Keywords
breast cancer - PET - subtype - neoadjuvant
Introduction
Breast cancer is one of the diseases that may cause death in women. In the United
States, there are 240,000 new cases per year, and approximately 40,000 patients have
breast cancer-related deaths. One in eight women face breast cancer throughout their
lifespan.[1] The disease was diagnosed with conventional techniques, such as ultrasonography
(USG), mammography, and computerized tomography (CT). 18F Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) was mostly used to determine the treatment method of the disease.[2] Studies have revealed that 18F-FDG PET/CT is effective in breast cancer treatment management and disease staging.[3]
18F-FDG PET/CT has not been found effective in early-stage breast cancer (stage I–II).[4] In previous studies, 18F-FDG PET/CT staging and CT and USG staging are compared. 18F-FDG PET/CT cannot completely replace USG and CT due to inadequate sensitivity.[5] According to the European Society for Medical Oncology (ESMO) guidelines, clinically
positive lymph node, tumor size of 5 cm and more, aggressive tumor biology, and clinical
findings to suggest metastasis are indications for CT, USG, magnetic resonance, and
bone scintigraphy examinations. If sufficient results cannot be obtained from these
tests, 18F-FDG PET/CT is applied, which is a low level of evidence.[6] Patients may not receive appropriate treatment when 18F-FDG PET/CT is not performed. In our study, we collected data to find out number
of these patients. As with all other treatments, it was aimed to provide the patients
with the most benefit and do the least harm surgically. The known benefits of preoperative
staging for patients enable neoadjuvant therapy and operation to be performed at the
most convenient time, preventing possible complications in patients and reducing morbidity.
For example, it is challenging to fight lymphedema developing after axillary lymph
node dissection. In addition, arm, shoulder pain, nerve damage, hematoma, and shoulder
motion limitation deteriorating quality of life and increasing morbidity.[7]
18F-FDG PET/CT helps make neoadjuvant treatment decisions by medical oncologists, but
it is controversial whether 18F-FDG PET/CT guides for excision width, sentinel lymph node, and the need for axillary
dissection for surgical oncologists.[8]
[9] In locally advanced breast cancer cases, neoadjuvant therapy is administered for
breast-conserving surgery and to enable less resection for patients requiring extensive
resection. It also aims to control the disease before surgery for hormone receptor-positive
patients. It is definitely the primary treatment for advanced-stage patients with
distant metastasis.[10]
In our study, we aimed to investigate to what extent the treatment plan of these patients
has changed after 18F PET/CT in patients who have been diagnosed with breast cancer and whose surgery
decision has been made, and the reasons for this change.
Materials and Methods
All cases (n = 151) with 18F-FDG PET/CT examination were included in this study. These female patients were between
41 and 85 years of age. Patients were decided to undergo surgery treatment by a surgeon
before 18F-FDG PET/CT examination. These patients were diagnosed with breast cancer and admitted
to Mersin University Hospital Breast Outpatient Clinic between January 2016 and December
2019. Our surgical treatment criteria were as follows: patients who were not locally
advanced (T1 or T2 lesions), patients who were planned for breast-conserving surgery
with a low tumor/breast ratio, patients with T3-T4 lesions, and planned modified radical
mastectomy patients without chronic disease for which surgical treatment was contraindicated.
Sentinel lymph node biopsy was performed in all patients. Patients with positive lymph
nodes underwent axillary dissection, regardless of neoadjuvant therapy. Demographic
features of these patients and whether they received neoadjuvant therapy were evaluated.
Pathology results of the patients, tumor size, type, subtypes, side of the disease,
and centricity were evaluated within the variables. In addition, lesion maximum standard
uptake value (SUVmax), axilla 18F-FDG PET/CT involvement, axilla SUVmax and distant metastasis findings were recorded,
sentinel lymph node involvement was also evaluated.
Normality controls of continuous measurements were tested using the Shapiro–Wilk test.
Mann–Whitney U test was used for group comparisons of continuous measurements. Minimum,
maximum, median, and 25 to 75% were given as descriptive statistics for lesion size
and SUVmax level, axilla SUVmax level, and Ki 67 parameters. Pearson chi-squared and likelihood ratio chi-squared tests were used
for the differences between categorical variables. Number and percentage values were
given as descriptive statistics. Statistical significance was taken as p < 0.05.
Results
The direction, centricity, axillary involvement in 18F-FDG PET/CT, presence of distant metastasis, and neoadjuvant status in current patients
are shown in [Table 1].
Table 1
Features of patients
|
Feature
|
n = 151
|
%
|
|
Side of tumor
|
Right
|
67
|
44.4
|
|
Left
|
75
|
49.7
|
|
Bilateral
|
9
|
6.0
|
|
Centricity
|
Unicentric
|
103
|
68.7
|
|
Multicentric
|
47
|
31.3
|
|
İnvolvement axilla in PET/CT
|
No
|
76
|
50.3
|
|
Yes
|
70
|
46.4
|
|
Uncertain
|
5
|
3.3
|
|
Distant metastasis
|
No
|
128
|
84.8
|
|
Yes
|
23
|
15.2
|
|
Neoadjuvant therapy
|
No
|
123
|
81.5
|
|
Yes
|
28
|
18.5
|
Abbreviation: PET/CT, positron emission tomography/computed tomography.
The average age of 151 patients included in this study was calculated as 57.6 ± 11.4.
One-hundred twenty-three (81.5%) of these patients did not receive neoadjuvant therapy
and 28 (18.5%) received neoadjuvant therapy. It was determined by 18F-FDG PET/CT examination. The lymph nodes present in the axilla before neoadjuvant
treatment were not seen in 14% of the patients (n: 5) during the surgery performed after the treatment. These patients were protected
from undesirable effects by axillary dissection. Complete response was seen with neoadjuvant
therapy in 10% (n: 3) patients and these patients were not operated on. One patient (3.5%) died during
the neoadjuvant treatment phase. Accordingly, 18F-FDG PET/CT was performed on patients who were decided to undergo surgical treatment,
and the treatment plan changed to neoadjuvant therapy in 18% of patients. When the
groups with and without neoadjuvant treatment were examined concerning average age,
there was a statistically significant difference between them (p = 0.001). The average age of the treated group was 51.5 ± 9.6, and the average age
of the nontreated group was 59.0 ± 11.3. The mean age of the patients who received
neoadjuvant therapy by changing the treatment plan was significantly lower ([Table 2]).
Table 2
Age of patients
|
Neoadjuvant
|
n
|
Mean
|
SD
|
SE
|
p-Value
|
|
Age
|
No
|
123
|
58.99
|
11.311
|
1.020
|
< 0.01
|
|
Yes
|
28
|
51.46
|
9.617
|
1.817
|
Abbreviations: SD, standard deviation; SE, standard error.
The differences between those who received and did not receive neoadjuvant therapy
concerning continuous parameters are given in [Table 3]. When [Table 3] was examined, differences were found significant regarding lesion size and axilla
SUVmax parameters (p < 0.0001 and p = 0.010, respectively). In patients who were decided to receive neoadjuvant therapy
by changing the treatment plan after 18F-FDG PET/CT, SUVmax values of the lymph nodes involved in the axilla of these patients
were significantly higher in 18F-FDG PET/CT. There was no significant difference in Ki-67 percentages ([Table 3]).
Table 3
Characteristics of lesions of those who received and did not receive neoadjuvant therapy
|
Not neoadjuvant
(n = 123)
|
Neoadjuvant
(n = 28)
|
p-Value
|
|
Min–Max
|
Median
(% 25–75)
|
Min–Max
|
Median
(% 25–75)
|
|
Size (mm)
|
5–100
|
20
(15–27)
|
7–98
|
35
(20–50)
|
< 0.001
|
|
Lesion SUVmax
|
1–275
|
7
(4.68–11.02)
|
1.8–34
|
8
(4.9–14.3)
|
0.300
|
|
Axilla SUVmax
|
0–27
|
4
(2.29–9.62)
|
2.29–23
|
7
(5–12.3)
|
0.010
|
|
Ki67
PI (%)
|
4–80
|
20
(15–40)
|
5–70
|
30
(15–50)
|
0.185
|
Abbreviation: SUVmax, maximum standard uptake value.
No significant relationship was found between the disease on the right, left or bilateral
breast and patients whose treatment plan was changed. There was no significant difference
concerning the pathological type of the tumor. In most cases, the pathology was reported
as nonspecific type invasive ductal carcinoma (82.1%). Four percent were lobular carcinomas.
There was no difference in terms of the tumor as ductal or lobular and other types
of ductal carcinoma as papillary, medullary, mucinous, tubular, and cribriform. However,
a difference was found regarding subtypes.
When the subtypes of luminal A, luminal B, Her 2 Neu, and triple negative were compared
among themselves, the subtype of the lesion was significantly higher as luminal A
and B in patients who were decided to treat using neoadjuvant therapy. The breast
lesions of these patients, which were decided to have an operation, were multicentric.
While breast-conserving surgery and sentinel lymph node excision were planned for
other patients, mastectomy was recommended for these patients (31.3%), whose mass
was multicentric. Treatment plan changes were significantly associated with being
multicentric. In 18F-FDG PET/CT, lymph node involvement in the axilla or out of axilla was significantly
higher in cases where neoadjuvant treatment decision was taken. There was also a significant
correlation with sentinel lymph node positivity. Distant metastasis in patients was
significantly higher in cases where neoadjuvant treatment decision was taken. There
was no significant relationship between E-cadherin or pancreatin staining in tumor
cells and treatment change ([Table 4]).
Table 4
Pathologic features of cases
|
Neoadjuvant (%)
|
Not neoadjuvant (%)
|
p-Value
|
|
+
|
−
|
+
|
−
|
|
|
Axillary lymph node involvement (%)
|
34.3
|
10.7
|
37.4
|
59.3
|
< 0.001
|
|
Extraaxillary lymph node
|
69.2
|
30.8
|
25.4
|
74.6
|
< 0.001
|
|
Sentinel lymph node
|
76.9
|
23.1
|
47.5
|
52.5
|
0.006
|
|
Multicentric
|
53.6
|
46.4
|
26.2%
|
73.8
|
0.005
|
|
Distant metastasis
|
50
|
50
|
7.3
|
92.7
|
< 0.001
|
|
E-cadherin
|
83.3
|
16.7
|
93.4
|
6.6
|
0.147
|
|
Pancreatin
|
33.3
|
667
|
29.7
|
70.3
|
0.897
|
|
Luminal A
|
32
|
59.5
|
0.015
|
|
Luminal B
|
56
|
23.4
|
0.021
|
|
Her 2 Neu
|
4
|
5.4
|
0.393
|
|
Triple negative
|
8
|
11.7
|
0.256
|
Discussion
With 18F-FDG PET/CT examination important advantages are provided concerning treatment planning
in breast cancer patients. Distant metastases and axillary involvement are some of
them. In the review of Bahl et al, it was emphasized that patients were saved from
many invasive procedures with the measurements obtained with 18F-FDG PET/CT. An example of this is determining the stage of the patient more clearly
with the detection of axillary involvement or distant metastasis and changing the
treatment plan accordingly.[11] In our study, distant metastasis and axillary involvement were more common in patients
whose treatment plan was changed after 18F-FDG PET/CT examination, as a significant difference. SUVmax values of the lymph
nodes involved in the axilla were significantly higher in patients who had a neoadjuvant
treatment decision. 18F-FDG PET/CT also shows axilla involvement and provides an advantage in staging the
patient. Robertson et al in their review stated that there are not enough data for
the opinion of using 18F-FDG PET/CT instead of sentinel lymph node sampling.[12] In our study, most patients receiving neoadjuvant therapy had extraaxillary lymph
node involvement, and this difference was found significant. Bernsdorf et al compared
18F-FDG PET/CT with conventional diagnostic methods in 103 patients with a breast cancer
mass of 2 cm or more. Extraaxillary lymph node involvement was significantly higher
with 18F-FDG PET/CT.[13] Axilla SUVmax was significantly higher in our patients planned to be administered
neoadjuvant therapy. Although valuable information for preoperative staging is obtained
with this examination, which is very sensitive for axillary macrometastases, Guller
et al in their study concluded that 18F-FDG PET/CT misses micrometastases and is not yet fully sufficient for preoperative
staging.[14] In the study in which Senkus et al examined the ESMO guideline, it was stated that
the preexisting sentinel lymph node could not be found after neoadjuvant therapy and
this would result in false negativity. Thus, it has been emphasized that sentinel
lymph node biopsy is still the gold standard.[15] Some of the subtypes of breast cancer have been associated with SUVmax in 18F-FDG PET/CT. However, it has been shown that there is a correlation between SUVmax
and tumor size and it is also associated with axillary lymph node metastasis.[16] The lesion SUVmax of our patients for whom neoadjuvant treatment decision was made
after 18F-FDG PET/CT examination did not differ from those who did not decide on neoadjuvant
treatment. However, it was found that there was a correlation between the neoadjuvant
treatment decision and the lesion size. In their study, Kajáry et al examined the
subtypes, proliferation rate, and FDG uptake rate of the tumor. Uptake was also high
in cases with high grade and high proliferation rate with negative hormone receptors.
They even showed that Her2 + subtype was more aggressive.[17] In contrast, in our study, patients with neoadjuvant therapy decisions were shown
to have more luminal A and B. Also, no relation could be shown with the proliferation
rate. In our study, while there was a significant relationship between the decision
of neoadjuvant treatment and low age, no relation was found between the pathological
type of the tumor. There was no significant relationship between whether the tumor
was on the right or the left. In a study evaluating the effects of 18F-FDG PET/CT findings on treatment, tumor side, age, and pathological type did not
affect treatment.[18]
Conclusion
Conventional imaging examinations are used in patients with breast cancer. These examinations
may not be sufficient to determine advanced disease requiring neoadjuvant treatment.
With 18F-FDG PET/CT examination, these advanced stage patients are not overlooked. In our
study, approximately one in five patients, treatment plan changed after 18F-FDG PET/CT examination. Further clinical studies are needed for 18F-FDG PET/CT to be accepted as the standard in breast cancer staging.
