We conducted a retrospective analytical cohort study in the reference hospitals involved in breast cancer management in Cote d'Ivoire, which are located in Abidjan. The study period extended from January 1, 2021, to December 31, 2022, corresponding to the recruitment period.

Patients were included if they met the following criteria: histologically confirmed breast cancer classified as metastatic; HER2-positive status determined by immunohistochemistry and/or fluorescence in situ hybridization; treated with dual anti-HER2 blockade (trastuzumab plus pertuzumab) combined with chemotherapy using a taxane; received at least 4 cycles of treatment with dual antiHER2 blockade; and underwent regular clinical and radiological evaluations every 4 cycles.

text[[80, 860, 475, 904], [523, 66, 917, 95]] Patients were excluded if they were male, had nonmetastatic breast cancer, had HER2-negative breast cancer or unknown HER2 status, did not receive dual anti-HER2 blockade, or had incomplete medical records.

The parameters studied included epidemiological data, such as age, menopausal status, and medical history; clinical data, including consultation delay and type and location of metastases; anatomopathological data, such as histological type, histoprognostic grade, hormone receptor status, and HER2 expression; and therapeutic and disease evolution data, including the type of treatment received, total number of cycles received, clinical and radiological response to treatment, adverse effects, adherence, date of and reason for treatment discontinuation, and status at the last consultation.

The administration of dual blockade with trastuzumab and pertuzumab was decided during a multidisciplinary tumor board meeting. Treatment was administered every 21 days. All patients had a performance status between 0 and 2 and received concomitant chemotherapy. Radiological assessment was performed after 4 cycles. All adverse events were reported on a pharmacovigilance form. Cardiac function was monitored throughout anti-HER2 therapy using transthoracic echocardiography, conducted at baseline and then every 3 months. Left ventricular ejection fraction, the primary marker of systolic function, was measured when technically feasible.

The patients were identified from the paper and electronic databases of the centers participating in the study. An electronic form was used to collect information from the medical records.

Analyses were performed using the survival package of R software, version 4.3.1. Categorical variables were presented as frequencies and percentages, and continuous variables as mean (SD) or median (range). Survival curves were estimated using the Kaplan-Meier method and compared with the log-rank test. A univariable Cox regression model was used to test factors associated with progression-free survival. Variables with P < 0.10 were included in the multivariable model. A P value less than 0.05 was considered statistically significant.

Progression-free survival (PFS) was defined as the time from initiation of dual anti-HER2 blockade to the first documented event of either disease progression or death. Patients with no event were censored at the date of last follow-up. Overall survival (OS) was defined as the time from initiation of treatment to the date of death from any cause. Patients who were still alive were censored at the date of their last follow-up. Objective response refers to a quantifiable reduction in tumor burden, usually evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), which classifies treatment response as complete response, partial response, stable disease, or progressive disease. Objective response rate (ORR) was defined as the percentage of patients who experienced either a complete response or a partial response as assessed by radiological imaging. Stable disease and progressive disease were not included in the ORR. Treatment adherence was evaluated indirectly through the Medication Possession Ratio (MPR), defined as the ratio of the number of days for which medication was supplied to the total number of days in the treatment period. Patients with an MPR of 80% or greater were considered adherent.

The study included 30 patients. The median age was 47.2 years (interquartile range, 25 years) at the time of diagnosis of metastatic disease. All patients had invasive carcinoma of no special type. The majority of patients (20 [66.7%]) had de novo metastatic disease. Pulmonary metastases were the most frequent, found in 19 patients (63.3%). Additionally, half of the tumors (15 [50.0%]) exhibited overexpression of hormone receptors. Table 1 details the clinical and pathological characteristics of the patients.

The median follow-up was 20.1 months (range, 5.8–25.0 months). The dual anti-HER2 blockade was administered as first-line therapy in 18 patients (60.0%). Paclitaxel was combined with dual HER2 blockade (trastuzumab plus pertuzumab) in 22 patients (73.3%) and docetaxel in 8 (26.7%). Approximately two-thirds of patients (20 [66.7%]) received between 6 and 12 treatment cycles. Treatment adherence was considered satisfactory in 20 patients (66.7%). Discontinuation of trastuzumab or pertuzumab was the most frequent cause of poor adherence. Objective responses were observed in 18 patients (60.0%). Table 2 details the treatment and outcome characteristics.

Regarding adverse effects, anemia was the most commonly observed (93.3%) followed by neutropenia (73.3%). No cardiac toxicity was reported. Cutaneous reactions, in the form of rashes, were observed in 3 (10.0%) patients. Table 3 summarizes the observed side effects.

The median PFS was 15.3 months, while the median OS had not yet been reached at the time of the analysis (Figure 1).

No statistically significant association was found between PFS and factors such as hormone receptor status, the presence of liver or pulmonary metastases, or the de novo metastatic nature of the disease. However, the use of dual HER2 blockade in the first line was associated with longer survival, and the presence of brain metastases was correlated with shorter survival. Patients who received dual antiHER2 blockade as first-line treatment had a median PFS of 17.6 months, compared with 8.6 months for those who received it later (P = 0.015) (Figure 1). Similarly, the median progression-free survival was 8.5 months in patients with brain metastases, compared to 15.7 months in those without brain metastases at the time of metastatic disease diagnosis (P = 0.024) (Figure 2). The results of regression analyses are presented in Table 4.

The median age of the patients was 47.2 years, which is younger than that observed in the PERUSE study (54 years). This trend is consistent with epidemiological data reported in sub-Saharan Africa, where breast cancer diagnosis is often made at an earlier age. The most frequent metastatic sites were pulmonary (63.3%) followed by liver involvement (20.0%). These distributions are similar to those reported in the literature.

The ORR was 60.0% lower than the 80.0% reported in the PERUSE study. This difference could be related to several factors, notably insufficient adherence (30.0% of patients exhibiting poor treatment adherence) and a more aggressive tumor biology in younger patients. The median PFS was 15.3 months, shorter than the 17.2 months in the CLEOPATRA trial and the 20.6 months in the PERUSE study. However, the administration of dual blockade as first-line therapy significantly improved PFS (17.6 months vs 8.6 months; P = 0.015), highlighting the importance of initiating this treatment at the time of metastatic disease diagnosis. The shorter survival could be explained by the selection of more aggressive tumor clones under the pressure exerted by initial treatments. The presence of brain metastases was associated with poorer PFS (15.7 months vs 8.5 months; P = 0.024). This could be explained by insufficient diffusion of trastuzumab across the blood-brain barrier, with concentrations of this treatment in the central nervous system being up to 300 times lower than those observed in the bloodstream. This result aligns with the findings of other studies that highlight the unfavorable prognosis of central nervous system involvement. However, certain drugs such as tucatinib have revolutionized the medical management of brain metastases through the HER2CLIMB study. Conversely, no significant difference was found based on the presence of liver or lung metastases, which is also reported in the literature.

The most frequent toxic effects were hematological, with a high prevalence of anemia (93.3%) and neutropenia (73.3%). These adverse effects are comparable to those reported in the PERUSE and CLEOPATRA studies. The absence of cardiac toxic effects could be explained by the small size of our sample or the short follow-up duration. A major challenge highlighted in this study is accessibility to treatments. Indeed, 30.0% of the patients experienced treatment delays, mainly due to supply shortages of trastuzumab and pertuzumab. This difficulty could have affected the results and underscores the importance of improving access to treatments in our context.