Relationship Between Axillary Metastasis and Tumoral
Response and Biomarkers in Breast Cancer Patients Who Received Neoadjuvant
Chemotherapy
Neoadjuvan
Kemoterapi Almış Meme Kanseri Hastalarında Aksiller Metastaz ve Tümöral Yanıtın
Biyobelirteçlerle İlişkisi
Uğraş Daban1
1Bursa City Hospital, Department of Surgical Oncology, Bursa, Türkiye
ABSTRACT
Introduction: The molecular subtype of the disease is related
to the patient's clinical course, response to chemotherapy, and pathological
response rates.
Objective: The molecular subtype of the disease is related
to the patient's clinical course, response to chemotherapy, and pathological
response rates. This research aimed to elucidate the relationship between
neoadjuvant chemotherapy and treatment response in breast cancer patients who
received neoadjuvant therapy and were evaluated with axillary lymph nodes after
surgery.
Method: This retrospective analysis investigated the
relationship between axillary metastasis status, tumoral and pathological
complete response status, and molecular subtypes in 103 patients who received
neoadjuvant chemotherapy for breast cancer and whose axillary lymph nodes were
evaluated. Patients' age, menopause status, type of surgery, tumor side,
axillary involvement, nodal involvement, T staging, histopathological type and
subtypes, tumor receptors, perineural invasion, lymphovascular invasion, and
tumor necrosis data were obtained from hospital records.
Results: A total of 103 female patients were included in
the study. Histopathologically, the most common subtype was invasive ductal
carcinoma (89.3%), and hormone receptor status was determined as ER-positive
(73.8%) and PR positive (63.1%). Molecular subtypes were defined as Luminal B
(36.9%) and Luminal A (34%), and the most common tumor grade was grade 2
(57.3%). The most common surgical method after neoadjuvant chemotherapy was
radical mastectomy (97.1%). Among the cancer subgroups evaluated after
neoadjuvant therapy, the most frequent subgroups with tumoral complete response
were HER2 positive (47.4%), and triple-negative (45.5%) groups, the most
frequent groups showing nodal complete response were HER2 positive (47.4%) and
triple negative (63.6%) groups. The most frequent subgroups showing
pathological complete response were HER2 positive (21.1%) and triple negative
(36.4%) groups.
Conclusion: Breast cancer genetic subgroups are associated with treatment responses
following neoadjuvant chemotherapy. Among breast cancer subgroups, the
subgroups that provide the best tumoral, nodal, and pathological complete
response to neoadjuvant chemotherapy are HER2-positive breast cancers and
triple-negative breast cancer types.
Keywords: Breast Cancer,
Neoadjuvant Chemotherapy, Tumor Subtype, Tumor Biology, Pathological Response.
ÖZET
Giriş: Hastalığın moleküler alt tipi hastanın klinik
seyri, kemoterapiye yanıtı ve patolojik yanıt oranları ile ilişkilidir.
Amaç: Bu araştırma, neoadjuvan tedavi alan ve
ameliyattan sonra aksiller lenf nodları ile değerlendirilen meme kanseri
hastalarında neoadjuvan kemoterapi ile tedavi yanıtı arasındaki ilişkiyi
açıklamayı amaçlamaktadır.
Yöntem: Bu retrospektif analiz, meme kanseri için
neoadjuvan kemoterapi alan ve aksiller lenf nodları değerlendirilen 103 hastada
aksiller metastaz durumu, tümöral ve patolojik tam yanıt durumu ve moleküler
alt tipler arasındaki ilişkiyi araştırmıştır. Hastaların yaşı, menopoz durumu,
ameliyat türü, tümör tarafı, aksiller tutulum, nodal tutulum, T evrelemesi,
histopatolojik tip ve alt tipler, tümör reseptörleri, perinöral invazyon,
lenfovasküler invazyon ve tümör nekrozu verileri hastane kayıtlarından elde
edildi.
Bulgular: Çalışmaya toplam 103 kadın hasta dahil edildi.
Histopatolojik olarak en sık görülen alt tip invaziv duktal karsinom (%89.3)
iken, hormon reseptör durumu ER-pozitif (%73.8) ve PR pozitif (%63.1) olarak
belirlendi. Moleküler alt tipler Luminal B (%36.9) ve Luminal A (%34) olarak
tanımlandı ve en sık görülen tümör derecesi 2 (%57.3) olarak belirlendi.
Neoadjuvan kemoterapi sonrası en sık uygulanan cerrahi yöntem radikal
mastektomi (%97.1) idi. Neoadjuvan tedavi sonrası değerlendirilen kanser alt
grupları arasında tümöral tam yanıt gösteren en sık alt gruplar HER2 pozitif
(%47.4) ve üçlü negatif (%45.5) gruplardı, nodal tam yanıt gösteren en sık
gruplar HER2 pozitif (%47.4) ve üçlü negatif (%63.6) gruplardı. Patolojik tam
yanıt gösteren en sık alt gruplar HER2 pozitif (%21.1) ve üçlü negatif (%36.4)
gruplardı.
Sonuç: Meme kanseri genetik alt grupları neoadjuvan kemoterapi sonrası tedavi
yanıtlarıyla ilişkilidir. Meme kanseri alt grupları arasında, neoadjuvan
kemoterapiye en iyi tümöral, nodal ve patolojik tam yanıtı sağlayan alt gruplar
HER2 pozitif meme kanserleri ve üçlü negatif meme kanseri tipleridir.
Anahtar Kelimeler: Meme Kanseri,
Neoadjuvan Kemoterapi, Tümör Alt Tipi, Tümör Biyolojisi, Patolojik Yanıt.
INTRODUCTION
According to the World Health
Organization (WHO) data, it is stated that cancer is the second cause of death
over the globe. Lung cancer in men and breast cancer in women are the most
common cancer types, and breast cancer is the fifth most common type of cancer
among all cancer deaths (1). In Turkey, breast cancer is seen at a frequency of
20/100.000 in our eastern region and 40-50/100.000 in our western region. It is
stated that factors such as excessive hormone replacement therapy, shorter
lactation periods, differences in nutritional habits, and adopting a Western
lifestyle are influential in this situation. According to the National Breast
Cancer Database, the incidence of breast cancer in women in Turkey was reported
as 26% in 2020, which was consistent with the rest of the world (2).
Most patients diagnosed with
operable breast cancer and indicated for chemotherapy are given chemotherapy
before surgery. Neoadjuvant chemotherapy aims to reduce the tumor burden and
size before surgical resection, to reduce the axillary metastasis burden, and
to eliminate possible small-scale systemic metastasis foci. The reduction of
tissue to be resected offers the patient the chance of breast-conserving
surgery. In addition to the tumor-reducing effect of neoadjuvant therapy, it
can convert local lymph node positivity into node-negative disease. Although
the focal response varies according to the subtype and genetics of the cancer,
it has been reported that neoadjuvant chemotherapy (CT) can result in a
complete nodal response, thus determining the patient's life expectancy (3). In
the initial treatment planning, knowing the tumor subgroup and marker load is
essential in choosing the most personalized and effective treatment type.
Breast cancers are divided into subtypes that vary in their behavioral
characteristics, response to treatment, and prognosis (4).
Although molecular subtyping is the
most accurate classification, it is often classified according to the status of
hormone receptors and human epidermal growth factor receptor-2 in clinical
practice. The molecular subtype of the disease is related to the patient's
clinical course, response to chemotherapy, and pathological response rates.
Within the scope of this research, we aimed to elucidate the relationship between
neoadjuvant chemotherapy and treatment response (tumoral, nodal, pathological,
and complete response) in breast cancer patients who received neoadjuvant
therapy and were evaluated with axillary lymph nodes after surgery.
METHOD
This retrospective analysis
investigated the relationship between axillary metastasis status, tumoral and
pathological complete response status, and molecular subtypes in 103 patients
who received neoadjuvant chemotherapy for breast cancer and whose axillary
lymph nodes were evaluated. All procedures followed were in accordance with the
ethical standards of the responsible committee on human experimentation
(institutional and national) and with the Helsinki Declaration of 1975, as
revised in 2008. Ethics committee approval has been granted from our
institution with protocol number 1608, and informed consent has been obtained
from all participants.
The patients (n=103) who underwent
axillary dissection after neoadjuvant chemotherapy were selected from a decade
between 01.01.2010 and 01.01.2020. Patients' age, menopause status, type of
surgery, tumor side, axillary involvement, nodal involvement, T staging,
histopathological type and subtypes, tumor receptors, perineural invasion,
lymphovascular invasion, and tumor necrosis data were obtained from hospital
records.
Inclusion Criteria
The inclusion criteria for the
study were patients aged 18 years and over who had undergone surgery, who had
female breast cancer, who had received neoadjuvant chemotherapy, who had
undergone axillary dissection, and who had no deficiencies in their treatment
and file records.
Exclusion Criteria
Exclusion criteria for the study
were patients with incomplete files, patients who did not continue their
follow-up, male patients under 18 years of age, and patients who did not
undergo axillary dissection or core needle biopsy.
Statistical Analysis
Patient data collected within the
scope of the study were analyzed with the IBM Statistical Package for the
Social Sciences (SPSS) for Windows 26.0 (IBM Corp., Armonk, NY) package
program. Frequency and percentage for categorical data and mean and standard
deviation for continuous data were given as descriptive values. For comparisons
between groups, the “Independent Sample T-test” was used for two groups, and
the “Pearson Chi-Square Test” was used to compare categorical variables. The
results were considered statistically significant when the p-value was less
than 0.05.
RESULTS
This analysis included 103 patients
who underwent axillary dissection after neoadjuvant CT between 2010 and 2020.
All patients were female; their mean age was 55±11.8 (Min 26, Max 89 years). It
was determined that 24 (23.3%) patients were in menopause. No statistically
significant relationship was found between tumoral response, nodal response,
and complete pathological response regarding menopausal status (p>0.05).
Table 1. Histopathology Results of Core Needle Biopsy
Performed Before Neoadjuvant LT
|
|
N |
% |
|
lnvazive Ductal Carcinoma |
92 |
89.3 |
|
Invazive Lobular Carcinoma |
7 |
6.8 |
|
Medullary Carcinoma |
2 |
1.9 |
|
Mucinous Carcinoma |
2 |
1.9 |
|
Total |
103 |
100.0 |
Table 2 examines preoperative tumor
location and staging. It determined that 58.3% of the patients had left breast
involvement, 93.2% had axillary involvement, 48.5% had T2 involvement, and
59.2% had I involvement. The number of patients with negative lymph node scores
before neoadjuvant administration was 7 (Table 2). There was no statistically
significant relationship between tumoral response, nodal response, and
pathological complete response regarding the side of the tumor (p>0.05).
Invasive ductal carcinoma was
detected (89.3%) in the thick needle biopsy performed before neoadjuvant CT
(Table 1). Estrogen receptor positivity (ER +) was detected in 73.8%, and
progesterone receptor positivity (PR +) in 63.1%. The most commonly detected
thick needle biopsy was a Grade 2 tumor (Table 2). The KI-67 of the patients
was 27.4 ± 21.6 in the preoperative biopsy.
In the subtype calculations, KI-67
was 20% and above positive. The most common tumor subtype was Luminal B (36%),
followed by Luminal A (34%). The distribution of other subtypes is given in
Table 3. After neoadjuvant KT, 97.1% of the patients underwent modified radical
mastectomy. The mean number of dissected lymph nodes in the patients was
17.5±66 (median: 17, min: 5, max: 39). The mean positivity in the obtained
lymph nodes was 2.9±4.5 (median: 1, min: 0, max: 21).
Table 2. Histopathology
Results and Receptor Status of Bone Needle Biopsy Performed Before Neoadjuvant
KT
|
|
N |
% |
|
|
ER |
Negative |
27 |
26,2 |
|
Positive |
76 |
73,8 |
|
|
PR |
Negative |
38 |
36,9 |
|
Positive |
65 |
63,1 |
|
|
C-ERB2 |
Negative |
64 |
62,1 |
|
Positive |
39 |
37,9 |
|
|
Tumor Necrosis |
Negative |
84 |
81,6 |
|
Positive |
19 |
18,4 |
|
|
Lymphovascular Invasion |
Negative |
56 |
54,4 |
|
Positive |
47 |
45,6 |
|
|
Perineural Invasion |
Negative |
91 |
88,3 |
|
Positive |
12 |
11,7 |
|
|
Tumor Grade |
I |
7 |
6,8 |
|
II |
59 |
57,3 |
|
|
III |
37 |
35,9 |
|
*ER: Estrogen Receptor, PR: Progesterone Receptor,
C-ERB2: protein involved in normal cell growth.
Table 3. Subtype
Result Distribution of Core Needle Biopsy Performed Before Neoadjuvant KT
|
|
N |
% |
|
Luminal A |
35 |
34 |
|
Luminal B |
38 |
36,9 |
|
HER-2 (+) |
19 |
18,4 |
|
TRIPPLE (-) |
11 |
10,7 |
|
TOTAL |
103 |
100 |
*HER-2: human epidermal growth factor receptor 2.
|
|
|
Tumor Response |
Complete Nodal
Response |
Complete Pathologic Response |
|||
|
|
|
N |
% |
N |
% |
N |
% |
|
ER |
Negative |
12 |
38,7 |
15 |
36,6 |
7 |
39 |
|
Positive |
19 |
61,3 |
26 |
63,4 |
11 |
61 |
|
|
PR |
Negative |
17 |
54,8 |
20 |
48,8 |
9 |
50 |
|
Positive |
14 |
45,2 |
21 |
51,2 |
9 |
50 |
|
|
C-ERB2 |
Negative |
13 |
41,9 |
23 |
56,1 |
9 |
50 |
|
Positive |
18 |
58,1 |
18 |
43,9 |
9 |
50 |
|
|
Tumor
Necrosis |
Negative |
27 |
87,1 |
33 |
80,5 |
14 |
78 |
|
Positive |
4 |
12,9 |
8 |
19,5 |
4 |
22 |
|
|
Lymphovascular Invasion |
Negative |
19 |
61,3 |
26 |
63,4 |
12 |
67 |
|
Positive |
12 |
38,7 |
15 |
36,6 |
6 |
33 |
|
|
Perineural Invasion |
Negative |
30 |
96,8 |
37 |
90,2 |
18 |
100 |
|
Positive |
1 |
3,2 |
4 |
9,8 |
o |
o |
|
|
Tumor
Grade |
I |
2 |
6,5 |
2 |
4,9 |
1 |
5,6 |
|
II |
21 |
67,7 |
14 |
58,5 |
12 |
67 |
|
|
III |
8 |
25,8 |
15 |
36,6 |
5 |
28 |
|
Table 4.
Histopathological
Features and Receptor Status of Thick Needle Biopsies Before Neoadjuvant LT
Distribution of Tumoral, Nodal, and Pathological Diagnosis After Treatment
*ER: Estrogen Receptor, PR: Progesterone Receptor,
C-ERB2: protein involved in normal cell growth.
The mean follow-up period of the
patients was 21.6±10.1 months. The number of patients with surgical smear
positivity was 0%. No patient was surgically positive. While the mean
preoperative tumor size was 30.0±17.5 mm, the mean tumor size in the final
specimen was 20.9±22.7. This difference in tumor size was statistically
significant (p<0.05).
Complete Response (CR)
The mean age of 31 patients (30.1%)
who showed a complete response (CR) was 51.5±10.7, while the mean age of 72
patients who did not show a complete response was 57.6±11.8 with a
statistically significant difference (p=0.0l6). No statistically significant
relationship was found between tumor grade, ER (+), number of removed lymph nodes,
tumoral necrosis, lymphovascular invasion, and perineural invasion (p>0.05)
(Table 4). No statistical significance was found between ER (+), C-ERB (+),
tumor grade, tumoral necrosis, KI-67, lymphovascular invasion, and perineural
invasion (p>0.05). However, PR (-) was statistically significant in nodal
complete response (p=0.042). The PR (-) (p=0.013) and C-ERB2 (+) (p=0.011) were
statistically significant in tumoral complete response (Table 4). There was no
statistically significant difference in ER (+), PR (+), C-ERB2 (+), tumor
necrosis, or lymphovascular invasion (p>0.05). Perineural invasion (p=0.026)
and KI-67 (+) (p=0.045) were statistically significant in pathological complete
response. The number of removed lymph nodes was 1±1.82 in the group with
tumoral complete response, while it was 3.76±4.98 in the group without complete
response (p=0.002).
Nodal Complete Response
The mean age of the 41 (39.8%)
patients with nodal complete response was 54.39±11.14, while the mean age of
the group with no nodal complete response was 56.7±12.21 (p=0.03). No
statistically significant difference was found between nodal complete response
and histopathological distribution in the breast (p>0.05). Nodal complete
response was the least in luminal A (28.6%), while it was most common in TRIPLE
(-) patients.
Pathological Complete Response
The mean age of the 18 (17.4%)
patients with pathological complete response was 51.33±11.57, while the mean
age of the group without pathological complete response was 56.72±11.69. Although
the age of the group with a pathological complete response was lower, this
difference was not statistically significant (p=0.078). No statistically
significant difference was found between pathological complete response and
histopathological distribution in the breast (p>0.05). Tumoral complete
response was detected at least in luminal A (20%), while it was most frequently
detected in HER-2 (+) and TR.IPPLE (-) (47.4%, 45.5%), respectively. The tumor
complete response rate was higher in patients with KI-672 than in patients with
lower KI-67 values, which was statistically significant (p=0.042) (Table 3).
Pathological complete response was
11.42% (n=4) in luminal A and 15.78% (n=6) in luminal B. It was 21% (n=4) in
HER2 and 36.6% in the TRIPPLE (-) group. For all groups, the number of axillary
(+) lymph nodes detected in the TRIPPLE (-) group was 3.2±4.6, while the mean
number of positive lymph nodes in other subtype groups was 0.5±0.8 (p=0.021).
DISCUSSION
Neoadjuvant therapy refers to
systemic treatment of breast cancer before surgical treatment. Neoadjuvant
chemotherapy (NACT) aims to reduce tumor size in locally advanced breast
cancers, to provide the patient with a chance of breast cancer surgery (BCS),
and to prevent micrometastatic foci while awaiting surgery. Neoadjuvant
chemotherapy can eliminate disease in regional lymph nodes and convert
node-positive disease into node-negative disease, reducing the size of primary
tumors (5). Knowing the subtype of the disease affects the choice of chemotherapeutic
agent, response to chemotherapy, and the risk of recurrence. Some studies have
shown nodal pathological complete response rates of approximately 40% after
NACT, and it has been demonstrated that the tumor molecular subtype is associated
with the level of response (6). However, 20% of known cases do not receive the
necessary response to neoadjuvant chemotherapy, and this patient group is
delayed with ineffective treatment options, exposed to unnecessary
chemotherapeutic toxicity burden, and loses the chance of early surgery (7).
This situation requires a detailed examination of the tumor group in which NACT
treatment is sufficiently compelling to make personalized treatment plans.
In our clinic, 103 patients
underwent neoadjuvant chemotherapy and then breast surgery in 10 years. The
current study was conducted to determine whether the molecular structure of the
tumor affects the type of breast surgery and to what extent tumor
histopathology and tumor subtypes are related to the response to treatment after
AKT. To investigate the effectiveness of neoadjuvant chemotherapy, we examined
the patients' tumoral response, nodal response, and pathological complete
response levels.
Factors that give an idea about the
risk of disease recurrence independent of the treatment are prognostic factors,
among which axillary node involvement status, tumor diameter, histological
grade, and age are the most essential factors. In this study, patients with
histopathologically proven clinical stage T0-T4 0-N2 M0 who received neoadjuvant
treatment before surgery were examined. The mean age of these patients, all
women, was determined to be 55 years. It was determined that a smaller portion
of the patients included in the study (23.3%) were in menopause. The age and
menopause status of our patients in the survey were unrelated to tumoral,
nodal, and pathological complete responses. According to our study, age and
menopause status were not found to be independent factors affecting the
response of the disease to ACT. In our study, the mean age showed a significant
difference only in patients who showed tumoral complete response; the mean age
of patients who showed tumoral complete response (TCR) was 51 and 57 in those
who did not show TCR, respectively.
As is known from the literature,
the incidence of breast cancer is up to 4 times higher in women over 50 years
of age than in younger women (8,9). Although it has been reported that younger
patients may respond better to neoadjuvant therapy because proliferative tumors
are frequently seen (10), studies also show that age is not related to response
but inversely related (9). In addition to variable reports of results regarding
response to treatment, studies on the effects of age and menopausal status on
clinical course and prognosis are also variable; some studies fail to show a
relationship between age and response, and publications suggest an inverse
relationship (9). It is seen that large-scale meta-analyses are needed to
standardize information regarding parameters such as age, menopausal status,
breast cancer clinical course, prognosis, and response to neoadjuvant therapy.
It was observed that most of the
patients in our study presented with left breast involvement. It was observed
that the side of the disease was not related to the treatment response and was
not a factor affecting the treatment. At the time of presentation, it was
observed that all cases, except 6.7%, presented with non-involvement. The tumor
size of the patients included in the study was 30 mm on average. The tumor size
decreased to 20 mm after surgery and was found to be significantly different
from the pre-surgery one. It was shown that the tumor diameter, clinical T
stage, and clinical non-involvement stage (N I and N2) of the patients before
neoadjuvant therapy were similarly distributed in the tumor subtypes.
Second-degree tumors and I involvement were more frequent in number, although
not significant. It can be suggested that this difference is not essential due
to the relatively small number of our study patients. Similarly, it has been
shown in the literature that in patients diagnosed with locally invasive breast
cancer, the side of the breast affected by the disease is not related to the
prognosis. Still, the disease burden, tumor size, and axillary node involvement
have predictive value (10,11). In their study, Mamounas et al. reported that
age, clinical features of the tumor, and initial lymph node involvement were
factors affecting treatment success and locoregional recurrence after
neoadjuvant CT (12).
In our study, the most common tumor
type was invasive ductal carcinoma. Hormone (ER and PR) positivity was the most
common receptor positivity in the entire cancer group, and the most common
subtypes were Luminal B and Luminal A, respectively. The preoperative mean
Ki-67 level was 27%. This information, which is consistent with the widely
known general characteristics and distribution rates of locally invasive breast
cancers, is consistent with many studies (13,14), as well as the latest data
from the Surveillance, Epidemiology, and End Results (SEER) database of the
National Cancer Institute (15). It is known that ER and PR expression
(especially ER positivity), as in Luminous A subgroup tumors, is generally
associated with a good prognosis in the short term. This receptor status
determines whether breast cancer requires adjuvant endocrine therapy (16–18).
Knowing the genetic subtypes of cancer is essential for the type of neoadjuvant
therapy to be planned. Personalization of breast cancer treatment should form
the basis of the treatment strategy. Our study determined the mean value of
Ki-67 before neoadjuvant CT to be 27%. TTY was found to be significantly higher
in patients with lower Ki-67 positivity. Based on studies correlating Ki-67
expression with poor prognosis, it seems consistent that lower levels of Ki-67
are associated with better TTY response.
In our study, only 2.9% of the
patients underwent BCS after neoadjuvant therapy, and the remaining patients
underwent radical mastectomy. This result is far below the data in the
literature. In one of the most comprehensive prospective clinical studies
examining the effect of neoadjuvant therapy on surgery, the American College of
Surgeons Oncology Group (ACOSOG) Z1071 study, it was reported that the
breast-conserving surgery (BCS) rate after NACT increased to 40% (19). Another
survey by Buzdar et al. (20), which examined the effect of subtypes on surgical
options after neoadjuvant therapy, reported this rate as 38% in the Z1041
study. In addition, the triple-negative and HER2-positive tumor subtypes were
significantly associated with selecting BCS as interventional treatment (19).
According to the data obtained from this study, although the treatment success
rates according to subgroups after ACT were parallel to the study reports
presented by Palmer et al. (19) in 2018, the BCS rate was found to be
significantly low in our clinic. The low rate of preventive surgery can be
explained by the fact that our study was retrospective, and the preferences
depended on the surgeon and patient preferences. We can report that the ongoing
surgical treatments in our clinic are changing more in line with the current
literature.
In our study, the treatment
responses evaluated after neoadjuvant chemotherapy showed that the HER2 positive
and triple negative groups showed the most common tumoral complete response,
the most common nodal complete response, and the most common pathological
complete response among the cancer subgroups. Histopathologically, Medullary
carcinoma was the pathological subtype showing the most common tumoral complete
response, nodal complete response, and pathological complete response (although
not statistically significant). Ki-67 antibody deficiency was associated with
pathological diagnosis response.
Our study determined that the
molecular subtype in which TIY was most frequently observed in patients whose
tumoral response was evaluated was HER2-positive patients. The subgroup with
the least TTY response was Luminal A. Our results were consistent with other studies
examining breast tissue and regional lymph node responses to AKT; according to
ACOSOG 21071 (Alliance) study reports, the breast complete response rate in
HER2 patients was determined as 49.8% (54), and according to Gem1an Breast
Group reports, it was defined as 32.9% (21).
Ki-67 ratios were also evaluated in
patients whose TTY was assessed. It was determined that Ki-67 expression load
was lower in 23 patients who were TTY positive and that this was significantly
associated with TTY. Although Ki-67 antibody expression is a parameter used in
breast cancer follow-up, reports on its reliability vary. The relationship
between Ki-67 expression dw-um and prognosis in early-stage breast cancer is
being studied extensively. The use of Ki-67 as a prognostic marker in clinical
care remains controversial due to the heterogeneity and inconsistency of
studies. Azambuya (22) and Stuart-Harris (23) conducted the two most
comprehensive meta-analyses.
The axillary lymph node involvement
status changes the patient's prognosis and treatment options. To determine the
treatment algorithm that minimizes the lymph node metastasis burden among
breast cancer subtypes, it is essential to decide on which molecular subtype
responds more effectively after ACT. In our study, nodal response was most
frequently detected in triple negative patients and least in Luminal A subgroup
patients. Among histopathological subtypes, nodal complete response was most
commonly seen in medullary carcinoma, but it was not statistically significant
(2 cases). Another reason focal diagnostic response rates are reported at
different rates in the literature is that the degree of nodal involvement of
the patients included in the study before neoadjuvant therapy differs (12). In
some studies, only node-positive patients were included; in others, as in our
research, it is included in O patients. Neoadjuvant chemotherapy is effective
in reducing the size of the primary tumor as well as in reducing the disease
burden in regional lymph nodes. In our study, the number of lymph nodes removed
in axillary dissection was significantly lower in patients who obtained CR
after neoadjuvant CT; an average of 1 node was removed in patients with CR, and
an average of 4 nodes were removed in those without. As seen in our study, the
probability of conversion from node-positive to node-negative disease is higher
in women with Tripple-negative breast cancer than in those with hormone
receptor-positive disease (24,25). Neoadjuvant chemotherapy offers
opportunities to minimize the extent of surgery for both the breast and axilla.
With the conversion of OD-positive disease to node-negative, axillary staging
with sentinel lymph node surgery allows patients who convert to node-negative
to prevent axillary lymph node dissection potentially. In cases where there is
a positive sentinel node in breast cancer patients, axillary treatment is also
indicated and is most commonly in the form of standard axillary lymph node
dissection.
Axillary lymph node dissection
provides effective regional control, but it also brings with it many side
effects and patient morbidity. The EORTC 10981-22023 AMAROS study, presented in
the Lancet Journal 2014, showed that axillary radiotherapy could provide
regional control with fewer side effects. Donker et al. have shown that
axillary radiotherapy provides effective regional control and results in less
morbidity in patients with T1-T2 primary breast disease and no palpable
lymphadenopathy. Axillary lymph node dissection should be performed if the
axilla is clinically positive or if there is metastasis in SL biopsy after
neoadjuvant CT (26,27).
In our study, the tumor subgroup
with the most pathological complete response rate was the triple-negative group
(36.4%), and the second most was the HER2-positive subgroup (21.1%). However,
no significant relationship was found between pathological CR after adjuvant CT
and the histopathological distribution of the tumor. This study's response
rates to neoadjuvant chemotherapy, including pathological CR rates in patients
with triple-negative or HER2-positive disease, are consistent with previous
studies. Treatment response rates for triple-negative tumors in the breast and
axilla have been reported as 35.8% in the German Breast Group analysis, 35% in
the SPY 1 study (28), and 38% in the report from the US MD Anderson Cancer
Center (25). In addition, all patients in Z1071 had node-positive disease. In
contrast, in the other studies cited, there was a mixture of clinically
node-negative and node-positive disease, explaining some of the differences in
the pathological CR rates reported here.
Breast cancer treatment is a
complex process with medical treatment, surgical intervention, and axilla
management. The aim should be to provide minimally invasive optimal treatment
options to control the disease and reduce patient morbidity. It has been
reported that neoadjuvant chemotherapy, when given to patients with surgical
indications before the intervention, can reduce the burden and size of the
primary tumor, reduce axillary lymph node involvement, and even bring the node
to a negative stage, thus saving the patient from axilla intervention. In this
study, we found that the molecular subtypes of the tumor are associated with
the response that develops in the breast tissue and regional lymph nodes after
neoadjuvant chemotherapy. Specifically, it was observed that patients with
triple-negative or HER2-positive breast cancer have a higher chance of
achieving a pathological complete response in both the breast tissue and
regional lymph nodes.
CONCLUSION
In this study, breast cancer
subtypes were associated with tumoral, nodal, and pathological complete
response levels after neoadjuvant treatment. Tumoral, nodal, and pathological
complete response rates were higher in triple-negative subgroup patients and
HER2-positive patients, respectively. The number of lymph nodes excised after
neoadjuvant chemotherapy was lower in patients with a complete tumor response
than in those without a complete tumor response among all subgroups. Regardless
of the success of the treatment response, the number of lymph nodes excised
after neoadjuvant chemotherapy was highest in the triple-negative subgroup.
DESCRIPTIONS
No financial support.
No conflict of interest.
AI Statement: The authors used AI and AI-assisted
Technologies (Grammarly and MS Word Editor) in the writing process. These
technologies improved the readability and language of the work. Still, they did
not replace key authoring tasks such as producing scientific or medical
insights, drawing scientific conclusions, or providing clinical
recommendations. The authors are ultimately responsible and accountable for the
contents of the whole work.
Data Availability: The data supporting this study's
findings are available on request from the corresponding author. The data are
not publicly available due to privacy or ethical restrictions.
Ethical Declaration: All procedures followed were in
accordance with the ethical standards of the responsible committee on human
experimentation (institutional and national) and with the Helsinki Declaration
of 1975, as revised in 2008. Our institution has granted ethics committee
approval. As this was retrospective research, no informed consent was obtained
from participants.
Note: Converted from a subspeciality thesis into an
article.
Acknowledgments: Prof. Dr. Alper Parlakgümüş, Op. Dr. Murat
Kaya, Op. Dr. Süleyman Sürmeli.
REFERENCES
1. Burstein HJ,
Curigliano G, Thürlimann B, et al. Customizing local and systemic therapies for
women with early breast cancer: the St. Gallen International Consensus
Guidelines for treatment of early breast cancer 2021. Ann Oncol.
2021;32(10):1216-1235. doi:10.1016/j.annonc.2021.06.023
2. Luleci D, Kilic
B. Factors Affecting Women's Participation in Breast Cancer Screening in
Turkey. Asian Pac J Cancer Prev. 2022;23(5):1627-1634. Published 2022 May 1.
doi:10.31557/APJCP.2022.23.5.1627
3. Ofri A, Elstner
K, Mann GB, Kumar S, Warrier S. Neoadjuvant chemotherapy in non-metastatic
breast cancer: The surgeon's perspective. Surgeon. 2023;21(6):356-360.
doi:10.1016/j.surge.2023.04.001
4. Aldrich J,
Canning M, Bhave M. Monitoring of Triple Negative Breast Cancer After
Neoadjuvant Chemotherapy. Clin Breast Cancer. 2023;23(8):832-834.
doi:10.1016/j.clbc.2023.08.001
5. Chaloupková Z,
Coufal O, Gabrielová L. Current trends in breast cancer surgery. Aktuální
trendy v chirurgii karcinomu prsu. Rozhl Chir. 2024;103(7):247-254.
doi:10.48095/ccrvch2024247
6. von Minckwitz G,
Untch M, Blohmer JU, et al. Definition and impact of pathologic complete
response on prognosis after neoadjuvant chemotherapy in various intrinsic
breast cancer subtypes. J Clin Oncol. 2012;30(15):1796-1804.
doi:10.1200/JCO.2011.38.8595
7. Mamtani A,
Barrio AV, King TA, et al. How Often Does Neoadjuvant Chemotherapy Avoid
Axillary Dissection in Patients With Histologically Confirmed Nodal Metastases?
Results of a Prospective Study. Ann Surg Oncol. 2016;23(11):3467-3474.
doi:10.1245/s10434-016-5246-8
8. Collaborative
Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast
cancer risk: individual participant meta-analysis, including 118 964 women with
breast cancer from 117 epidemiological studies. Lancet Oncol.
2012;13(11):1141-1151. doi:10.1016/S1470-2045(12)70425-4
9. Colditz GA,
Rosner B. Cumulative risk of breast cancer to age 70 years according to risk
factor status: data from the Nurses' Health Study. Am J Epidemiol.
2000;152(10):950-964. doi:10.1093/aje/152.10.950
10. Gierach GL,
Ichikawa L, Kerlikowske K, et al. Relationship between mammographic density and
breast cancer death in the Breast Cancer Surveillance Consortium. J Natl Cancer
Inst. 2012;104(16):1218-1227. doi:10.1093/jnci/djs327
11. Barrio AV,
Mamtani A, Edelweiss M, et al. How Often Is Treatment Effect Identified in
Axillary Nodes with a Pathologic Complete Response After Neoadjuvant
Chemotherapy?. Ann Surg Oncol. 2016;23(11):3475-3480.
doi:10.1245/s10434-016-5463-1
12. Mamounas EP,
Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after
neoadjuvant chemotherapy: results from combined analysis of National Surgical
Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol.
2012;30(32):3960-3966. doi:10.1200/JCO.2011.40.8369
13. Parlakgumus A,
Karakoc D, Ozenc A. Nine years' experience of needle localized breast biopsy in
a university hospital: results and evaluation of the role of the surgeon in
decision making. Acta Chir Belg. 2008;108(5):548-551.
doi:10.1080/00015458.2008.11680283
14. Prat A, Pineda
E, Adamo B, et al. Clinical implications of the intrinsic molecular subtypes of
breast cancer. Breast. 2015;24 Suppl 2:S26-S35.
doi:10.1016/j.breast.2015.07.008
15. Li CI, Uribe
DJ, Daling JR. Clinical characteristics of different histologic types of breast
cancer. Br J Cancer. 2005;93(9):1046-1052. doi:10.1038/sj.bjc.6602787
16. Loi S,
Haibe-Kains B, Desmedt C, et al. Definition of clinically distinct molecular
subtypes in estrogen receptor-positive breast carcinomas through genomic grade
[published correction appears in J Clin Oncol. 2007 Aug 20;25(24):3790]. J Clin
Oncol. 2007;25(10):1239-1246. doi:10.1200/JCO.2006.07.1522
17. Prat A,
Chaudhury A, Solovieff N, et al. Correlative Biomarker Analysis of Intrinsic
Subtypes and Efficacy Across the MONALEESA Phase III Studies [published
correction appears in J Clin Oncol. 2021 Nov 1;39(31):3525. doi: 10.1200/JCO.21.02277]
[published correction appears in J Clin Oncol. 2023 Apr 20;41(12):2299-2301.
doi: 10.1200/JCO.23.00175]. J Clin Oncol. 2021;39(13):1458-1467.
doi:10.1200/JCO.20.02977
18. Voduc KD,
Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer
subtypes and the risk of local and regional relapse. J Clin Oncol.
2010;28(10):1684-1691. doi:10.1200/JCO.2009.24.9284
19. Palmer JAV,
Flippo-Morton T, Walsh KK, et al. Application of ACOSOG Z1071: Effect of
Results on Patient Care and Surgical Decision-Making. Clin Breast Cancer.
2018;18(4):270-275. doi:10.1016/j.clbc.2017.10.006
20. Buzdar AU,
Suman VJ, Meric-Bernstam F, et al. Fluorouracil, epirubicin, and
cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus
paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant
treatment for patients with HER2-positive breast cancer (Z1041): a randomised,
controlled, phase 3 trial. Lancet Oncol. 2013;14(13):1317-1325.
doi:10.1016/S1470-2045(13)70502-3
21. Kuehn T,
Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast
cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective,
multicentre cohort study. Lancet Oncol. 2013;14(7):609-618.
doi:10.1016/S1470-2045(13)70166-9
22. de Azambuja E,
Cardoso F, de Castro G Jr, et al. Ki-67 as prognostic marker in early breast
cancer: a meta-analysis of published studies involving 12,155 patients. Br J
Cancer. 2007;96(10):1504-1513. doi:10.1038/sj.bjc.6603756
23. Stuart-Harris
R, Caldas C, Pinder SE, Pharoah P. Proliferation markers and survival in early
breast cancer: a systematic review and meta-analysis of 85 studies in 32,825
patients. Breast. 2008;17(4):323-334. doi:10.1016/j.breast.2008.02.002
24. Boughey JC,
McCall LM, Ballman KV, et al. Tumor biology correlates with rates of
breast-conserving surgery and pathologic complete response after neoadjuvant
chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance)
Prospective Multicenter Clinical Trial. Ann Surg. 2014;260(4):608-616.
doi:10.1097/SLA.0000000000000924
25. Caudle AS, Yu
TK, Tucker SL, et al. Local-regional control according to surrogate markers of
breast cancer subtypes and response to neoadjuvant chemotherapy in breast
cancer patients undergoing breast-conserving therapy. Breast Cancer Res.
2012;14(3):R83. Published 2012 May 23. doi:10.1186/bcr3198
26. Bilani N, Elson
L, Liang H, Elimimian EB, Nahleh Z. Effect of Surgery at Primary and Metastatic
Sites in Patients With Stage IV Breast Cancer. Clin Breast Cancer.
2021;21(3):170-180. doi:10.1016/j.clbc.2020.08.008
27. Denlinger CS,
Sanft T, Moslehi JJ, et al. NCCN Guidelines Insights: Survivorship, Version
2.2020. J Natl Compr Canc Netw. 2020;18(8):1016-1023.
doi:10.6004/jnccn.2020.0037
28. Esserman LJ,
Berry DA, Cheang MC, et al. Chemotherapy response and recurrence-free survival
in neoadjuvant breast cancer depends on biomarker profiles: results from the
I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657). Breast Cancer Res Treat.
2012;132(3):1049-1062. doi:10.1007/s10549-011-1895-2