In a study reported in JAMA Oncology, Steven A. Narod, MD, FRCPC, of Women’s College Research Institute, Women’s College Hospital, and the University of Toronto, and colleagues found that the risk of breast cancer mortality was elevated in patients with ductal carcinoma in situ compared with the general population, with risk being higher among younger vs older women and black vs white women.¹ Approximately half of breast cancer deaths occurred without development of in-breast invasive recurrence. Breast cancer mortality was not reduced with the prevention of ipsilateral invasive recurrence by the addition of radiotherapy to lumpectomy or with unilateral mastectomy vs lumpectomy.

Study Details

The study involved Surveillance, Epidemiology, and End Results (SEER) 18 registries data on 108,196 women diagnosed with ductal carcinoma in situ from 1988 to 2011. Patients had a mean age at diagnosis of 53.8 years (range = 15–69 years), and mean duration of follow-up was 7.5 years (range = 0–23.9 years).

Among all patients, estrogen receptor status was positive in 43%, negative in 8%, and unknown in 49%; tumor grade was low in 10%, intermediate in 30%, high in 34%, and unknown in 26%; 45% received radiotherapy, 69% had lumpectomy, 21% had unilateral mastectomy, 6.6% had bilateral mastectomy, and 2.4% had no surgery; and 7.1% had a second primary breast cancer.

Mortality and Risk Factors

At 20 years, overall breast cancer–specific mortality was 3.3% (95% confidence interval [CI] = 3.0%–3.6%), with risk being 1.8 times higher vs the general population (standardized mortality ratio = 1.8, 95% CI = 1.7–1.9). The standardized mortality ratio decreased with increasing age, from 17.0 among women aged < 35 years (1.2% of study population) to 1.4 among those aged > 65 years. The 10-year breast cancer mortality rate was 1.1%.

On multivariate analysis, 20-year risk was significantly higher for women diagnosed at age < 35 years vs older women (7.8% vs 3.2%; hazard ratio [HR] = 2.58, P < .001) and for black vs white women (7.0% vs 3.0%; HR = 2.55, P < .001). Other factors that predicted breast cancer mortality included tumor size (HR = 1.28, P = .02 for 1.0–1.9 cm; HR = 1.58, P < .001 for 2.0–4.9 cm; and HR = 1.8, P < .001 for ≥ 5.0 cm, all vs < 1.0 cm), grade (HR = 1.73, P < .001 for poorly vs well differentiated), estrogen receptor status (HR = 0.61, P < .001 for positive vs negative), and comedonecrosis (HR = 1.20, P = .02 vs solid-type intraductal histology).

Recurrence and Mortality

Among 42,250 women who received lumpectomy and radiotherapy, 547 (1.3%) developed ipsilateral invasive recurrence and 163 (0.4%) died from breast cancer. Among 19,762 women who received lumpectomy without radiotherapy, 595 (3.0%) developed ipsilateral invasive recurrence, and 102 (0.5%) died from breast cancer. Among 25,527 who received unilateral or bilateral mastectomy, 200 (0.8%) had ipsilateral invasive recurrence and 154 (0.6%) died from breast cancer.

Among all patients, estimated 20-year risks were 5.9% for ipsilateral invasive recurrence and 6.2% for contralateral invasive recurrence, with estimated risks of 9.5% among patients with breast-conserving surgery without radiotherapy and 4.5% among those with breast-conserving surgery with radiotherapy. Risk of death from breast cancer increased after ipsilateral invasive recurrence (HR = 18.1, P < .001) and contralateral invasive recurrence (HR = 13.8, P < .001) but not after ductal carcinoma in situ ipsilateral or contralateral recurrence.

No Invasive Recurrence in Half of Deaths

A total of 956 women died from breast cancer; of them, 517 (54%) did not develop in-breast invasive recurrence and 395 (41%) developed ipsilateral (n = 210) or contralateral (n = 165) invasive recurrence. No in-breast invasive recurrence before death was observed in 94 (58%) of 163 who received lumpectomy and radiotherapy, 51 (50%) of 102 who received lumpectomy without radiotherapy, and 112 (73%) of 154 who received unilateral or bilateral mastectomy.

No Survival Benefit With Reduced Recurrence Risk

Among patients who received lumpectomy, 10-year risk of ipsilateral invasive recurrence was significantly reduced among those receiving vs not receiving radiotherapy (2.5% vs 4.9%; adjusted HR = 0.47, P < .001), but no reduction in risk of death from breast cancer was observed (0.8% vs 0.9%; adjusted HR = 0.81, P = .10). The 10-year risk of ipsilateral invasive recurrence was significantly lower among women receiving unilateral mastectomy vs lumpectomy (1.3% vs 3.3%; adjusted HR = 0.81, P < .001).

On unadjusted analysis, breast cancer mortality at 10 years was significantly higher in those receiving unilateral mastectomy (1.3% vs 0.8%; unadjusted HR = 1.45, P < .001), but the increased risk was no longer significant after adjustment for age at diagnosis, year of diagnosis, income, estrogen receptor status, tumor size, tumor grade, and ethnicity (HR = 1.20, P = .11).

The investigators observed:

[A]lthough it is accepted that, for women with invasive breast cancer, prevention of in-breast recurrence does not prevent death, this has not been widely accepted for women with [ductal carcinoma in situ]. Also, for women with invasive cancers it is accepted that, in terms of survival, lumpectomy is equivalent to mastectomy, even though patients who undergo mastectomy experience fewer local recurrences. In the SEER database, these relationships between local recurrence and mortality hold equally well for patients with [ductal carcinoma in situ].

They concluded:

The risk of death increases after a diagnosis of an ipsilateral second primary invasive breast cancer, but prevention of these recurrences by radiotherapy does not diminish breast cancer mortality at 10 years.

In addition, they noted:

Some cases of [ductal carcinoma in situ] have an inherent potential for distant metastatic spread. It is therefore appropriate to consider these as de facto breast cancers and not as preinvasive markers predictive of a subsequent invasive cancer. The outcome of breast cancer mortality for [ductal carcinoma in situ] patients is of importance in itself and potential treatments that affect mortality are deserving of study. ■

Disclosure: Dr. Narod holds a Canada Research Chair in Breast Cancer, and coauthor Javaid Iqbal, MD, has received a Canada Graduate Scholarship (Master’s) from the Canadian Institute of Health Research. No other potential conflicts of interest were reported.

Reference

1. Narod SA, Iqbal J, Giannakeas V, et al: Breast cancer mortality after a diagnosis of ductal carcinoma in situ. JAMA Oncol. August 20, 2015 (early release online).