Analysis of trastuzumab therapy's efficacy with or without pertuzumab combination in the metastatic HER2-positive breast cancer an oncology hospital of Pernambuco

Breast cancer (BC) is the most common type of cancer among women and is the central public health problem in the world.1 Breast cancer is a heterogeneous disease with different molecular subtypes in four main patterns: luminal A, luminal B, HER2-positive, and triple-negative.2 Several factors are related to the increased predisposition for breast cancer, such as hormone use, parity, breastfeeding and hormone replacement therapy,3 family history of breast/ovarian cancer, obesity, alcohol consumption, and sedentary lifestyle.4

Tumors expressing the HER2 receptor are associated with a poor prognosis but benefit from targeted therapies such as trastuzumab and pertuzumab.5 In Brazil, in 2012, the National Commission for the Incorporation of Technologies (CONITEC) incorporated trastuzumab in the National Relationship of Essential Medicines of Brazil's Unified Public Health System (SUS) for the treatment of HER2-positive BC at the early and locally advanced stages.6 Later in 2017, CONITEC decided to incorporate trastuzumab and pertuzumab as first-line of HER2targeted therapies for metastatic HER2-positive BC and was another significant advance for Brazil's public health.7

In 2021, the CLEOPATRA study showed that combined trastuzumab plus pertuzumab therapy in metastatic breast cancer was associated with an increase of 15.6 months in overall survival.8

Before incorporating the HER2-targeted therapies (trastuzumab plus pertuzumab) into the public service in Brazil, the rate of judicial requests for the free supply of these therapies in the public network was high, generating high costs and significant budgetary impact for Brazilian public health.9 In this study, we observed an improvement in the overall survival (OS) of the metastatic HER2-positive BC patients who submitted the combined chemotherapy with pertuzumab plus trastuzumab, proving the outstanding achievement of the incorporation of pertuzumab therapy into Brazil's Unified Public Health System (SUS).

In this sense, we saw an improvement in the OS in metastatic HER2-positive BC patients treated with pertuzumab plus trastuzumab, proving the outstanding achievement of incorporating pertuzumab into SUS. Therefore, it is critical to evaluate the efficacy between trastuzumab-only or pertuzumab plus trastuzumab therapies in metastatic HER2-positive breast cancer patients.

The median age was 50.4 years (range 25-86) when they were diagnosed with tumor metastasis. The average body surface was 1.67m² (Table 1). The patients treated with trastuzumab-only had a mortality rate of 13/100 women per year (95% CI: 9.19 to 18.38). The patients treated with trastuzumab plus pertuzumab had a mortality rate of 4.14/100 women per year (95% CI: 2.50 to 6.87). The estimated risk ratio (HR) for the trastuzumab-only group was 3.16fold higher of death compared to the trastuzumab plus pertuzumab-treated group (Table 2).

At diagnosis, the patients presented with metastatic clinical stage had a borderline association (p=0.061) with HR 2.34. The group of patients who evolved into metastasis during follow-up had a risk 3.12-fold higher of death compared to the group in tumor metastases at initial diagnosis (Table 3).

In the multivariate analysis, the HR estimate adjusted by age, early clinical stage, time course between diagnosis and evolution to the metastatic stage, it was found that the trastuzumab-only treated group had a risk 3.58-fold higher of death compared to the trastuzumab plus pertuzumab group (Table 4).

The mean follow-up time was three years (range 15 days to 14.7 years) (Figure 1). The estimated mortality rate was 7.73/100 diagnosed women per year (95% CI: 5.80 to 10.3). In the analysis of OS, there was a significant difference between the groups treated with trastuzumab-only or trastuzumab plus pertuzumab (p<0.001) (Figure 2).

In the present study, patients with breast cancer and metastatic stage at diagnosis had a median age of 50.4 years (range 25 to 86 years), comparable results reported in a previous observational study.11 There is not only one risk factor for breast cancer, but age over 50 is also considered the most important because when the incidence rate is considered, the number of women with breast cancer and age over 50 rapidly increases. Therefore, the World Health Organization (WHO) and the Brazilian Ministry of Health recommend screening by mammography examination every two years in age over 50.12

The mortality rate was higher in the patients treated with trastuzumab-only than those treated with trastuzumab plus pertuzumab. Our results confirm the CLEOPATRA phase III study, despite the limitation that we did not evaluate the association with paclitaxel use.13 In turn, OS was longer in the trastuzumab plus pertuzumab group than trastuzumab-only. A retrospective study in Singapore (2020)13 showed more benefits for patients treated with trastuzumab plus pertuzumab and a longer overall survival time.14 An important observation found in this study was that some patients survived from 15 days to 14.7 years, i.e., despite treatment in advanced or metastatic stages, neoadjuvant and/or adjuvant therapy with trastuzumab may be associated with remission and late recurrence, which may explain the prolonged survival time.

This study was relevant, despite its limitations, mainly because it was conducted in a hospital for cancer patient care and exclusively serves SUS users, whose exposure to risk factors is more prominent and differentiated than those who have access to private health services. In addition, there are benefits in incorporating new therapies into Brazil's public health network for the treatment of women with metastatic HER2-positive breast cancer, impacting increased OS and better quality of life, even those diagnosed in more advanced stages. Perhaps the difficulty of accessing the public health service is responsible for the high rate of metastatic disease and a low life expectancy for these patients.

It is worth noting that innovative treatments with current drugs can significantly reduce costs for SUS bring about significant changes in therapeutic conduct, leading to adequate cancer treatment with excellent chances of healing. In addition, the costs of low-efficiency treatments may lead to long-term hospitalization, long-term incapacity; or even death, generating a significant financial burden on health institutions, suffering, and a high overall cost to the patient and their family.