Vol. 104, Issue 20 | October 17, 2012
Advance Access publication September 17, 2012
1542 Commentaries | JNCI
© The Author 2012. Published by Oxford University Press. All rights reserved.
For Permissions, please e-mail: email@example.com.
Benefits and Harms of Detecting Clinically occult
Eitan Amir, Philippe L. Bedard, Alberto Ocaña, Bostjan Seruga
Manuscript received August 15, 2011; revised July 31, 2012; accepted August 16, 2012.
Correspondence to: Eitan Amir, MD, Division of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave 5–124, Toronto, ON
M5G 2M9, Canada (e-mail: firstname.lastname@example.org).
Over the last few decades there has been an increase in the use of strategies to detect clinically occult breast cancer with the aim
of achieving diagnosis at an earlier stage when prognosis may be improved. Such strategies include screening mammography in
healthy women, diagnostic imaging and axillary staging in those diagnosed with breast cancer, and the use of follow-up imaging
for the early detection of recurrent or metastatic disease. Some of these strategies are established, whereas for others there are
inconsistent supportive data. Although the potential benefit of early detection of clinically occult breast cancer seems intuitive,
use of such strategies can also be associated with harm. In this commentary, we provide an extended discussion on the potential
benefits and harms of the routine and frequent use of screening interventions to detect clinically occult breast cancer and question
whether we may be causing more harm than good.
J Natl Cancer Inst 2012;104:1542–1547
early stage breast cancer can be cured, whereas metastatic disease
is generally incurable. It is therefore intuitive to assume that detec-
tion of early stage breast cancer will lead to improved outcomes.
Advances in imaging allow clinicians to detect primary breast
cancer, loco-regional involvement, and recurrent disease before
it becomes symptomatic. Some of these interventions, such as
screening mammography and axillary surgery, have become stand-
ards of care; however, their optimal use remains unclear. For other
interventions, such as follow-up imaging, there remain questions
regarding the balance between absolute benefits and risks. here
we provide a discussion on the use of strategies aimed at detecting
clinically occult breast cancer.
Despite an increase in breast cancer diagnoses, mortality rates
have fallen. In the united States, data from the Surveillance,
epidemiology, and end results database show a greater than 40%
reduction in the rate of death from breast cancer in the last 30 years
(1). Although this finding has been attributed to the combined
effects of increased use of screening mammography, better patient
awareness, and improved adjuvant therapy, the differential effects
of these factors is not known (2). results of both randomized clini-
cal trials and health outcomes analyses of the benefit of screening
mammography have shown inconsistent results. Systematic reviews
and meta-analyses have been conducted to define the true benefit
of screening mammography. the united States Preventive Services
taskforce (uSPStF) concluded that in average-risk women mam-
mography was associated with a statistically significant relative
reduction in breast cancer–specific mortality in women between
the ages of 39 and 69 years (3). Similar data were presented by the
Canadian task Force on Preventive health Care and the Cochrane
Collaborative, both of which concluded that mammography
reduced the relative risk of breast cancer mortality in average risk
women aged 50 years or older (4,5). the authors of the Cochrane
review suggested that some trials included in their analysis suffered
methodological limitations such as inclusion of women with prior
breast cancer, selection bias such as postrandomization exclusion,
nonconcealed randomization, or suspected contamination. When
these studies were excluded, the benefit from screening mammog-
raphy was no longer statistically significant.
In absolute terms, the benefit of mammography appears less
impressive. Based on data from randomized trials, to prevent one
death from breast cancer in women aged 50–69 years, more than
700 women would need to be screened for about 10 years (4).
therefore, in a hypothetical cohort of 10 000 women aged 50 years
undergoing mammographic screening for 10 years, it would be
expected that around 40 breast cancer deaths would occur. If these
women were not screened, between 50 and 55 breast cancer deaths
would occur (6).
one of the criticisms of data reporting the benefit from
screening mammography is that the data are based on
randomized studies that were carried out in an era before the
routine use of adjuvant therapy. It has been argued that in
the setting of modern adjuvant treatment, benefits are even
smaller (2). randomized screening trials are also susceptible to
participation bias, a type of selection bias that can enrich trials
with motivated and health-seeking individuals. Data from such
studies may, therefore, not be representative of the intended
target of population-based screening programs. the importance
of validation of randomized data with population-based
assessments is, therefore, important.
by guest on October 29, 2015
JNCI | Commentaries 1543
Although initial observational studies suggested mammogra-
phy is associated with an independent reduction in breast cancer
mortality (7,8), more recent population-based analyses have ques-
tioned the benefit from screening mammography after adjustment
for important confounders. An analysis from Western countries
with population-based screening programs showed that following
establishment of such programs there were stable or increasing
rates of advanced disease (9). the authors concluded that screen-
ing could not account for reduced mortality from breast cancer
because there was no evidence that the introduction of such pro-
grams led to a shift from advanced presentation to more early stage
disease (“stage shift”). Improvements in breast cancer outcome
may have instead resulted from improvements in patient awareness
and advances in systemic and loco-regional therapy. A Norwegian
study showed statistically nonsignificant reductions in breast can-
cer–specific mortality associated with mammography in women
aged 50–69 years (10). In this study, authors attempted to isolate
the benefit of mammographic screening from other factors that
may have changed over time, including increased breast cancer
awareness and improvements in treatment. results showed that
approximately two-thirds of the apparent improvement in mortal-
ity was likely related to improvements in the multidisciplinary man-
agement of breast cancer. Similar results were reported in a study
of the World health organization database (11). Investigators
showed reductions in breast cancer mortality of up to 29% between
1989 and 2006. however, after adjustment for time differences in
implementation of mammographic screening, the reductions in
mortality between three independent country pairs suggested that
screening did not play a direct part in the reductions in breast can-
cer mortality. the absolute benefit of screening mammography
in isolation was, therefore, questioned. A possible explanation for
these findings is that screen-detected tumors appear to have less
aggressive biology as determined by both standard pathology (12)
and gene expression profiling (13). In tumors with such good out-
comes, it would be more difficult to detect statistically significant
improvements in mortality resulting from screening.
A further area of concern is that most trials of screening mam-
mography have predominantly assessed breast cancer–specific
mortality. Data describing disease-specific outcomes should be
interpreted with caution because there can be inconsistencies in
determination of cause of death in screening trials—even in those
with prospective randomized designs (14). All-cause mortality
is more robust in this setting, but observing differences in this
endpoint requires high statistical power. Among trials reporting
all-cause mortality, approximately 1000 of the 23 000 deaths were
attributed to breast cancer. this sample compares favorably with
many studies of adjuvant therapy in breast cancer in which dif-
ferences in all-cause outcome were evident. Failure to detect any
differences in all-cause mortality despite improvements in breast
cancer–specific survival (5) is, therefore, surprising.
In women aged less than 50 years, a lower incidence of breast
cancer combined with increased breast density make mammo-
graphic detection more difficult (15). Consequently, the number
of patients that would need to be screened to reduce the inci-
dence of breast cancer deaths by one is substantially higher (4).
mammography for unselected (ie, average-risk) women aged less
than 50 years has, therefore, not been consistently recommended in
all jurisdictions with population-based screening programs.
Screening mammography can be associated with harm. over a
10-year period, between 30% and 50% of women screened every
1–2 years can expect a false-positive result (16,17), and between 7%
and 20% receive a false-positive biopsy recommendation (16,18).
Furthermore, compared with unselected patients not undergo-
ing mammography, screened patients are more likely to undergo
surgery, chemotherapy, and/or radiation therapy (5). this finding
appears counterintuitive because it would be expected that mam-
mographic screening would reduce presentation with regional
or advanced stage disease and therefore require less aggressive
loco-regional or systemic therapy.
Another potential source of harm is over-diagnosis, a scenario
which refers to the detection of cancer that would have other-
wise not been identified in a patient’s lifetime. over-diagnosis is
an inevitable outcome of all screening tests because some patients
will die of causes other than cancer before their screen-detected
tumors would have appeared clinically (19). Autopsy data has
shown that in women not known to have had breast cancer during
their lives, the median prevalences of invasive and in-situ breast
cancer were 1.3% and 8.9%, respectively (20). Furthermore,
recent data from the Swedish mammography screening program
showed that some invasive breast cancers detected by repeated
mammography screening do not persist to be detected by imaging
in later years, suggesting that the natural course of a proportion
of screen-detected invasive breast cancers is spontaneous regres-
sion (21). early detection of occult indolent breast cancer may,
therefore, lead to an apparent increase in the incidence of breast
cancer as well as potentially leading to an erroneous association
with improved outcome. Analysis of randomized trials suggests
that approximately 10% of invasive cancers are over-diagnosed
(22). In population-based cohorts, estimates of over-diagnosis are
much higher, with suggestions that between 15% and 50% of can-
cers may be over-diagnosed (23,24). All these analyses are limited
by relatively short follow-up. With longer follow-up, it would be
expected that the differences in incident cancers between screened
and unscreened groups would diminish as more tumors in the
unscreened group would become clinically apparent. Because of
these and other methodologic and epidemiologic limitations (25),
accurate estimates of over-diagnosis are difficult to determine.
Nevertheless, over-diagnosis is a limitation of screening mam-
mography and results in unnecessary treatment with its attendant
the balance between absolute benefits and harms of annual
mammography is therefore uncertain (26). Based on the evidence
described above as well as computer modeling, the uSPStF
has recommended biennial mammography for women aged
50–74 years (27). the Canadian task Force on Preventive
health Care suggested screening every 2–3 years in the same age
group of patients (4). the rationale for extending the screening
intervals was based on statistical modeling with this interval
showing the best balance between benefit and harm (4,28). these
recommendations have been criticized for not being inclusive of
all evidence supporting mammography. especially for women aged
40–49 years (29,30).
by guest on October 29, 2015
Vol. 104, Issue 20 | October 17, 2012
1544 Commentaries | JNCI
the use of breast magnetic resonance imaging (mrI) for assess-
ment of breast lesions has become widespread. In women with
biopsy-proven breast cancer, breast mrI increases the detection
of further loco-regional disease by 16% (31). Breast mrI may also
influence surgical planning, resulting in a change from the origi-
nal planned surgery in up to one-third of women (32). Because of
the higher prevalence of multifocal, multicentric (multiple quad-
rant), and bilateral disease, mrI appears particularly useful for
invasive lobular carcinoma (33) and for those with germline muta-
tions in BRCA1 and BRCA2 genes (34). however, two prospec-
tive randomized trials conducted in unselected women with breast
cancer demonstrated no influence of breast mrI on reoperation
rate, including both margin re-excision and conversion to mas-
tectomy (35,36). observational data confirm these findings (37)
and also show that preoperative mrI does not lead to a reduc-
tion in local recurrence or a reduction in mortality (38,39). Breast
mrI is also associated with undesired effects. A substantial rate of
false-positive results (31) and high inter-observer variability have
been reported (40). Breast mrI also leads to avoidable mastec-
tomy in 1%–2% of patients (31,35,37) and increased rates of con-
tralateral mastectomy (41).
the optimal patient selection for preoperative breast mrI
remains unknown, but the balance between benefit and risks of pre-
operative breast mrI in unselected cases appears detrimental (42).
Preoperative mrI may be useful to identify the primary tumors in
patients who present with axillary nodal metastases and no detect-
able breast tumor or assessment of the extent of residual tumor
after neoadjuvant chemotherapy, although there are currently few
data to inform its optimal use in these settings.
Completion axillary dissection to remove occult metastatic disease
has generally been recommended in the presence of positive lymph
nodes after sentinel lymph node biopsy. retrospective analyses
showed a substantial rate of detection of further axillary nodal
involvement (43). more recently, two randomized trials of com-
pletion axillary dissection or observation in patients with positive
nodes on sentinel node biopsy have reported results. the American
College of Surgeons oncology Group (ACoSoG) Z0011 clini-
cal trial randomized patients with early-stage breast cancer and
positive sentinel lymph nodes (detected by hematoxylin and eosin
staining) to completion axillary dissection or observation. eligible
patients completed breast conserving surgery for t1–2 tumors
with no more than two positive sentinel nodes. Further involved
axillary lymph nodes were detected in more than 27% of those
who underwent completion axillary node dissection. After more
than 6 years of follow-up, there was no significant difference in
either disease-free or overall survival between the study arms, with
lower event rates seen in the observation group (44). Similar data
were presented by the International Breast Cancer Study Group
(IBCSG). In protocol 23-01, patients with evidence of micro-
metastasis in sentinel lymph nodes were randomized to comple-
tion axillary dissection or observation. Similarly to the ACoSoG
Z0011 trial, preliminary data showed that after a median follow-up
of 57 months, there were no differences in either disease-free or
overall survival, with numerically lower number of events in the
observation group (45). Both these trials closed early because of
low accrual but remain the most comprehensive assessments of the
benefit of completion axillary dissection for patients with limited
nodal metastatic disease. the rate of local recurrence in both trials
was low [<5% of trial populations (45,46)], and this likely explains
why the addition of further local intervention did not influence
outcome. All women in the ACoSoG trial and 90% of those in the
IBCSG trial received adjuvant breast radiation, and many received
adjuvant systemic therapy. With low rates of loco-regional recur-
rence and overall and disease-free survival numerically favoring
the observation arms in both studies, it is unlikely that a difference
between the two intervention arms would have become evident
even with higher accrual and longer follow-up. It is possible that
the administered adjuvant therapies were sufficient to control any
occult residual axillary disease.
Axillary dissection does have substantial excess morbidity com-
pared with sentinel node biopsy. randomized data show that there
is reduced arm morbidity and better quality of life for those treated
with sentinel node biopsy alone (47). Axillary dissection is also
associated with increased risk of lymphedema as well as both motor
and sensory neuropathy (45).
health outcome data indicate that surveillance mammography
can detect early-stage in-breast recurrences (48). however, when
compared with the use of mammography in healthy women,
follow-up mammography was associated with a higher frequency
of interval cancers (48). the positive predictive value for mam-
mography was less than 30%, suggesting a high frequency of
false-positive screens. the benefit of surveillance mammography
has also been questioned. there are currently no data support-
ing the routine use of mrI as follow-up for patients with prior
breast cancer (42). randomized clinical trials have also assessed
the benefit of the addition of chest radiography, liver sonography,
and bone scintigraphy to clinical examination and mammography
in early breast cancer patients. Although intensive radiographic
surveillance led to the earlier detection of recurrent disease,
this did not improve overall survival (49,50). Furthermore, the
provision of intensified surveillance did not enhance emotional
well-being or quality of life (49). Such investigations are there-
fore not recommended in practice guidelines (51,52). Despite
this, use of surveillance imaging in the adjuvant setting remains
prevalent. Linked data from the Surveillance, epidemiology, and
end results and medicare databases show that 30% of women
with breast cancer received at least one computerized tomogra-
phy scan and 19% received at least one bone scan in the first
4 years after diagnosis (53).
It is unclear whether more sensitive diagnostic methods will be
beneficial. At present, there is no evidence that earlier and more
aggressive treatment of asymptomatic occult metastatic disease is
associated with improved outcome. Furthermore, there is little data
to support the benefit of aggressive local therapy for oligometastatic
disease. Because such patients represent a very small minority of
all patients with recurrent breast cancer, the ability to study this
by guest on October 29, 2015
JNCI | Commentaries 1545
Table 1. Absolute benefits and harms of detecting clinically occult breast cancer
Primary breast cancer
Breast cancer mortality
Need for biopsy;
20%–30% of patients†
2%–5% of patients†15%–50% of all invasive
Breast MRI in addition to
mammography and clinical
Detection of further
~15% of patients
10%–15% of patients1%–2% of patients
Completion axillary dissection
after sentinel node biopsy
Detection of further
~25% of patients
3%–12% of patients‡
Recurrent or metastatic disease
Detection of in-breast
~65% of recurrences§
~70% of patients§
~8% lower at 5 years
<1% increase from
* Chest x-ray, abdominal sonography, and bone scintigraphy conducted every 6 months.† After 10 years of regular screening.‡ Dependent on whether axillary radiation therapy also provided.§ After 5 years of regular screening.
by guest on October 29, 2015
Vol. 104, Issue 20 | October 17, 2012
1546 Commentaries | JNCI
population is limited, and the absolute impact of any improvements
in therapy are likely going to be small.
Data from randomized clinical trials and well-conducted health
outcomes studies show that the detection of clinically occult pri-
mary breast cancer, loco-regional disease, and recurrent disease
may not be associated with a consistent improvement in either
breast cancer–specific or all-cause mortality. With the exception
of screening mammography, other strategies for detecting clini-
cally occult breast cancer in asymptomatic women have not shown
benefit in randomized trials. even for screening mammography,
the true benefit is difficult to isolate from other improvements in
treatment over time.
there are a number of possible explanations for these findings.
First, because of their long, asymptomatic phase, slow-growing
tumors are over-represented in tests designed to detect clinically
occult disease. this length-time bias can lead to over-diagnosis and
unnecessary treatment if slow-growing tumors, which may never
produce symptoms, are detected and treated. Second, early detec-
tion of breast cancer may not have a large impact on outcome, and
such lead-time bias may overestimate the benefit of detection of
clinically occult disease. the impact of tumor size on prognosis has
recently been questioned. Data from patients with node-positive,
triple-negative breast cancer suggest that tumor size does not
substantially influence prognosis (54,55). Finally, improvements
in breast cancer outcomes are strongly influenced by advances in
modern therapy (10). Such treatment may improve the ability to
cure patients presenting with early breast cancer and may prevent
or delay progressive disease in advanced breast cancer. In an era of
highly effective adjuvant breast cancer therapy, it is increasingly
recognized that biological factors that affect response to treatment
may influence prognosis more than the anatomic extent of disease.
Screening mammography has benefit in healthy women aged
50–74 years, but the balance between benefit and harm means that
screening every 2–3 years is likely the optimal frequency. more fre-
quent screening of these women or screening of women younger
than 50 years or older than 75 years remains contentious and likely
only benefits subgroups at higher risk. evidence suggests that
imaging to detect occult loco-regional disease or recurrent and/or
metastatic disease and surgical staging of residual axillary disease
may have limited or no benefit. oncologists should be dissuaded
from overuse of screening investigations that may have reduced
benefit and that are associated with harm (see table 1). It is also
imperative that women are made aware of uncertainties in the bal-
ance between benefit and harm for many investigations designed to
detect clinically occult breast cancer.
For strategies for which benefit has been established, such as
screening mammography, it is likely that a more favorable bal-
ance between benefit and risk will be derived from ongoing but
less-frequent screening. For strategies for which the balance
between benefit and risk has not yet been fully established, such as
preoperative breast mrI and completion axillary staging, clinicians
should carefully consider the use of these methods only in settings
where there are supportive data. For other strategies for which evi-
dence of benefit is uncertain, such as follow-up imaging, clinicians
should be discouraged from requesting such tests. As physicians, we
should ask ourselves, “Could we be causing more harm than good?”
1. National Cancer Institute. Surveillance epidemiology and end results.
Age-Adjusted u.S. mortality rates for Breast Cancer 1975–2009. http://
seer.cancer.gov/faststats. Accessed August 21, 2012.
2. Welch hG. Screening mammography—a long run for a short slide? N
Engl J Med. 2010;363(13):1276–1278.
3. Nelson hD, tyne K, Naik A, Bougatsos C, Chan BK, humphrey L.
Screening for breast cancer: an update for the u.S. Preventive Services
task Force. Ann Intern Med. 2009;151(10):727–742.
4. Canadian task Force on Preventive health Care, tonelli m, Gorber SC,
et al. recommendations on screening for breast cancer in average-risk
women aged 40–74 years. CMAJ. 2011;183(17):1991–2001.
5. Gotzsche PC, Nielsen m. Screening for breast cancer with mammography.
Cochrane Database Syst Rev. 2009;oct(4):CD001877.
6. Amir e, Freedman oC, Seruga B, evans DG. Assessing women at high
risk of breast cancer: a review of risk assessment models. J Natl Cancer Inst.
7. otto SJ, Fracheboud J, Looman CW, et al. Initiation of population-based
mammography screening in Dutch municipalities and effect on breast-cancer
mortality: a systematic review. Lancet 2003;361(9367):1411–1417.
8. Duffy SW, tabar L, Chen hh, et al. the impact of organized mammog-
raphy service screening on breast carcinoma mortality in seven Swedish
counties. Cancer 2002;95(3):458–469.
9. Autier P, Boniol m, middleton r, et al. Advanced breast cancer inci-
dence following population-based mammographic screening. Ann Oncol.
10. Kalager m, Zelen m, Langmark F, Adami ho. effect of screening
mammography on breast-cancer mortality in Norway. N Engl J Med.
11. Autier P, Boniol m, Gavin A, Vatten LJ. Breast cancer mortality in neigh-
bouring european countries with different levels of screening but simi-
lar access to treatment: trend analysis of Who mortality database. BMJ.
12. Groenendijk rP, Bult P, tewarie L, et al. Screen-detected breast cancers
have a lower mitotic activity index. Br J Cancer. 2000;82(2):381–384.
13. esserman LJ, van ‘t Veer LJ, Perou C, et al. Biology of breast cancers that
are screen detected vs. locally advanced or young age should inform how
we approach early detection and prevention [abstract 6034]. Cancer Res.
2009;69(2 Suppl):Abstract 6034.
14. Black WC, haggstrom DA, Welch hG. All-cause mortality in randomized
trials of cancer screening. J Natl Cancer Inst. 2002;94(3):167–173.
15. Carney PA, miglioretti DL, yankaskas BC, et al. Individual and combined
effects of age, breast density, and hormone replacement therapy use on
the accuracy of screening mammography. Ann Intern Med. 2003;138(3):
16. Woloshin S, Schwartz Lm. the benefits and harms of mammography
screening: understanding the trade-offs. JAMA. 2010;303(2):164–165.
17. elmore JG, Barton mB, moceri Vm, Polk S, Arena PJ, Fletcher SW.
ten-year risk of false positive screening mammograms and clinical breast
examinations. N Engl J Med. 1998;338(16):1089–1096.
18. hubbard rA, Kerlikowske K, Flowers CI, yankaskas BC, Zhu W,
miglioretti DL. Cumulative probability of false-positive recall or biopsy
recommendation after 10 years of screening mammography: a cohort
study. Ann Intern Med. 2011;155(8):481–492.
19. Welch hG, Black WC. overdiagnosis in cancer. J Natl Cancer Inst.
20. Welch hG, Black WC. using autopsy series to estimate the disease “res-
ervoir” for ductal carcinoma in situ of the breast: how much more breast
cancer can we find? Ann Intern Med. 1997;127(11):1023–1028.
21. Zahl Ph, Gotzsche PC, maehlen J. Natural history of breast cancers
detected in the Swedish mammography screening programme: a cohort
study. Lancet Oncol. 2011;12(12):1118–1124.
22. Zackrisson S, Andersson I, Janzon L, manjer J, Garne JP. rate of
over-diagnosis of breast cancer 15 years after end of malmo mammo-
graphic screening trial: follow-up study. BMJ. 2006;332(7543):689–692.
by guest on October 29, 2015
JNCI | Commentaries 1547 Download full-text
23. Kalager m, Adami ho, Bretthauer m, tamimi rm. overdiagnosis of
invasive breast cancer due to mammography screening: results from the
Norwegian screening program. Ann Intern Med. 2012;156(7):491–499.
24. Jorgensen KJ, Gotzsche PC. overdiagnosis in publicly organised mam-
mography screening programmes: systematic review of incidence trends.
25. Kopans DB, Smith rA, Duffy SW. mammographic screening and “overdi-
agnosis.” Radiology 2011;260(3):616–620.
26. Jorgensen KJ, Keen JD, Gotzsche PC. Is mammographic screening jus-
tifiable considering its substantial overdiagnosis rate and minor effect on
mortality? Radiology 2011;260(3):621–627.
27. Screening for breast cancer: u.S. Preventive Services task Force recom-
mendation statement. Ann Intern Med. 2009;151(10):716–726.
28. mandelblatt JS, Cronin KA, Bailey S, et al. effects of mammography
screening under different screening schedules: model estimates of poten-
tial benefits and harms. Ann Intern Med. 2009;151(10):738–747.
29. Kopans DB. the 2009 uS Preventive Services task Force (uSPStF)
guidelines are not supported by science: the scientific support for mam-
mography screening. Radiol Clin North Am. 2010;48(5):843–857.
30. hendrick re, helvie mA. united States Preventive Services task Force
screening mammography recommendations: science ignored. Am J
31. houssami N, Ciatto S, macaskill P, et al. Accuracy and surgical impact of
magnetic resonance imaging in breast cancer staging: systematic review
and meta-analysis in detection of multifocal and multicentric cancer. J Clin
32. houssami N, hayes DF. review of preoperative magnetic resonance imaging
(mrI) in breast cancer: should mrI be performed on all women with newly
diagnosed, early stage breast cancer? CA Cancer J Clin. 2009;59(5):290–302.
33. mann rm, hoogeveen yL, Blickman JG, Boetes C. mrI compared to
conventional diagnostic work-up in the detection and evaluation of inva-
sive lobular carcinoma of the breast: a review of existing literature. Breast
Cancer Res Treat. 2008;107(1):1–14.
34. Kuhl CK, Schrading S, Leutner CC, et al. mammography, breast ultra-
sound, and magnetic resonance imaging for surveillance of women at high
familial risk for breast cancer. J Clin Oncol. 2005;23(33):8469–8476.
35. turnbull L, Brown S, harvey I, et al. Comparative effectiveness of mrI
in breast cancer (ComICe) trial: a randomised controlled trial. Lancet
36. Peters Nh, van eS, van den Bosch mA, et al. Preoperative mrI and surgi-
cal management in patients with nonpalpable breast cancer: the mo. Eur J
37. miller Bt, Abbott Am, tuttle tm. the influence of preoperative mrI on
breast cancer treatment. Ann Surg Oncol. 2012;19(2):536–540.
38. Solin LJ, orel SG, hwang Wt, harris ee, Schnall mD. relationship of
breast magnetic resonance imaging to outcome after breast-conservation
treatment with radiation for women with early-stage invasive breast carci-
noma or ductal carcinoma in situ. J Clin Oncol. 2008;26(3):386–391.
39. Große r, Kantelhardt eJ, Steer S, et al. Does routine use of preopera-
tive magnetic resonance imaging (mrI) in breast cancer influence the
uutcome? [abstract P2-08-13]. Cancer Res. 2011;15(Suppl):Abstract
40. Wedegartner u, Bick u, Wortler K, rummeny e, Bongartz
G. Differentiation between benign and malignant findings on
mr-mammography: usefulness of morphological criteria. Eur Radiol.
41. King tA, Sakr r, Patil S, et al. Clinical management factors contribute
to the decision for contralateral prophylactic mastectomy. J Clin Oncol.
42. morrow m, Waters J, morris e. mrI for breast cancer screening, diagno-
sis, and treatment. Lancet 2011;378(9805):1804–1811.
43. mcCready Dr, yong WS, Ng AKt, miller N, Done S, youngson B.
Influence of the new AJCC breast cancer staging system on senti-
nel lymph node positivity and false-negative rates. J Natl Cancer Inst.
44. Giuliano Ae, hunt KK, Ballman KV, et al. Axillary dissection vs no axillary
dissection in women with invasive breast cancer and sentinel node metas-
tasis: a randomized clinical trial. JAMA. 2011;305(6):569–575.
45. Galimberti V, Cole BF, Zurrida S, et al. update of international breast
cancer study group trial 23-01 to compare axillary dissection versus no
axillary dissection in patients with clinically node negative breast can-
cer and micrometastases in the sentinel node [abstract S3-1]. Cancer Res.
46. Giuliano Ae, mcCall L, Beitsch P, et al. Locoregional recurrence after sen-
tinel lymph node dissection with or without axillary dissection in patients
with sentinel lymph node metastases: the American College of Surgeons
oncology Group Z0011 randomized trial. Ann Surg. 2010;252(3):426–432.
47. mansel re, Fallowfield L, Kissin m, et al. randomized multicenter trial of
sentinel node biopsy versus standard axillary treatment in operable breast
cancer: the ALmANAC trial. J Natl Cancer Inst. 2006;98(9):599–609.
48. houssami N, Abraham LA, miglioretti DL, et al. Accuracy and out-
comes of screening mammography in women with a personal history of
early-stage breast cancer. JAMA. 2011;305(8):790–789.
49. Ghezzi P, magnanini S, rinaldini m, et al. Impact of follow-up testing on
survival and health-related quality of life in breast cancer patients. A mul-
ticenter randomized controlled trial. the GIVIo Investigators. JAMA.
50. Palli D, russo A, Saieva C, et al. Intensive vs clinical follow-up after
treatment of primary breast cancer: 10-year update of a randomized trial.
51. Khatcheressian JL, Wolff AC, Smith tJ, et al. American Society of Clinical
oncology 2006 update of the breast cancer follow-up and management
guidelines in the adjuvant setting. J Clin Oncol. 2006;24(31):5091–5097.
52. Aebi S, Davidson t, Gruber G, Castiglione m. Primary breast can-
cer: eSmo Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol. 2010;21(Suppl. 5):v9–14.
53. Panageas KS, Sima CS, Liberman L, Schrag D. use of high technology
imaging for surveillance of early stage breast cancer. Breast Cancer Res Treat.
54. Wo Jy, Chen K, Neville BA, Lin Nu, Punglia rS. effect of very small
tumor size on cancer-specific mortality in node-positive breast cancer. J
Clin Oncol. 2011;29(19):2619–2627.
55. hernandez-Aya LF, Chavez-macgregor m, Lei X, et al. Nodal status and
clinical outcomes in a large cohort of patients with triple-negative breast
cancer. J Clin Oncol. 2011;29(19):2628–2634.
Affiliations of authors: Division of Medical Oncology and Hematology,
Princess Margaret Hospital and the University of Toronto, Toronto, Canada
(EA, PLB, AO); Albacete University Hospital and AECC Unit, Albacete, Spain
(AO); Sector of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana,
by guest on October 29, 2015