The standard treatment of DCIS is associated with excellent survival and includes surgical excision by lumpectomy or mastectomy, with or without adjuvant radiation or endocrine therapy. While little data exist on the natural history of untreated DCIS, some small studies suggest that 40 to 50 percent of low-to-intermediate-grade DCIS will progress to invasive carcinoma.
Two current European trials are comparing the safety of observation to standard surgical excision, with or without adjuvant therapy, for women with low-risk DCIS. Patients are randomized to surgery versus observation alone, consisting of an annual mammogram and exam, and the primary endpoint is ipsilateral invasive disease-free survival at five years.
Only 16 percent of our patients with DCIS met these inclusion and exclusion criteria, emphasizing that the observation study results will apply to a minority of our patients. However, even among this highly select cohort of our patients who underwent surgical excision, 20 percent were found to have invasive breast cancer on final pathology.
This upgrade rate is very similar to that reported in a meta-analysis of all patients with DCIS at the time of surgical excision, regardless of tumor grade or presentation. While adjuvant therapy is often considered optional for women with DCIS alone, it is the standard of care for women with invasive cancer. Thus, the finding of invasive cancer at excision significantly changed management. Recruitment is scheduled to end in March The primary outcome measure is new diagnoses of ipsilateral invasive breast cancer after 2 years, with completion planned for Wolmark, who helped develop the Oncotype DX and Oncotype DX DCIS risk of recurrence assays, said he would have liked to see these data-collection efforts integrate genetic testing, as well.
The DCIS test would be more useful if it also looked at biomarkers in the tissues surrounding the cancer, he said. Schnitt focused on 3 types of tissue in the microenvironment: myoepithelial cells that surround the ducts with DCIS, stromal components that include fibroblasts and blood vessels, and tumor-infiltrating lymphocytes TILs. Investigators said the potential for development of immunotherapy-based prevention of DCIS progression is worth further investigation.
Tumor-associated fibroblasts in the stroma have a promoting effect on tumor growth and invasion, he noted. Experimental data show that combining these fibroblasts with DCIS cells in a mouse model provides an environment that permits the DCIS to become invasive. Investigators are even looking at alterations in the collagen around the DCIS using a variety of methods, including an imaging technique called second harmonic generation microscopy, Schnitt said. For example, collagen fibers perpendicular to the duct perimeter were found to be more frequent in DCIS lesions with features typical of poor prognosis, although collagen alignment and expression of the protein syndecan-1 in the stroma did not predict recurrence.
A number of research groups are evaluating the DCIS microenvironment using multiplexed immunofluorescence methods to simultaneously identify different molecules on paraffinembedded specimens, Schnitt said. His team uses cyclic immunofluorescence, which allows the study of up to 60 markers on a single slide using repetitive cycles of immunofluorescence.
A colorful image of a DCIS sample stained from multiple immune cell marks shows how the methods can distinguish elements of the microenvironment, quantify the number of cells of each type, and elucidate their relationship to the DCIS, he said. Much more research is needed to improve the understanding and treatment of DCIS, Schnitt said, and he wants to emphasize the importance of investigating a variety of cell types and markers. March 13, Meir Rinde. Norman Wolmark, MD Identifying patients with ductal carcinoma in situ DCIS who are more likely to develop invasive breast cancer remains a challenge, despite decades of research and the development of stratification methods to predict progression and recurrence, experts say.
How do we frame and communicate the risks involved? In this review, we describe the current approaches to diagnosing DCIS, the perception of the risk of developing invasive breast carcinoma, the treatment options available following a diagnosis and a current knowledge of the progression of DCIS, before outlining future endeavours and the need for an integrated approach that blends clinical and patient insights with scientific advances.
The diagnosis of DCIS labels women as being at risk for invasive breast cancer. Despite the good prognosis and normal life-expectancy, women diagnosed with DCIS may experience substantial psychological distress 29 and overestimate the implications of a DCIS diagnosis. And, finally, iii what is the impact on quality of life for active surveillance of women diagnosed with low-grade DCIS? Addressing these questions requires central involvement of patient voices to improve clarity not only for patients but also for healthcare providers about the implications and risks of a diagnosis of DCIS.
The number of women diagnosed with DCIS over the past few decades largely follows the introduction of population-based breast cancer screening.
DCIS is usually straightforward to detect by mammography because of its association with calcifications; the proliferation of cells itself is not visible on the mammogram. After detection, the lesion is classified by the pathologist by histological features as low, medium or high grade, which is assumed to correspond to the level of aggressiveness.
Surprisingly, many grading systems exist. Despite an excellent prognosis and normal life-expectancy, women diagnosed with DCIS experience stress and anxiety. The need for effective doctor—patient communication is therefore essential for patients to understand the risk of recurrence.
The development of a prediction tool could help to classify patients into risk groups and provide accurate guidance to patients, as well as healthcare professionals, in their choice of an appropriate treatment option. Currently, breast-conserving treatment for DCIS is frequently recommended. A mastectomy is advised if the DCIS is too extensive to allow breast conservation. According to Elshof et al. Adding radiotherapy to breast-conserving treatment reduces local recurrence rates but does not influence overall survival or breast-cancer-specific survival.
In general, such a procedure is done with mastectomy for DCIS since there is no opportunity to perform a subsequent sentinel node biopsy or where there is a high suspicion for invasive disease even where DCIS alone is present in the preoperative biopsy.
Owing to the side effects of hormonal therapy and ambiguous results from clinical trials, postmenopausal women with DCIS are rarely treated with endocrine therapy in many countries. In addition, the notion of systemic treatment for a localised disease with an excellent outcome is perceived as being counterintuitive.
Although anastrozole administration more often causes side effects such as musculoskeletal pain, hypercholesterolaemia and strokes, tamoxifen is associated with muscle spasm, deep vein thrombosis and the development of gynaecological symptoms and gynaecological cancers.
To address the question whether some patients with DCIS are overtreated, a group of patients not treated with conventional therapies should be studied. A prospective study with long-term follow-up is the only way to gain confidence regarding the natural course of DCIS, and therefore the potential need for interventions.
Patients receive annual mammography in COMET biannual mammography in the active surveillance arm to monitor the lesions. Patients in the control arm will get conventional treatment surgery often supplemented with radiotherapy. Although the natural course of the intraductal process is unknown, DCIS is considered to be a non-obligate precursor of invasive breast cancer. Four evolutionary models have been proposed to describe the progression of DCIS into invasive breast cancer Fig.
Overview of models showing four different theories of progression from ductal carcinoma in situ to invasive breast cancer. The first model is the independent lineage model. On the basis of mathematical simulations of the observed frequencies of the histological grade of DCIS and the histological grade of invasive disease in the same biopsy sample, Sontag et al. Recent studies elucidating molecular differences between DCIS and invasive breast cancer further support the relevance of this model.
The convergent phenotype model proposes that different genotypes of DCIS could lead to invasive breast cancer of the same phenotype. Furthermore, this model assumes that all the cells within the DCIS duct have the same genetic aberrations but that the combination of aberrations could differ between ducts within the same DCIS lesion.
However, in some cases, DCIS and adjacent invasive breast cancer differ in copy number and gene mutations, supporting the notion that, at least in some cases, progression is driven by specific clones leading to the same phenotype. In the evolutionary bottleneck model , individual cells within a duct are considered to accumulate different genetic aberrations; however, only a subpopulation of cells with a specific genetic profile is able to overcome an evolutionary bottleneck and invade into the adjacent tissue.
In the multiclonal invasion model , multiple clones have the ability to escape from the ducts and co-migrate into the adjacent tissues to establish invasive carcinomas 63 , 64 Casasent et al.
Shifts in clonal frequencies were observed, suggesting that some genotypes are more invasive than others. The same subclones were present in both in situ and in invasive regions with no additional copy number aberrations acquired during invasion and few invasion-specific mutations. These findings are, however, limited by their small sample size and comparison of contemporaneous DCIS and invasive disease. These putative models illustrate the potential complexity of the invasion process in DCIS and indicate that indolent lesions might become invasive via a combination of more than one of the proposed mechanisms.
Some molecular analyses have shown that pre-invasive lesions and invasive breast cancer display remarkably similar patterns, 73 , 74 , 75 , 76 indicating a common ancestor 77 ; other groups have found that progression from DCIS to invasive breast cancer might be driven by a subset of cells with specific genetic aberrations, implying contribution to tumour initiation.
Strikingly, their results showed that these properties, specific for the PAM50 subtypes, reflect changes that involve the microenvironment rather than molecular changes specific for epithelial cells. This supports increasing evidence for the role of the microenvironment in tumour progression and disease outcome more generally.
A caveat of molecular studies on DCIS is the fact that most studies examine relatively small series of DCIS lesions with a contemporaneously adjacent invasive component, instead of a metachronous subsequent invasive lesion developing during follow-up. Thus these series are inherently biased, because the majority of the DCIS lesions will never develop an invasive component. In addition, most studies do not distinguish between in situ or invasive recurrences after DCIS.
However, the assays only discriminate between the risk of an in situ versus an invasive recurrence after DCIS to a limited extent. This difference is important for the women involved, especially regarding treatment choices, prognosis and psychosocial impact.
Furthermore, intratumoural heterogeneity complicates our understanding of the relationship between DCIS and its invasive counterpart, as most studies only analyse a small proportion of an often heterogeneous lesion or analyse a bulk tissue sample in which small cell populations are easily overlooked. Uncertainty exists about how DCIS develops, and global consensus is lacking as to how best to optimally manage this disease. A better understanding of the biology of DCIS and the natural course of the disease is required to support patients and healthcare professionals in making more informed treatment decisions, in turn reducing the current overtreatment of DCIS.
In , Gierisch et al. By reviewing the existing literature and using a forced-ranking prioritisation method, a list of ten evidence gaps was created Table 1. Issues that needed immediate attention include the effective communication of information about diagnosis and prognosis and dedicated efforts to fill the knowledge gaps regarding long-term implications and risks of a diagnosis of DCIS.
To address these priorities in DCIS, a multidisciplinary approach with scientific, clinical and patient expertise is needed. Data from large retrospective cohorts should be integrated with in vitro and in vivo studies and the results should be validated to transform clinical practise.
PRECISION ultimately aims to develop novel tests that promote informed and shared decision-making between patients and clinicians, without comprising the excellent outcomes for DCIS management that are presently achieved. WP1 enables the collection of large tissue resources.
WP5 comprises functional validation of the key drivers in in vitro and in vivo models and WP6 will incorporate all the information obtained in a clinical risk prediction model. The three prospective studies will be used for overall validation through collection of blood and tissue samples WP7.
Importantly, patient advocates are actively involved in every part of the project. Ultimately, all these efforts may contribute to a more balanced perception of risk regarding non-life-threatening precancerous lesions in general, reducing anxiety, and preserving quality of life.
Current perceptions of the risk-framing dialogue between clinicians and women diagnosed with DCIS are currently resulting in the overdiagnosis and overtreatment of DCIS. The need to reframe perceptions of risk and to avoid overtreatment is urgent, as overtreatment leads to physical and emotional harm for patients and to unnecessary costs for society.
Specifically, knowing when a lesion could be or will not be life-threatening requires a thorough understanding of the progression and evolution of DCIS. This knowledge will contribute to informed decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS that are presently achieved. Dealing with this challenge demands an integrated approach that blends clinical and patient insights with scientific advances in order to improve the diagnosis, treatment and management of DCIS.
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