Keywords: Breast neoplasms - Receptor - ErbB-2 - Antibodies - Monoclonal
Descritores: Neoplasias mamárias - Receptor - ErbB-2 - Anticorpos - Monoclonais
INTRODUCTION
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.
MATERIAL AND METHODS
Study design and participants
At Hospital de Cancer de Pernambuco (HCP), Recife, Brazil, a cross-sectional study
was carried out. This human study was approved by HCP-approval: CAAE40729520.2.0000.5205.
All adult participants provided written informed consent to participate in this study.
One hundred seventy-two patients with HER2positive metastatic breast cancer were divided
into two groups. One group of patients underwent chemotherapy with trastuzumab-only
between 2013 and 2016, and another group of patients underwent treatment with pertuzumab
plus trastuzumab between 2017 and 2020. The inclusion criteria for the patients were
women with invasive breast cancer, HER2 3+
expression, and clinical stage IV (metastatic), according to the 8th
edition classification of solid tumors.[10 ]
Chemotherapy and HER2-targeted therapies
Chemotherapy regimens included a dense dose of adriablastin RD 60mg/m2
and cyclophosphamide 600mg/m2 every two weeks, during four cycles followed by paclitaxel 80mg/m2 everyone week for 12 weeks. Chemotherapy was administered for a median of four cycles
(range 2-6 cycles). The combination chemotherapy with trastuzumab-only or pertuzumab
plus trastuzumab was performed until one treatment year.
Statistical analysis
The results presented as absolute and relative frequencies for categorical parameters.
Continuous normally distributed data are expressed as mean and standard deviation
(SD), while continuous non-normally distributed data were in median and Interquartile
(IQR). Shapiro-Wilk test was used to evaluate the normality of data distribution.
Qualitative variables were analyzed with chi-square and Fisher's exact tests. Unpaired
Student's t-test performed continuous data. Kaplan-Meier survival curves with log-rank
tests were used to estimate OS. The stratified Cox proportional-hazards model was
used to estimate the hazard ratio (HR) and its 95% confidence interval (CI). Multivariate
analysis was used Cox regression to estimate the adjusted HR. Data analysis was performed
by Stata v. 14.0 software. For all analyzes, values of p <0.05 were considered significant.
RESULTS
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 ]).
Table 1
Clinical variables
TOTAL
TRASTUZUMAB
H+P
p-value
VARIABLES
N=172
N=69
N=103
Mean (±SD)
Mean (±SD)
Mean (±SD)
Age (years)
50.4 ± 12.1
53.4 ± 12.4
48.3 ± 11.6
0.007a
Time course (months)
Between diagnosis and evolution to metastasis
2.5 (0; 22.9)
3.7 (0; 23.7)
2.3 (0; 21.4)
0.599
Body surface (m2)
1.67 ± 0.18
1.67 ± 0.16
1.67 ± 0.19
0.908
Age group (years) <40
N (%) 33 (19.2)
N (%) 8 (11.6)
N (%) 25 (24.3%)
>40 ≥59
108 (62.8)
31 (59.4)
67 (65.1%)
0.003a
≥60
31 (18.0)
20 (29.0)
11 (10.7%)
H + P: Trastuzumab plus pertuzumab; SD = Standard deviation.
Table 2
Types of chemotherapy and time course
VARIABLES
VALUES
Between diagnosis and 1st dose of trastuzumab
Median (P25 ; P75 )
Time course (months)
6.0 (1.8; 24.7)
Between first and final doses of trastuzumab
Median (P25 ; P75 )
Time course (days)
535 (463; 594)
Maintenance dose: trastuzumab
Median (P25 ; P75 )
Time course (days)
402 (347; 448)
Start of treatment: trastuzumab plus pertuzumab
Median (P25 ; P75 )
Time course (months)
5.0 (0; 11.3)
Drugs acquisition
N (%)
Brazilian Ministry of Health
55 (53.9%)
Judicialization
47 (46.1%)
Table 3
Association of treatment outcome with the type of treatment and clinical variables
of patients
VARIABLES
DEATH RATE (/100 peoples-years)
HAZARD RATIO (CI 95%)
p-value
HER2-targeted therapies Trastuzumab plus pertuzumab
4.14
Reference
-
Trastuzumab
13.0
3.16 (1.71 - 5.86) <0.001
[a ]
Age group (years) <40
6.77
Reference
-
>40 ≥59
8.37
1.26 (0.58 - 2.75)
0.554
≥60
6.25
1.13 (0.39 - 3.30)
0.826
Stage at diagnosis I - II
6.88
Reference
-
III - IIIA
7.47
1.31 (0.51 - 3.33)
0.574
IIIB - IIIC
7.87
1.39 (0.61 - 3.16)
0.428
IV
8.51
2.34 (0.96 - 5.73)
0.061
Time course between diagnosis and evolution to metastasis Same day
9.71
3.12 (1.43 - 7.14)
0.005[a ]
Up to one years
8.98
1.49 (0.68 - 3.33)
0.316
Over one years
6.37
Reference
a Statistically significant: p <0.05.
Table 4
Multivariate analysis
VARIABLES
HAZARD RATIO (CI 95%)
p-value
HER2-targeted therapies
Trastuzumab plus pertuzumab
Reference
-
Trastuzumab
3.58 (1.89 - 6.78)
<0.001[a ]
a Adjusted for age, early clinical staging and time course: between diagnosis and evolution
to metastasis.
Analysis of trastuzumab therapy's efficacy with or without pertuzumab combination
in the metastatic HER2-positive breast cancer an oncology hospital of Pernambuco
Figure 1 Kaplan-Meier survival curve of metastatic HER2-positive breast cancer patients.
Figure 2 Overall survival curves in metastatic HER2-positive breast cancer patients treated
with trastuzumab or trastuzumab plus pertuzumab.
DISCUSSION
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.
Bibliographical Record
