The evolution of the role of surgery in the management of breast
cancer lung metastasis
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University and Massey Cancer Center, Richmond, Virginia, USA
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Review Article
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Abstract
Breast cancer is the second leading cause of cancer death among women in the United States. Patients with metastatic
disease have a median survival of 12 to 24 months and most present with disseminated disease; however, some present with
isolated pulmonary metastases which may benefit from surgical resection. Although the initial experience with resection
of pulmonary metastases in the late 19th and early 20th centuries produced some encouraging results, patient selection
criteria for resection were strict until the mid-1960’s when a significant improvement in survival resulted from aggressive
management of pulmonary metastasis in osteosarcoma patients. The application of this approach to breast cancer patients
similarly produced encouraging results, with five year survival rates in select patients ranging from 36-54%, but this was
not without controversy. In this review, we discuss the evaluation of the breast cancer patient with a pulmonary nodule, the
historical evolution of the role of surgery in the management of pulmonary metastasis, as well as the latest evidence to guide
patient selection and management.
Key words
Breast cancer lung metastasis
J Thorac Dis 2012;4(4):420-424. DOI: 10.3978/j.issn.2072-1439.2012.07.16 |
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Introduction
Breast cancer is the second leading cause of cancer death among
women in the United States (1). Breast cancer progresses from
local tumor invasion, to regional lymph nodes, and then to
distant organs such as the lung, brain, bone and liver. In fact,
breast cancer is considered a systemic disease even during early
stages of the disease. Patient mortality in breast cancer is due to
metastatic disease with a median survival in metastatic breast
cancer patients of only 12-24 months (1,2). Unfortunately,
metastatic disease in breast cancer is often widespread, in which
case surgery offers no benefit to control disease or prolong
survival. However, there are instances where patients present
with limited metastatic disease for which surgical resection of
the metastatic lesion should be considered.
The challenge for clinicians is to determine which patients
will benefit from surgical intervention. When appropriately
selected, for example, a series of patients with metastatic breast
cancer demonstrated a 0.4% rate of solitary lung metastasis
amenable to complete resection with a subsequent five
year survival of 35.6% after surgery (3). As the experience
with pulmonary metastasectomy has increased over the
last 130 years, the approach to the breast cancer patient with
pulmonary metastasis has evolved with an important role for
surgery in select cases. In this review, we discuss the approach to
the breast cancer patient with a pulmonary nodule, the evolution
of the role of surgery in the management of pulmonary metastasis,
and the latest evidence to guide patient selection and management.
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Evaluation of the breast cancer patient with a pulmonary nodule
The breast cancer patient who presents with a pulmonary
mass must be evaluated for metastatic disease, which can pose
a diagnostic challenge because of nonspecific radiographic
findings. It should be noted that most lung metastases are
asymptomatic and found incidentally. Symptoms only occur in
15-20% of patients, which usually reflects proximity to central
airways, such as cough, hemoptysis or dyspnea (4). Chest
computed tomography is the standard imaging modality to
evaluate a pulmonary nodule, and because of the high likelihood of disseminated disease, a scan within 4 weeks of resection is
required (5,6). In addition, positron emission tomography
should also be considered as an additional modality to determine
if there is evidence of other metastatic disease not detected on
physical examination or other imaging (5,6).
Histologic diagnosis is an important factor in management
because of the possibility of a primary lung cancer or a benign,
inflammatory, or infectious pulmonary process in a patient with
breast cancer. In breast cancer patients with lung nodules, series
have reported a rate of 34.2-75% of metastatic lesions, 11.5-
48.1% of primary lung cancer, and 13.5-17.7% of benign lesions
(7,8). Tissue diagnosis can be obtained by imaging guided
biopsy (radiologic or endoscopic) or by surgical excisional
biopsy (6). The choice of approach depends on the location
and size of the mass, the experience of the institution, and the
preference of the patient.
Once the mass is diagnosed as a metastatic lesion, there
are several considerations required before proceeding with
surgery. First, it must be determined if the primary tumor can
be controlled prior to or contemporaneously with the lung
metastasis (6). Second, there must be a thorough evaluation
for extrathoracic disease which would otherwise prevent any
benefit from controlling thoracic disease (6). Third, the number
and resectability of pulmonary disease as well as the ability of
the patient to physiologically tolerate resection as opposed to
other treatment alternatives must be considered (6). Fourth, the
disease-free interval from resection of the primary tumor and
development of metastatic disease as well as the tumor doubling
time should be considered in evaluation of the potential benefits
of resection (6). How clinicians have weighed these factors
in patient selection has changed over time as experience has
evolved in the management of these lesions.
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Historical evolution of patient selection criteria
The first resections of pulmonary metastasis were reported in the age
of Billroth in the 1880’s in Vienna by Dr. Weinlechner and Zurich
by Dr. Kronelin (9), and the first in North America in the 1930’s
by Drs. Barney and Churchill where a patient with metastatic renal
carcinoma survived disease free for over 20 years (4). However,
from 1940-1960 resection of isolated pulmonary metastasis was
restricted to specialized centers in only highly selected patients (4).
At Memorial Sloan-Kettering Cancer Center (MSKCC), patients
had to have a long disease free interval between primary tumor
resection and presenting with metastatic disease, and had to have
only three lesions or fewer in one lung, or else surgery was thought
to provide no benefit (10). Applying such criteria, only 25 such
patients were treated surgically from 1940-1965 (10).
During the same time frame the Mayo Clinic also applied
similar restrictions and treated 205 patients surgically (11).
However, a review of outcomes demonstrated that during that
era patients with osteogenic sarcoma with pulmonary metastasis
had an 81% five year mortality rate due to pulmonary metastasis
when not resected (12,13). Therefore, in the 1960’s a more
aggressive approach was applied to the management of lung
metastases in osteogenic sarcoma which increased five year
survival from 17% to 32% in 22 consecutive patients at MSKCC
who had undergone 59 thoracotomies to achieve complete
resection of pulmonary disease (6). Because of this experience
in the 1960’s, since the 1970’s a more aggressive approach was
applied to the management of lung metastases for other cancers,
including breast cancer (12,13).
The experience at M.D. Anderson from 1981 to 1991 in 44
women with metastatic breast cancer demonstrated a five year
survival rate of 49.5% when all pulmonary metastatic disease
was removed (14). When compared to a median survival of
12 to 24 months, those outcomes in breast cancer patients
further supported the more aggressive approach applied since
the 1970’s in patients who could tolerate thoracic surgery and
pulmonary resections. A Japanese series of 90 patients treated
between 1960 and 2000 demonstrated 54% and 40% five year
and ten year survival rates in patients with complete resection
of lung metastases (15). That study also demonstrated that
disease free interval and initial stage at diagnosis were important
prognostic factors (15). The International Registry of Lung
Metastases published five year survival rates after complete
versus incomplete pulmonary metastasectomy in 467 breast
cancer patients was 38% versus 16% (16). In the complete
resection group five, ten and fifteen year survival rates were
38%, 22% and 20%, respectively (16). When the authors
further selected patients by subgroup analysis applying disease
free interval, number of metastases, and complete resection as
additional criteria, the five year survival rate was 50%, ten and
fifteen year survival rates were both 26%, and median survival
was 59 months (16). However, in the era of multimodality
therapy, there has been controversy whether surgery has been
the determining factor for this observed survival benefit.
A German series from 1998-2007 evaluated 47 patients
with metastatic breast cancer who underwent pulmonary
metastasectomy and found that the number of metastases, tumor
stage at initial presentation, complete resection and pleural/chest
wall involvement did not prognosticate survival (2). Instead,
estrogen receptor and HER2-neu expression predicted survival
with a five year survival rate of 76% versus 12% accordingly for
estrogen receptor positive versus negative patients, and similar
statistically significant differences by HER2-neu expression (2).
Their interpretation of the findings from other series, such as
the M.D. Anderson and Japanese series cited above (14,15),
was that hormone receptor status was unknown in many of
these patients or that the excellent outcomes were due to highly
selected patients as illustrated by the importance of disease
free interval and initial tumor stage (2). Their implication was that such prognostic factors were essentially a proxy for such
factors as estrogen receptor or HER2-neu expression status, even
though their own results did not demonstrate any correlation to
the prognostic factors reported in the other studies. However,
the limitations of their study did not allow for conclusions to
be drawn on the benefits of resection of lung metastasis versus
chemotherapy alone (2).
Although the authors conceded that their results were limited
by small sample size and a single institution retrospective design,
they hypothesized that patients with minimal tumor burden and a
complete response to chemotherapy may receive the most benefit
from surgical resection (2). However, their study was limited in
its ability to provide specific guidelines by estrogen receptor or
HER2-neu expression status. Instead, the main contribution of
their findings was their suggestion that the surgical approach to
lung nodules in breast cancer include (I) diagnosing and treating
other primary lung lesions and (II) establishing the histology,
grade, estrogen receptor and HER2-neu expression status to
guide further medical management (2). When those results
and conclusions are taken together with reports that disease
free interval, initial tumor stage, and tumor doubling time are
important prognostic factors, there may be a greater role in
the future for these and other biological markers in selecting
the appropriate candidates for surgical management as cancer
biology is better understood. As greater advances are made, the
role for pulmonary metastasis resection may evolve further for
tumor genetic profiling of resected lung metastases in order
to further guide medical therapy focused on specific targets
to prolong survival. As future therapies are developed, it is
conceivable that neoadjuvant therapy may also play a future role
in converting patients with unresectable metastatic disease to
patients in whom surgical resection may become an option by
decreasing the size of pulmonary lesions.
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Surgical approach
With technological advances in cardiothoracic surgery
and anesthesia, there has been a proliferation of surgical
interventions available to the thoracic surgeon. In a recent survey
of European surgeons the approaches and preferences for each
included anterolateral thoracotomy (36.3%) video-assisted
thoracic surgery (28.8%), posterior muscle sparing thoracotomy
(26%), posteriolateral thoracotomy (22.6%), horizontal axillary
thoracotomy (10.3%, vertical axillary thoracotomy (6.9%),
steronotomy (1.4%), bilateral staged thoracotomy (66.2%),
single stage sternotomy (26.9%), single stage bilateral sequential
thoracotomy (19.3%), bilateral staged versus single stage videoassisted
thoracic surgery (12.4%, 7.6%), and clamshell single
stage thoracotomy (7.6%) (17).
Although there have been numerous studies which
have demonstrated no difference in survival rates between
thoracoscopic and open approaches, the determining factor
among surgeons was whether there was a need for palpation
to localize the lesion (6,17). There has yet to be developed an
adequate intraoperative localization alternative to palpation,
with studies demonstrating failure rates as high as 56% when
comparing CT scan combined with thoracoscopy to intraoperative
palpation (6,18). One option to enjoy both the advantages of
minimally invasive technology and the increased sensitivity
of manual palpation may be our hybrid technique for videoassisted
thoracoscopic surgery (VATS) (19,20). As described in
detail previously, our hybrid-VATS utilizes an 8-10 cm “utility
incision”, most commonly in the fifth interspace, in addition to
a thoracoscopy port placed in the eighth interspace (19). The
original intention of this utility incision was to enable direct
visualization, an additional direct light source from headlamp,
conventional instrument access, and immediate direct access in
case of emergency such as massive bleeding; however, certainly
manual palpation for localization can be added to this list. We
have reported our experience of 1,170 cases that underwent
this technique and demonstrated that it is safe and feasible at
community hospital-based practices, which implicates that with
our technique it may broaden the indication for this disease (20).
The question of staging resections for bilateral disease
is determined by how well the patient can tolerate a single
bilateral procedure and the length of recovery required between
procedures (6,21). For patients who require staged procedures,
it is important to consider once again that beyond an interval
of 3-6 weeks the patient must be re-evaluated for progression of
metastatic disease with interval computed tomography (21).
There is far less controversy regarding the extent of resection
required with 89% of the respondents reporting margin
free resection achieved by stapled wedge resection (17).
Anatomic segmentectomy and lobectomy rates were 4.8% and
2.1%, respectively (17). Furthermore, over 60% considered
pneumonectomy to be a relative contraindication and 23%
to be an absolute contraindication to surgical management of
metastatic disease (17). In fact, among all pulmonary metastatic
resections the International Registry reported a rate of 2.6% with
a perioperative mortality rate of 4%. Similar rates were reported
in North American centers as well (6). The selection criteria
for pneumonectomy are quite strict, limited to a patient with
a long disease free interval who has a single central pulmonary
lesion with a previous soft tissue or bone tumor and no
previous pulmonary resections (22). Because of the results and
controversies in the surgical management of pulmonary breast
cancer metastases, pneumonectomy has had no role (6).
The role of mediastinal lymph node sampling and dissection
in the management of pulmonary metastases is controversial (6).
Based on their series, the Mayo clinic advocates systematic
implementation of routine mediastinal lymphadenectomy
in patients undergoing surgical management of pulmonary metastasis (6). First, they cite a high rate of positive lymph
nodes found after dissection in their series (26%) and in the
International Registry (22%) (6,23). Second, in their series and
other series lymph node status was an important prognostic
indicator in multiple tumor types, and thus may further guide
management (6). However, they concede that excluding patients
from subsequent surgical therapy because of lymph node status is
even more controversial than lymph node staging itself (6). In fact,
the International Registry only reported a lymph node dissection
or sampling rate of only 4.6% and a survey of European surgeons
demonstrated that only 3.4% of respondents routinely did
so (17). Furthermore, in the series of breast cancer patients
undergoing pulmonary metastasectomy, mediastinal lymph
node status was not reported as a prognostic factor. Although
this may be due to the fact that it is not routinely performed,
even the reported Mayo Clinic series lymph node status was
not a significant prognostic indicator among their treated breast
cancer patients. Therefore, routine lymph node staging in this
patient population remains controversial.
Surveillance after pulmonary metastasectomy should include
repeat computed tomography every six months for two years and
then yearly for at least five years (5,6). However, if lung palpation
was not performed or if tumor doubling time was short, then
the patient may be at a higher risk of recurrence and thus may
require more frequent surveillance because of the potential for
radiographically occult lesions and a subsequently higher rate
of recurrence or metachronous lesions (5,6). Unfortunately,
recurrent pulmonary metastasis is common, with rates
reported as high as 53% among all cancers and a median time
to recurrence of 10 months (5,6). Evaluation of these patients
entails the same principles described above. In breast cancer
patients the International Registry reported 19 cases of resection
of recurrent metastases which resulted in a five year survival
rate of 53% (16). While the sample sizes are small and there
may be an element of survivor bias confounding the results,
the European and North American centers advocate surgical
management in select patients (6,16).
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Conclusions
In summary, breast cancer is a leading cause of cancer death
among women and metastatic disease is the leading cause
of mortality. Although the great majority of patients with
metastatic breast cancer have disseminated disease, there
is a small subgroup of patients who present with isolated
pulmonary lesions who may benefit from surgical management.
In addition to the standard preoperative approach to patients
with pulmonary nodules, the breast cancer patient presents with
unique characteristics of importance for clinicians to consider.
Over the last 130 years there has been a shift towards aggressively
managing patients who meet selection criteria, but this has not
been without controversy. Although debate continues regarding
the factors which determine the survival benefits for patients
who meet criteria for resection of pulmonary metastases, as
research advances in neoadjuvant therapy and tumor biology,
surgical intervention promises to further guide the management
of these patients, particularly in the evolving new era of targeted
and personalized therapy.
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Acknowledgements
Kazuaki Takabe is supported by United States National
Institute of Health grants (R01CA160688 and K12HD055881)
and Susan G. Komen for the Cure (Investigator Initiated
Research Grant (222224) and Career Catalyst Research Grant
KG090510).
Disclosure: The authors declare no conflict of interest. |
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References
Cite this article as: Rashid OM, Takabe K. The evolution
of the role of surgery in the management of breast cancer
lung metastasis. J Thorac Dis 2012;4(4):420-424. doi:
10.3978/j.issn.2072-1439.2012.07.16
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