Introduction
The diagnostic workup of a suspicious mammographic finding includes taking biopsies to determine whether abnormal findings represent malignancy, with the goal of identifying invasive cancer (IC) at the earliest stage, thereby reducing mortality. There is, however, a considerable variation in the rate of biopsy across the United States as well as internationally, with cancer-to-biopsy yields relatively low, ranging from 22 to 33 % [
1‐
4] and over half a million breast biopsies performed annually [
5]. In addition, negative surgical open biopsy rates have been shown to be twice as high in the United States as they are in the United Kingdom, despite similar cancer detection rates [
6]. Over a 10-year period, 61 % of women undergoing annual mammographic screening will be called back for an abnormality, and 7–9 % will receive a false-positive biopsy recommendation [
7‐
9]. The negative consequences of benign biopsies include fear, pain, anxiety, direct financial expenses, indirect costs related to work missed, and risk of complications [
10‐
12].
A Breast Imaging Reporting and Data Systems (BI-RADS) 4 assessment is given to lesions that carry a risk of malignancy between 2 and 95 % and, in the United States, most BI-RADS 4 lesions are biopsied (69–95 %) [
13,
14]. The 4th Edition (2003) of the BI-RADS guidance chapter provided more refined categories of risk within the BI-RADS Category 4 creating three sub-categories (4A, 4B, and 4C) [
15], and the 5th Edition (2013) recommends risk estimates for malignancy (Table
1) [
16]. However, there is no distinction between the risk of ductal carcinoma in situ (DCIS) or IC, instead using an overall risk estimate for malignancy. The opportunity of sub-classifying BI-RADS 4 is that low-risk 4A lesions may clinically be evaluated separately and followed rather than immediately biopsied as is done for most 4B and 4C lesions.
Table 1
BI-RADS 4 subcategories
4A: low suspicion | Biopsy should be performed in the absence of clinical contraindication | ≥2 to <10 |
4B: moderate suspicion | ≥10 to <50 |
4C: high suspicion | ≥50 to <95 |
This pilot study evaluates the diagnostic accuracy of an experienced radiologist in assigning separate risk estimates for both DCIS and IC. We tested the impact of several different thresholds for biopsy, using risk estimates, to determine if more refined thresholds would safely reduce false-positive biopsies, and whether there is a category of risk for which immediate intervention could be safely replaced with short-term follow-up similar to BI-RADS 3, with little impact on delaying the diagnosis of consequential invasive breast cancer.
Discussion
Current criticisms of mammography screening programs include concern about overdiagnosis, the generation of false positives, and associated biopsies [
17,
18]. While overdiagnosis is controversial for IC, there is a developing disquiet about overtreatment of DCIS, especially low-to-intermediate grade DCIS [
19]. It is likely that majority of these lesions would not progress to IC, and if they do progress, the risk is 5–15 years from the original time of detection. High-grade DCIS may be associated with a higher risk of developing invasive breast cancer, and this risk is usually within 5 years of diagnosis. However, most DCIS is treated like invasive disease. Increasing awareness of the potential for overtreatment is leading to a reconsideration of the approach to DCIS, especially for low-to-intermediate grade DCIS, and a shift to explore chemoprevention as an alternative. Certainly, there is no urgency to detect such lesions. This pilot study was designed to determine whether it was possible to give a separate risk estimate for DCIS and IC and to lay the groundwork for predicting biologic type. Increasingly, we understand that breast cancer is a heterogeneous collection of diseases, where the tempo of disease ranges from indolent to aggressive. The results of this study show that an experienced radiologist can accurately provide risk estimates for both DCIS and IC. Revising thresholds for biopsy demonstrates that there is only a very low risk of delaying diagnosis, and the lesions for which diagnosis is delayed appear to be those with more indolent behavior. If these risk estimates can be validated by a larger study, then they could be used to place some calcifications in the BI-RADS 4A, 3, or even 2 categories and generate new biopsy threshold recommendations.
Given the substantial number of biopsies performed for benign lesions we sought to identify potential new thresholds to refine biopsy recommendations and to optimize management. Experienced mammographers are likely to be highly accurate in their ability to assign more refined risk estimates of both DCIS and IC, as set by BI-RADS subcategories. These categories can be used to assign new biopsy thresholds that may result in safely avoiding many benign biopsies, which is bourn out by some units reporting a high PPV for malignancy.
In this study of 124 lesions, 2 hypothetical thresholds for biopsy, scenario #1 and #2, seem most promising. In this pilot study, a biopsy threshold of ≥ 10 % DCIS or ≥ 10 % IC risk (scenario #1) avoids 22 % of biopsies with a cancer-to-biopsy yield of 36 % without delaying diagnosis for any malignant lesions. A biopsy threshold of ≥ 50 % DCIS or ≥ 10 % IC risk (scenario #2) results in avoiding 48 % of biopsies, a cancer-to-biopsy yield of 47 %, but postpones diagnosing one IC and four non-invasive (DCIS) lesions. However, the IC was only 3 mm and low grade, and it is highly likely to have been identified 6 months later, still as stage 1a or 1b, with little consequence.
The introduction of mammographic screening led to a significant rise in detection of DCIS, which has become a target for screening [
20]. The question is whether only high-grade DCIS should be a focus of early detection. DCIS now accounts for 20–30 % of all “malignant” diagnoses of breast cancer, almost entirely from screening. Yet after removal of approximately 60,000 DCIS cases annually for over 10 years, there has not been a concomitant drop in IC, suggesting that many of these lesions would not necessarily progress to IC if left undetected [
17]. Although the natural history of DCIS is unknown, autopsy data indicate the existence of a reservoir of DCIS in the population that is never diagnosed and never attains clinical relevance [
21,
22]. The consequence of delayed diagnosis of DCIS is likely to be negligible. In addition, there is a great value in risk stratifying low and intermediate versus high-grade DCIS. Low-grade DCIS lesions have an uncertain risk for progression to IC, as our understanding of the natural history of these lesions is poor. After excision, the risk of an IC developing ranges from 5 to 30 % over a period of 2–15 years after excision [
23‐
25]. If a high-grade DCIS progresses, it will do so over a period of 2–5 years [
26].
BI-RADS 4, with a wide range of risk of malignancy from 2 to 95 %, does not differentiate between a low-grade DCIS, which may never have clinical significance [
27], and a consequential IC [
17]. BI-RADS 4 includes many patients who do not have malignant or even high-risk lesions. The results demonstrate that with new biopsy thresholds, the United States can decrease biopsies performed for benign lesions to approach the cancer-to-biopsy yield rates of other countries such as Sweden (30–47 %) [
28] and the United Kingdom (50–64 %) [
6,
29]. Focusing on diagnosing IC or high-grade DCIS lesions may be one way to arrive at a threshold that lowers false positives while maintaining sensitivity for ICs.
BI-RADS 4 lesions that are ultimately benign are those that are most frequently thought to have a risk of non-high-grade DCIS. There is a fear of missing associated IC, although that is usually only identified in conjunction with the high-grade DCIS lesions that have fairly characteristic appearances on mammogram and are usually assigned a >50 % chance of being DCIS. The fact that DCIS is not an emergency, and does not require urgent intervention, may allow us to consider recommending a 6-month follow-up instead of biopsy. This is unlikely to have an impact on survival, even if the lesion ultimately is diagnosed as DCIS.
The fear of missing cancers is a potent driver of excess biopsies. Although controversial, there is increasing support for the view that some proportion of screen-detected cancers are slow-growing low-risk tumors, with indolent behavior [
30‐
32]. A delay of 6 months in the detection of such lesions is unlikely to cause harm. The challenge is to distinguish benign and slow-growing lesions from those where there is an urgent need for resolution, recommending a short-term follow-up for the former and biopsy for the latter. For many low-risk radiographic findings, evidence of growth over time may help sort out which lesions require biopsy: IC lesions will progress and change over 6 months of observation and can be detected in a timely manner at an early stage.
The findings of this study demonstrate the potential clinical utility of experienced radiologists, providing separate risk estimates for DCIS and IC. In this small study, lesions that might have been missed and recommended for a 6-month follow-up were likely to have little if any immediate risk if diagnosis is delayed for 6 months. Biopsy thresholds also give radiologists and clinicians the justification and support for allowing disease dynamics to determine what is consequential and worthy of bringing to clinical attention [
33].
This study has several weaknesses. First, as a pilot study, we have a small number of cases, which may not be representative. Also, intervention decisions may not be properly made at 6-month follow-up and diagnosis may be delayed. Women may not fully understand risk and the importance of follow-up. Lastly, only one experienced radiologist generated the risk estimates for this study. Our experienced radiologist’s predictive ability may not be representative of other radiologists. We are in the process of validating this hypothesis in a reader study of 750 BI-RADS 4 and 5 lesions across five University of California Medical Centers as part of the Athena Breast Health Network. This will test academic radiologists of varying experience. If validated, we also plan to extend our study to community radiologists to show that this can work outside of academia.
This study suggests that using a biopsy threshold of risk estimates ≥50 % for DCIS and ≥10 % for IC may effectively and potentially safely improve cancer-to-biopsy yields. It was only intended as a pilot study to explore and validate new thresholds for biopsy, and has subsequently led to the above reader study. Management of lower risk lesions with a 6-month observation may increase patient anxiety and may only postpone biopsy, but may also enable us to safely observe specific lesions and decrease the biopsy rate. If validated, it will be necessary for clinicians to educate their patients about the safety of observation and communicate the plan for follow-up.
This pilot study found that following risk-based biopsy thresholds for BI-RADS 4 lesions by recommending a 6-month follow-up for the lowest-risk lesions, reclassifying to a BI-RADS 3 equivalent, may safely reduce biopsy rates and increase cancer-to-biopsy yields. These thresholds are not meant to be the definitive standards for biopsy but rather a starting point to move forward to determine what thresholds best improve cancer-to-biopsy yields while avoiding a delay in diagnosis for consequential invasive lesions.