A single-center study of pertuzumab-trastuzumab chemotherapy versus trastuzumab-chemotherapy in neoadjuvant treatment of breast cancer

Authors

Abstract

AimIn recent years, neoadjuvant chemotherapy constitutes the basic building blocks of thetreatment scheme in the treatment of breast cancer. Randomized controlled studies in recent years have shown that neoadjuvant chemotherapy and dual anti-Her2(human epidermal growth factor receptor 2) combinations increase the pathological complete response and contribute to overall survival in Her2 positive breast cancer. The aim of this study is to compare the pathological complete response rates of patients receiving neoadjuvant chemotherapy-trastuzumab (CT) and patients receiving neoadjuvant chemotherapy-trastuzumab-pertuzumab (CTP) and present real-life data.
Methods79 patients who received neoadjuvant CT and 155 patients who received CTP were included in the study. Pathological complete response rates of two independent groups were compared. Variables that predicted pathological complete response in both groups were examined.
ResultsIn real life, we found that the pathological complete response rates in patients receiving neoadjuvant CTP were much higher than the rates in patients receiving neoadjuvant CT, even higher than the rates in randomized controlled studies that led to the introduction of dual blockade into the literature.
ConclusionWe think that neoadjuvant chemotherapy and dual anti-Her2 therapy are the optimal treatment for Her2 positive breast cancer.

Keywords

Introduction

In women, breast cancer is the most common type of cancer and the second leading cause of death from cancer.¹ Among breast cancers, 20–25% overexpress HER2 (human epidermal growth factor receptor 2) and are associated with poor prognosis if untreated.² Signaling pathways that support cell proliferation, resistance to apoptotic signals, enhanced cell motility, and neoangiogenesis are constitutively activated as a result of HER2 gene amplification.³
In comparison to chemotherapy alone, addition of trastuzumab, a HER2‑directed humanized monoclonal antibody, dramatically increases response rate and overall survival in patients with metastatic HER2‑positive breast cancer.⁴ Trastuzumab inhibits ligand‑independent signaling and prevents HER2 cleavage.⁵ Specifically, between HER2 and HER3, ligand‑dependent signaling is inhibited by pertuzumab, which is how it produces its effects. Trastuzumab and pertuzumab have complementary modes of action because they bind to separate locations.⁶
In patients with localized or locally advanced HER2‑positive breast cancer, the pathological complete response rates (pCR) were increased by adding pertuzumab alongside trastuzumab as a neoadjuvant therapy.⁷ In the phase 2 NeoSphere study, the pCR rate was increased by adding neoadjuvant docetaxel and trastuzumab alongside pertuzumab (29% vs. 46%). Another phase 2 trial, TRYPHAENA, increased the effectiveness of trastuzumab‑docetaxel by combining it with pertuzumab. In this study, the carboplatin arm’s pCR was 51%, compared to 45% and 50% in the anthracycline arms.⁸ At the same time, studies have shown that pCR is associated with overall survival.⁹
Our study aims to compare the pathological complete response rates of neoadjuvant pertuzumab‑trastuzumab‑chemotherapy and trastuzumab‑chemotherapy, and to evaluate the correlation of real‑world data with the literature.

Materials and Methods

The patients who received neoadjuvant chemotherapy and trastuzumab in 2014–2018, and patients who received neoadjuvant pertuzumab, trastuzumab, and chemotherapy in 2018–2022 were evaluated in this retrospective study. T1–T4 and N0–N3, HER2‑positive breast cancer patients over 18 years of age were included. Patients with metastatic disease at the time of diagnosis and those who could not complete neoadjuvant four cycles of pertuzumab‑trastuzumab therapy were excluded. In the trastuzumab group, patients who could not complete the neoadjuvant 12 cycles of trastuzumab were excluded.
Pertuzumab was given at a dose of 840 mg (cycle 1), followed by 420 mg every 3 weeks. Trastuzumab was given every 3 weeks at 8 mg/kg (cycle 1), followed by 6 mg/kg in the other cycles. In the group receiving only trastuzumab, trastuzumab was given as 4 mg/kg in the first week and 2 mg/kg in the following weeks. Docetaxel was given at 75–100 mg/m² every 3 weeks. Paclitaxel was given at 80 mg/m² on days 1, 8, and 15 or 175 mg/m² every 3 weeks. Anthracycline protocol was administered to patients as Adriamycin‑cyclophosphamide (AC) or fluorouracil, epirubicin, and cyclophosphamide (FEC). The AC protocol contained 60 mg/m² Adriamycin + 600 mg/m² cyclophosphamide every 3 weeks. The FEC protocol contained fluorouracil 600 mg/m², epirubicin 90 mg/m², and cyclophosphamide 600 mg/m² intravenously every 3 weeks. Patients received trastuzumab or trastuzumab emtansine (TDM‑1) for 1 year after surgery.
Data of HER2‑positive breast cancer patients receiving neoadjuvant chemotherapy were obtained from hospital records. Demographic characteristics, treatment regimens in the neoadjuvant period, surgical information, pathology reports, last examination dates, and if applicable, date of death were recorded.
The primary endpoint was determined as pCR. The absence of invasive tumors in primary breast tissue and axilla was considered a pathological complete response. The presence of only residual ductal carcinoma in situ (DCIS) was also evaluated as pCR.
Patients were divided into two groups: those who received taxane‑pertuzumab‑trastuzumab and those who received taxane‑trastuzumab. Demographic features, clinicopathological features, and pCR of these two groups were compared. Then, both groups were divided into two subgroups as those with and without pCR, and their clinicopathological features were compared.
Ethical Approval
This study was approved by the Ethics Committee of Dr. Abdurrahman Yurtaslan Oncology Education and Research Hospital (Date: 26.07.2023, Decision No: 2023‑07/297).
Statistical Analysis
In the descriptive statistics, continuous variables were expressed as mean ( ± standard deviation), median (range); categorical variables were presented as frequency (%). Chi‑square or Fisher’s Exact test was used to compare categorical variables of two independent groups. Independent sample t‑test was used for parametric data; Mann‑Whitney U test was used for non‑parametric data. A logistic regression model was created with variables with p<0.100, and independent factors predicting pathological complete response were identified.

Results

A total of 79 patients in the trastuzumab group and 155 patients in the pertuzumab‑trastuzumab group were included in the study. The median age was 49 years in both groups. While the T stage was distributed as T2–T4 in the group receiving trastuzumab, the T2 stage was predominant in the group receiving pertuzumab‑trastuzumab (p<0.001, Table 1). While axilla positivity was observed in all patients receiving trastuzumab at the time of diagnosis, 11 (7.1%) of the patients receiving pertuzumab‑trastuzumab were axilla negative at the time of diagnosis (p=0.015). Ki‑67 median was 40 in both groups. Patients receiving neoadjuvant anthracyclines predominated in both groups, and a minority of patients in both groups received dose‑dense AC (Table 1).
The median age in the all‑patient group was 49 years. When the factors predicting pathological complete response were evaluated in the all‑patient group, the estrogen receptor status was observed to be significant (p=0.046), while the progesterone receptor status (p=0.107) and T stage (p=0.087) were at the border. Estrogen receptor status was found to be significant when the logistic regression model was applied for the all‑patient group.
The median age of patients with pCR and non‑pCR was 53 vs. 47 years in the trastuzumab group (p=0.022). In the pertuzumab‑trastuzumab group, premenopausal patients were found to be significantly higher in patients with pCR than in patients with non‑pCR (53.7% vs. 36.4%, p=0.041). In the pertuzumab‑trastuzumab group, progesterone receptor positivity was lower in patients with pCR than in patients with non‑pCR (p=0.039). In the pertuzumab‑trastuzumab group, estrogen receptor status, progesterone receptor status, and menopausal status were evaluated with a logistic regression model. Progesterone receptor (95% CI 0.154–1.291, p=0.039) and menopause status (95% CI 0.210–0.866, p=0.041) were the independent predictive factors for pCR (Table 2).
When the pathological complete response rates of the patients receiving trastuzumab and the patients receiving pertuzumab‑trastuzumab were compared, pathological complete response was observed in 95 (61.2%) patients in the pertuzumab‑trastuzumab group, while it was observed in 33 (41.7%) patients in the trastuzumab group. This difference was statistically significant (p=0.002).

Discussion

In our study, pathological complete response (pCR) rates were found to be significantly higher in the group receiving dual blockade compared to the group receiving only trastuzumab. In the NeoSphere study, the pCR was reported as 45% in the group receiving pertuzumab‑trastuzumab‑docetaxel, while in our study, the pCR was 61% in this group. It was thought that the higher pCR rates in our study were due to the addition of anthracycline and cyclophosphamide in the neoadjuvant period.¹⁰
The difference between the pCR rates of patients receiving trastuzumab and those receiving pertuzumab‑trastuzumab was significant. Since the study was retrospective, the patients were not distributed at similar stages in both groups. The frequency of T4 and N3 disease was higher in the trastuzumab group. Although this difference was not statistically significant, it was thought that starting neoadjuvant therapy at a later stage might reduce the pCR and make the difference between the two groups more pronounced. The fact that patients were more advanced in the trastuzumab group reflects the shift in our treatment trend to neoadjuvant therapy after the dual blockade. Likewise, the tendency of surgeons in recent years has been to refer patients to neoadjuvant treatment at an earlier stage.
In the pertuzumab group, 53 (55.7%) of the patients with pCR were progesterone receptor positive, while 42 (44.3%) were negative. In the non‑pCR group, 40 (72.7%) patients were progesterone receptor positive and 15 (27.3%) were negative. Pathological complete response was found to be lower in progesterone receptor‑positive patients, consistent with the literature.¹¹ It is known that the frequency of residuals after neoadjuvant therapy in triple‑positive breast cancer is higher than in the HER2‑positive hormone receptor‑negative group.¹² In a study published in 2016, pCR rates were compared according to tumor subtypes. The rate of pCR in HER2 and ER/PR‑positive patients was found to be lower than in HER2‑positive and ER/PR‑negative patients.¹¹ This is associated with a lower treatment response of the hormone receptor‑positive component.
In the all‑patient group, pCR was statistically lower in estrogen receptor‑positive patients. Pathological complete response was significantly higher in premenopausal patients in the pertuzumab group (p=0.039). In the study conducted by Silva et al., pCR was found to be high in premenopausal patients, consistent with our findings.¹³ However, there are also studies in the literature supporting the opposite. In a study conducted in France in 2021, pCR was seen at a lower rate in young and premenopausal HER2‑positive patients, and this was associated with low DFS.¹⁴ Similarly, in another study published in 2013, a lower rate of pCR was found in premenopausal HER2‑positive patients.¹⁵ It is also known that tumors are more aggressive in young premenopausal patients.¹⁶ The higher detection of pCR in premenopausal patients in our study may be associated with a better response of aggressive tumors to neoadjuvant chemotherapy. This result suggested that aggressive tumors may benefit more from neoadjuvant dual blockade.

Limitations

As for the limitations of our study; since it was retrospective, the clinicopathological features of the patients were not similarly distributed in the trastuzumab and pertuzumab-trastuzumab groups. Survival analyses could not be performed because the median follow-up time was short.

Conclusion

In conclusion, it is the standard combination of dual anti-Her2 and chemotherapy in neoadjuvant treatment in Her2 positive breast cancer. It has been shown in prospective studies and real-life data that it increases the pathological complete response.

Declarations

References

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About This Article

Received:

July 18, 2024

Accepted:

August 19, 2023

Published Online:

September 17, 2024

Printed:

November 1, 2024