Survival Analysis of Patients with Luminal and Non-Luminal Subtype Breast Cancer Receiving Vinorelbine Therapy at Sanglah General Hospital, Denpasar, Bali
Dewa Putu Satria Juristiasa
1*, Putu Anda Tusta Adiputra
2, Dewa Made Sukrama
31 Department of General Surgery, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
2 Department of General Surgery, Oncology Division, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
3 Department of Clinical Microbiology, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
*Corresponding author:
Dewa Putu Satria Juristiasa Department of General Surgery, Faculty of Medicine, University of Udayana, Sanglah General Hospital, Denpasar, Bali, Indonesia
dpe.satrija13@yahoo.com
INTRODUCTION
Breast cancer is one of the most common cancers and is the most lethal in women. The worldwide incidence of breast cancer in women is 46.3 cases per 100.000 year-people with a cumulative risk for populations aged neonate to 74 years of 5.03%.
Meanwhile, the mortality rate due to breast cancer is 13.0 deaths per 100,000 year-people with a cumulative death risk of 1.41% [1]. In Indonesia, data showed that
breast cancer ranked first in new cancer cases in 2018, with 58,256 new breast cancer cases or 16.7% of the total new cases in that year, regardless of gender. In addition, breast cancer ranked second in mortality due to cancer, with 22,692 deaths or 11.0% of the total death caused by cancer in Indonesia in 2018 [2].
Moreover, breast cancer is classified into several subtypes based on the mutation characteristics and immunohistochemistry. The most commonly used classification is the luminal and non-luminal subtype.
A R T I C L E I N F O
Received : 19 December 2021 Reviewed : 14 January 2022 Accepted : 18 March 2022 Keywords:
breast cancer,
immunohistochemical markers, survival, vinorelbine
A B S T R A C T
Background: Breast cancer is the most common type and lethal cancer affecting women.
Meanwhile, vinorelbine is one of the chemotherapy agents used for luminal and non-luminal breast cancer. Therefore, this study aims to determine the survival difference between patients with luminal and non-luminal subtype breast cancer treated with vinorelbine.
Methods: This study was a retrospective cohort. Women with breast cancer treated with vinorelbine were classified based on estrogen receptor (ER), progesteron receptor (PR), human epidermal growth factor receptor-2 (HER-2) markers, and subtypes. The subjects were followed up to chemotherapy visits with vinorelbine recorded in the medical record. The survival analysis between subtypes was analyzed by the Kaplan-Meier curve.
Results: One hundred women were obtained with a mean age of 52.36 ± 10.45 years. Based on immunohistochemistry, 60% were ER-positive, 53% were PR positive, and 57% were HER-2- positive. Based on the subtype, 67% were luminal, while 33% were non-luminal. All subjects had a mean survival duration of 155.38 days (95% CI 128.05-182.71). The stratified survival analysis showed a significant difference in survival duration based on HER-2 marker and subtype. The subjects with HER-2 positive survived longer with a mean of 203.37 days (190.72–216.02) than those with HER-2 negative with a mean of 90.10 days (65.68-114.53) (p<0.001). In addition, the subjects with the luminal subtype survived longer with a mean of 174.84 (142.72-206.94) than those with non-luminal with a mean of 90.10 (65.68-114.53) (p = 0.04).
Conclusions: There was a significant difference in survival duration between women with breast cancer treated with vinorelbine chemotherapy who were HER-2 positive, HER-2 negative, and luminal and non-luminal subtypes.
breast cancer with HER-2 positive and triple-negative subtypes. The exclusion criteria in this study were patients with incomplete medical records.
All patients who met the inclusion and exclusion criteria were included in this study. All patients were observed following vinorelbine intravenous administration until the outcome was obtained. The outcome assessed as the final observational status of the study subject was the mortality status. The patient’s mortality status was categorized into two nominal categorical variables:
alive and deceased, based on the medical record. The events of this study were found dead within one month of the last visit for vinorelbine chemotherapy. Patients were removed from the study when 1) the study period ended (July 2020), 2) there was no death up to one month since the last vinorelbine chemotherapy visit, meaning the patient was lost to follow-up, or 3) vinorelbine was stopped due to other indications in the medical record. The minimum follow-up period was one month for each subject. The duration-of-survival variable was measured in days (numerical). The numerical data variables would be presented in mean, whereas the categorical variables would be presented in frequency and percentage.
The researchers conducted two analyses in this study.
The first was the descriptive analysis, including frequency and univariate numerical data analysis. This analysis was conducted to show the characteristics data, such as the distribution of gender and age. The second analysis was the bivariate analysis, the Kaplan-Meier curve for describing the survival duration of patients with breast cancer undergoing vinorelbine chemotherapy in both subtype groups. Finally, the Cox regression analysis was conducted to show the effect of the breast cancer subtype on the survival of patients with breast cancer undergoing vinorelbine chemotherapy. The normality test was then conducted for numerical data to determine the distribution using the Kolmogorov- Smirnov method. All data analysis was conducted utilizing SPSS ver. 25.0 software and p <0.05 indicated a statistically significant result.
RESULTS
The study included one hundred subjects who met the inclusion and exclusion criteria. The basic characteristics are shown in Table 1. The mean age was 52.36 ± 1.21 years. The subjects’ age was considered young with a minimum of 32 years; 24% of subjects were less than 45 years, and only 12% were above 65 years old or elderly. The classification based on immunohistochemistry showed that 60% of the subjects were positive for estrogen receptor (ER), 53% were positive for progesterone receptor (PR), and 57% were positive for HER-2. The subtype classifications revealed Breast cancer with luminal subtype is usually found with
ER mutation without HER-2 mutation. On the other hand, the non-luminal subtype can further be classified into HER-2 positive and triple-negative. Each of these subtypes has a different clinical profile and responds differently to breast cancer management approaches [3].
Meanwhile, chemotherapy is a form of systemic therapy in managing breast cancer, including administering cytotoxic drugs or inhibiting cancer cell division. These drugs can be administered through intravenous, oral, or other administration routes, in which the active compound will be distributed through the bloodstream until they reach the site of action, which is the cancer tissue [4]. Vinorelbine, in this case, is a chemotherapy agent that can be used for breast cancer. Specifically, vinorelbine is indicated for metastatic breast cancer or non-responsive to first-line chemotherapy regimens, such as doxorubicin. In an effectiveness evaluation of vinorelbine by Cybulska-Stopa et al. [5], vinorelbine has been proven effective as a second or more line chemotherapy agent, either as a single agent or combined with 5-fluorouracil.
Further, the effectiveness of a breast cancer therapeutic regimen varies based on the type and subtype of cancer.
A study by Fallahpour et al. [6] found that breast cancer patients with luminal subtype had a longer mean survival duration than non-luminal subtype. In addition, a recent paradigm of personalized medicine requires a doctor to select the best drug, both in terms of benefits and risks, for a patient by specifically considering the type and subtype of the disease; therefore, further studies regarding vinorelbine are still needed. In this study, the authors would like to determine the survival duration of patients with luminal and non-luminal breast cancer treated with vinorelbine chemotherapy.
METHODS
This study was a survival analysis conducted in the General Hospital (RSUP) of Sanglah, Denpasar, from January 2015 until June 2020. The population in this study was patients with breast cancer who underwent single vinorelbine chemotherapy at Sanglah General Hospital, Denpasar, from January 2015 to June 2020.
The samples were recruited with total consecutive sampling. With two groups of observations, the total sample size was 100 people, with 50 samples in each group. The inclusion criteria in this study included patients with breast cancer undergoing single vinorelbine chemotherapy in Sanglah General Hospital, Denpasar, during the study period. The subjects were categorized into two groups: the luminal subtype breast cancer group, consisting of patients with luminal subtype breast cancer (ER+, PR+, and HER2-), both luminal A and B, and non-luminal subtype, consisting of patients with
DISCUSSION
There is a preferential difference in systemic therapy based on the breast cancer subtype suffered by the patients. Each breast cancer subtype has a different sensitivity to a different systemic therapeutic agent.
European Society for Medical Oncology (ESMO) recommends endocrine therapy for breast cancer subtypes with hormone receptors, the luminal A and B subtypes. Meanwhile, chemotherapy is preferred for breast cancers without endocrinology oncogene expression (negative for estrogen and progesterone receptors) and those with oncogene expression other than the two endocrinal receptors, such as the HER-2.
Therefore, chemotherapy is recommended for luminal B, HER-2, and triple-negative subtypes. In addition, anti- HER-2 therapy with trastuzumab is also recommended for breast cancer that expresses HER-2, which is half of the luminal B and HER-2 positive cases [3].
The recommended chemotherapy regimen for breast cancer is the anthracycline and taxane classes administered sequentially [7]. Anthracycline is an enzyme inhibitor class of chemotherapy agents, which are derivatives of the bacterial toxin of the Streptomyces genus. On the other hand, the taxane is an anti- microtubule class chemotherapy agent extracted from plant sources. The two most commonly used and combined drugs in a chemotherapy regimen are doxorubicin, an anthracycline class chemotherapy agent, and paclitaxel, a taxane class chemotherapy agent [8].
In addition to combination, chemotherapy administration should also consider the contraindications for the agent and replacement with an alternative second-line or more that most subjects had luminal subtypes, both luminal
A and B, namely 67% of subjects. In addition, 16% of the subject had HER-2 enriched subtype breast cancer, and 17% had triple-negative breast cancer (TNBC). In the dichotomous classification, 67% of the subject had luminal subtype breast cancer, and the remaining 33%
had non-luminal subtype breast cancer.
The researchers only found 32 deaths in this survival study throughout the study period, which were the events assessed as the outcome. Only 32 (32%) subjects were deceased during this study period; the remaining 68 (68%) subjects completed the observational period alive and were censored due to the end of the study or vinorelbine stoppage due to other indications. All subjects had a mean survival duration of 155.38 days (95% CI 128.05-182.71). In addition, the mean observation duration was 58.17 (CI 95% 48.75-67.59).
The survival analysis with a Kaplan-Meier curve is shown in Figure 1 and Table 2.
Moreover, there was a significant difference between breast cancer subtype luminal and non-luminal in Cox regression (p=0.04). The mean survival duration in the luminal group was 174.84 days (CI 95% 142.72-206.94), whereas in the non-luminal group was 90.10 days (CI 95% 65.68-114.53). In further stratifications based on the immunohistochemical markers, a significant difference was found between HER-2 positive and negative in Cox regression (p< 0.001). The subjects with positive HER-2 marker were found to have a longer survival with a mean of 203.37 days (95% CI 190.72- 216.02). In addition, the researchers did not find a statistically significant survival difference in the ER or PR markers classification.
Table 2. Survival based on the subtype and immunohistochemistry
Variable Median
Survival (days)
95% CI p
Subtype Luminal
Non-luminal 174.84
90.10 142.72 – 206.94
65.68 – 114.53 0.040 ERPositive
Negative 172.26
99.76 138.18 – 206.35
77.38 – 122.14 0.231 PRPositive
Negative 168.26
108.64 129.28 – 205.24
87.97 – 129.31 0.386 HER-2
Positive
Negative 203.37
90.10 190.72 – 216.02
65.68 – 114.53 < 0.001 ER, estrogen receptor; PR, progesteron receptor; HER-2, human epidermal growth factor receptor-2; CI, confidence interval Table 1. Subjects’ basic characteristics
Variable n (%)
Age (mean ± SD, years) 52.36 ± 1.21
Observation duration (mean ± SD, days) 58.17 ± 5.44 Final status
Alive
Deceased 68 (68.0)
32 (32.0) Immunohistochemical marker
ERPR HER-2
60 (35.30) 53 (31.17) 57 (33.53) Subtype
Luminal HER-2 enriched TNBC
67 (67.0) 16 (16.0) 17 (17.0) HER-2, human epidermal growth factor receptor-2; TNBC, triple negative breast cancer; SD, standard deviation
On the survival analysis curve, the main result of this study was the mean survival duration of 155.38 days (CI 95% 128.05–182.71) for all subjects without stratification. A previous study by Eng et al. [11] showed that the mean survival of patients with advanced-stage breast cancer was 2.3 years. Another study that specifically evaluated the survival of patients with advanced-stage breast cancer who received vinorelbine chemotherapy, both as single and combination agents, showed a mean survival of 11.5 months [12]. Meanwhile, another study specifically studied the survival of women with breast cancer who received vinorelbine as the second-line chemotherapy and found a mean progression- free survival of 18 weeks [5].
In the classifications based on the subtype, two- thirds of the subjects, or 67%, had luminal subtype, 16% had HER-2 enriched subtype, and 17% had TNBC.
These distributions are in accordance with other studies agents. The consideration for selecting alternative
chemotherapy agents also includes resistance to first- line chemotherapy agents or the patient’s preference to avoid certain side effects, such as alopecia. The second line of chemotherapy, also recommended by ESMO, includes capecitabine and vinorelbine [9].
Specifically, vinorelbine is indicated as the second- line or more therapy in patients with breast cancer unresponsive to the first-line chemotherapy with anthracycline and taxane. As advanced chemotherapy, vinorelbine can be used as a single agent or combined with other agents. Vinorelbine can be administered orally or intravenously. The indication for single therapy is progressive breast cancer despite having anthracycline chemotherapy for less than one year or patients with breast cancer with chemotherapy indications but are contraindicated for anthracycline and/or taxane classes [9].
Figure 1. Kaplan-Meier survival curve based on A) breast cancer subtype, B) ER marker, C) PR marker, and D) HER-2 marker.
These situations should be considered in interpreting the data presented in this study.
CONCLUSIONS
Based on this study, there was a significant difference in survival duration based on subtypes and immunohistochemical markers in women with breast cancer with vinorelbine chemotherapy.
DECLARATIONS
Ethics ApprovalThis study was approved by the ethics committee of Sanglah General Hospital (RSUP) and the Faculty of Medicine, University of Udayana.
Competing of Interest
The authors declare no competing interest in this study.
Acknowledgment Not applicable.
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From the discussions, the authors identified various strengths and limitations of this study. To the best of the authors’ knowledge, few studies have specifically studied the difference in survival duration based on the breast cancer subtypes, specifically in a population of women with breast cancer receiving vinorelbine as a chemotherapy agent. This study is also rare, especially in the research locations of Sanglah General Hospital, Denpasar, in particular, and Bali and Indonesia in general. One of the limitations of this study is the relatively short follow-up duration. In addition, there was no data regarding the cause of vinorelbine stoppage in 68% of the subject that completed the observation.
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