Middle Eastern Cancer and Oncology Journal

Breast cancer remains an important cause of cancer morbidity and mortality worldwide, representing the most frequently diagnosed malignancy among women worldwide and accounting for a significant healthcare burden in both developed and developing regions (Łukasiewicz et al., 2021). In the context of molecular subtypes, it has been observed that approximately 15–20% of cases overexpress the human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase encoded by the ERBB2 gene (Schettini et al., 2020). HER2 amplification activates downstream proliferative signalling via pathways such as PI3K/AKT and MAPK, resulting in rapid tumour growth, reduced apoptosis, higher recurrence risk, and an aggressive clinical phenotype when left untreated (Gaibar et al., 2020; Ishii et al., 2019; Yu et al., 2020). Despite the historical association of this subtype with poor outcomes, the advent of HER2-targeted therapy has resulted in a significant shift in its prognosis, thereby establishing targeted monoclonal antibodies as pivotal components of contemporary breast cancer management (Korde et al., 2021; Y. Liu et al., 2022; Tse et al., 2021).

Neoadjuvant systemic therapy has become of particular importance in cases of HER2-positive disease, due to the dual benefits of primary tumour shrinkage and the early eradication of potential micrometastatic disease (Holmes et al., 2015). The achievement of a pathological complete response (pCR) after neoadjuvant treatment has emerged as a reliable surrogate endpoint for long-term clinical outcomes, including disease-free and overall survival, particularly in HER2-positive and triple-negative breast cancer (Buzdar et al., 2005; Pathak et al., 2018). Consequently, the optimisation of neoadjuvant protocols has focused not only on tumour reduction but also on maximising pCR, thereby improving survival trajectories in patients with this molecular subtype. While HER2 overexpression has long been recognised as a driver of aggressive tumour behaviour, advances in targeted therapy have shifted clinical focus toward optimising treatment combinations that maximise response in the neoadjuvant setting. The efficacy of dual HER2 blockade using trastuzumab and pertuzumab has been demonstrated to exceed that of single-agent HER2 inhibition; however, the majority of supporting evidence originates from controlled clinical trials conducted in high-resource settings. The extent of research conducted on the comparative evaluation of pertuzumab-based and non-pertuzumab neoadjuvant regimens in real-world contexts remains limited, particularly in regions where factors such as diagnostic delay, advanced presentation, and restricted access to targeted therapy may influence treatment outcomes.

The incorporation of pertuzumab into trastuzumab-based regimens signifies a substantial advancement in the realm of dual HER2 blockade therapy. In contrast to trastuzumab, which exerts its effects by inhibiting HER2 activation and promoting antibody-dependent cell death, pertuzumab functions by preventing HER2/HER3 dimerisation. This process has been identified as a critical driver of oncogenic signalling (Hall et al., 2022). Pivotal trials, including NeoSphere, have demonstrated that the combination of trastuzumab and pertuzumab with chemotherapy results in a significant increase in pCR rates when compared with single-agent HER2 blockade (Gianni et al., 2012). The TRYPHAENA study further confirmed that pertuzumab-based dual blockade can be safely incorporated into both anthracycline and non-anthracycline neoadjuvant regimens, showing efficacy without substantial cardiotoxicity (Schneeweiss et al., 2013). The validity of these results is further reinforced by meta-analyses and real-world studies that consistently highlight superior response rates when pertuzumab is used alongside trastuzumab (Chica-Parrado et al., 2020; Ding et al., 2023; Fazal et al., 2023; Kim et al., 2022).

Notwithstanding the global transition towards dual HER2 blockade, the extant evidence base remains constrained in low- and middle-income regions, including the Middle East, where factors such as diagnostic delays, advanced disease presentation, and inconsistent access to targeted therapy may exert an influence on treatment outcomes. In Iraq, HER2-positive breast cancer frequently manifests with lymph node involvement and high-grade pathology, thereby prompting inquiries into the extent to which international neoadjuvant practices are effectively transposed into local clinical contexts. The evaluation of real-world outcomes in such contexts is imperative for the comprehension of treatment effectiveness, the guidance of resource allocation, and the tailoring of therapeutic decisions in environments where accessibility to pertuzumab may be constrained.

The present study investigates the pathological complete response rates associated with pertuzumab-containing versus non-pertuzumab neoadjuvant regimens in HER2-positive breast cancer patients treated at a major oncology centre in Iraq. The objective of this study is to provide region-specific evidence regarding the utility of dual HER2 blockade in real-world practice. To this end, the clinical characteristics, reproductive history and tumour pathology of patients will be integrated with treatment outcomes.

Study Design and Setting

A retrospective case-control study was conducted at the Oncology Teaching Hospital, which is part of the Medical City Complex in Baghdad, Iraq. A retrospective study of medical records was conducted for women diagnosed with HER2-positive breast cancer who received neoadjuvant systemic therapy between January 2022 and December 2024. The hospital functions as a tertiary referral centre, with a specialism in the management of breast cancer. Consequently, it receives a high volume of locally advanced cases, thus facilitating the evaluation of real-world responses to contemporary targeted neoadjuvant strategies. The objective of this study was to compare pathological response outcomes between patients treated with pertuzumab-containing regimens and those treated with trastuzumab-based protocols without pertuzumab. A case-control framework was utilised to facilitate a comparison of pathological response outcomes between patients receiving pertuzumab-containing regimens and those treated without pertuzumab in a retrospective real-world setting.

Eligibility Criteria

Patients were eligible for inclusion if they were female, aged 18 years or older, had histologically confirmed HER2-positive breast cancer based on immunohistochemistry and/or fluorescence in situ hybridization, received neoadjuvant chemotherapy with or without pertuzumab, and underwent definitive surgery with an available postoperative pathology report. Cases were excluded if they presented with metastatic disease at the time of diagnosis, if they had incomplete or missing clinical or pathological data, or if they did not complete the full course of neoadjuvant therapy followed by surgical management. The employment of these criteria ensured the accurate assessment of treatment exposure and pathological endpoints.

Classification of Study Groups

Participants were stratified into two groups according to the neoadjuvant regimen received. The initial group consisted of patients who received treatment with pertuzumab-containing protocols, encompassing anthracycline-based and taxane-carboplatin–based combinations such as AC-THP and TCHP. The second group comprised patients who received trastuzumab-based regimens devoid of pertuzumab, such as AC-TH and TCH. The allocation of groups was based exclusively on the incorporation of pertuzumab, while all other characteristics of treatment were recorded to facilitate comparison of protocol components and potential confounding factors.

Data Collection and Variables

The data extraction process was carried out by trained research clinicians, who utilised a standardised data collection template to ensure consistency and minimise transcription bias. The pathological complete response (pCR) was defined in accordance with the American Joint Committee on Cancer (AJCC) criteria as the absence of invasive tumour in both the breast and the axillary lymph nodes (ypT0/Tis, ypN0). This definition was consistently applied across all postoperative pathology reports. The patient-related variables encompassed age at diagnosis, parity, breastfeeding history, oral contraceptive use, and family history of breast cancer. The tumor-related characteristics encompassed the following: histopathological subtype, tumor grade, presence of lymphovascular invasion, hormone receptor status, clinical tumor size (T stage), nodal status (N stage), and overall clinical stage at presentation. The data extraction process was carried out by trained research clinicians, who utilised a standardised data collection template to ensure consistency and minimise transcription bias. The patient-related variables encompassed age at diagnosis, parity, breastfeeding history, oral contraceptive use, and family history of breast cancer. Tumor-related characteristics were obtained from clinical and pathological records and included histopathological subtype, tumor grade, presence of lymphovascular invasion, hormone receptor status, clinical tumor size (T stage), nodal involvement (N stage), and overall clinical stage at presentation. The pathological complete response (pCR) was defined in accordance with the American Joint Committee on Cancer (AJCC) criteria as the absence of invasive tumour in both the breast and the axillary lymph nodes (ypT0/Tis, ypN0). This definition was consistently applied across all postoperative pathology reports.

Treatment-related variables encompassed the type of neoadjuvant systemic therapy administered, as well as the incorporation of pertuzumab into the treatment regimen. Information regarding specific chemotherapy protocols was obtained from institutional chemotherapy records. Patients were categorised according to whether they received pertuzumab-containing regimens or trastuzumab-based regimens devoid of pertuzumab. The additional regimen components were documented to facilitate a comparison of treatment characteristics and potential confounding factors.

Statistical Analysis

The subsequent analysis of the data was conducted utilising both descriptive and inferential statistical methodologies. Categorical variables were summarised as frequencies and percentages and then compared between groups using the Chi-square test. Fisher's exact test was applied when expected cell counts were less than five. The association between treatment regimen and pCR was further assessed using correlation statistics, including the Phi coefficient for binary associations and Cramer's V for multi-category comparisons. A two-tailed p-value of less than 0.05 was considered to be statistically significant. The objective of these analyses was twofold: firstly, to ascertain the statistical discrepancy in response rates, and secondly, to determine the magnitude of association between clinical variables and pathological outcomes.

Patient Demographic and Reproductive Characteristics

The analysis comprised a total of 75 women with HER2-positive breast cancer. The mean age at diagnosis was 52.5 years (± 22.5). The majority of patients were parous (88.0%), and 70.6% reported a history of breastfeeding. The use of oral contraceptives was documented in 21.3% of the cohort, and 37.3% of the subjects had a first-degree family history of breast cancer. The reproductive and familial characteristics of the subjects are outlined in Table 1, which reflects a population profile typical of women presenting with breast cancer in the region.

Tumor Pathology and Clinical Presentation

Invasive ductal carcinoma was observed in almost all cases (98.6%), while the presence of invasive lobular histology was infrequent. The majority of tumours exhibited moderate differentiation, with 80.0% of patients exhibiting grade II pathology.

Lymphovascular invasion (LVI) was observed in 65.3% of cases, suggesting an aggressive biological behaviour. Intermediate tumour size was predominant, with 65.3% of cases presenting as T2 tumours at diagnosis, and nodal assessment revealed that 69.3% had N1 disease. Stage II was the most prevalent overall presentation (40.0%), followed by stages I and III. These findings are presented in Table 2 and reflect a pattern of locally advanced disease at first presentation.

Comparison of Neoadjuvant Regimens and Pathological Response

Patients were divided into two groups based on their treatment exposure: those who received pertuzumab-containing neoadjuvant regimens and those treated with trastuzumab-based protocols without pertuzumab. A significantly higher pathological complete response (pCR) rate was observed in the pertuzumab group (80.0%) compared with the non-pertuzumab group (48.0%), demonstrating a statistically significant improvement in tumour eradication with dual HER2 blockade (p = 0.007).

In the context of the pertuzumab subgroup, anthracycline-containing protocols exhibited a strong correlation with the achievement of pCR, demonstrating the highest response rate across all evaluated regimens. Conversely, non-anthracycline combinations demonstrated comparatively lower pCR rates (p = 0.003). The specific responses of each regimen are outlined in Table 3.

Furthermore, LVI exhibited a substantial correlation with the probability of achieving pCR among patients undergoing pertuzumab therapy (p = 0.005), thereby indicating that more biologically aggressive tumours might derive a heightened benefit from intensified blockade, as outlined in Table 4.

Strength of Associations

The findings of the present study lend support to the magnitude of benefit that has been observed with pertuzumab-based therapy. This is evidenced by the Phi coefficient and Cramer's V values, which indicate moderate to strong associations between regimen type and pCR. The statistical measures employed serve to reinforce the robustness of the observed effect, thereby highlighting the clinical relevance of treatment selection in this particular population.

The present study demonstrated that neoadjuvant regimens incorporating pertuzumab significantly increased pathological complete response (pCR) rates in women with HER2-positive breast cancer compared with trastuzumab-based therapy alone. The objective response rate (pCR) of 80% observed in the dual blockade group was significantly higher than the 48% achieved with non-pertuzumab regimens. This finding serves to reinforce the therapeutic advantage of dual HER2 inhibition, a phenomenon which has been reported in a number of randomised controlled trials and real-world data sets (Swain et al., 2015; von Minckwitz et al., 2017; Wuerstlein & Harbeck, 2017). The marked variation in response underscores the pivotal function of pertuzumab in augmenting tumour eradication, corroborating the findings that pCR is demonstrably linked with enhanced disease-free and overall survival in HER2-positive breast cancer (Cortazar et al., 2014; Spring et al., 2020).

The efficacy of pertuzumab was particularly evident among patients treated with anthracycline-based combinations, where the strongest association with pCR was observed. This observation is consistent with reports indicating that anthracycline-containing regimens enhance the induction of DNA damage, which is further amplified through HER2 blockade pathways (Pondé et al., 2019; Slamon et al., 2011). The suppression of HER2/HER3 dimerization and downstream PI3K/AKT signalling, a pathway frequently implicated in chemoresistance (Hurvitz et al., 2013), is achieved by dual HER2 inhibition. It can therefore be hypothesised that a biological mechanism exists which underlies the enhanced pCR which was observed in this study, especially in patients exhibiting more aggressive tumour biology. This hypothesis is supported by the evidence of synergy between anthracyclines and anti-HER2 agents.

A noteworthy finding was the substantial correlation between lymphovascular invasion (LVI) and the augmented probability of attaining pCR in the pertuzumab group. LVI is conventionally regarded as a negative prognostic indicator and a marker of metastatic potential (Liu et al., 2016). However, recent literature suggests that tumours with highly proliferative phenotypes, which are prevalent in HER2-driven disease, may exhibit a more robust response to potent cytotoxic and targeted therapy combinations (Akrami et al., 2021). The observed association in our cohort suggests that LVI may not solely reflect poor prognosis, but could also indicate biological susceptibility to intensified HER2 blockade. This finding necessitates further investigation to determine whether LVI could serve as a predictive biomarker of treatment responsiveness rather than merely an adverse prognostic sign.

The tumour characteristics observed within the present cohort reflect the regional patterns seen in Middle Eastern women, where a high proportion of HER2-positive cancers present with T2 tumours, nodal involvement, and intermediate to high grades (Hashim et al., 2021). Limited access to routine screening, diagnostic delays, and cultural barriers often contribute to later-stage presentation. However, the robust response to pertuzumab-based therapy in this population indicates that achieving higher pCR rates is feasible even in patients with initially aggressive features. These findings provide a robust rationale for the implementation of dual HER2 blockade as a standard neoadjuvant option, particularly in settings where disease burden at diagnosis is high, and access to this treatment is feasible.

The present study demonstrates that neoadjuvant regimens incorporating pertuzumab are associated with substantially higher pathological complete response (pCR) rates in patients with HER2-positive breast cancer compared with trastuzumab-based protocols without pertuzumab. This finding is consistent with international evidence supporting dual HER2 blockade as a more effective neoadjuvant strategy for tumour eradication in this molecular subtype.

Significantly, the present findings augment extant trial evidence by providing real-world data from an Iraqi clinical setting, where patients frequently present with locally advanced disease and access to targeted therapies may be limited. The high prevalence of nodal involvement and intermediate to high-grade tumours in this cohort underscores the clinical relevance of achieving pCR in routine practice. The observed benefit of pertuzumab in this context suggests that dual HER2 blockade remains effective even in populations with aggressive disease features and supports its prioritisation where resources permit.

Notwithstanding the encouraging results, the study is constrained by its retrospective design and comparatively limited sample size. Despite the standardisation of pathology and clinical criteria, the influence of unmeasured confounders, such as molecular subtype heterogeneity within HER2-positive disease, on treatment response remains a significant consideration. The recommendation is for future multicentre prospective studies incorporating molecular stratification in order to validate predictive factors and optimise regimen selection. The enhancement of access to pertuzumab constitutes a pivotal challenge in Iraq and analogous health systems characterised by resource limitations. The adoption of contemporary neoadjuvant protocols on a national scale has the potential to significantly reduce disease progression, recurrence, and mortality in this high-risk breast cancer subgroup.

Pertuzumab-containing neoadjuvant regimens were found to be associated with significantly higher pathological complete response rates in HER2-positive breast cancer when compared with non-pertuzumab protocols. These findings lend support to the clinical value of dual HER2 blockade in real-world practice, particularly in settings where patients often present with aggressive disease and advanced stage at diagnosis.

Ethics Approval and Consent to Participate

The study protocol was approved by the Iraqi Board for Medical Specializations – Oncology Department and the Oncology Teaching Hospital at the Medical City Complex. Prior to analysis, all data were anonymised, and no identifiable patient information was accessed beyond that which was necessary for scientific evaluation. The study was conducted in accordance with the ethical standards outlined in the Declaration of Helsinki and followed institutional regulations governing retrospective research on medical records.

Consent for Publication

Not applicable.

Availability of Data and Material

The data that supports the findings of this study are available from the corresponding author upon reasonable request.

Conflicts of Interest / Competing Interests

The authors declare that there are no conflicts of interest.

Funding

The authors declare that this research received no external funding.

Authors' Contributions

M.S.H.: Methodology, Formal analysis, Data curation, Writing of the original draft.

A.M.J.: Conceptualization, Resources, Writing – review & editing, Supervision.

Acknowledgment

Not applicable

Use of Generative AI and AI-Assisted Technologies

The authors declare that no generative AI or AI-assisted technologies were used in the preparation of this work.