Ductal carcinoma in situ (DCIS) of the breast refers to a heterogeneous group of "cancerous" or neoplastic lesions that reside within the mammary ducts and lobules. DCIS is frequently an incidental finding as abnormal-appearing microcalcifications on screening mammogram and represents about 20 percent of breast cancer diagnoses each year, and is therefore a significant public health issue.
DCIS is an important diagnosis as it is generally accepted that it is a direct precursor of invasive breast cancer (IBC) based on a multitude of evidence. For example, nearly all IBCs are found adjacent to DCIS on histologic examination. In the small number of studies using paired DCIS and IBC from the same breast, similar genomic alterations were observed, although there was an overall trend toward an increase in the number of genetic alterations in IBC.
The risk factors for DCIS are similar to those of IBC. The natural history of DCIS to evolve to IBC has also been demonstrated in long-term follow-up studies of patients with retrospectively recognized DCIS that was incompletely excised. In these studies, IBC was subsequently diagnosed at the same site as the index lesion in up to 50 percent of the cases with prolonged follow-up.
With the above information, DCIS has been generally accepted as a surgical disease, and current guidelines for the treatment of DCIS recommend complete surgical excision with negative margins. The advent of radiation followed by lumpectomy reduced the risk of recurrence of both invasive and non-invasive recurrence, and led to less disfiguring surgery such as mastectomy. This approach effectively reduced ipsilateral invasive and non-invasive recurrence. For ER+ disease, tamoxifen or aromatase inhibitors have also been shown to further reduce recurrence, although there is no impact on survival.
However, the recent JAMAOncology publication by Narod et al (bit.ly/1ElF5yI) has raised concerns with this seemingly logical approach. In this large observational study which included 108,196 women diagnosed with DCIS between 1988 and 2011 in the Surveillance, Epidemiology, and End Results (SEER) 18 registries database, an extremely low breast cancer specific mortality of 3.3 percent (95% CI, 3.0%-3.6%) overall was observed. Radiation therapy following lumpectomy reduced the risk of ipsilateral IBC recurrence, but did not impact breast cancer specific survival.
Interestingly, half of the recurrences were in the contralateral breast and 517 patients died of breast cancer without an in-breast invasive recurrence. In addition, although high-grade DCIS was associated with increased breast cancer mortality, it was not associated with an increased risk of ipsilateral invasive recurrence compared with low-grade DCIS.
Young age (<35 years) (7.8% vs. 3.2%; HR, 2.58 [95%CI, 1.85-3.60]; P < 0.001) and black ethnicity (7.0% vs. 3.0%; HR, 2.55 [95%CI, 2.17-3.01]; P < 0.001) were associated with significantly higher risk of breast cancer specific mortality compared with that in older women and non-Hispanic whites, respectively. Other important risk factors included ER status, high grade, tumor size, and comedonecrosis.
In addition, similar to the recurrence pattern observed in IBC, ER-negative DCIS associated recurrence is often within the first 10 years after diagnosis, while ER+ DCIS was associated with a slower but persistent risk of recurrence during the follow-up.
Challenges to Current Paradigm
Despite potential limitations associated with observational studies using the SEER data bases, including the lack of formal pathology review, information regarding resection margin and adjuvant hormonal therapy, and the possibility of underestimating the non-invasive breast cancer recurrence due to coding issues, results from the study raised important issues that challenge the current screening and treatment paradigm of DCIS.
It is clear that:
1. Some DCIS may never progress to IBC in a women's life time;
2. Some DCIS may progress slowly over years to come; and
3. Some DCIS, however, could take an aggressive course, with simultaneous occurrence or early metastatic dissemination of invasive disease with or without in-breast diagnosis of IBC.
For patients with DCIS in the first two categories, perhaps watchful waiting or approaches to delay the progression is an acceptable option, while for those with DCIS in the third categories, local therapy is necessary-but more effective systemic therapy that prevents or eliminates metastatic spread of potential invasive disease is crucial to prevent subsequent breast cancer morbidity and mortality.
The question is how do we risk-stratify patients into these categories. Clinical and pathologic parameters, including age, ethnicity, ER and HER2 status, grade, tumor size, and presence or absence of comedonecrosis, perhaps could guide in our decisions in future practice.
Clinical Trials
We encourage participation in clinical trials. The CALGB 40903 (schema below) will determine which subsets of ER+ DCIS might be most amenable to systemic treatment so that surgery could be avoided. It is a single-arm trial for postmenopausal women with ER+ DCIS, who will be treated with letrozole and monitored for six months followed by surgery for biomarker changes.
For high-risk HER2+ DCIS, NSABP B-43, a Phase III study that compares trastuzumab given concurrently with radiation therapy with radiation alone for women with HER2+ DCIS resected by lumpectomy, has completed enrollment. Perhaps strategies like trastuzumab or other targeted agents are the key to eliminate the potential for IBC and metastatic spread.
In conclusion, the diagnosis of DCIS has significant implications on an individual patient's risk of subsequent invasive breast cancer, either derived from this DCIS or not, but in general DCIS carries a low breast cancer specific mortality risk. However, a small number of patients have high-risk disease that mandates aggressive treatments.
We must recognize the highly heterogeneous biology and behavior of DCIS. Accumulating evidence from population studies and clinical trials calls for reconsideration of the current screening and treatment paradigm. An individualized risk-assessment tool and treatment strategy, however, is needed to assist clinical decision-making.