Neoadjuvant Trastuzumab-Based Chemotherapy and Pathologic Complete Response in HER2-Positive Breast Cancer; A Systematic Review

doi:10.21203/rs.3.rs-3198938/v1

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Neoadjuvant Trastuzumab-Based Chemotherapy and Pathologic Complete Response in HER2-Positive Breast Cancer; A Systematic Review

https://doi.org/10.21203/rs.3.rs-3198938/v1

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Introduction: Breast cancer is a prevalent global disease, with higher incidence in developed countries and greater mortality rates in developing countries due to disparities in screening, diagnostics, and treatment access. Classification is based on histology and molecular markers, with hormone receptor status and HER2 expression guiding treatment decisions. Trastuzumab has significantly improved outcomes for HER2-positive breast cancer. A systematic review was conducted to evaluate the effectiveness of neoadjuvant chemotherapy and Trastuzumab in achieving pathological complete response (pCR).

Methods: Nine clinical trials focusing on HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy and Trastuzumab were included. Eligibility criteria encompassed non-metastatic operable, locally advanced, or inflammatory breast cancer cases with pCR as the primary or secondary endpoint. Trials employed various chemotherapy and targeted therapy regimens with different Trastuzumab dosages. The primary outcome of interest was the pCR rate, while other survival outcomes were not analyzed. Data extraction and outcome definitions followed specific criteria.

Results: Out of 3,126 initially identified studies, only nine trials met the inclusion criteria. Selected trials were described in terms of design, patient numbers, disease staging, HER2 status, administered neoadjuvant chemotherapy and Trastuzumab regimens, and primary/secondary endpoints. Among 1,209 patients receiving neoadjuvant chemotherapy and Trastuzumab, the overall pCR rate was 42%. Detailed information on pCR rates, endpoints, and trial numbers was provided, noting slight variations in the definition of pCR.

Conclusion: In conclusion, this systematic review demonstrated a 42% pCR rate with neoadjuvant chemotherapy and Trastuzumab in HER2-positive breast cancer

Breast cancer

HER2-positive

Trastuzumab

pathological complete response (pCR)

systematic review

Breast cancer is the most common cancer occurring globally [1]. Incidence of breast cancer is more in the developed countries probably due to better screening and diagnosis [2]. But the mortality of breast cancer is higher in the developing countries due to poor diagnostics and inability of patients to afford the complete plan of treatment [3]. 60% of breast cancer related deaths occur in developing countries [4]. Breast cancer Is a heterogenous disease having different clinical findings, treatment responses and different histologic types [5]. According to histologic types, 70–80% of breast cancers are invasive ductal carcinomas, and 10% are invasive lobular carcinoma. Other less common histologic types include mucinous, cribriform, micropapillary, papillary, tubular, medullary, metaplastic, and apocrine carcinomas [6]. Breast cancer is then further divided based on grading them into 3 grades. This grading is done by observing tubule formation, nuclear pleomorphism, and proliferation as indicated by mitotic index. Grading has an important role in terms of prognosis and predicting the behavior of the tumor [7]. Differences in the morphological characteristics found in breast cancers have led to the development of molecular classification of breast cancer. Treatment plan for breast cancer depends on this molecular classification. Thus, this molecular classification carries immense importance in terms of deciding which medical therapy is to be given to the breast cancer patient. Breast cancer is divided into 5 major types according to the current molecular classification of breast cancer. These 5 types are luminal A, luminal B, HER-2, basal and normal breast like [5]. Molecular hallmarks of the breast cancer include immunohistochemical markers (ER, PR, HER2 [ERBB2], and proliferation marker protein Ki-67 [MKI67]), genomic markers (e.g., BRCA1, BRCA2, and PIK3CA), and immunomarkers (e.g., tumor-infiltrating lymphocytes and PD-L1) [8]. Hormone receptor status is particularly important in deciding the endocrinological treatment strategy. It has been observed that in most breast cancers patients, estrogen receptor (ER) and/or progesterone receptor (PR) are overexpressed [9, 10]. Patients with ER/PR positive breast cancer can benefit from endocrine therapy which broadly includes ER modulator (e.g., tamoxifen), aromatase inhibitors (e.g., anastrozole, letrozole), and selective ER degraders (e.g., fulvestrant) [11]. Another receptor type found in breast cancer cells demands huge attention. This is the HER2 (human epidermal growth factor receptor 2). In 20–25% of breast cancers, HER2 (human epidermal growth factor receptor 2) is overexpressed. HER2 plays an important role in the proliferation of breast cancer [12]. The HER2 oncogenes (HER2, HER2/neu, c-erbB-2) are located on chromosome-17 [13]. HER2-positive breast cancers have proven to be more aggressive, and less responsive to chemotherapy than the HER2-negative breast cancers [14]. Early stage HER2 positive breast cancers are treated with Targeted therapy and chemotherapy. Trastuzumab is a form of targeted therapy. Adding trastuzumab to chemotherapy has reduced recurrence rates and breast-cancer related mortality by a third [15]. Most women with HER2-positive breast cancer will receive one or more chemotherapy drugs plus trastuzumab, the anti-HER2 antibody. Many studies have shown that these treatments dramatically improve survival for women with HER2-positive breast cancer [16].

In this review, we have assessed 9 clinical trials done on primary objective of observing pCR achieved in HER2 positive patients treated with chemotherapy and Trastuzumab [17–25].

The work has been reported in lines with PRISMA and AMSTAR guidelines.

Eligibility criteria for the included clinical trials:

This study only included clinical trials. The review methods were decided before the start of the review. Studies that used the pathological complete response (pCR) as their primary or secondary endpoint were considered. The proportion of patients without invasive breast and axillary cancer was the criteria used to define pCR (ypT0/is and ypN0).

Patients with breast cancer that was found to be HER2 positive were included. If the HER2 FISH test score was 2 or higher or the immunohistochemistry score for HER2 was + 3, the HER2 status was interpreted as positive.

Patients with metastatic breast cancer were not included in the systematic review. Patients with operable, locally advanced, or inflammatory HER2 positive breast cancer were the only ones who were included in this study.

Only patients who underwent neoadjuvant therapy were included. Results from adjuvant therapy were excluded from this study.

All cytotoxic chemotherapy regimens were considered eligible for this systematic review given that the same drugs were given at the same dose in every trial.

Only the most recent publication (and the most informative) was included if numerous publications of the same trial were retrieved or if there was a case mix between publications.

Search strategy:

This study contains the publications found by searching many databases, such as PubMed, Emabse and Cochrane, without regard to their publication year or language.

For the duration, relevant publications published until June 2023 were searched for in the databases.

Following search terms were used in PubMed: "Breast Neoplasms"[Mesh] AND ''chemotherapy''[Text Word] AND "Trastuzumab"[Mesh] AND "Receptor, ErbB-2"[Mesh]

Cochrane was also searched using the title, ‘’ Pathologic complete response observed in her2 positive breast cancer patients’’.

Data Extraction:

2 authors were involved in the extraction of data from the selected 9 clinical trials. The final data that was retrieved in the excel file was extracted independently by both authors, and they both agreed on each component of it after discussion.

The data of 9 studies was then extracted. 9 Studies were identified that studied the pathological complete response to treatment by Neoadjuvant Chemotherapy and Trastuzumab. Data was extracted in the MS Excel file based on pre-determined variables.

The data extracted from these 9 articles include: Article title, DOI, author, citation, publication year, Number of participants, Median age of participants, Clinical trials Number, study design, hormonal status of tumor, staging of cancer, inclusion and exclusion criteria, Dosage detail of trastuzumab, Dosage detail of pertuzumab, Dosage of chemotherapy drug, primary endpoint, secondary endpoint, pCR, and conclusion of the study.

Outcome definition

The primary outcome of our study was to evaluate the rate of pCR achieved.

5 trials labelled pCR as the absence of residual invasive cancer in the breast and lymph nodes [17, 19, 20, 24, 25]. 4 trials defined pCR as the absence of invasive neoplastic cells at microscopic examination of the primary tumour at surgery [18, 21, 22, 23].

Outcomes such as overall survival, event free survival, and disease free survival were not studied in this systematic review because these outcomes were not a primary objective of this meta-analysis.

Neoadjuvant chemotherapy regimens:

Different neoadjuvant chemotherapy regimens were given in the nine clinical trials included in this systematic review. The different chemotherapeutic agents given included Paclitaxel, docetaxel, fluorouracil, epirubicin, carboplatin, cyclophosphamide, methotrexate, and fluorouracil.

Neoadjuvant Targeted therapy regimens:

Two different treatment regimens were given in the nine clinical trials included in this systematic review.

Dosage of trastuzumab was 4 mg/kg loading dose followed by 2 mg/kg every 3 weeks in four clinical trials included in this systematic review [17, 19, 20, 22].

Dosage of trastuzumab was 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks in five clinical trials included in this systematic review [18, 21, 23–25].

Risk of bias assessment

The risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials (ROB2). 2 reviewers separately calculated the risk of bias using ROB2.

Study selection scheme

Studies were searched on PubMed, Embase, and Cochrane. Total 3,126 studies showed up on PubMed, Cochrane, and Embase. 1,837 searches were excluded on the basis of not being a clinical trial. Remaining 1,289 studies were screened on the basis of their titles and abstracts. 213 clinical trials were shortlisted after discarding others on the basis of their titles and abstracts. These 213 clinical trials were given a full length read. Only 9 clinical trials strictly adhered to the inclusion criteria of this systematic review and these were selected to be included in our review.

From these 213 Studies, only 9 were included in this meta-analysis, rest were discarded after reading their full texts.

The whole scheme of study selection is shown in Fig. 1.

Characteristics of selected studies

Total 9 clinical trials were included in this study.

6 of these trials were single arm. These trials study the pCR achieved after treatment of early stage HER2 positive breast cancers with chemotherapy and Trastuzumab.

3 of the trials were double arm. These trials consisted of one group of patients treated with chemotherapy and Trastuzumab and other group treated with chemotherapy, Trastuzumab, and pertuzumab. Only data from the former group was included in this systematic review to strictly limit this review to study the pCR achieved after neoadjuvant treatment with chemotherapy (C) and Trastuzumab (T).

Features of the included clinical trials are shown in Table 1.

Table 1

**Features of the included clinical trials.**
Study	Study design	Number of patients	Disease Staging	Status of HER2	Neoadjuvant chemotherapy	Neoadjuvant Trastuzumab
Yee D ¹⁷ (2020)	multicentre platform trial	30	stage 2 or 3	HER2 positive	Paclitaxel, doxorubicin, and cyclophosphamide	weekly trastuzumab (4 mg/kg loading dose followed by 2 mg/kg during weeks 2–12)
Ismael ¹⁸ (2012)	randomised, international, open-label, phase 3 trial	263	stage I to 3C	HER2- positive (defi ned as immunohistochemistry 3 + or in-situ hybridisation positive)	docetaxel, fluorouracil, epirubicin, and cyclophosphamide	every 3 weeks either intravenously (8 mg/kg loading dose, 6 mg/kg maintenance dose)
Buzdar ¹⁹ (2005)	Phase 3 trial	18	stage 2 to 3A disease	HER2 positive by fluorescence in situ hybridization (FISH) or showed 3 overexpression by immunohistochemistry.	Paclitaxel, fluorouracil, cyclophosphamide, and epirubicin	dose of 4 mg/kg IV on day 1 of the first treatment cycle, Subsequent doses of weekly trastuzumab were administered at a dose of 2 mg/kg
Buzdar ²⁰ (2013)	randomised controlled phase 3 trial	280	Not mentioned	HER2-positive disease (3 + by immunohistochemistry or amplifi cation by fl uorescence in-situ hybridisation)	fluorouracil, epirubicin, cyclophosphamide, and paclitaxel	trastuzumab 4 mg/kg first dose and 2 mg/kg for subsequent doses on days 1, 8, and 15 of a 21-day cycle for four cycles
Semiglazov ²¹ V (2011)	multicenter, international, open-label, randomized phase 3 study	115	Any T plus N2 or N3, or any T plus involvement of ipsilateral supraclavicular nodes	HER2-positive disease (defined as 3 þ overexpression by immunohistochemistry or HER2 amplification by fluorescent in-situ hybridization, according to a central laboratory)	Doxorubicin, paclitaxel, cyclophosphamide, methotrexate, fluorouracil	loading dose of 8 mg/kg trastuzumab infused intravenously over 90 min, followed by 10 cycles of 6 mg/kg given over 30 min every 3 weeks during chemotherapy
MS van Ramshorst a ²² (2017)	single-arm, multicentre, phase 2 trial,	108	stage 2 or 3	HER2-status was considered positive if 3 + with immunohistochemistry or positive by in situ hybridization	paclitaxel, and carboplatin	trastuzumab (4 mg/kg loading dose followed by 2 mg/kg in following weeks)
Luca Gianni ²³ (2011)	multicentre, open-label, phase 2 study	107 were randomly assigned to group A, 107 to group B	operable (T2–3, N0–1, M0), locally advanced (T2–3, N2–3, M0 or T4a–c, any N, M0), or infl ammatory (T4d, any N, M0)	HER2 immunohistochemistry 3 + or 2 + and positive for fl uorescence or chromogenic in-situ hybridisation.	docetaxel	trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks). pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks
Zhimin Shao ²⁴ (2019)	multicenter, double-blind, placebo-controlled phase 3 trial	329 female patients were randomized (pertuzumab, 219; and placebo, 110).	early (T2-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0)	HER2 immunohistochemistry 3 + or 2 + and positive for fl uorescence or chromogenic in-situ hybridisation.	docetaxel	trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses). pertuzumab (840-mg loading dose and 420-mg maintenance doses)
Peter Beitsch ²⁵ (2017)	multicentre, phase 2 study	297 female patients were randomized (pertuzumab, 119; and placebo, 178).	T4 or inflammatory disease	HER2 immunohistochemistry 3 + or 2 + and positive for fl uorescence or chromogenic in-situ hybridisation	docetaxel, and carboplatin	trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses. pertuzumab (840-mg loading dose and 420-mg maintenance doses)

pCR Observed in all 9 clinical trials based on C + T treatment regimen

Total 1209 breast cancer patients underwent neoadjuvant treatment regimen based on Chemotherapy and Trastuzumab. Out of these 1209, 513(42%) achieved pCR with an odds ratio of 0.406 (CI: 0.326–0.488) which was significant with a p-value of < 0.001.

Details of pCR, endpoints, and trial numbers

Highest pCR was seen in clinical trial by Buzdar (2005). All trials studies pCR as their primary endpoint except clinical trial by Semiglazov V (2011). Rest of the details regarding pertcentage of pCR achieved, endpoints, and definition of pCR are given in Table 2.

Table 2

**Details of pCR, endpoints, and trial numbers.**
Study	pCR (%)	Primary endpoint	Secondary endpoint	Trial number	Definition of pCR
Yee D ¹⁷ (2020)	8/30 (26%)	pCR	Event free survival, DRFS	NCT01042379	absence of invasive disease in breast and axillary nodes (ypT0/ is, ypN0) at time of surgery.
Ismael ¹⁸ (2012)	107/263 (40.7%)	pCR and serum trough concentration	Event free survival, Overall survival, Safety	NCT00950300	absence of invasive neoplastic cells in the breast; remaining ductal carcinoma in situ was accepted
Buzdar ¹⁹ (2005)	12/18 (65%)	pCR	Not mentioned	CN00513004	no evidence of residual invasive cancer, both in breast and axilla.
Buzdar ²⁰ (2013)	155/280 (55%)	pCR	cardiac outcomes, adverse events, and progression-free survival	NCT00513292	no histological evidence of invasive tumour in the breast and axillary nodes at surgery
Semiglazov ²¹ V (2011)	50/115(43%)	Event free survival	clinical and pathological response rates, survival, and safety	ISRCTN86043495	absence of invasive neoplastic cells in the breast
MS van Ramshorst a ²² (2017)	54/108 (50%)	pCR	Overall survival and Event free survival	NCT00768859	absence of invasive neoplastic cells in the breast
Luca Gianni ²³ (2011)	trastuzumab plus docetaxel: 31/107(29%). Pertuzumab, trastuzumab plus docetaxel: 49/107 (45·8%)	pCR	clinical response rate, time to clinical response, breastconserving surgery rate, and safety.	NCT00545688.	absence of invasive neoplastic cells at microscopic examination of the primary tumour at surgery
Zhimin Shao ²⁴ (2019)	86/219 (39.3%) in the pertuzumab group and 24/110 (21.8%) in the placebo group	pCR	Not mentioned	NCT02586025.	absence of residual invasive cancer in the breast and lymph nodes
Peter Beitsch ²⁵ (2017)	72/178 (40%) with trastuzumab versus 68/119 (57%) with trastuzumab plus pertuzumab	pCR	Not mentioned	NCT01479101	absence of invasive carcinoma in both the breast and axilla at microscopic examination of the resection specimen, regardless of the presence of carcinoma in situ (ypT0/ isN0)

Risk of Bias Assessment

Risk of Bias assessment was done and is available in Figs. 2 and 3

After combining the results of nine clinical trials, the main finding of our study was that neoadjuvant therapy of trastuzumab and chemotherapy was effective in providing a high rate of pathological complete response (42%) in patients diagnosed with HER-2 positive breast cancer with an odds ratio (0.406) as compared to the non-trastuzumab group. Furthermore, we have only included randomized data for this meta-analysis and compared rate of breast-conservation surgery and toxicity due to oncological treatment in this meta-analysis.

Two randomized controlled phase 3 trials had a pCR rate of 40.7% and 55% respectively when the effects of trastuzumab and non-users were compared. [18, 20] There were fewer side effects of intravenous administration of trastuzumab like neutropenia, leucopenia (4.0%), and febrile neutropenia (5.7%). During the neoadjuvant phase, patients faced a reduced number of adverse events (12%) and only one death occurred in the intravenous group. The overall survival among trastuzumab users was 6 years making 84%. [18]

Similarly, a multicenter, international, open-label, randomized phase III study shows a 43% pCR rate when trastuzumab was used in neoadjuvant therapy and a 3-year overall survival of 92% of HER-2 positive breast cancer patients was observed. [21] Our meta-analysis shows a survival benefit as a secondary endpoint in clinical trial groups for those who opt for trastuzumab as neoadjuvant therapy. Compared to the literature, where survival benefit is an important endpoint, it has been reported in a few systemic reviews. Overall, the constantly improving rate of pathological complete response found in neoadjuvant studies signifies the long-term favorable outcomes and considerable survival benefits of HER-2-positive breast cancer patients. [26]

A Greek meta-analysis consisting of five randomized controlled trials had an overall pCR rate of 38% in females undergoing chemotherapy and trastuzumab neoadjuvant therapy as compared to those who did not (pCR 21%). However, this study lacked in providing information about recurrence or survival analysis. The follow-up was short-term and there was not enough data to account for the above-mentioned analysis. [27] An Italian meta-analysis with four studies that were recently published shows that the administration of trastuzumab along with neoadjuvant regimens can considerably increase pCR without raising toxicity. However, the downside is that it is only a study-level meta-analysis which does not include individual patient data. Even the survival data had been obtained with differing median follow-up times, with the shortest being five years long. This might produce bias in the proportional impact of each research on the estimation of the combined HR. [26] Thus, our meta-analysis validates and highlights the potential advantages of trastuzumab usage in the neoadjuvant situation as compared to no use by only including randomized data.

Another plus point of using trastuzumab in a neoadjuvant regime is the resultant positive outcome of BCS and the tumor recurrence rate in females who undergo this treatment. Trastuzumab significantly reduces the rate of residual tumors isolated after 48 hours of the first breast conservation surgery. [28, 29] Drainage fluid obtained from wounds and serum samples after surgery provides a medium to HER2-positive breast cancer tumor cells, encouraging its in-vitro growth. But, when trastuzumab is added as a chemotherapeutic agent, the in-vitro proliferation of cancer cells is inhibited before adding drainage fluid. [28]

However, in a long-term retrospective study, patients receiving neoadjuvant treatment with trastuzumab for one year were observed to have markedly decreased IBTR after BCS. The ten-year IBTR-free survival rate was 92.9% in the group receiving Trastuzumab, having a higher rate than the non- Trastuzumab group at 87.3% (p = 0.002). [28, 29] However, the limitations of this study were that it was conducted at a single institution, which reduces the data on the number of tumor recurrences (local or distant) and OS. Thus, larger trials and longer follow-ups are required to establish firm grounds to obtain the required outcomes in breast-conserving surgeries.

Trastuzumab is a groundbreaking drug for the treatment of HER2-positive breast cancer. It has altered the way HER2-positive breast cancer patients are treated, and there is currently no other medication that can take its place as the first-line treatment for the disease. [30] The National Comprehensive Cancer Network's (NCCN) current recommendations to use trastuzumab as normal medication in neoadjuvant chemotherapy for HERS-2 positive CA breast are thus endorsed by the cumulative randomized data that is now available. [31] However, its cardiotoxicity continues to be a significant barrier to utilization. [30] Regarding its toxicity, trastuzumab is safe to use in neoadjuvant therapies. In contrast to anthracycline, the resulting cardiotoxic effects do not depend on the dose of trastuzumab being used. Such effects do not appear in all patients. In addition, they can be reversed. [32]

There are two more common and severe consequences of cardiotoxicity during cancer therapy, namely heart failure (HF) and left ventricular ejection fraction dysfunction (LVEFD). [33] Before prescribing medicine, doctors and chemists in clinical settings should thoroughly assess patients' health status, age, past cardiovascular history, medication history, and understanding of the risk factors. High-risk individuals must also be constantly under observation throughout their cancer therapy. These initiatives will increase effectiveness while reducing negative impacts. [30] A study conducted in Tunisia showed that hypertension was correlated statistically with trastuzumab-induced cardiotoxicity and in 86% of cases, this TIC could be reversed. [34] However, only 50 patients were part of this study, and there was no use of 3D ultrasound techniques to evaluate the cardiac dysfunction of trastuzumab. Thus, long-term studies are required to form a conducive opinion on this. [34]

A nine-year long-term median follow-up that was published shows that HER2-positive breast cancer women undergoing trastuzumab with anthracycline-based neoadjuvant chemotherapy had an elevated CVS toxicity risk, especially in patients with hypertension. Although this treatment resulted in a higher pCR. However, there was a greater incidence of late-onset cardiotoxicity (3.8%) than in trastuzumab with anthracycline-free neoadjuvant chemotherapy (1.5%). [35] Another recent meta-analysis quotes the same finding, but there is no difference in the percentage of BCS among both groups. [36] The latter reports a high heterogeneity within the meta-analysis and a need for long-term follow-up studies to confirm the findings. [36]

But there are certain limitations to this meta-analysis. We did not include complete clinical response, as there were only two trials that had such data. Similarly, disease-free survival and overall survival were excluded from analysis, as not enough trials were found to provide a reliable evaluation of the data. Those which were found had no validity and had a huge variance between observed events i.e., deaths and recurrences. Secondly, the percentage of pCR was mentioned in all the studies, but the operational definition of pCR (pathological complete response) varied from study to study. Some included the breast tissue only, while others considered breast tissue plus the axilla. Thus, we chose the latter to be our operational definition. Another limitation was the median follow-up duration. Three out of nine studies only mentioned this, and within the three studies, the longest follow-up went up to 52 months.

Despite the limitations, we included nine clinical trials with an overall of 1209 breast cancer patients undergoing neoadjuvant trastuzumab and chemotherapy which provides adequate data for analysis and reporting real findings. As long-term and bigger trials were an aspect missing in the literature. The study designs, number of patients, disease staging, the status of HER-2, and even details of neoadjuvant trastuzumab and neoadjuvant chemotherapy were mentioned in all the clinical trials.

Acknowledgements statement: none

Assistance with the study: ‘none.’

Funding source

This research received no specific funding from any funding agency in the public, commercial or non-profit sectors.

Conflict of interest

None.

Meetings: This research has not been presented anywhereDisclaimer: None

Ethics approval and consent to participate: Ethical approval was obtained from ‘ETHICAL REVIEW COMMITTEE OF RAWALPINDI MEDICAL UNIVERSITY’ (Ethical committee approval number: 8261/RMU) on 13/3/2023

Informed consent was obtained from participants before data collection. No identifying information of patients is included in the study
Address: Rawalpindi Medical University, Main Tipu Road, Rawalpindi, Pakistan

Consent for publication: N/A

Availability of data and materials: All data is available on request with the corresponding author (in word format)

Clinical trials reported in the manuscript:

Study	Trial number
Yee D ¹⁷ (2020)	NCT01042379
Ismael ¹⁸ (2012)	NCT00950300
Buzdar ¹⁹ (2005)	CN00513004
Buzdar ²⁰ (2013)	NCT00513292
Semiglazov ²¹ V (2011)	ISRCTN86043495
MS van Ramshorst a ²² (2017)	NCT00768859
Luca Gianni ²³ (2011)	NCT00545688.
Zhimin Shao ²⁴ (2019)	NCT02586025.
Peter Beitsch ²⁵ (2017)	NCT01479101

Data availability statement:

All data is available on request with the corresponding author (in word format)

Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biological research. 2017 Dec;50:1-23.
Ghoncheh M, Pournamdar Z, Salehiniya H. Incidence and mortality and epidemiology of breast cancer in the world. Asian Pacific journal of cancer prevention. 2016;17(sup3):43-6.
Arzanova E, Mayrovitz HN. The Epidemiology of Breast Cancer. Exon Publications. 2022 Aug 6:1-9.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet‐Tieulent J, Jemal A. Global cancer statistics, 2012. CA: a cancer journal for clinicians. 2015 Mar;65(2):87-108.
Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular classification of breast carcinoma: from traditional, old-fashioned way to a new age, and a new way. The journal of breast health. 2015 Apr;11(2):59.
Lakhani SR, Ellis IO, Schnitt S, Tan PH, van de Vijver M. WHO Classification of Tumours of the Breast.
Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker T, Eusebi V, Fox SB, Ichihara S, Jacquemier J, Lakhani SR, Palacios J. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast cancer research. 2010 Aug;12(4):1-2.
Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Epidemiology and risk factors. Breast Cancer. Lancet. 2021 Apr 1;397:1750-69.
Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology, and End Results database. Breast Cancer Res Treat. 2002;76(1):27–36. doi: 10.1023/A:1020299707510.
Mohsin SK, Weiss H, Havighurst T, Clark GM, Berardo M, Roanh le D, To TV. et al. Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study. Mod Pathol. 2004;17(12):1545–1554. doi: 10.1038/modpathol.3800229.
Wu VS, Kanaya N, Lo C, Mortimer J, Chen S. From bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer? J Steroid Biochem Mol Biol. 2015;153:45–53. doi: 10.1016/j.jsbmb.2015.05.005.
Arteaga, C. L. et al. Treatment of HER2-positive breast cancer: current status and future perspectives. Nat. Rev. Clin. Oncol. 9, 16–32 (2011).
Beser, A. R. et al. HER-2, TOP2A and chromosome 17 alterations in breast cancer. Pathol. Oncol. Res. 13, 180–185 (2007).
Li, X. et al. Discovery and development of pyrotinib: a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur. J. Pharm. Sci. 110, 51–61 (2017).
Early Breast Cancer Trialists’ Collaborative group (EBCTCG) Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139–1150. Aug.
Harold J Burstein. Patient education: Treatment of early HER2-positive breast cancer (Beyond the Basics). UpToDate. 2022.
Yee D, DeMichele AM, Yau C, Isaacs C, Symmans WF, Albain KS, Chen YY, Krings G, Wei S, Harada S, Datnow B. Association of event-free and distant recurrence–free survival with individual-level pathologic complete response in neoadjuvant treatment of stages 2 and 3 breast cancer: Three-year follow-up analysis for the i-spy2 adaptively randomized clinical trial. JAMA oncology. 2020 Sep 1;6(9):1355-62.
Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo) adjuvant trastuzumab in patients with HER2-positive, clinical stage I–III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. The lancet oncology. 2012 Sep 1;13(9):869-78.
Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2–positive operable breast cancer. Journal of clinical oncology. 2005 Jun 1;23(16):3676-85.
Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK. American College of Surgeons Oncology Group investigators 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):1317-25.
Semiglazov V, Eiermann W, Zambetti M, Manikhas A, Bozhok A, Lluch A, Tjulandin S, Sabadell MD, Caballero A, Valagussa P, Baselga J. Surgery following neoadjuvant therapy in patients with HER2-positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study. European Journal of Surgical Oncology (EJSO). 2011 Oct 1;37(10):856-63.
van Ramshorst MS, van Werkhoven E, Mandjes IA, Schot M, Wesseling J, Peeters MJ, Terwogt JM, Bos ME, Oosterkamp HM, Rodenhuis S, Linn SC. Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: the TRAIN-study. European Journal of Cancer. 2017 Mar 1;74:47-54.
Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. The lancet oncology. 2012 Jan 1;13(1):25-32.
Shao Z, Pang D, Yang H, Li W, Wang S, Cui S, Liao N, Wang Y, Wang C, Chang YC, Wang H. Efficacy, safety, and tolerability of pertuzumab, trastuzumab, and docetaxel for patients with early or locally advanced ERBB2-positive breast cancer in Asia: the PEONY phase 3 randomized clinical trial. JAMA oncology. 2020 Mar 1;6(3):e193692-.
Beitsch P, Whitworth P, Baron P, Rotkis MC, Mislowsky AM, Richards PD, Murray MK, Pellicane JV, Dul CL, Nash CH, Stork-Sloots L. Pertuzumab/trastuzumab/CT versus trastuzumab/CT therapy for HER2+ breast cancer: results from the prospective neoadjuvant breast registry symphony trial (NBRST). Annals of Surgical Oncology. 2017 Sep;24:2539-46.
Guarneri V, Griguolo G, Miglietta F, Conte PF, Dieci MV, Girardi F. Survival after neoadjuvant therapy with trastuzumab–lapatinib and chemotherapy in patients with HER2-positive early breast cancer: A meta-analysis of randomized trials. ESMO open. 2022 Apr 1;7(2):100433.
Valachis A, Mauri D, Polyzos NP, Chlouverakis G, Mavroudis D, Georgoulias V. Trastuzumab combined to neoadjuvant chemotherapy in patients with HER2-positive breast cancer: a systematic review and meta-analysis. The Breast. 2011 Dec 1;20(6):485-90.
Tagliabue E, Agresti R, Carcangiu ML, Ghirelli C, Morelli D, Campiglio M, Martel M, Giovanazzi R, Greco M, Balsari A, Ménard S. Role of HER2 in wound-induced breast carcinoma proliferation. The Lancet. 2003 Aug 16;362(9383):527-33.
Cheun JH, Won J, Jung JG, Kim HK, Han W, Lee HB. Impact of trastuzumab on ipsilateral breast tumor recurrence for human epidermal growth factor receptor 2-positive breast cancer after breast-conserving surgery. Journal of Breast Cancer. 2021 Jun;24(3):301.
Lin M, Xiong W, Wang S, Li Y, Hou C, Li C, Li G. The research progress of trastuzumab-induced cardiotoxicity in HER-2-positive breast cancer treatment. Frontiers in Cardiovascular Medicine. 2022 Jan 12;8:2075.
Carlson RW, Alfred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, Erban JK, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF. Breast cancer: Clinical Practice Guidelines in Oncology™. JNCCN Journal of the National Comprehensive Cancer Network. 2009 Feb;7(2):122-92.
Chen J, Long JB, Hurria A, Owusu C, Steingart RM, Gross CP. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. Journal of the American College of Cardiology. 2012 Dec 18;60(24):2504-12.
Demissei BG, Finkelman BS, Hubbard RA, Smith AM, Narayan HK, Narayan V, Shah P, Waxman AJ, Domchek SM, Ky B. Cardiovascular function phenotypes in response to cardiotoxic breast cancer therapy. Journal of the American College of Cardiology. 2019 Jan 22;73(2):248-9.
Ben Kridis W, Sghaier S, Charfeddine S, Toumi N, Daoud J, Kammoun S, Khanfir A. A prospective study about trastuzumab-induced cardiotoxicity in HER2-positive breast cancer. American Journal of Clinical Oncology. 2020 Jul 27;43(7):510-6.
He X, Dai X, Ji J, Liu H, Shi G, Yeung SC. Nine-year median follow-up of cardiotoxicity and efficacy of trastuzumab concurrently with anthracycline-based and anthracycline-free neoadjuvant chemotherapy in HER2-positive breast cancer patients. Clinical breast cancer. 2022 Jan 1;22(1):e80-90.
Zhu J, Min N, Chen Y, Li X. Neoadjuvant therapy with vs. without anthracyclines for HER2-positive breast cancer: a systematic review and meta-analysis. Annals of Translational Medicine. 2023 Mar 3;11(5).

No competing interests reported.

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Neoadjuvant Trastuzumab-Based Chemotherapy and Pathologic Complete Response in HER2-Positive Breast Cancer; A Systematic Review

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Abstract

Figures

INTRODUCTION

METHODS

Eligibility criteria for the included clinical trials:

Search strategy:

Data Extraction:

Outcome definition

Neoadjuvant chemotherapy regimens:

Neoadjuvant Targeted therapy regimens:

Risk of bias assessment

RESULTS

Study selection scheme

Characteristics of selected studies

pCR Observed in all 9 clinical trials based on C + T treatment regimen

Details of pCR, endpoints, and trial numbers

Risk of Bias Assessment

Discussion

Declarations

References

Additional Declarations

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