Women's College Hospital in Toronto, also suggested changes in management in an email to Medscape Medical News.

First, he explained that there are two "desirable" goals for the treatment of DCIS: to prevent local invasive recurrence, and to prevent death from breast cancer.

"If the goal is to prevent in-breast recurrence, then radiotherapy and mastectomy are good treatments options,' he said.

"If the goal is to prevent death from breast cancer, the best option might be watchful waiting followed by chemotherapy at the time of invasive in breast recurrence," he explained.

Both treatment approaches are contrary to standard practice, which is lumpectomy followed by radiation therapy.

Results Both Confirmatory and Surprising

In their study, Dr Narod and his colleagues identified 108,000 cases of DCIS diagnosed from 1988 to 2011 in the Epidemiology, and End Results (SEER) database. The average follow-up was 7.5 years.

The team culled a range of information, including cause of death, from the data. They then compared the risk of dying from breast cancer in women with DCIS and in women in the general population, and estimated the hazard ratio for death from DCIS using a variety of factors, including age and treatment

Their results were both confirmatory and surprising.

At 20 years, breast-cancer-specific mortality was 3.3%, which is lower than previous findings, although not much. This rate is "not dissimilar to the statistic that the American Cancer Society says is the chance that the average woman will die of breast cancer," the editorialists report.

However, the risk of dying from breast cancer at 20 years was much higher in women with certain characteristics. For example, the mortality rate was higher in women younger than 35 years at diagnosis than in women older than that (7.8% vs 3.2%; hazard ratio [HR], 2.58; < .001), and was higher in black women than in white women (7.0% vs 3.0%; HR, 2.55; < .001).

A higher rate of breast cancer mortality was also tied to DCIS characteristics, such as estrogen-receptor status, grade, size (>5 cm), and comedonecrosis. These are all confirmatory findings. For instance, women with high-grade DCIS were 1.88 times more like likely to die of breast cancer than women with low-grade DCIS (P < .001).

In total, about 20% of the women diagnosed with DCIS had one or more of these characteristics associated with a higher risk for breast cancer death.

The study also showed, as expected, that when invasive disease shows up, death is much more likely to follow. Specifically, the risk of dying from breast cancer increased greatly after the development of an ipsilateral invasive breast cancer (HR, 18.1; < .001).

But the finding of "greatest clinical importance" was that prevention of ipsilateral invasive recurrence did not prevent death from breast cancer, according to Dr Narod's team.

An intuitive expectation is that if you prevent DCIS from recurring as invasive disease with a specific treatment approach, you will, in turn, reduce the risk for breast cancer death.

But that is not what happened, the investigators found.

Instead, for patients who underwent lumpectomy, the addition of radiotherapy was associated with a reduction in the risk for ipsilateral invasive recurrence at 10 years (2.5% vs 4.9%; adjusted HR, 0.47; < .001), but not of breast-cancer-specific mortality at 10 years (0.8% vs 0.9%; HR, 0.86; = .22).

Thus, the more intense therapy for DCIS (lumpectomy plus radiation), compared with the less intense therapy (lumpectomy alone), was good at reducing the risk for invasive disease, but not at reducing the risk for death.

In their editorial, Drs Esserman and Yau note that this has been reported previously, but nevertheless highlight this as "key" finding: "aggressive treatment (radiation therapy after lumpectomy) of almost all DCIS does not lead to a reduction in breast cancer mortality."

They also call for a change in management: "Radiation therapy should not be routinely offered after lumpectomy for DCIS lesions that are not high risk because it does not affect mortality," they write.

There were also women in the study who underwent mastectomy. Again, the investigators found the same pattern — the more intensive treatment was good for reducing recurrence, but not death.

Although risk for ipsilateral invasive recurrence at 10 years was lower in patients who underwent unilateral mastectomy than in those who underwent lumpectomy (1.3% vs 3.3%), the risk for breast-cancer-specific mortality was higher in mastectomy patients than in lumpectomy patients (1.3% vs 0.8%). This finding is not as surprising, however, because the mastectomy patients had larger and higher-grade tumors, on average. In fact, when those factors were controlled for, the difference in 10-year survival was not significant.

However, it was still the case that the more intensive treatment (mastectomy) improved recurrence but not mortality.

Most Surprising Finding

Dr Narod said that the most surprising finding from the study is "that the majority of women who died of breast cancer following a diagnosis of DCIS in the United States [during the study period] never experienced an invasive in-breast recurrence prior to developing metastatic breast cancer."

He reported that 517 patients died of breast cancer after a diagnosis of DCIS without experiencing an in-breast invasive cancer prior to death. This is 54% of all breast cancer deaths in the study, but accounts for only 0.48% of the 108,000 study participants originally diagnosed with DCIS.

In other words, some DCIS is deadly by itself.

That finding runs counter to the dogma that DCIS is a precursor to cancer and cannot cause death unless it progresses to invasive disease, say the study investigators.

Drs Esserman and Yau point out that DCIS that proceeds to breast cancer death without first progressing to an invasive cancer is not common (<1%), but they highlight this as an important insight from the study: "There are uncommon cases in which DCIS has a higher risk than has been appreciated."

However, they emphasize that 80% of DCIS is low risk.

"Much of DCIS should be considered a 'risk factor' for invasive breast cancer and an opportunity for targeted prevention," the editorialists write.

In some cases, this would include endocrine therapy with tamoxifen/raloxifene or aromatase inhibitors, whereas women with the lowest risk might not be treated at all but might be followed, instead, with observation and prevention strategies, they suggest. These would include diet, exercise, and alcohol moderation, and avoiding postmenopausal hormone therapy with progesterone-containing regimens.

The study authors and the editorialists have disclosed no relevant financial relationships.

JAMA Oncol. Published online August 20, 2015. Abstract, Editorial


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