Research

JAMA Surgery | Original Investigation | PACIFIC COAST SURGICAL ASSOCIATION

Factors Associated With Underestimation of Invasive Cancer

in Patients With Ductal Carcinoma In Situ
Precautions for Active Surveillance
Carlos Chavez de Paz Villanueva, MD; Valentina Bonev, MD; Maheswari Senthil, MD; Naveenraj Solomon, MD;
Mark E. Reeves, MD, PhD; Carlos A. Garberoglio, MD; Jukes P. Namm, MD; Sharon S. Lum, MD

IMPORTANCE Recent recognition of the overdiagnosis and overtreatment of ductal carcinoma

in situ (DCIS) detected by mammography has led to the development of clinical trials
randomizing women with nonhigh-grade DCIS to active surveillance, defined as imaging
surveillance with or without endocrine therapy, vs standard surgical care.

OBJECTIVE To determine the factors associated with underestimation of invasive cancer in

patients with a clinical diagnosis of nonhigh-grade DCIS that would preclude active
surveillance.

DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted using
records from the National Cancer Database from January 1, 1998, to December 31, 2012, of
female patients 40 to 99 years of age with a clinical diagnosis of nonhigh-grade DCIS who
underwent definitive surgical treatment. Data analysis was conducted from November 1,
2015, to February 4, 2017.

EXPOSURES Patients with an upgraded diagnosis of invasive carcinoma vs those with a

diagnosis of DCIS based on final surgical pathologic findings.

MAIN OUTCOMES AND MEASURES The proportions of cases with an upgraded diagnosis of
invasive carcinoma from final surgical pathologic findings were compared by tumor, host, and
system characteristics.

RESULTS Of 37 544 women (mean [SD] age, 59.3 [12.4] years) presenting with a clinical
diagnosis of nonhigh-grade DCIS, 8320 (22.2%) had invasive carcinoma based on final
pathologic findings. Invasive carcinomas were more likely to be smaller (>0.5 to 1.0 cm vs
0.5 cm: odds ratio [OR], 0.73; 95% CI, 0.67-0.79; >1.0 to 2.0 cm vs 0.5 cm: OR, 0.42;
95% CI, 0.39-0.46; >2.0 to 5.0 cm vs 0.5 cm: OR, 0.19; 95% CI, 0.17-0.22; and >5.0 cm vs
0.5 cm: OR, 0.11; 95% CI, 0.08-0.15) and lower grade (intermediate vs low: OR, 0.75; 95%
CI, 0.69-0.80). Multivariate logistic regression analysis demonstrated that younger age
(60-79 vs 40-49 years: OR, 0.84; 95% CI, 0.77-0.92; and 80 vs 40 to 49 years: OR, 0.76;
95% CI, 0.64-0.91), negative estrogen receptor status (positive vs negative: OR, 0.39; 95%
CI, 0.34-0.43), treatment at an academic facility (academic vs community: OR, 2.08; 95% CI,
1.82-2.38), and higher annual income (>$63 000 vs <$38 000: OR, 1.14; 95% CI, 1.02-1.28)
were significantly associated with an upgraded diagnosis of invasive carcinoma based on final
pathologic findings.

CONCLUSIONS AND RELEVANCE When selecting patients for active surveillance of DCIS,
Author Affiliations: Division of
factors other than tumor biology associated with invasive carcinoma based on final Surgical Oncology, Department of
pathologic findings may need to be considered. At the time of randomization to active Surgery, Loma Linda University
surveillance, a significant proportion of patients with nonhigh-grade DCIS will harbor School of Medicine, Loma Linda,
California.
invasive carcinoma.
Corresponding Author: Sharon S.
Lum, MD, Division of Surgical
Oncology, Department of Surgery,
Loma Linda University School of
Medicine, 11175 Campus St, Coleman
JAMA Surg. doi:10.1001/jamasurg.2017.2181 Pavilion 21111, Loma Linda, CA 92350
Published online July 12, 2017. (slum@llu.edu).

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 Research Original Investigation Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ

D
uctal carcinoma in situ (DCIS) is a noninvasive neo-
plastic lesion of the breast, but it displays an unpre-
dictable risk for developing into invasive cancer1 that
can rarely lead to death.2 Widespread implementation of
screening mammography has been linked to the increasing in-
cidence of DCIS in asymptomatic women.3,4 Ductal carci-
noma in situ is detected in 0.5 to 3.6 cases per 1000 women
screened,5 and the annual incidence of DCIS in the United
States approaches 60 000.4 It is unclear what proportion of
these cases represents overdiagnosis of pathologic findings that
would not otherwise progress to an adverse outcome. Be-
cause multimodal treatment is recommended for DCIS after
identification, overdiagnosis results in overtreatment.6 To ad-
dress overdiagnosis of breast cancer, purported to represent
as many as 30% of new breast cancer cases,3 updated mam-
mography screening guidelines recommend increasing the age
to initiate screening as well as increasing the screening
interval.7,8
Although controversy exists regarding the degree to which
screening mammography prevents breast cancer deaths,3,5 the
harms of overtreatment are well accepted. To address over-
treatment of DCIS detected by screening mammography, the
concept of active surveillance has been proposed to monitor
the breast in which DCIS has been diagnosed and to inter-
Key Points
Question What factors are associated with underestimation of
invasive cancer in patients presenting with low-risk ductal
carcinoma in situ that would preclude active surveillance?
Findings In this cohort study using the National Cancer Database,
22.2% of patients with a clinical diagnosis of nonhigh-grade
ductal carcinoma in situ were found to have invasive carcinoma
based on final pathologic findings at surgical excision. Factors that
were significantly associated with an upgraded diagnosis of
invasive carcinoma included younger age, negative hormone
receptor status, more comorbidities, higher annual income,
diagnosis in a more recent year, and treatment at an academic
facility.
Meaning When selecting patients for active surveillance of ductal
carcinoma in situ, consideration should be given to
sociodemographic and biological factors that may be associated
with underlying invasive cancer.
vene only in the event of progression to invasive disease.6,9-11
Three clinical trials have been developed to evaluate the out-
comes of active surveillance of DCIS in patients with a low risk
of progression.9,10,12 The details of each trial are compared in
Table 1. 9,10,12 All 3 trials use a randomized clinical study

Table 1. Comparison of Current Active Surveillance Protocols

Characteristic LORIS10 LORD9 COMET12

Title The Low Risk DCIS Trial
Sponsor University of Birmingham,
England
Design Multicenter, randomized, clinical
phase 3 trial of surgery vs active
monitoring in patients with
low-risk DCIS; noninferiority
Control Surgery, annual mammography
for 10 y
Intervention Annual mammography for 10 y
Main outcome Ipsilateral invasive breast
measure cancerfree survival time
Selected secondary Any invasive cancer, OS, QOL,
outcome measures cost-effectiveness
Accrual goal, No. 932
Inclusion criteria Female, age 46 y,
microcalcifications detected on
mammography screening,
nonhigh-grade DCIS, VACB with
or without open surgical biopsy
with positive margins
Exclusion criteria Mass lesion, comedo necrosis,
bloody nipple discharge, high
risk, prior breast cancer
Duration of 10 y
follow-up
Status Recruiting
Low Risk DCIS Comparison of Operative to
Monitoring and Endocrine
Therapy Trial for Low Risk
DCIS
European Organization for Alliance
Research and Treatment of
Cancer
Multicenter, randomized, Multicenter, randomized,
clinical phase 3 trial to assess clinical phase 3 trial
safety of active surveillance
for low-risk DCIS;
noninferiority
Surgery, with or without Surgery, with or without
radiotherapy, with or without radiotherapy, with or without
endocrine therapy, annual endocrine therapy,
mammography for 10 y mammography every 12 mo
for 5 y
Annual mammography for 10 y Mammography every 6 mo
for 5 y
Ipsilateral invasive breast Proportion of new diagnoses
cancerfree rate at 10 y of ipsilateral invasive cancer
in guideline-concordant care
and active surveillance arms
at 2-y follow-up
Any invasive or in situ cancer, Patient-centered outcomes,
OS, QOL, cost-effectiveness any invasive cancer, OS, BSS,
QOL, MRI use
1240 1200
Female, age 45 y, Female, age 40 y, grade I/II
asymptomatic, DCIS, ER positive and/or PR
microcalcifcations detected on positive, postmenopausal
mammography screening, pure
low-grade DCIS, VACB, life
Abbreviations: BSS, breast
expectancy >5 y
cancerspecific survival; DCIS, ductal
Prior breast cancer, BRCA Prior breast cancer, mass
carcinoma in situ; ER, estrogen
carrier family, symptoms lesion, bloody nipple
(mass lesion, nipple discharge) discharge receptor; MRI, magnetic resonance
imaging; OS, overall survival;
10 y 7y
PR, progesterone receptor;
QOL, quality of life; VACB,
Not yet recruiting Recruiting
vacuum-assisted core biopsy.

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 Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ
design in which women with low- to intermediate-grade DCIS
diagnosed without an attempt to clear margins by either core
and/or surgical biopsy are assigned to receive conventional care
(surgery, with or without radiotherapy or endocrine therapy,
followed by routine imaging surveillance) or active surveil-
lance (imaging follow-up only), with a main outcome mea-
sure of the occurrence of ipsilateral invasive breast cancer.
A considerable barrier to active surveillance of DCIS is the
risk of understaging invasive cancer when DCIS is found based
on core biopsy. A meta-analysis of the underestimation of in-
vasive cancer in the finding of DCIS based on diagnostic bi-
opsy reported a significantly increased risk of understaging
with the use of a smaller-gauge, nonvacuum-assisted de-
vice; high-grade DCIS; and the presence of a mass.13 These fac-
tors, which are available preoperatively, were incorporated into
the exclusion criteria of the active surveillance trials, but the
meta-analysis also showed that 20% of women with core bi-
opsyproven, nonhigh-grade DCIS (low and intermediate
grades) still had invasive cancer when surgically treated.13 In
a risk analysis predicting disease-specific cumulative mortal-
ity for active surveillance of DCIS compared with usual surgi-
cal and adjuvant care, the variable with the greatest risk of
mortality was understaging invasive cancer at the time of
diagnosis.11
We sought to determine the factors associated with an up-
graded diagnosis of invasive cancer in patients with nonhigh-
grade DCIS that would preclude active surveillance by apply-
ing active surveillance study criteria to relevant cases in the
National Cancer Database (NCDB), a joint project of the Com-
mission on Cancer (CoC) of the American College of Surgeons
and the American Cancer Society.
Methods
We performed a retrospective cohort review using data from
the NCDB from January 1, 1998, to December 31, 2012. We se-
lected a study cohort based on combining selection criteria
available in the NCDB from the protocols of the LORIS (Low
Risk DCIS) trial,10 the LORD (Low Risk DCIS) study,9 and the
COMET (Comparison of Operative to Monitoring and Endo-
crine Therapy)12 trial. The study cohort included women 40
years or older with clinical stage 0 (cTisN0M0), nonhigh-
grade (low and intermediate grade) DCIS histologic findings.
All patients underwent definitive cancer-directed surgery to
confirm the final pathologic diagnosis that was recorded as
non-upgraded (pTis) or upgraded (pT1-4). Cases missing data
on final American Joint Commission on Cancer pathologic tu-
mor, node, or metastasis stage from definitive cancer-
directed surgery were excluded from the study. Variables that
were analyzed included year of diagnosis, age group, race/
ethnicity, estrogen receptor (ER) status, Charlson/Deyo Score,14
insurance status, annual income, and facility type. Racial/
ethnic groups were identified by medical record or surname.15
The Charlson/Deyo Score is a weighted score derived from the
sum of the scores for each of the comorbid conditions listed
in the Charlson Comorbidity Score.14 Commission on Cancer
facility type designation requires that a community cancer pro-
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Original Investigation Research
Figure. Patient Selection Flowchart
2 807 544 Patients with malignant
neoplasm of the breast
408 406 With cTisN0M0
406 145 Female patients
189 191 With ductal carcinoma
in situ histologic findings
72 857 With low- or intermediate-
grade neoplasm
37 544 With pathologic stage
available
gram treat 100 to 499 new cancer cases yearly, a comprehen-
sive community cancer program treat 500 or more new can-
cer cases annually, and an academic or research program treat
500 or more new cancer cases annually and include research
and training programs.16 The Loma Linda University institu-
tional review board approved this study and waived the need
for patient consent.
In the NCDB, grade17 and tumor size18 are reported based
primarily on pathologic findings when available, with tumor
size supplemented by radiographic and clinical findings sec-
ondarily. To select nonhigh-grade DCIS, we limited the analy-
sis to cases with low- and intermediate-grade DCIS. For pa-
tients whose diagnosis was upgraded to invasive carcinoma
based on final surgical pathologic findings, the pathologic stage
and receipt of adjuvant radiotherapy, chemotherapy, and en-
docrine therapy were noted.
The 2 and Fisher exact tests were used to compare pro-
portions, as well as frequencies and percentages, whereas the
t test and the Mann-Whitney Wilcoxon test were used to com-
pare nonparametric quantitative variables ( = .05, assuming
normal distribution and homogeneity of variance). Odds ra-
tios (ORs) and 95% CIs were calculated for each covariate in
the unadjusted and adjusted model using logistic regression.
Missing variables were excluded from statistical analyses,
which were conducted from November 1, 2015, to February 4,
2017, using SAS, version 9.4 (SAS Institute Inc). P < .05 was
considered significant.
Results
Between 1998 and 2012, there were 2 807 541 cases of malig-
nant neoplasms of the breast in the NCDB. Case selection cri-
teria yielded 37 544 women 40 years or older with nonhigh-
grade DCIS who underwent definitive surgical therapy with
pathologic stage available in the study cohort (mean [SD] age,
59.3 [12.4] years) (Figure). Removing cases with missing patho-
logic stage eliminated 35 313 cases from analysis. Overall, 8320
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 Research Original Investigation Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ

Table 2. Demographic, Clinical, and Pathologic Features for Upgraded and Non-Upgraded Patients

No. (%)
Univariate OR Multivariate OR
Characteristic Overalla Upgradedb Non-Upgradedb (95% CI) P Value (95% CI) P Value
Preoperative Variables
Age group, y (n = 36 250)
80 2192 (6.05) 416 (19.0) 1776 (81.0) 0.79 (0.70-0.88) .001 0.76 (0.64-0.91) .002
60-79 15 775 (43.5) 3297 (20.9) 12 478 (79.1) 0.89 (0.84-0.93) <.001 0.84 (0.77-0.92) <.001
40-59 18 283 (50.4) 4202 (23.0) 14 081 (77.0) 1 [Reference] NA 1 [Reference] NA
Race/ethnicity
(n = 37 189)
Hispanic 1688 (4.5) 365 (21.6) 1323 (78.4) 0.97 (0.86-1.10) .58 1.09 (0.92-1.29) .31
Non-Hispanic black 4527 (12.2) 966 (21.3) 3561 (78.7) 0.951 (0.88-1.03) .19 0.98 (0.88-1.10) .72
Other 1613 (4.3) 384 (23.8) 1229 (76.2) 1.095 (0.97-1.23) .13 0.98 (0.84-1.15) .83
Non-Hispanic white 29 361 (79.0) 6516 (22.2) 22 845 (77.8) 1 [Reference] NA 1 [Reference] NA
Hormone receptor status
(n = 22 774)
ER positive 20 616 (90.5) 6192 (26.2) 17 424 (73.8) 0.42 (0.38-0.46) <.001 0.39 (0.34-0.43) <.001
ER negative 2158 (9.5) 993 (46.0) 1165 (54.0) 1 [Reference] NA 1 [Reference] NA
Insurance status
(n = 36 922)
Private 22 518 (61.0) 5148 (22.9) 17 370 (77.1) 0.90 (0.81-1.00) .05 0.90 (0.77-1.05) .17
Medicare 12 354 (33.5) 2568 (20.8) 9786 (79.2) 0.80 (0.71-0.89) <.001 0.91 (0.77-1.08) .27
Medicaid or none 2050 (5.6) 508 (24.8) 1542 (75.2) 1 [Reference] NA 1 [Reference] NA
Annual income category
(n = 36 827), $
>63 000 14 221 (38.6) 3345 (23.5) 10 876 (76.5) 1.33 (1.23-1.44) <.001 1.14 (1.02-1.28) .02
48 000-62 999 9705 (26.4) 2170 (22.4) 7535 (77.6) 1.24 (1.14-1.35) <.001 1.10 (0.97-1.23) .13
38 000-47 999 7545 (20.5) 1664 (22.1) 5881 (78.0) 1.22 (1.12-1.33) <.001 1.09 (0.97-1.23) .16
<38 000 5356 (14.5) 1007 (18.8) 4349 (81.2) 1 [Reference] NA 1 [Reference] NA
Year of diagnosis
(n = 37 544)
2008-2012 22 133 (59.0) 6122 (27.7) 16 011 (72.3) 2.30 (2.18-2.43) <.001 1.64 (1.50-1.80) <.001
1998-2007 15 411 (41.1) 2198 (14.3) 13 213 (85.7) 1 [Reference] NA 1 [Reference] NA
Charlson/Deyo Score
(n = 31 737)
2 677 (2.1) 182 (26.9) 495 (73.1) 1.19 (1.00-1.41) .16 1.28 (1.03-1.60) .03
1 3622 (11.4) 921 (25.4) 2701 (74.6) 1.10 (1.02-1.20) .84 1.14 (1.02-1.26) .02
0 27 438 (86.5) 6478 (23.6) 20 960 (76.4) 1 [Reference] NA 1 [Reference] NA
Facility type (n = 37 536)
Academic or research 10 463 (27.9) 2670 (25.5) 7793 (74.5) 1.95 (1.77-2.14) <.001 2.08 (1.82-2.38) <.001
Comprehensive 22 882 (61.0) 5014 (21.9) 17 868 (78.1) 1.60 (1.46-1.75) <.001 1.47 (1.30-1.66) <.001
community cancer
Community cancer 4191 (11.2) 625 (15.0) 3554 (85.0) 1 [Reference] NA 1 [Reference] NA
Postoperative Variables
Grade (n = 37 544)
Intermediate 26 163 (69.7) 5639 (67.8) 20 524 (70.2) 0.89 (0.85-0.94) <.001 0.75 (0.69-0.80) <.001
Low 11 381 (30.3) 2681 (32.2) 8700 (29.8) 1 [Reference] NA 1 [Reference] NA
Tumor size, cm
(n = 23 230)
>5 803 (3.4) 57 (0.8) 746 (4.7) 0.12 (0.09-0.15) <.001 0.11 (0.08-0.15) <.001
>2 to 5 2396 (10.3) 326 (4.5) 2160 (13.5) 0.23 (0.20-0.26) <.001 0.19 (0.17-0.22) <.001
>1 to 2 4668 (20.0) 1090 (15.0) 3578 (22.3) 0.46 (0.42-0.50) <.001 0.42 (0.39-0.46) <.001
>0.5 to 1 4958 (21.3) 1636 (22.5) 3322 (20.7) 0.74 (0.69-0.79) <.001 0.73 (0.67-0.79) <.001
0.5 10 405 (44.6) 4159 (57.2) 6246 (38.9) 1 [Reference] NA 1 [Reference] NA
b
Abbreviations: ER, estrogen receptor; NA, not applicable; OR, odds ratio. Row percentages listed for preoperative variables and column percentages
a
Column percentages listed. listed for postoperative variables.

patients with nonhigh-grade DCIS (22.2%) had invasive car- Demographic, clinical, and pathologic features of the study
cinoma based on final surgical pathologic findings. population are listed in Table 2. Most patients were younger

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 Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ
than 80 years, with 18 283 of 36 250 (50.4%) between
40 and 59 years. Younger age (40-59 years) was associated
with increased odds of an upgraded diagnosis to invasive
carcinoma when compared with those 60 to 79 years
of age (OR, 0.84; 95% CI, 0.77-0.92; P < .001). A total of
29 361 of 37 189 patients (79.0%) were non-Hispanic white,
4527 (12. 2%) were non-Hispanic black, 1688 (4.5%)
were Hispanic, and 1613 (4.3%) were other race/ethnicity.
There was no difference in the rates of diagnoses of
DCIS upgraded to invasive carcinoma among the racial/
ethnic groups. Most tumors (20 616 of 22 774 [90.5%])
were ER positive and demonstrated a protective effect
against an upgraded diagnosis (OR, 0.39; 95% CI, 0.34-0.43;
P < .001).
For annual income categories, only the highest income
category remained at risk for an upgraded diagnosis com-
pared with the lowest income category on multivariate
analysis (>$63 000 vs <$38 000: OR, 1.14; 95% CI, 1.02-1.28;
P = .02) (Table 2). Most patients (27 438 of 31 737 [86.5%])
did not report any comorbidities; those with more comor-
bidities had increased odds of an upgraded diagnosis
(Charlson/Deyo Score of 2 vs 0: OR, 1.28; 95% CI, 1.03-1.60;
P = .03; Charlson/Deyo Score of 1 vs 0: OR, 1.14; 95% CI,
1.02-1.26; P = .02). Insurance status was not associated with
upgrade rates.
There was an increase in the number of nonhigh-grade
DCIS cases after 2007, with 22 133 of 37 544 patients (59.0)
who received a diagnosis between 2008 and 2012 and
15 411 patients (41.0%) who received a diagnosis between
1998 and 2007, as well as an increase in the odds of
an upgraded diagnosis for the most recent group (OR, 1.64;
95% CI, 1.50-1.80; P < .001) (Table 2). Comprehensive com-
munity cancer centers treated most patients (22 882 of
37 536 [61.0%]), while 10 463 patients (27.9%) were seen
in academic research centers and 4191 patients (11.2%)
were seen in community centers. Patients treated in
an academic or comprehensive cancer center had higher
odds of an upgraded diagnosis than did those treated in
a community cancer center (OR, 2.08; 95% CI, 1.82-2.38;
P < .001).
Based on postoperative findings, invasive carcinomas were
more likely than DCIS to be smaller than 1 cm (5795 of 7268
[79.7%] vs 9568 of 16 052 [59.6%]; P < .001) and lower grade
(2681 of 8320 [32.2%] vs 8700 of 29 224 [29.8%]; P < .001)
(Table 2).
Table 3 shows the tumor characteristics and adjuvant
treatment for 8320 patients for whom invasive carcinoma
was identified based on final pathologic findings. Most inva-
sive cancers were ER positive (6192 [74.4%]). Although 552
patients (6.6%) had ERBB2 (formerly HER2) amplification,
most cases (5733 [68.9%]) did not report ERBB2 findings.
The final pathologic tumor stage was T1 for 6388 patients
(76.8%), with 1051 (12.6%) reporting microinvasion. Of the
patients with node-positive carcinoma, 237 of 862 (27.5%)
had micrometastatic neoplasms. The final pathologic stage
was stage I for 7074 patients (85.0%), stage II for 862
patients (10.4%), stage III for 104 patients (1.3%), and stage
IV for 13 patients (0.2%).
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Original Investigation Research
Discussion
In our analysis of NCDB data, 22.2% of women presenting with
a clinical diagnosis of nonhigh-grade DCIS were found to have
invasive carcinoma at definitive surgery. This overall up-
grade rate is comparable to that in the published literature. In
a meta-analysis of 7350 cases from 52 studies that evaluated
factors associated with invasive cancer based on final surgi-
cal pathologic findings when DCIS was diagnosed initially, the
pooled risk of understaging was 25.9%. Core biopsies with high-
grade DCIS had a significantly higher risk of underestimation
at 32.3% compared with a 21.1% risk for nonhigh-grade (low-
or intermediate-grade) DCIS. 13 To estimate survival out-
comes with an active surveillance protocol for DCIS, Ryser et al11
developed a risk projection model incorporating rates of pro-
gression of DCIS and invasive carcinoma and screening para-
meters using an 18.9% probability of understaging invasive
cancer. The numbers of patients needed to treat to avoid 1
breast cancer death when diagnosed at 40 years was 28.3, when
diagnosed at 55 years was 67.3, and when diagnosed at 70 years
was 157.2. The variable with the greatest effect on model out-
come was the probability of underestimating invasive cancer
at the time of diagnosis. Our higher upgrade rate of 22.2%
would estimate a greater mortality risk for active surveillance
and decrease the number needed to treat to prevent 1 breast
cancer death.
We found that younger age was associated with approxi-
mately a 20% higher risk of underestimation of invasive can-
cer, while ER-negative status was associated with approxi-
mately a 60% higher risk. There was no significant difference
in upgrade rates based on race or ethnicity. Although young
age, hormone receptor negativity, and black race are known
risk factors for poorer outcomes with DCIS,2,4,19 these vari-
ables have been less consistently studied as predictors of
understaging of invasive cancer at diagnosis. Yen et al20 cor-
roborated a 2-fold higher odds of upstaging (OR, 2.19; 95% CI,
1.11-4.34; P = .02) with age younger than 55 years compared
with older women. However, other studies have failed to show
a significant association between patient age and risk of un-
derstaging at diagnosis.13,20-27 The effect of hormone recep-
tor status of DCIS at initial diagnosis has rarely been re-
ported; Park et al25 did not find a significant association
between ER status and risk of underestimation of invasive can-
cer. The COMET trial uniquely mandates hormone receptor
sensitive DCIS as inclusion criteria.12 To our knowledge, the
effect of race and ethnicity on the likelihood of upgrading of
DCIS has not been previously reported.
Other factors assessed in this study were not specific to tu-
mor biology. Patients with more comorbidities were at higher
risk of understaging (14% higher odds with 1 comorbidity and
28% higher odds with >1 comorbidity). The presence of mul-
tiple comorbidities could preclude optimal imaging or biopsy
technique and decrease diagnostic accuracy. Treatment at an
academic or research center or a comprehensive community
cancer center was associated with up to a 2-fold higher rate
of upgrading to invasive cancer than was treatment at a com-
munity cancer program. This finding could reflect higher
(Reprinted) JAMA Surgery Published online July 12, 2017 E5
 Research Original Investigation Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ

volumes of definitive cancer therapy at these institutions, as

Table 3. Tumor Characteristics and Treatment of Cases Upgraded
to Invasive Carcinoma at Surgical Excision CoC facility type classification designates hospital case
volume.16 The association of higher annual income with up-
No. (%)
Variable (N = 8320) grade could mirror the higher incidences of breast cancer and
Estrogen receptor mammography screening uptake that have been docu-
Positive 6192 (74.4) mented in women of higher income levels.28,29
Negative 993 (11.9) More than half of the patients with DCIS (59.0%) re-
ceived a diagnosis in the last 5 years of the study period (2008-
Missing 1135 (13.6)
2012). In 2008, the CoC required reporting of clinical stage by
Progesterone receptor
registrars30; this mandate may have contributed to the in-
Positive 5222 (62.7)
crease in the number of cases staged as cTisN0M0. However,
Negative 1924 (23.1)
the increasing incidence of DCIS during the mammography
Missing 1174 (14.1) screening era has been well recognized.3-5 That later years of
ERBB2 expressiona study were associated with a 64% increased odds of under-
Positive 552 (6.6) staging could be attributed to greater use of percutaneous
Negative 2035 (24.5) needle biopsy for diagnosis, which has been shown to be as-
Missing 5733 (68.9) sociated with understaging.20 The association of study year
Pathologic tumor stage with upgrade rates was corroborated by Brennan et al,13 with
T1mi 1051 (12.6) cases diagnosed in 2001 and after having the highest odds of
T1a 3474 (41.8)
upgrade compared with cases diagnosed in earlier years.

T1b 1833 (22.0)

Limitations
T1c 1081 (13.0)
A major limitation with the use of NCDB data during this study
T2 311 (3.7)
period is that tumor size and grade primarily reflect final patho-
T3 39 (0.5)
logic findings.17,18 Because tumor size is recorded from the sur-
T4 17 (0.2) gical pathologic report, we could not evaluate tumor size as a
Missing 527 (6.3) preoperative predictor of underestimation of invasive cancer
Pathologic nodal stage in this study. More than half of occult invasive cancers (57.2%)
N0 7321 (88.0) were 0.5 cm or less. For patients whose diagnosis was not up-
N1mi 237 (2.9) graded to invasive cancer, the extent of DCIS based on final
N1 603 (7.3) pathologic findings was larger, with 4.7% of patients having a
N2 22 (2.6) tumor size larger than 5 cm. On January 1, 2016, the CoC man-
dated reporting of both pathologic and clinical tumor size data
Missing 137 (1.7)
in the NCDB30; subsequent studies could evaluate tumor size
Final pathologic stage
as a preoperative variable.
I 7074 (85.0)
Similarly, tumor grade is recorded in the NCDB based on
IIA 770 (9.3)
the most definitive pathologic findings available. We limited
IIB 92 (1.1) case selection to clinical TisN0M0 with low- or intermediate-
IIIA 86 (1.1) grade histologic findings to reflect the patient population
IIIB 3 (0.04) screened for active surveillance. However, in doing so, cases
IIIC 15 (0.2) upgraded to high-grade invasive carcinoma based on final
IV 13 (0.2) pathologic findings were potentially eliminated, as were cases
Missing 267 (3.2) of high-grade DCIS upgraded to low- or intermediate-grade in-
Radiotherapy vasive carcinoma. Because the grade on core biopsy reflects
Yes 4873 (58.6)
the grade on final pathologic findings in most cases (71.1%),
with correlation improved for high grade (83.8% for high grade,
No 3289 (39.5)
66.0% for intermediate grade, and 68.7% for low grade),31 we
Missing 158 (1.9)
thought it a reasonable assumption for the majority of pa-
Endocrine therapy
tients to use the grade variable in the NCDB. Furthermore, ge-
Yes 2817 (33.9)
nomic analyses have shown that, when progression occurs,
No 4502 (54.1) low-grade in situ lesions lead to low-grade invasive lesions and
Missing 1001 (12.0) high-grade in situ lesions lead to high-grade invasive lesions;
Chemotherapy dedifferentiation from low-grade tumors to high-grade tu-
Yes 1469 (17.7) mors occurs rarely and is marked by differences in both the
No 6282 (75.5) frequency and the mechanism of 16q loss.32 We evaluated all
Missing 569 (6.8) cTisN0M0 cases in this data set unselected by grade and found
a
upgrading in only 5.4% (5446 of 101 075). Grade assignment
Formerly HER2.
could also be affected by lack of documentation of the source

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 Factors Associated With Underestimation of Invasive Cancer in Patients With Ductal Carcinoma In Situ Original Investigation Research

of pathologic findings (eg, core biopsy, excisional biopsy, or par-
tial or total mastectomy specimen) and interobserver
variability.31,33 Although the meta-analysis by Brennan et al13
demonstrated a significant difference on univariate analysis
between upgrade rates of high-grade vs nonhigh-grade DCIS
diagnosed preoperatively, other single-institution series failed
to show significant differences in upgrade rates based on DCIS
grade in multivariate analyses.25,27
As expected, the majority of invasive carcinomas identi-
fied at surgery were hormone sensitive (74.4% ER positive),
small (54.4% T1a or T1mi), and node negative (88.0% N0). How-
ever, these cases represent potential missed, or at least de-
layed, diagnoses in a population undergoing active surveil-
lance. A significant proportion of patients with a diagnosis of
invasive cancer received adjuvant therapies. Several studies
have attempted to predict outcomes of active surveillance ret-
rospectively. Pilewskie et al34 stratified patients by LORIS cri-
teria after breast-conserving surgery for pure DCIS and found
that the 10-year risk of any ipsilateral breast tumor recur-
rence was lower for patients who met LORIS criteria (10.3%)
than those who did not (15.4%), but the difference was not sta-
tistically significant (P = .08). In this study, all patients re-
ceived standard surgical care, and upgrade to invasive carci-
noma at the time of definitive surgery was excluded. Although
the rate of progression to ipsilateral breast tumor recurrence
was low overall, the authors acknowledged that patients not
receiving initial excision would likely have higher rates of in-
vasive cancer. Sagara et al35 reviewed cases of DCIS in the Sur-
veillance, Epidemiology, and End Results database and com-
pared the 2% of patients who did not receive surgery with the
98% of patients who received surgery. Although there were sig-
nificant differences in patients with intermediate-grade and
high-grade DCIS, there was no significant difference in 10-
year breast cancerspecific survival in patients with low-
grade DCIS who did or did not undergo definitive cancer sur-
gery (98.6% vs 98.8%; hazard ratio, 0.85; 95% CI, 0.21-3.52;
P = .83). Overall, the 10-year breast cancerspecific survival for
those who did not receive surgery was 93.4% compared with
98.5% for those who underwent surgery (P < .001). Grade re-
porting in the Surveillance, Epidemiology, and End Results da-
tabase is subject to similar considerations in the present study,17
and with active surveillance of DCIS, final pathologic grade is
not available from a surgical specimen.
In addition to the limitations stated, we could not deter-
mine presenting symptoms or method of diagnosis. Factors as-
sociated with increased rates of upgrade to invasive cancer af-
ter an initial diagnosis of DCIS include the presence of a mass
lesion detected during physical examination or imaging, bloody
nipple discharge, and the use of needle biopsy for
diagnosis.13,20-27 Data on the use of initial breast imaging or
breast imaging results are not available in the NCDB. The use
of needle biopsy for diagnosis rather than surgical excision
could have contributed to increased rates of upgrade ob-
served in recent years as percutaneous biopsy technology be-
came widespread, academic and research or comprehensive
community cancer programs adopted new technology, pa-
tients with comorbidities underwent less invasive proce-
dures, and higher-income patients had access to more screen-
ing and percutaneous biopsy procedures. Moreover, risk factors
for breast cancer were not available for review. Because many
of the exclusion criteria for the active surveillance trials (Table 1)
were not available in the NCDB and the study spans a time
frame in which diagnostic technology has improved, the
present analysis could overestimate projected upstaging in
active surveillance protocols.
Successful use of active surveillance for patients with DCIS
to diminish harmful effects of overtreatment resulting from
overdiagnosis will depend on accurate diagnosis and dili-
gent follow-up. One study documented that only 34% of
patients with DCIS underwent annual mammography 5
years after breast conservation and 15% reported having
annual mammography at 10 years.36 Novel imaging technol-
ogy, such as digital breast tomosynthesis or abbreviated and
functional magnetic resonance imaging, and algorithms to
optimize screening indications and intervals are being stud-
ied to improve diagnostic accuracy and decrease false
positives. 37 Refinement of molecular assays 38 to predict
which DCIS are obligate and nonobligate precursors to inva-
sive disease could be used to help stratify risk of progres-
sion and would be particularly useful in the unavoidable
event of understaging at diagnosis.
Conclusions
Our study showed that approximately 1 in 5 women present-
ing with nonhigh-grade DCIS will have an underlying inva-
sive carcinoma and adds to the burgeoning evidence for so-
cial determinants of health outcomes. In addition to biological
factors, sociodemographic factors, such as treatment at aca-
demic or research centers and higher annual income, were as-
sociated with an increased risk of understaging at diagnosis.
The use of active surveillance must be implemented cau-
tiously because the patients at greatest risk for harboring un-
derlying invasive carcinoma are also most likely to be offered
entry into an active surveillance protocol.

ARTICLE INFORMATION
Accepted for Publication: April 1, 2017.
Published Online: July 12, 2017.
doi:10.1001/jamasurg.2017.2181
Author Contributions: Dr Lum had full access to all
the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data
analysis.
Study concept and design: Chavez de Paz
Villanueva, Bonev, Garberoglio, Lum.
Acquisition, analysis, or interpretation of data:
Chavez de Paz Villanueva, Senthil, Solomon,
Reeves, Namm, Lum.
Drafting of the manuscript: Chavez de Paz
Villanueva, Bonev, Lum.
Critical revision of the manuscript for important
intellectual content: Chavez de Paz Villanueva,
Senthil, Solomon, Reeves, Garberoglio, Namm,
Lum.
Statistical analysis: Chavez de Paz Villanueva, Lum.
Administrative, technical, or material support:
Chavez de Paz Villanueva, Senthil, Lum.
Study supervision: Chavez de Paz Villanueva,
Senthil, Solomon, Garberoglio, Namm, Lum.
Conflict of Interest Disclosures: None reported.
Disclaimer: The data used in the study are derived
from a deidentified National Cancer Database file.
The American College of Surgeons and the
Commission on Cancer have not verified and are

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 Research Original Investigation
not responsible for the analytic or statistical
methods used, or the conclusions drawn from
these data, by the investigator.
Meeting Presentation: This paper was presented
at the 88th Annual Meeting of the Pacific Coast
Surgical Association; February 18, 2017; Indian
Wells, California.
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