Introduction

Ductal Carcinoma In Situ (DCIS) is a noninvasive disease where cancerous cells are found within the milk duct of the breast but have not yet invaded through the basement membrane. It is a non-obligate precursor to invasive breast cancer and represents roughly 25% of all newly diagnosed malignant breast lesions [1, 2]. The increased use of breast imaging and screening has resulted in an increasing incidence of DCIS. Patients diagnosed with DCIS on image-guided core needle biopsy (CNB) have the possibility of upstaging to invasive carcinoma on surgical excision [3, 4]. The goals of management for DCIS therefore include ruling out concurrent invasive disease, averting progression to invasive carcinoma, and preventing breast cancer related mortality. Recently, current treatment patterns have been questioned due to the increased incidence of DCIS without an overall reduction in breast cancer related mortality. This article aims to elucidate current controversies and opportunities for treatment changes in patients diagnosed with DCIS.

Sentinel Lymph Node Biopsy

Since DCIS is a non-invasive disease, theoretically patients with pure DCIS should not have locoregional spread to axillary lymph nodes. However, current published literature shows upstaging rates from DCIS to invasive carcinoma on excision range from 11–50% with most studies showing between 20–30% [5, 6]. When invasive breast cancer is discovered, sentinel lymph node biopsy (SLNB) is often then indicated to properly stage the axilla. Therefore, much effort has been placed in identifying which patients are likely to be upstaged to properly select those for upfront SLNB. This would eliminate the need for a second operation which often subjects the patient to increased cost, potential complications of a second anesthetic, and delay in additional treatment. Furthermore, in the case of mastectomy as an index breast operation, SLNB may not be technically feasible during a second trip to the operating room. Thus, early prediction of upstaging has warranted attention.

Historically, predictors of upstaging included palpable masses, mammographically seen masses, larger size of lesion, higher grade, and presence of necrosis. However, alternative studies show varied risk of upstaging using these features [7, 8]. Recent literature suggests that biomarkers may also play a role in risk of upstaging. HER2 + DCIS has a significantly higher risk of local recurrence and a two-fold increased risk of upstaging on final excision compared to those who are HER2 negative [9]. Despite the effect that HER2 positivity may have, not all institutions test for HER2 on specimens diagnosed with DCIS.

Given the conflicting data, groups have attempted to create nomograms to accurately predict upstaging of DCIS and therefore, the need for SLNB. One nomogram described in 2017 by Jakub and colleagues at Mayo Clinic used clinicopathologic features including grade, presence of mass, multicentric disease, and largest measurement in linear dimension [10]. Age did not influence the model performance and was not included. This nomogram’s success was measured with an area-under-the-curve (AUC) c-statistic of 0.71 [10]. An additional European model was recently validated in a registry and institutional cohort [11]. It includes the method of detection of DCIS (screening vs other), presence of a palpable mass, DCIS grade, Breast Imaging Reporting and Data System (BiRADS) score, and a pathologic suspicion of an invasive component on biopsy. In this model, the AUC was between 0.65 and 0.73, with analysis showing that the model provided the greatest benefit with a risk of 14% or higher [11]. Whether these nomograms are useful in determining the need for SLNB remains unknown, and in fact they have not shown significant benefit when applied to patients undergoing excision and possible axillary staging [12].

The rates of utilization of SLNB in DCIS have been examined. In a single institution review of all patients presenting with pure (not upstaged) DCIS undergoing breast conservation, 135 of 315 patients underwent SLNB. SLNB was most commonly performed in patients with a palpable mass or high-grade tumor [5]. Additional single-institution studies show rates of SLNB in all patients with DCIS undergoing BCS and mastectomy of 19% and 88%, respectively [13]. In a meta-analysis and systematic review of 16 papers published in 2022, 67% of patients who underwent a mastectomy and 33% who underwent breast conservation also had a SLNB performed. In total, 73% of patients underwent a SLNB [14•].

Evaluating rates of overall SLNB positivity in patients with DCIS on CNB may help decision making on the use of SLNB with a diagnosis of DCIS. Rates as high as over 10% lymph node positivity in patients with DCIS have been demonstrated in certain studies. One study from a dataset of patients from MD Anderson Cancer Center showed that patients were more likely to have a positive SLNB if they had a disease span of > 2 cm. [15]. In a more recent cohort of 170 patients with DCIS on CNB undergoing total mastectomy and SLNB, only 4.2% of total patients were found to have positive lymph nodes on excision [16]. Finally, in a national database, 1787 women with DCIS who underwent SLNB were examined for rates of lymph node positivity. In this group, 4% of patients had positive sentinel lymph nodes, with only 0.8% demonstrating macrometastases, 2.4% with micrometastases, and 0.8% with isolated tumor cells [17]. Pooled analyses over 15 trials also show a positive SLNB rate < 5% in patients with DCIS on CNB [14•]. With these low rates of disease detection, some argue that SLNB for DCIS is overused. Patients undergoing mastectomy do not routinely have the option of delayed SLNB. For these patients, those who would be most likely to benefit from SLNB at index operation include those with HER2 positive DCIS, those with a larger span of disease, and those with suspicion for invasion on biopsy.

One reported technique to help minimize unnecessary SLNB utilizes Superparamagnetic Iron Oxide Nanoparticles (SPIO), injected at the time of index operation. The SPIO deposits in the SLNB at the time of the index operation and could potentially allow for delayed SLNB in patients who are upstaged from DCIS to invasive carcinoma. In a study evaluating this technique, SPIO was injected at the time of index operation for DCIS [18]. Patients found to have invasive disease on final pathology underwent SLNB where at the repeat operation, radioactive isotope and in some cases, blue dye, were also injected. Ninety five percent of patients who originally underwent mastectomy were able to have successful delayed SLNB after injection of SPIO at index operation and radioactive isotope at repeat operation. Including SPIO at index operation resulted in avoiding upfront SLNB in over 78% of patients [18].The benefit of SPIO would only be seen if all patients were injected at the time of index operation, and this study did not perform a cost–benefit analysis. Additional new techniques and/or utilization of nomograms may help elucidate which patients with DCIS on CNB can avoid SLNB.

Genomic Assays and Effect on Treatment

Given the increasing incidence of DCIS and the overall favorable prognosis, another strategy for reduction in treatment is to forego or limit adjuvant radiation to patients. Local recurrence rates after surgical excision alone range from 15–60%, with half of those returning as invasive disease [19]. While radiotherapy is known to decrease subsequent ipsilateral breast events by upwards of 50%, studies have shown no benefit to overall breast cancer specific survival [20]. Several factors have been shown to influence recurrence risk, including age, size, grade, necrosis, and margins, though it remains a challenge to identify patients who would benefit from omission of radiotherapy [21]. Thus, attempts have been made to utilize genomic assays to determine which patients are most likely to benefit from radiation.

The first such assay is a score based on the expression of 12-genes within the tumor itself. The Oncotype DCIS® score categorized patients into low, intermediate, and high risk groups which corresponded to risks of recurrence of 10.6%, 26.7%, and 25.9% for an ipsilateral breast event, respectively, and 3.7%, 12.3%, and 19.2% for an invasive recurrence, respectively [22]. These original data do not help determine the need for additional therapy, however, and simply demonstrated prognostic information. Thus, further analysis was attempted in a multicenter trial of 10 sites enrolling patients with DCIS undergoing breast conservation surgery. Patients who had invasive disease and those undergoing mastectomy were excluded from the study. One hundred and fifteen patients had Oncotype DCIS® performed on their pathology specimen, with a median score of 29. Seventy three percent of patients were recommended to undergo radiation pre-assay results, with only 59% recommended to complete radiation after results were revealed to physicians [23].

Despite its promise as a decision-aid tool, Oncotype DCIS® score remains a prognostic indicator and not a predictive assay. Therefore, further development occurred with the DCISionRT® biosignature, which combines biomarkers with clinicopathological factors, giving a continuous score between 0–10. This score corresponds to 10-year risks after BCS with and without radiotherapy. This test was originally validated in 455 patients where patients categorized into the high-risk group had at least a 2-times greater 10-year risk of total breast events [24]. The score was then validated further using a large, long-term randomized national database. Patients underwent excision and were subsequently randomized to receive or omit radiotherapy. These patients then had their specimens tested for DCISionRT®. In patients classified into the low-risk group by their score, radiation did not reduce the risk of ipsilateral DCIS or invasive recurrence. Recurrences at 10-years without radiation increased significantly with an increasing DCISionRT® score [25••]. One limitation of the study is that some patients in this analysis were recruited prior to widespread mammographic screening and therefore may not represent a modern cohort. Despite not being routinely tested, high levels of Platelet-Derived Growth Factor (PDGFRb) expression have been associated with radio-resistant breast cancer, and this biomarker was not included in the analysis to produce a DCISionRT® score [26].

The clinical utility of this score was then evaluated in a group of 539 women from multiple centers. Use of DCISionRT® resulted in a change in recommendation for radiation in 42% of the study population [27]. In addition, the recommendation for radiation decreased by 20%. Compared to using the selection criteria in RTOG 9804, a prospective randomized trial of women diagnosed with less than 2.5 cm of low-to-intermediate grade DCIS excised with margins of ≥ 3 mm who were randomized to observation or radiation post-excision, DCISionRT® allowed for greatest reduction in use of radiation [28]. In fact, radiation was spared in up to 48% of patients [28]. In evaluating its clinical utility, the cost–benefit of using DCISionRT® has also been evaluated. In a study using a model which simulated 10-year outcomes for 60-year old women diagnosed with DCIS, the use of DCISionRT® was more cost-effective than a “radiation to all” strategy if the cost of the test remained below $4588 [29]. Thus, using these scores may be beneficial to both an individual patient and health system when considering treatment for DCIS.

Active Surveillance

Given the epidemiological trends of increasing diagnosis of DCIS without changes in rates of metastatic disease and breast-cancer related mortality, there has been question of whether current treatment strategies of DCIS are overtreatment and potentially harmful. Therefore, in addition to the potential for omission of SLNB and radiation, there is growing momentum behind performing “active surveillance” in individuals diagnosed with DCIS as an alternative management strategy. These have been proposed after multiple retrospective, large database studies demonstrated no benefit to conventional treatment strategies. Initial analyses on Medicare-based databases did not show a difference in either all-cause or breast-cancer specific mortality between patients undergoing conventional treatment and those undergoing active surveillance [30]. In addition, mortality was substantially high from causes not related to breast cancer regardless of treatment group in the same population [30]. Similarly, a systematic review and meta-analysis performed, including over 9600 patients of all ages, showed similar 10-year overall survival and 10-year breast cancer-specific survival with both treatment strategies [31•].

Given these data, there are currently several ongoing international trials assessing the feasibility and long-term outcomes of such strategies which include randomization to standard treatment including surgical excision, or watchful waiting and/or treatment with endocrine therapy (LORD, LORIS, COMET). These trials have similar, albeit slightly different inclusion criteria which are worth examining. The LORD trial is a multicenter trial based in the Netherlands which includes women aged 45 years or older who have screen-detected, asymptomatic, low-grade DCIS diagnosed on a vacuum-assisted core needle biopsy (CNB) of mammographically visualized calcifications, and are then randomized to imaging surveillance versus standard treatment (surgery, surgery with radiation, ± endocrine therapy). Patients must not have other imaging findings in the area of DCIS (ie, mass), and must have a life expectancy greater than 5 years, without having a pathogenic BRCA gene mutation, LCIS, bilateral DCIS, or Paget’s disease, and are monitored with annual mammography [32]. Similarly, the LORIS trial, which is currently ongoing in the United Kingdom, randomizes patients aged 46 or older who also have screening detected low grade DCIS, or DCIS with low to intermediate grade features based on vacuum-assisted CNBto either annual mammography with active surveillance or to standard surgical therapy with or without endocrine blockade. The LORIS trial requires patients to have their pathology be reviewed centrally and excludes patients whose pathologic features included comedonecrosis or more than occasional mitotic figures [33, 34]. The COMET trial has wider inclusion criteria than these trials. COMET, run through the Alliance for Clinical Trials in Oncology cooperative group network has over 100 sites in the United States. Its eligibility criteria include women aged 40 or older who have grade I or II DCIS by any biopsy type. They can be enrolled if they have multifocal or bilateral DCIS, but must also have estrogen and/or progesterone receptor positive DCIS. Males, or women with grade III DCIS are excluded, as are those patients with a mass associated with DCIS either on exam or imaging, symptomatic DCIS with bloody nipple discharge or skin changes, and those women who have previously undergone treatment with an aromatase inhibitor or tamoxifen [35]. Patients are randomized to annual mammography, with or without endocrine therapy, or to standard treatment with surgical excision, radiation when appropriate, and the option of endocrine therapy. Surveillance on the COMET trial requires mammography every 6 months.

A criticism of these active surveillance trials is that a percentage of these patients diagnosed with DCIS may in fact have invasive cancer which would be upstaged at the time of excision. There is concern that treating this subset of patients with active surveillance will result in inferior oncologic outcomes. Therefore, work has been done to attempt to identify which patients eligible for these trials would be upstaged to invasive carcinoma should surgical excision occur. Two studies have examined the rates of upstaging in these patients. In 858 women diagnosed with DCIS treated with surgical excision at an academic medical center in the US, 58% were eligible for the COMET trial, 11.8% for the LORD trial, and 40% for the LORIS trial. Of these patients, upgrading to invasive carcinoma would have occurred in 12% of those eligible for COMET, 5% for the LORD trial, and 11.1% for the LORIS trial [36]. Additional data from Japan investigated 152 patients with calcifications diagnosed as DCIS by CNB and underwent definitive surgery. Of these, 35%, 59%, and 16% would have been eligible for LORIS, COMET, and LORD trials respectively. In this study, 32 patients were upstaged to invasive carcinoma. This comprised19% of those eligible for LORIS, 16% of those eligible for COMET, and 25% of those eligible for LORD [37]. Thus, 5–25% of patients diagnosed with DCIS and eligible for active surveillance trials may harbor invasive disease.

Another criticism of these trials has been the difficulty in enrollment and therefore, there is the potential limitation of feasibility of treatment and generalizability. In the LORIS trial, for example, by the date of the study’s original closing in March of 2020, only roughly 19% of those patients eligible underwent enrollment. Many have argued that poor enrollment is due to strong patient preferences as well as differences in patient education and information. In a study from the Netherlands of patients eligible for active surveillance trials, both patients and oncologists completed a discrete choice experiment where the relative importance of different attributes in care were examined. Patients cited extensiveness of locoregional treatment as the most important factor in decision making. In contrast, risk of invasive breast carcinoma was most important to oncologists who were polled [38]. In similar patients, those opting for active surveillance had lower educational levels, but also cited more shared decision making than those who chose conventional treatment [39]. In a separate cohort of patients, 85% of those choosing conventional treatment did so to avoid anxiety of disease progression. Interestingly, over 99% of those who chose conventional treatment and underwent therapy would still choose locoregional conventional treatment [40]. Final data regarding enrollment success, oncologic outcomes, and patient as well as provider satisfaction are all forthcoming in the current trials.

Conclusion: DCIS remains a large percentage of newly diagnosed breast cancers with new treatment options constantly being considered. The combination and use of these options must be discussed with the patients, taking into consideration their own goals, comorbidities, and personal options.