The effect of prolonged neoadjuvant endocrine therapy on the efficacy of treatment with breast cancer

Abstract

BACKGROUND:

At present, there is no consensus on the required duration of neoadjuvant endocrine therapy (NET), yet there is no consistent conclusion on the factors influencing the efficacy of treatment with breast cancer after prolonged treatment.

OBJECTIVE:

To explore the effect of prolonged NET on the efficacy of patients with breast cancer and analyze the factors influencing the efficacy of treatment with breast cancer after the treatment duration is prolonged.

METHODS:

The case histories of 51 patients who were diagnosed with breast cancer and received NET in our hospital from September 2017 to December 2021 were retrospectively analyzed. All patients received NET for over 12 months. The clinical efficacy and tumor size changes after treatment for six months and 12 months were compared, and the factors influencing the efficacy of treatment with breast cancer after patients’ treatment duration was prolonged were analyzed.

RESULTS:

(1) Among the 51 patients, the objective remission rate (ORR) of NET, at T $=$ 6 months was 21.6%, and the average tumor size was 15.52 $\pm$ 7.30 mm. The ORR of the NET at T $=$ 12 months was 52.9%, and the average tumor size was 13.79 $\pm$ 7.43 mm. (2) After the treatment duration was prolonged, the clinical ORRs of patients with estrogen receptor (ER) (+) and progesterone receptor (PR) (+) were significantly higher than that of patients with ER (+) and PR (-) and patients with ER (-) and PR (+), which was (P < 0.05). (3) There was no significant difference between the patients’ axillary lymph node status and the Ki67 expression before treatment and the clinical ORR after prolonged treatment, which was ( $P>$ 0.05).

CONCLUSIONS:

(1) Prolonging the NET duration for patients with breast cancer can improve their clinical ORR and further reduce the tumor size, but patients’ conditions should be closely monitored during the treatment process to prevent the progression of disease due to drug resistance. (2) The expression state of ER or PR may be used as a factor influencing the efficacy of treatment with breast cancer after prolonged treatment. (3) There was no significant effect on the patients’ axillary lymph node status and the Ki67 expression before treatment on the clinical efficacy after prolonged treatment.

Keywords

Breast cancer hormone receptor-positive neoadjuvant endocrine therapy (NET)anastrozole

1. Introduction

According to the latest statistical data, the incidence rate of breast cancer is 11.7% among all types of cancer. It has exceeded the incidence rate of lung cancer and has become the most common cancer around the world [1]. Evidence-based medicine has shown that breast cancer is not a local disease but a systemic disease, so the idea of surgery upon identification has fallen behind. During the comprehensive treatment of breast cancer, the application value of neoadjuvant endocrine therapy (NET) became more prominent. Patients with hormone receptor-positive breast cancer account for about 80% of all breast cancer patients, and NET plays an important role for these patients [2]. The NET was initially applied to the elderly who could not tolerate neoadjuvant chemotherapy. It was found that there was no significant difference in the clinical objective remission rate (ORR) and the breast conservation rate in patients with hormone receptor-positive breast cancer between NET and neoadjuvant chemotherapy, but the incidence rate of adverse reactions after NET declined significantly [3, 4]. The NET can reduce tumor staging, improve the breast conservation rate, and provide information on the endocrine reactivity of tumors to help determine drug efficacy and guide individualized treatment [5]. As the precision medical model developed rapidly, making an individualized NET regimen became especially important. At present, there is no consensus on the required duration of NET, yet there is no consistent conclusion on the factors influencing the efficacy of treatment with breast cancer after prolonged treatment. This study aims to explore the effect of prolonged NET on patients with hormone receptor-positive breast cancer, analyze the factors influencing the efficacy of treatment with breast cancer after prolonged treatment, and provide a diagnosis and treatment basis for clinicians.

NET was first used for elderly patients who cannot underwent surgery or chemotherapy. Its application has significantly expanded its population through time. A 2016 meta-analysis by Laura et al. that included 20 studies about NET showed that NET had similar response rates to neoadjuvant chemotherapy, but the NET showed better performance with significantly reduced toxicity than chemotherapy [6].

More studies showed that the NET simply or combined with other therapy had similar efficiency with chemotherapy for the luminal BC, which showed a better tolerance for the BC patients who had to take NCT [7, 8]. However, there is no evidence in China about the NET in the certain population of BC. NET has the characteristics of low toxicity, low trauma, and low recurrence. However, its efficiency come slower than chemotherapy, requiring longer treatment and more monitoring, thus more suitable patients needed to be chosen. The TransNEOS study, which attempted to analyze the predictive effect of 21 gene testing on NET, proposed that RS $<$ 18, 18 $<$ RS $<$ 30, and RS $\geqslant$ 31 were three groups, with clinical response rates of 54%, 42%, and 22%, respectively. This suggests that there is a significant difference in clinical response rates between the low and high RS subgroups [9].

2. Methods

2.1 Study data

2.1.1 General data

A total of 51 patients with breast cancer who initially received NET at Baotou Cancer Hospital from September 2017 to December 2021 were chosen, and their case histories and examination reports were collected and recorded. All patients could receive NET according to the examination results, and the patients and their family members signed the informed consent form. See Table 1 for general data on the patients.

Table 1
General data of 51 patients with hormone receptor-positive breast cancer

	$n$	%
Age
$\leqslant$ 60 years old	20	39.2%
$>$ 60 years old	31	60.8%
Primary tumor staging
Phase I	8	15.7%
Phase II	40	78.4%
Phase III	3	5.9%
Hormone receptor expression
ER+, PR+	27	52.9%
ER+, PR-	14	27.5%
ER-, PR+	10	19.6%
Axillary lymph node status
Positive	23	45.1%
Negative	28	54.9%
Ki67 expression before treatment
$\geqslant 14\%$	30	58.8%
$ï ¼ œ$ 14%	21	41.2%

2.1.2 Inclusion criteria

Patients were diagnosed with hormone receptor-positive invasive breast cancer by hollow needle puncture, and the estrogen receptor (ER) and/or progesterone receptor (PR) was positive.

Human epidermal growth factor receptor 2 (HER-2) was negative: HER-2 (-) or (1+). If patients with HER-2 (2+) received fluorescence in situ hybridization (FISH) and the result showed no amplification, they were also deemed to be negative [10].

Patients had no other tumors and never received any anti-tumor treatment, such as radiotherapy.

Patients had no distant metastasis.

Patients reached the menopausal stage.

Patients had no other autoimmune diseases.

Patients had no active bleeding, serious infections, disseminated intravascular coagulation, heparin therapy, or connective tissue disease in the past three months.

Patients underwent surgery after two weeks of NET, and their postoperative histopathology data were complete.

2.1.3 Exclusion criteria

HER-2 overexpression: HER-2 (3+) or FISH (+).

Patients with secondary breast cancer.

Patients had distant metastasis before treatment.

Patients had contralateral breast cancer.

Patients failed to take medication or receive reexamination regularly.

Patients had gastrointestinal diseases affecting endocrine drug absorption, like ulcerative disease and malabsorption syndrome.

Male patients with breast cancer.

2.2 Study methods

2.2.1 Basic information assessment before NET

Routine examination: Blood routine examination, hepatic and renal function, tumor markers, coagulation function, urine routine examination, electrocardiogram, and other examinations were completed.

Tumor conditions: Palpation was adopted to determine the size, location, and lymph node metastasis of the tumor. Furthermore, ultrasonography and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were used to examine bilateral mammary glands and regional lymph nodes, measure and describe the tumor size, location, and regional lymph nodes, and determine the tumor T staging and regional lymph nodes. Axillary lymph node puncture was chosen to determine the N staging.

Distant metastasis: Whole body bone scanning was performed to test osseous metastasis, and the abdominal organs were examined by abdominal, gynecological, and urinary ultrasound and upper abdominal magnetic resonance imaging (MRI). Chest computed tomography (CT) was used to examine chest organs, and bone mineral density examination was conducted to check whether the patients had osteoporosis.

2.2.2 Tumor biopsy

Before the biopsy, the patients’ imageological examinations and blood assays were completed, and contraindications related to needle biopsy were ruled out. In addition, the conditions and relevant precautions were communicated to the patients and their families, and the informed consent forms for puncture biopsy were signed.

The patients were in the supine position, and the sites were chosen for positioning under the guidance of ultrasound. After routine disinfection and draping, 2% lidocaine was used for local anesthesia. A 16 G disposable puncture needle was used to collect 4–6 tissue specimens at different locations of the lump, and the tissue specimens were placed in formalin and sent to the pathology department. The puncture wound was covered with a sterile bandage, and the patients were asked to press the designated sites.

2.2.3 Immunohistochemical staining

The ER, PR, and HER-2 were detected by immunohistochemical staining. The expressions of ER and PR were measured with the semi-quantitative method, including four levels: negative (-) and positive (+), (++), and (+++). The sign “+” or above meant a positive expression and was expressed as ER (+) or PR (+). Otherwise, ER and PR were expressed as ER (-) or PR (-) [11].

ER and PR were positive for brown yellow particles in the nucleus, while HER-2 was positive for obvious brown yellow particles in the cell membrane [12]. When the number of ER and PR positive cells is less than 10%, it is indicated as (-), when it is between 10% and 30%, it is indicated as (+), when it is between 30% and 50%, it is indicated as (++), and when it is greater than 50%, it is indicated as (+++).

HER-2 has no staining or less than 10% of infiltrating cancer cells and presents incomplete and weak membrane staining as (-), more than 10% of infiltrating cancer cells and presents incomplete and weak membrane staining as (1+), more than 10% of infiltrating cancer cells and presents incomplete and/or weak to moderate intensity membrane staining or less than or equal to 10% of infiltrating cancer cells and presents strong and complete membrane staining as (2+). More than 10% of invasive cancer cells present strong, complete, and uniform cell membrane staining as (3+).

In case of HER-2 (2+), FISH was required to further assess gene amplification. According to the St. Gallen International Expert Consensus Conference criteria, Ki67 $\geqslant$ 14% was defined as a high expression, and Ki67 $<$ 14% was defined as a low expression [13].

2.2.4 Treatment methods

After the patients were diagnosed with hormone receptor-positive breast cancer and after full communication and explanation of the conditions to them and their family members, the patients agreed to take NET. Anastrozole (Arimidex, AstraZeneca Pharmaceutical, lot No.: J20150021), 1 mg/d was administered orally. During NET, the patients took calcium supplements to prevent bone calcium loss, and patients with severe osteoporosis were given bisphosphonate treatment. All patients were treated with NET for at least 12 months.

2.2.5 Clinical efficacy test

All 51 patients took anastrozole orally for at least 12 months. Before and after NET, the tumor size was measured by the DCE-MRI. Before treatment, the baseline value of the lesion was measured by DCE-MRI, and it was performed every three months during the treatment to measure the size of the target lesion. The detection instrument was the Philips Achieva 1.5T MRI system. Two radiologists with the title of deputy director or above measured the maximum diameter of the target lesion in the same section. When the results were not consistent, the other chief radiologist made an assessment and measured it again.

2.2.6 Outcome measures

The clinical efficacy of NET was evaluated according to the Response Evaluation Criteria In Solid Tumors scoring: (1) Complete remission (CR): All target lesions disappeared completely; (2) Partial remission (PR): The sum of the maximum diameters of the tumor decreased by $\geqslant$ 30%; (3) Progressive disease (PD): The sum of the maximum diameters of the tumor increased by $\geqslant$ 20% or new lesions appeared; (4) Stable disease: The decrease degree of target lesions did not reach the PR level, and the increase degree did not reach the PD level. The ORR was the percentage of cases with efficacy evaluated as CR or PR in all patients.

2.2.7 Statistical method

SPSS statistical software version 26.0 was used for data processing. The measurement data were expressed with mean $\pm$ standard deviation, and the enumeration data were expressed with percentages (%). The patients’ clinical ORR at different treatment dates and after different prolonged treatment durations were analyzed by the $x^{2}$ test or the Fisher exact probability. The difference in the efficacy of treatment with breast cancer in different groups was tested by the contingency table $x^{2}$ test. A value of $P<$ 0.05 was considered statistically significant.

3. Results

3.1 Overall efficacy of prolonged NET duration for patients with hormone receptor-positive breast cancer

In this study, the 51 patients with hormone receptor-positive breast cancer receiving NET underwent DCE-MRI examination regularly to assess the efficacy. The results showed that at T $=$ 6 months, there were no cases with CR and 11 cases with PR, and the ORR was 21.6% (11/51). At T $=$ 12 months, there was one case with CR and 26 cases with PR, and the ORR was 52.9% (27/51). There was a significant difference in the ORR between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P<$ 0.05) as shown in Table 2.

Table 2
Comparison of clinical efficacy of different NET time

Treatment duration (months)	CR	PR	SD	PD	ORR
T $=$ 6	0	21.6% (11/51)	74.5% (38/51)	3.9% (2/51)	21.6% (11/51)
T $=$ 12	1.9% (1/51)	51.0% (26/51)	39.2% (20/51)	7.9% (4/51)	52.9% (27/51)

Note: Comparison of the ORR between the two groups at T $=$ 6 months and T $=$ 12 months, $x^{2}=$ 10.037, $P=$ 0.001.

The mean tumor size and the mean tumor size reduction (95% confidence interval, CI) measured by the DCE-MRI before treatment at T $=$ 6 months and T $=$ 12 months are described in Table 3. Before treatment, at T $=$ 6 months and T $=$ 12 months, the mean sizes of the patients’ tumors were 21.42 $\pm$ 7.57 mm, 15.52 $\pm$ 7.30 mm, and 13.79 $\pm$ 7.43 mm, respectively. As the treatment duration extended, the size of the patients’ tumors further decreased.

Table 3

Tumor size changes at different treatment time measured by DCE-MRI

Time (months)	Mean tumor size	Standard deviation	95% CI (mm)	Mean tumor size reduction	95% CI (mm)
T $=$ 0	21.42	7.57	19.31–23.52	0 (baseline)
T $=$ 6	15.52	7.30	13.49–17.55	5.90	4.75–7.05
T $=$ 12	13.79	7.43	11.72–15.86	7.63	6.09–9.17

Note: The mean tumor size reduction was compared with the baseline before treatment.

The above results showed that as the treatment duration extended, the size of the patients’ tumors further decreased and the ORR further rose, with significant differences. This suggests that prolonging the NET duration can significantly improve the clinical ORRs of patients with hormone receptor-positive breast cancer.

3.2 Effect of prolonged NET duration on the efficacy of different hormone receptor expression

The results of this study showed that among 27 patients with ER (+) and PR (+), at T $=$ 6 months, there were no cases with CR and seven cases with PR, and the ORR was 26.0% (7/27). At T $=$ 12 months, there was one case with CR and 17 cases with PR, and the ORR was 66.7% (18/27). There was a significant difference in the ORRs of patients with ER (+) and PR (+) between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P<$ 0.05).

Among 14 patients with ER (+) and PR (-), at T $=$ 6 months, there were no cases with CR and two cases with PR, and the ORR was 14.3% (1/14). At T $=$ 12 months, there were no cases with CR and five cases with PR, and the ORR was 35.7% (5/14). There was no significant difference in the ORRs of patients with ER (+) and PR (-) between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P>$ 0.05).

Among 10 patients with ER (-) and PR (+), at T $=$ 6 months, there were no cases with CR and two cases with PR, and the ORR was 20.0% (2/10). At T $=$ 12 months, there were no cases with CR and four cases with PR, and the ORR was 40.0% (4/10). There was no significant difference in the ORRs of patients with ER (-) and PR (+) between T $=$ 6 months and T $=$ 12 months of NET, which was statistically significant ( $P>$ 0.05) as shown in Table 4.

Table 4
Comparison of clinical efficacy of patients at different treatment time

Different hormone receptor expression	Time (month)	CR	PR	SD	PD	ORR	$X^{2}$	$P$
ER (+) PR (+)	T $=$ 6	0	26.0%	70.3%	3.7%	26.0%	9.012	0.003
	T $=$ 12	3.7%	63.0%	26.0%	7.3%	66.7%
ER (+) PR (-)	T $=$ 6	0	14.3%	85.7%	0	14.3%	–	0.038
	T $=$ 12	0	35.7%	57.1%	7.2%	35.7%
ER (-) PR (+)	T $=$ 6	0	20.0%	70.0%	10.0%	20.0%	–	0.629
	T $=$ 12	0	40.0%	50.0%	10.0%	40.0%
Axillary lymph node positive	T $=$ 6	0	17.4%	78.3%	4.3%	17.4%	4.487	0.028
	T $=$ 12	0	47.8%	43.5%	8.7%	47.8%
Axillary lymph node negative	T $=$ 6	0	25.0%	71.4%	3.6%	25.0%	5.976	0.015
	T $=$ 12	3.6%	53.6%	35.7%	7.1%	57.1%
Ki67 $\geqslant$ 14%	T $=$ 6	0	16.7%	76.7%	6.6%	16.7%	5.079	0.024
	T $=$ 12	0	43.3%	46.7%	10.0%	43.3%
Ki67 $<$ 14%	T $=$ 6	0	28.6%	71.4%	0	28.6%	6.109	0.013
	T $=$ 12	4.8%	61.9%	28.5%	4.8%	66.7%

The tumor size at T $=$ 6 months was used as the baseline to analyze the effect of different hormone receptor expressions on the efficacy of treatment with breast cancer after prolonged treatment. Among 27 patients with ER (+) and PR (-), at T $=$ 12 months, the ORR was 51.9% (14/27). Among 14 patients with ER (+) and PR (-), at T $=$ 12 months, the ORR was 21.4% (3/14). Among 10 patients with ER (-) and PR (+), at T $=$ 12 months, the ORR was 20.0% (2/10). The results showed that after the treatment duration was prolonged, the clinical ORRs of patients in the ER (+) and PR (+) group were significantly higher than that of patients in the ER (+) and PR (-) group and patients in the ER (-) and PR (+) group. The differences were statistically significant ( $P<$ 0.05) as shown in Table 5.

Table 5

Effects on patients’ clinical efficacy after prolonged treatment

	ORR after prolonged treatment	Rate of no remission after prolonged treatment	$X^{2}$	$P$
ER (+) PR (+)	51.9% (14/27)	48.1% (13/27)	30.332	$<$ 0.05
ER (+) PR (-)	21.4% (3/14)	78.6% (9/14)
ER (-) PR (+)	20.0% (2/10)	80% (8/10)
Axillary lymph node positive	39.1% (9/23)	60.9% (14/23)	0.013	0.908
Axillary lymph node negative	39.9% (11/28)	60.1% (17/28)
Ki67 $\geqslant$ 14%	40.0% (12/30)	60.0% (18/30)	3.093	0.078
Ki67 $<$ 14%	52.4% (11/21)	47.6% (10/21)

As the treatment duration was prolonged, the clinical ORRs of patients with ER (+) and PR (+) increased significantly. The efficacy difference between patients with ER (+) and PR (-) and patients with ER (-) and PR (+) was not significant, and there were significant differences in the clinical ORR among the three groups after prolonged treatment. This indicates that the ER or PR expression states may affect the efficacy of treatment with breast cancer after the NET duration extension. Furthermore, the clinical ORRs of patients in the ER (+) and PR (+) group were significantly higher than that of patients in the ER (+) and PR (-) group and patients in the ER (-) and PR (+) group after prolonged treatment.

3.3 Efficacy of prolonged NET duration for patients with different axillary lymph node statuses

The results of this study showed that among 23 patients with axillary lymph nodes positive at T $=$ 6 months, there were no cases with CR and four cases with PR, and the ORR was 17.4% (4/23). At T $=$ 12 months, there was one case with CR and 11 cases with PR, and the ORR was 47.8% (11/23). There was a significant difference in the ORRs of patients with axillary lymph nodes positive between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P<$ 0.05).

Figure 1.

Comparison of clinical efficacy of patients at different treatment time.

Figure 2.

Effects on patients’ clinical efficacy after prolonged treatment.

Among 28 patients with axillary lymph nodes negative, at T $=$ 6 months, there were no cases with CR and seven cases with PR, and the ORR was 25.0% (7/28). At T $=$ 12 months, there was one case with CR and 15 cases with PR, and the ORR was 57.1% (16/28). There was a significant difference in the ORRs of patients with axillary lymph nodes negative between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P<$ 0.05) as shown in Table 4.

The tumor size at T $=$ 6 months was used as the baseline to analyze the effect of the axillary lymph node status on the efficacy of treatment with breast cancer after prolonged treatment. Among 23 patients with axillary lymph nodes positive, at T $=$ 12 months, the ORR was 39.1% (9/23). Among 28 patients with axillary lymph nodes negative, at T $=$ 12 months, the ORR was 39.9% (11/28). After prolonged treatment, there was no significant difference in the efficacy of treatment with breast cancer with different axillary lymph node status, which was ( $P>$ 0.05) as shown in Table 5.

Whether the patients’ axillary lymph nodes were positive or negative, prolonging the treatment duration could improve the clinical ORR. Furthermore, there was no significant difference in the clinical ORRs of patients with different axillary lymph node statuses after prolonged treatment, indicating that different axillary lymph node statuses before treatment have no significant effect on the efficacy of treatment with breast cancer after prolonged treatment.

3.4 Efficacy of prolonged NET duration for patients with different Ki67 expressions

In this study, the Ki67 in 30 patients was greater than or equal to 14% before NET. At T $=$ 6 months, there were no cases with CR and five cases with PR, and the ORR was 16.7% (5/30). At T $=$ 12 months, there were no cases with CR and 13 cases with PR, and the ORR was 43.3% (13/30). There was a significant difference in the ORRs of patients with Ki67 $\geqslant$ 14 before treatment between T $=$ 6 months and T $=$ 12 months of NET, which was ( $P<$ 0.05).

The Ki67 in 21 patients was less than 14% before NET. At T $=$ 6 months, there were no cases with CR and six cases with PR, and the ORR was 28.6% (6/21). At T $=$ 12 months, there was one case with CR and 13 cases with PR, and the ORR was 66.7% (14/21). There was a significant difference in the ORRs of patients with Ki67 $<$ 14 before treatment between T $=$ 6 months and T $=$ 12 months, which was ( $P<$ 0.05) as shown in Table 4.

The tumor size at T $=$ 6 months was used as the baseline to analyze the effect of the Ki67 expression before treatment on the efficacy of treatment with breast cancer after prolonged treatment. The Ki67 in 30 patients was greater than or equal to 14% before NET. At T $=$ 12 months, the ORR was 40.0% (12/30). The Ki67 in 21 patients was less than 14% before NET. At T $=$ 12 months, the ORR was 52.4% (11/21). There was no significant difference in the efficacy of treatment with breast cancer of patients with different Ki67 expressions before treatment, which was ( $P>$ 0.05) as shown in Table 5.

After the NET duration was prolonged, the clinical ORRs of patients with Ki67 $\geqslant$ 14% and Ki67 $<$ 14% increased. There was no significant difference in the clinical ORRs of patients with different Ki67 expressions after the treatment duration extension, indicating that the Ki67 expression before treatment has no significant effect on the efficacy of prolonged NET.

3.5 Adverse reactions

Adverse reactions of the 51 patients in the treatment process included bone joint pain ( $n=$ 7), flush ( $n=$ 5), gastrointestinal disorder ( $n=$ 10), weakness ( $n=$ 4), hectic fever ( $n=$ 4), and white blood cell (WBC) decrease ( $n=$ 1). All symptoms were relieved after symptomatic treatment. No patient suspended medication due to adverse reactions.

4. Discussion

As one of the most common cancers in females, breast cancer seriously affects patients’ work and life. Most patients with breast cancer are hormone receptor-positive. The key to treatment is to reduce the stimulation of hormones on tumor cells. Therefore, endocrine therapy has become popular in recent years. A lot of research results show that NET can reduce tumor staging, improve the breast conservation rate, and provide information on the endocrine reactivity of tumors to help determine drug efficacy and guide individualized treatment [14]. The NET duration for patients with hormone receptor-positive breast cancer is still in the exploration stage, and the duration of medication for postmenopausal patients is mostly controlled in three to six months [15, 16]. An overwhelming majority of experts at the 2013 St. Gallen conference recommended NET for postmenopausal patients with hormone receptor-positive breast cancer until maximum clinical ORR was achieved [17]. Although most studies show that extending the NET duration can improve patients’ clinical ORR, not all patients could obtain benefits from the treatment duration extension. Therefore, this study aims to explore the effect of prolonged NET duration on the efficacy of treatment with breast cancer of patients with hormone receptor-positive breast cancer and analyze the factors influencing the efficacy of treatment with breast cancer after the treatment duration is prolonged.

4.1 Overall efficacy of prolonged NET duration for patients with hormone receptor-positive breast cancer

It was found that as the patients’ NET duration was extended, scarring appeared on tumors and their size further decreased, but the patients may be resistant to drugs. [18] A total of 51 patients were included in this study. At T $=$ 6 months, the ORR was 21.6% and at T $=$ 12 months, it was 52.9%. After treatment for six months, the efficacy of treatment with breast cancer of two patients was assessed to be PD. After treatment for 12 months, one patient was assessed to be CR and four patients were assessed to be PD. The clinical ORRs of patients with hormone receptor-positive breast cancer were only 2% (1/51) after the NET duration extension, but the ORR significantly increased as the treatment duration was prolonged. It is necessary to emphasize that four patients were assessed to be PD after the treatment duration was extended. In addition, compared with the baseline before treatment, the patients’ mean tumor size was 21.42 $\pm$ 7.57 mm before treatment. At T $=$ 6 months, the mean tumor size was reduced to 15.52 $\pm$ 7.30 mm. At T $=$ 12 months, it was 13.79 $\pm$ 7.43 mm. This suggests that prolonging the NET duration can improve patients’ clinical ORR and further reduce the tumor size, but the treatment duration cannot be extended continuously to pursue a CR state. Moreover, patients’ conditions should be closely monitored in the treatment process, and the efficacy of treatment with breast cancer should be assessed in time to prevent a state of PD due to drug resistance.

4.2 Effect of prolonged NET duration on the efficacy of different hormone receptor expressions

Among 27 patients with ER (+) and PR (+) at T $=$ 6 months, there were no cases with CR and seven cases with PR, and the ORR was 26.0%. At T $=$ 12 months, there was one case with CR and 17 cases with PR, and the ORR was 66.7%. Among 14 patients with ER (+) and PR (-) at T $=$ 6 months, there were no cases with CR and two cases with PR, and the ORR was 14.3%. At T $=$ 12 months, there were no cases with CR and five cases with PR, and the ORR was 35.7%. Among 10 patients with ER (-) and PR (+) at T $=$ 6 months, there were no cases with CR and two cases with PR, and the ORR was 20.0%. At T $=$ 12 months, there were no cases with CR and four cases with PR, and the ORR was 40.0%. After the treatment duration was prolonged, the clinical ORRs of patients with ER (+) and PR (+) increased significantly. The efficacy difference between patients with ER (+) and PR (-) and patients with ER (-) and PR (+) was not significant. In the comparison of clinical ORR among the three groups after the treatment duration extension, the clinical ORRs of patients in the ER (+) and PR (+) were significantly higher than that in the ER (+) and PR (-) group and the ER (-) and PR (+) group. This indicates that the efficacy of prolonged NET duration for patients with ER (+) and PR (-) and patients with ER (-) and PR (+) is not significant. This conclusion requires the support of a larger sample size.

It was found that if the ER and PR are still retained in case of cell canceration, the tumor grows relatively slowly, and the probability of distant metastasis is low. The higher the hormone receptor content in target cells, the more effective endocrine therapy is and the more ideal the prognosis is. In the event of an ER or PR deficiency, the tumor growth increases rapidly, endocrine response becomes low, and systemic metastasis may occur more easily. Furthermore, the prognosis is poor [19]. This study also showed that the efficacy of treatment with breast cancer of patients with ER (-) or PR (-) was not ideal after the NET duration was extended. Thus, determining the expression of ER and PR before treatment is of great value for assessing the patients’ efficacy and guiding endocrinotherapy [19].

4.3 Efficacy of prolonged NET duration for breast cancer patients with different axillary lymph node statuses

It was found that the axillary lymph node metastasis is an independent prognostic factor in breast cancer, and patients who are initially diagnosed with regional lymph node metastasis are locally advanced [20]. If the axillary lymph nodes of patients with hormone receptor-positive breast cancer are positive, they are expected to be reduced and even make their primary lesions and regional lymph nodes disappear through NET, increase the breast conservation rate, and lower the probability of axillary lymph node dissection. Among 23 patients with axillary lymph nodes positive in this study, at T $=$ 6 months, there were no cases with CR and four cases with PR, and the ORR was 17.4%. At T $=$ 12 months, there were no cases with CR and 11 cases with PR, and the ORR was 47.8%. Among 28 patients with axillary lymph nodes negative, at T $=$ 6 months, there were no cases with CR and seven cases with PR, and the ORR was 25.0%. At T $=$ 12 months, there was one case with CR and 15 cases with PR, and the ORR was 57.1%. The above results suggest that whether the patients’ axillary lymph nodes are positive or negative, prolonging the treatment duration could improve the clinical ORR. Furthermore, there was no significant difference in the clinical ORRs of patients with different axillary lymph node statuses after prolonged treatment, indicating that different axillary lymph node statuses before treatment have no significant effect on the efficacy of treatment with breast cancer after prolonged treatment.

4.4 Effect of the Ki67 expression on the efficacy of prolonged NET duration

The Ki67 is a nuclear antigen expressed in proliferating tissues and is closely related to cell mitosis [21]. The expression of Ki67 in tumor tissues is higher than that in normal tissues, so it is often used as an indicator to judge tumor activity. It plays an important role in the assessment of the NET’s efficacy. In this study, among patients with Ki67 $\geqslant$ 14% before treatment, at T $=$ 6 months, there were no cases with CR and five cases with PR, and the ORR was 16.7%. At T $=$ 12 months, there were no cases with CR and 13 cases with PR, and the ORR was 43.3%. Among patients with Ki67 $<$ 14% before treatment, at T $=$ 6 months, there were no cases with CR and six cases with PR, and the ORR was 28.6%. At T $=$ 12 months, there was one case with CR and 13 cases with PR, and the ORR was 66.7%. This indicates that after the NET duration was prolonged, the clinical ORRs of patients with Ki67 $\geqslant$ 14% and Ki67 $<$ 14% increased. There was no significant difference in the clinical ORRs of patients with different Ki67 expressions after the treatment duration extension, indicating that the Ki67 expression before treatment has no significant effect on the efficacy of prolonged NET.

4.5 Adverse reactions

Aromatase inhibitors often result in arthralgia and osteoporosis. Estrogens in postmenopausal patients with breast cancer mainly come from androgen metabolism, and aromatase is an enzyme responsible for the synthesis of estrogens from androgens and testosterone. Aromatase inhibitors reduce the level of estrogens in plasma by inhibiting or inactivating aromatase, but the lack of estrogens will lead to a decrease in bone density. Coates et al. studied 4922 postmenopausal patients with hormone receptor-positive breast cancer who were treated with tamoxifen or letrozole at random, and they found that the clinical fracture incidence in the letrozole group was significantly higher than that in the tamoxifen group, which was ( $P<$ 0.001) [22]. Therefore, aromatase inhibitors may accelerate patients’ bone loss and increase the risk of fractures [23]. In this study, all patients took calcium supplements during the treatment to prevent bone density and calcium losses. In the treatment process, four patients complained of aggravated arthralgia, but they improved after diphosphonate treatment.

4.6 Limitations of the study

(1) The limitation of this study is a small number of cases that may lead to sampling errors. The subgroup analysis was not further performed, and the conclusion needs to be verified by including more patients. (2) In this study, the NET duration was extended to 12 months, and further follow-up observations were required to check whether the results are applicable to longer NET and whether patients can obtain survival benefits. (3) This study is a retrospective analysis, and the factors included may be incomplete. A large sample prospective study is required. (4) This study only examines the effect of single factors on the treatment duration extension, and a multi-factor regression analysis was not conducted, which means that some interreference factors may be present. It is necessary to further screen independent relevant factors affecting the efficacy of the prolonged treatment duration.

5. Conclusions

(1)

Prolonging NET duration for patients with breast cancer can improve their clinical ORR and further reduce the size of their tumors, but the patients’ conditions should be closely monitored in the treatment process to prevent a state of PD due to drug resistance.

(2)

The expression state of ER or PR may be used as a factor influencing the efficacy included or a certain after prolonged NET.

(3)

The patients’ axillary lymph node statuses and the Ki67 expression before treatment had no significant effects on the clinical efficacy after prolonged NET.

Footnotes

Conflict of interest

None to report.

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The effect of prolonged neoadjuvant endocrine therapy on the efficacy of treatment with breast cancer

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Methods

2.1 Study data

2.1.1 General data

Table 1 General data of 51 patients with hormone receptor-positive breast cancer

2.1.3 Exclusion criteria

2.2 Study methods

2.2.1 Basic information assessment before NET

2.2.2 Tumor biopsy

2.2.3 Immunohistochemical staining

2.2.4 Treatment methods

2.2.5 Clinical efficacy test

2.2.6 Outcome measures

2.2.7 Statistical method

3. Results

3.1 Overall efficacy of prolonged NET duration for patients with hormone receptor-positive breast cancer

Table 2 Comparison of clinical efficacy of different NET time

Table 4 Comparison of clinical efficacy of patients at different treatment time

3.5 Adverse reactions

4. Discussion

4.1 Overall efficacy of prolonged NET duration for patients with hormone receptor-positive breast cancer

4.2 Effect of prolonged NET duration on the efficacy of different hormone receptor expressions

4.3 Efficacy of prolonged NET duration for breast cancer patients with different axillary lymph node statuses

4.4 Effect of the Ki67 expression on the efficacy of prolonged NET duration

4.5 Adverse reactions

4.6 Limitations of the study

5. Conclusions

Footnotes

Conflict of interest

References

Table 1
General data of 51 patients with hormone receptor-positive breast cancer

Table 2
Comparison of clinical efficacy of different NET time

Table 4
Comparison of clinical efficacy of patients at different treatment time