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ABSTRACT: AbstractSimple SummaryOvertreatment which means providing a patient with unnecessary medical intervention has recently become the center of attention in breast diseases. One of these lesions is low-risk ductal carcinoma in situ (DCIS), for which the standard of treatment is wide local excision/mastectomy, wit... |
## 1. Introduction |
Atypical ductal hyperplasia (ADH) belongs to the low-grade pathway of estrogen receptor (ER)-positive/luminal type invasive breast carcinoma (iBC) [1], and it is one of the earliest steps in this pathway [2]. Ductal carcinoma in situ (DCIS) is a noninvasive form of ductal carcinoma. Both ADH and DCIS are characterized ... |
With the increase in the detection of these lesions, the number of surgical excisions has increased in parallel. The prognosis of these lesions together with the early-stage ER-positive/HER2-negative low-grade iBC is excellent [7]. Therefore, a fundamental review of clinical practice and approach for these lesions has ... |
There are at least four ongoing international clinical trials aimed at studying the natural history of low-risk DCIS and defining specific clinical/pathological biomarkers for a subset of patients who may benefit from adjuvant therapies [15,16,17,18]. They all have a similar approach with performing active surveillance... |
In this article, the author presents: (1) Review of current AS trials, including enrollment criteria, overlaps, and controversies; (2) Overview of the spectrum of ductal lesion in terms of definition, histomorphology, biology, clinical presentation and significance; (3) Review of retrospective studies that simulate AS ... |
## 2. Active Surveillance Trials |
There are at least four AS trials worldwide, including Comparison of Operative to Monitoring and Endocrine Therapy (COMET) in the United States [15], the low risk DCIS trial (LORIS) in United Kingdom [16], the “LOw Risk Dcis” (LORD) in the Netherlands [17], and LORETTA in Japan [18]. They differ in the inclusion criter... |
[TABLE] Randomized active surveillance trials for low-risk DCIS. |
| COMET | LORIS | LORD | LORETTA |
Age | ≥40 | ≥46 | ≥45 | ≥40; ≤75 |
Inclusion criteria | Imaging criteria:-Unilateral DCIS or bilateral if imaging ≤120 days of registration-When mammographic extent of calcifications exceeds 4 cm, a second biopsy benign or both sites fulfilling pathology eligibility criteria | Imaging criteria:-Screen-detected or incidental microcalcification | Imaging ... |
Pathology Criteria:-ADH suspicious for DCIS-LG- or IG-DCIS-ER+ and/or PR+-HER2− if performedAmended to include any degree of necrosis, or DCIS involving margin of excisional biopsy | Pathology Criteria:-LG-, IG-DCIS | Pathology Criteria:-Pure and LG- DCIS-Amended to include LG and IG DCIS; or patient preferenceAddition... |
Exclusion criteria | -Males-HG-DCIS-Concurrent diagnosis of iBC-Bloody nipple discharge or skin changes-BI-RADS 4 or greater within 6 months-History of HT in the last 6 months | -Previous/current diagnosis of iBC or ipsilateral DCIS-Comedonecrosis-Mass lesion-Ipsilateral blood-stained nipple discharge-High risk group f... |
Hormonal therapy | Optional | Not possible | Not possible | Mandatory |
Design/Randomization | Two arms: Guideline concordant care +/− HTAS +/− HT | Two arms:SurgeryMonitoring | Two arms:Standard treatment, surgery, +/− RT, +/− HTAS | Single arm |
Follow-up | 2, 5, and 7 years | 10 years | 10 years | 5, 10 years |
Endpoint | Primary:At 2, 5, 7 years: -Ipsilateral iBC rateSecondary:At 2 years: -Mastectomy/breast conservation rate-Contralateral iBC rate-Overall survival and disease-specific survivalAt 5, 7 years:-Overall survival and disease-specific survival | Primary:-Ipsilateral iBC free survivalPrimary outcome measure:-Ipsilat... |
There have been few amendments since the start of the trials. The COMET trial amended the inclusion criteria to add patients whose surgical resection margin was positive for DCIS, and patients with a diagnosis of ADH bordering on DCIS. They also removed comedonecrosis as one of the exclusion criteria. LORIS amended the... |
The differences between these trials make the comparisons challenging. Mass lesion is included in LORETTA but excluded by the other three trials. Mass lesion is known to have high-risk of upgrading for either DCIS or ADH [19,20,21,22]. Comedonecrosis is another variable that has been debated as being a risk factor [23]... |
## 3. Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ Spectrum-Overview |
Atypical ductal hyperplasia and LG-DCIS have similar histomorphology, but they differ in the extent of disease. In this section, an overview of the controversy of separating these two diagnoses is discussed. |
### 3.1. Atypical Ductal Hyperplasia-Overview |
Atypical ductal hyperplasia is a preneoplastic mammary ductal lesion. It is mostly diagnosed in a mammogram screening setting in which microcalcifications are identified. The incidence of ADH remained stable after the implementation of population-based screening mammography, accounting for 2–14% of diagnoses [4,29,30,3... |
Histologically, ADH is composed of intraductal neoplastic epithelial proliferation that involves terminal ductal lobular units. The cells are small, round, and monomorphic with well-defined borders. The cells are arranged in complex atypical growth pattern including solid, cribriform or micropapillary. In the cribrifor... |
### 3.2. Ductal Carcinoma In Situ—Overview |
Ductal carcinoma in situ is a nonobligate precursor of iBC, defined as noninvasive proliferation of neoplastic ductal epithelial cells confined to the basement membrane, involving terminal ductal lobular units. Approximately 85% of DCIS cases are estimated to be detected mammographically, typically as microcalcificatio... |
There is evidence that LG- and HG-DCIS follow different pathways and have different molecular and genetic profiles. LG-DCIS, like ADH, belongs to the low-grade pathway of ER-positive/luminal type iBC [1]. HG-DCIS has more genetic complexity and more frequent genomic alterations than LG-DCIS [36]. |
### 3.3. Severe Atypical Ductal Hyperplasia Bordering on Ductal Carcinoma In Situ |
Both ADH and LG-DCIS have similar histomorphology, but they differ in the extent of the disease, except when the spaces are partially involved with atypical cells, then the diagnosis is ADH regardless of the extent of the disease. There have been multiple attempts to separate ADH from LG-DCIS. These attempts were made ... |
Due to the risk of overtreatment, the world health organization (WHO) working group recommended a more conservative approach, particularly in small and limited material such as core needle biopsy (CNB) [37]. Moreover, some authors accept lesions as large as 3–4 mm as ADH (Figure 2A,B) [38]. In the author’s opinion and ... |
## 4. Upgrading |
There have been many studies evaluating the rate of upgrading. Upgraded lesions are defined as lesions initially diagnosed as ADH in CNB but are found to harbor DCIS or iBC at excisional biopsy, or DCIS in CNB and are found to harbor iBC at the excisional biopsy. These studies suffer from many variabilities; they are a... |
One of the arguments for the AS trials is the low incidence of upgrading to iBC and/or HG-DCIS. In this section, studies that evaluated the upgrading rate for both ADH and low-risk DCIS are discussed. |
### 4.1. Upgrading of Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ—Overall Studies |
#### 4.1.1. Upgrading from ADH to Any Grade-DCIS and/or Invasive Carcinoma |
Schiaffino et al. performed a meta-analysis on 6458 cases from 93 studies and explored the risk of upgrading for ADH with emphasis on radiology confounders [39]. A wide range of upgrading rates were reported ranging from 0% [40] to 84% [41]. The main reason for this wide range of upgrading rate was the heterogeneity am... |
The acceptable imaging modality for the COMET, LORIS, and LORD trials is screening mammography, while for LORETTA, it is any imaging modality (Table 1). Therefore, abstracting the rates of upgrades using mammography as the imaging modality would be relevant to the first three AS trials. The overall rate of upgrading us... |
#### 4.1.2. Upgrading from Ductal Carcinoma In Situ to Invasive Carcinoma |
The upgrade of DCIS to iBC is another concern regarding this disease, with an overall rate estimated at approximately 20% [46]. |
Brennan et al. performed a meta-analysis to report the estimates of the upgrade rate for DCIS detected by CNB to iBC in the subsequent surgical excision. They identified 7350 DCIS cases from 52 studies. There were 1736 cases with iBC on the subsequent excision with random-effects pooled estimate of 25.9% (95% confidenc... |
Nicosia et al. found that the upgrade rate was significantly lower (8.2%) in patients who showed complete mammographic removal of the lesion. They concluded that the rate of upgrading is low enough to recommend AS instead of surgical removal. Moreover, they included all grades of DCIS, which means this ratio may be les... |
### 4.2. Upgrading of Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ—Studies Simulating Active Surveillance Trials |
One of the arguments against AS trials is that it is unethical to leave a clinically significant disease such as iBC or HG-DCIS without definitive treatment. However, not including potential high-risk cases would undermine the power of the studies, making them unfeasible. Those who develop iBC (primary endpoint) at a c... |
#### 4.2.1. Atypical Ductal Hyperplasia |
A single study by the author was conducted that simulated the COMET trial. The included cases (n = 165) were a spectrum of ADH, ADH bordering on DCIS, and low to intermediate grade DCIS with no comedonecrosis. The cases were reclassified upon reviewing dichotomously into ADH versus DCIS. There was a total of 9 (5.5%) u... |
#### 4.2.2. Ductal Carcinoma In Situ |
Few retrospective studies have simulated AS trials (Table 2). The upgrading rate to iBC was comparable between the COMET and LORIS trials, ranging from 6% to 22% and from 0% to 24%, respectively. The upgrading rate in the LORD trial ranged from 0% to 10%. The average upgrading rate for COMET, LORIS and LORD trials was ... |
[TABLE] List of studies simulating active surveillance trials for ADH or low-risk DCIS. |
Author (Year) (Ref.) | Eligibility Criteria | Type of Upgraded to No. Upgraded/Total (%) | Risk Factors |
Khoury (2019) [48] | COMET | iBC 2/124 (1.6) * | Not studied |
| | iBC 3/41 (7.3) | |
Grimm (2017) [50] | COMET | DCIS to iBC 5/81 (6) | -Intermediate grade-ER--PR- |
| COMET | HG-DCIS 6/81 (7) | |
| LORIS | iBC 5/74 (7) | |
| LORIS | HG-DCIS 5/74 (7) | |
| LORD | iBC 1/10 (10) | |
| LORD | HG-DCIS 1/10 (10) | |
Soumian (2013) [51] | LORIS | HG-DCIS 1/19 (5) | |
| | iBC 0/19 (0) | |
Pilewskie (2016) [52] | LORIS | iBC 58/296 (20) | -Intermediate Grade-Mixed pattern architecture |
Jakub (2017) [53] | LORIS | iBC 16/241 (6.6) | Not studied |
Patel (2018) [54] | COMET | iBC 5/23 (22) | Not studied |
| LORIS | iBC 6/25 (24) | Not studied |
Oseni (2020) [55] | COMET | iBC 60/498 (12) | Not studied |
| LORD | iBC 5/101 (5) | Not studied |
| LORIS | iBC 38/343 (11.1) | Not studied |
Zhan (2021) [23] | COMET | HG-DCIS and/or iBC 26/129 (20.2) | Span of mammographic calcifications (1.1 cm cutoff) |
| | iBC 12/129 (9.3) | -% space involved with comedonecrosis (53.5% cutoff)-Number of spaces with comedonecrosis |
Khoury (2021) [56] | COMET | HG-DCIS 14/129 (10.9) | -Touching tumor infiltrating lymphocytes-Intermediate grade |
Iwamoto (2021) [57] | LORIS | iBC 10/53 (19) | Not studied |
| COMET | iBC 14/90 (16) | Not studied |
| LORD | iBC 6/24 (25) | Not studied |
| LORETTA | iBC 4/34 (12) | Not studied |
Only a few studies evaluated the factors associated with the risk of upgrading. Intermediate grade was found to associate with upgrading to iBC in two studies [50,52]. Two studies by the author included women who met the amended COMET trial criteria. The first study evaluated the risk of upgrading to iBC and/or HG-DCIS... |
Pilewskie et al. reported the highest rate of upgrading to iBC of 20%, which is almost twice as much as any other study. It is noted that the CNB cases were not reviewed by a pathologist, and the nuclear grade was rather abstracted from the pathology report [52]. Given the high rate of interobserver variability in grad... |
One of the aims of the AS trials is to investigate the natural history of low-risk lesions. Therefore, leaving a high-risk lesion without definitive treatment would interfere with the final interpretation of the data. High-risk lesions are defined as tumors with positive lymph node or have adverse biology such as HER2-... |
### 4.3. Nomograms and Logistic Regression Analyses |
For practical reasons and to aid patients and treating physicians in the decision making regarding the treatment of ADH/DCIS detected on CNB, there have been some studies that constructed risk factors in logistic regression models. These models could serve as a reference to calculate the risk of upgrade. |
#### 4.3.1. Atypical Ductal Hyperplasia |
There are few studies that constructed the risk factors associated with upgrading in a nomogram format. The first nomogram published by the author included patients with mammography-detected lesions. Upgrading was defined as any type of DCIS or iBC in the subsequent surgical resection. The following variables were incl... |
#### 4.3.2. Ductal Carcinoma In Situ |
There have been several studies that performed logistic regression analyses on several significant variables to identify certain variables that can be reliable to certain extent dividing the cases into low-risk for upgrading vs. high-risk. However, these studies included HG-DCIS. Since HG-DCIS is not included in the AS... |
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