Abstract
AIM:
This study aims to describe the current state of multiple primary malignant neoplasms (MPMNs) breast cancer patients management, evaluate the predictive impact of different factors, optimise approaches to diagnosis and treatment of these patients and improve their life quality.
METHODS:
The study included 2,032 patients who received special treatment at the Department of Breast Tumours and it Reconstructive Surgery of the National Cancer Institute from 2008 to 2015 within an open randomized controlled trial. The sample included 195 patients with synchronous cancer or metachronous breast cancer.
RESULTS:
A more aggressive course of breast cancer is observed in patients exposed to radiation from the Chornobyl accident. The clinical course of disease in patients with synchronous breast cancer is worse and prognostically unfavourable comparing to metachronous one. The influence on clinical course of disease of primary localization, type of settlement, blood group and Rh factor, type of special treatment, and age in patients with synchronous and metachronous cancer was not statistically proven. The impact of operative intervention scope in patients with synchronous and metachronous breast cancer was statistically proven, i.e. the course of the underlying disease in patients who underwent mastectomy is worse comparing to patients who underwent conservative surgery. Plastic and reconstructive surgery in patients with synchronous cancer was statistically proven in this study as reasonable. The influence of local recurrence rates on overall survival in patients with synchronous cancer was proven. However, the influence of local recurrence rates in patients with metachronous cancer was not statistically proven.
CONCLUSIONS:
There should be paid a great attention to synchronous and metachronous breast cancer patients in order to find and provide the best options of their management. This is crucial to continue researches in this field of oncology.
Keywords
Introduction
Two or more unrelated primary malignant tumours that originate from different organs and occur simultaneously or one after another are called multiple primary malignant neoplasms (MPMNs). They fall into two main categories: synchronous (SMPMNs) and metachronous (MMPMNs). SMPMNs are defined if the tumours occur simultaneously or within 6 months of one another. If the interval time is more than 6 months, such tumours are called MMPMNs.
Clinically, MPMNs are often confused with metastasis or recurrence of malignant tumours. However, metastatic tumours are derived from the primary lesion, with both showing the same pathological characteristics and similar developmental processes. Conversely, MPMNs refer to the development of a new malignant lesion de novo; their characteristics are completely different from those of the original tumour lesions [1].
The occurrence of MPMN has increased in recent years. Breast cancer (BC) represents 30–50% of all second primary malignant tumours in women affected by primary breast cancer. They have 2–6 times higher risk of developing a new primary cancer in the contralateral breast during their life [2–4], corresponding to a risk of 0.3–1.0% per year [3,5]. There is uncertainty in the literature regarding the prognosis and survival of patients with primary MPMNs compared to primary unilateral breast cancer [6–11]. Debates are held over whether prophylactic bilateral mastectomies are reasonable. Given the importance of this issue, we investigated the clinical features and patterns of occurrence, prognosis and consequences of MPMNs in patients with breast tumours.
In the modern era, where breast-conserving surgery is a viable alternative to mastectomy, breast cancer patients and their healthcare providers have to consider the issue of quality of life in regards to the type of surgery. The choice of surgical procedure should consider the perceptions of women diagnosed with breast cancer as well as their functional and emotional well-being. A more holistic approach to the patient should be implemented with proper psychological evaluation before and psychological support after the crisis [12]. However, appropriateness of breast-conserving surgery in patients with MPMNs was not studied.
Objective of the study
To evaluate the predictive impact of adverse factors, optimise approaches to diagnosis and treatment of breast cancer associated with MPMNs, improve life quality and increase life expectancy of such patients.
Materials and methods
Diagnostic criteria
We considered synchronous cancer located in the contralateral breast or other sites occurred within 6 months from the first diagnosis. We considered metachronous cancer located in the contralateral breast or other sites occurred after 6 months from the first diagnosis. Patients were divided into 4 groups: (1) with synchronous breast cancer (SBC); (2) with synchronous breast cancer and cancer in other sites (SBCO); (3) with metachronous breast cancer (MBC); (4) with metachronous breast cancer and cancer in other sites (MBCO).
The study is conducted according to the ethics principles of Helsinki Declaration, GCP and Law of Ukraine “On medications” approved by the Commission on issues of ethics of the National Cancer Institute (Minutes No. 7 of 08.04.2010) and the Commission on issues of ethics of the Bogomolets National Medical University (Minutes No. 71 of 10.04.2013).
Data analysis
The study included 2,032 patients who received special treatment at the of Breast Tumours and it Reconstructive Surgery of the National Cancer Institute (Oncology Department Bogomolets National Medical University) from 2008 to December 2015 within an open randomized controlled trial to study objectification criteria for selection of operative intervention scope in patients with BC. 195 (9.6%) patients constituted a group with MPMNs; treatment results for these patients are presented in the article.
Follow-up
Overall survival and median survival were used as indicators to assess survival time. Overall survival was calculated from the tumour diagnosis date to the death or last follow-up date; if the patient was lost, the last follow-up date was defined as the study endpoint.
For patients with MPMN, the survival time was calculated according to the confirmed date of the first tumour, whereas for patients with MPMN, survival time was calculated from the confirmed date of the last diagnosis of the tumour.
Survival rates of 195 patients were evaluated according to the data of National Cancer Registry in Ukraine.
Statistical analysis
The methodological basis of the study consisted of the descriptive statistics methods and specific methods of statistical analysis that laid the basis for the statistical conclusion. For general characteristics of patients group that formed the sampling frame, methods of summarizing and grouping, construction of series of distribution, methods of absolute, relative and average values, and tabular and graphical methods were used.
The analytical basis for statistical conclusion was formed by special methods of in-depth statistical analysis. Thus, for the survival analysis based on incomplete (censored) data, the survivorship function was constructed, which characterizes the probability that the subject will survive longer than t . Also, the life tables were constructed and survival distribution was adjusted with simultaneous survival function assessment using the Kaplan-Meier procedure to compare survival in two or more groups.
To test the hypothesis about the difference between the averages periods of metachronous cancer development before and after 2008, the analysis was performed using the Student t -test, and to test the hypotheses that their variances are unequal – using the Levene’s criterion and the Brown-Forsythe criterion, which are more resistant to possible deviations of the normal distribution. Values of p < 0.05 were considered to be significant.
The standard data model was created in EXEL and the analytical data models - in STATISTICA. All calculations and graphs were made in STATISTICA application.
Tumour distribution
The sample included 195 patients of which 105 persons (53.9%) presented synchronous processes. Distribution of synchronous processes by localization is following: 55.2% – breast cancer and 44.8% – combination of cancer in breast and other sites. The percentage of metachronous processes is 46.1% of which 47.8% present breast cancer, and the rest 52.2% present a combination of cancer localizations (Table 1).
The most frequent secondary localization of tumours were breast (79.5%) and female reproductive system (12.3%) making together 91.8% of the cases (Table 2).
Distribution of patients by territorial basis
Most patients (83.1%) were urban dwellers, and the remaining 16.9% were rural dwellers. However, the reason of such distribution could be not only eventually worse ecology in big cities, less healthy lifestyle of urban citizens and other possible factors which differ city life from life in small villages. We consider also that primarily this could be also due to better access for healthcare, predominance of the urban population of Ukraine, better awareness, and higher social status of patients (Table 3).
The majority of patients (69.2%) were residents of central regions and the city of Kyiv, 13.3% – eastern regions, 11.8% – western regions. This could be also due to better access for healthcare in big cities, especially in Kyiv, and close to Kyiv territories (Table 4).
Age characteristics of patients
The average age of patients with MMPMNs was 46.6. The distribution of patients by age is following: women of reproductive age – 72 (37%), while postmenopausal women – 123 (63%) (Table 5).
Development of MPMNs is possibly associated with the consequences of the Chernobyl accident. The excess cases of BC due to radiation were identified among women exposed to radiation following the atomic bombings of Hiroshima and Nagasaki [11,13]. The development of this type of cancer in this population group depended on age at the time of radiation exposure. The highest frequency of tumours was in patients exposed to radiation at the age of 10–19. A lower incidence of breast cancer was in case of exposure at the age of 20 and at older ages. The average latency period for BC was independent of dose and approximated 18 years. It was also determined that the BC incidence in patients exposed to radiation at the age of 10–29 was higher than in patients exposed after age 30 [11,13].
While analysing patients with MBCs and MBCOs, namely the interval time between the first and the second occurrence of disease, the following data was obtained. The median interval time with MMPMNs in patients first diagnosed with BC before 2009 was 605 weeks, while after 2009 this median interval time was already 104 weeks ( p = 0.000001). Reduction of the interval between the second disease occurrence after 2009 is explained by the fact that the average age of patients with BC before 2009 at the time of the Chernobyl accident was 30.5, and after 2009 – 25.5 (p = 0.000798). These data may indicate that BC is more aggressive in patients exposed to radiation from the Chernobyl accident under the age of 30.
Most patients with MPMNs had A (II) and O (I) blood type representing 145 cases, and 84.1% had Rh +, confirming the population sample distribution (Table 6 and 7).
The sample included BC patients with stage I–IIIC. The distribution by BC stage is following: T 1-2 N 0 M 0 process was observed in 114 cases (58.5%), T 1-2 N 1 M 0 – in 17.9% and T 1-4 N 1-3 M 0 – in 46 patients (23.6%). The above distribution demonstrates the aggressiveness of these variants of BC (Table 8).
Treatment
All patients received special treatment in accordance with the National Standards for diagnosis and treatment of oncologic patients. The distribution of patients by type of special treatment is presented in Table 9. The systemic polychemotherapy was applied in 82.2% of patients, but its’ regimens and variants are not discussed herein.
As for surgery, we perform breast conserving surgery (BCS) or modified radical mastectomy with or without breast reconstruction. Our conception of choice among these options goes to the following: if the tissue volume we want to delete does not exceed 25% of the whole breast volume, the conservative surgery is performed. And if necessary, the correction of size and form of the contralateral breast also could be performed. But when the volume to delete exceeds 25% of the whole breast tissue volume, mastectomy is performed. The breast reconstruction with patient’s own tissues could be performed in case there are enough tissues in donor site. In case the donor site doesn’t have enough own tissues for the reconstruction, it could be performed either with prosthetics or with combination of prosthetics and own tissues. And if necessary, we may also make the correction of the other breast as well [7–10].
The overwhelming number of patients in our study had mastectomy – 114 cases (58.5%). BCS had 38.5%, we had 6 cases of BCS followed by mastectomy (Table 10).
We divided our patients into core and control groups. Patients of the core group underwent simultaneous oncoplastic and reconstructive surgery, while control group patients had special oncological treatment only. Distribution of patients to the core and control groups was 1:3. 46 patients (23.6%) were in the core group and 149 patients were in the control group (76.4%) (Table 11).
Table 12 statistically proves the nonrandomness of distribution of patients to the core and control groups by operative intervention scope. Thus, in the control group mastectomy was performed in 93 cases (62.42%), BCS – in 53 cases (35.57%), while in the core group mastectomy was performed in 21 cases (45.65%) and BCS – in 22 cases (47.83%), respectively.
Patients of the core group in 18 cases (69.2%) underwent skin-sparing mastectomy with immediate prosthetic replacement and in 7 cases (26.9%) – mastectomy (or biquadrantectomy) with immediate breast reconstruction using the TRAM flap or TDL flap (Table 13).
BCSs were performed in accordance with the oncoplastic surgery principles under K. Clough’s approach [14]. Thus, Level I envisaged the replacement of breast defect by mobilized skin flaps or mobilized flaps of breast parenchyma from other quadrants. Level II envisaged mastopexy or reduction mammoplasty. Level III – replacement of the removed breast segment by thoracodorsal flap and others. Distribution of oncoplastic surgeries by level of complexity is presented in Table 14.
Results
Assessment of survival in patients with synchronous and metachronous processes was made. Thus, the chance to live 3.5 years in patients with SMPMNs was 0.73, while in patients with MMPMNs was 0.92 (p = 0.00162) (Table 15). Thus, the clinical course of disease in patients with SMPMNs is more aggressive and prognostically unfavourable.
The survival of patients by subgroups was assessed, and the clinical course in patients with SBCs was reliably proved to be worse compared to other groups of patients (Table 16). Also, the difference in survival in patients with MBCs and MBCOs was not reliably proved.
The worst clinical course of the disease by stage was observed in patients with MPMNs, stage III, however, there is no significant difference in survival among patients with early stages and stage IIB (Table 17).
In addition to stage, the survival in patients is influenced by receptor status of the tumour and expression of Her2neu and Ki-67. MBCs presented higher grading and lower hormone receptors expression than UBCs. Meanwhile, SBCs presented higher hormone receptors expression than UBCs and lower grading than MBCs. The higher prevalence of estrogen receptors positivity in SBCs is also confirmed by the literature [15]. Anyway, both MBCs and SBCs had higher incidence of histologically negative prognostic factors (lobular invasive histology, high grading, multifocality and lymph node extracapsular invasion).
The clinical course of disease was also assessed by primary localization, type of settlement, blood group and Rh factor, type of special treatment and age (Tables 18–24). The influence of these factors on the overall survival in patients with SMPMNs and MMPMNs was not statistically proven. There was no significant difference in survival in SMPMNs and MMPMNs patients who received only surgical treatment comparing to those who received also radio- or chemotherapy (Tables 22–23).
The impact of operative intervention scope in patients with SMPMNs compared to patients with MMPMNs was statistically proven (Table 25). Thus, the course of the underlying disease in patients who underwent mastectomy is worse compared to patients who underwent BCS. Also, plastic and reconstructive surgery in patients with SMPMNs was statistically proven as reasonable according to survival rates (Table 26).
In this study the influence of local recurrence on overall survival was analysed. It was statistically proven that the worse course of the disease was in patients with SMPMNs, i.e. the reduction in overall survival by 71%. However, the influence of local recurrence on life expectancy in patients with MMPMNs was not statistically proven (Table 27).
Discussion
It was shown that the clinical course of disease in patients with SMPMNs is more aggressive and prognostically unfavourable comparing to patients with MMPMNs (Table 15). These results are different comparing to the results obtained by Xu and Gu. According to their results, there was no significant difference in survival time between SMPMN and MMPMN (p = 0.81). However, the structure of localizations was different in this research: among 344 tumour lesions there were 161 located in the digestive system, 48 in the respiratory system, only 63 in the breast, 7 in the reproductive system, 30 in the urinary system, 23 in the head and neck, and the other 12 occurred in the brain, blood system and soft tissue [1].
In cancer patients, the risk of developing second cancers varies from 1% to 10%, which is significantly higher than the risk among healthy individuals. In this study, the incidence of MPMNs was 9.6%. SBCs incidence was higher than MBCs incidence, at the ratio of 1.2:1. In addition, MPMNs incidence increases with age [16]. Thus, the average age of patients was 46.6, and the number of postmenopausal women was 63%.
Variability of the second tumour localization depends on the prevalence in a particular geographic region. Thus, in Japan diseases of the gastrointestinal tract prevail, especially stomach cancer, in China - nasopharyngeal cancer and in Ukraine - breast cancer (incidence of 39.9 per 100,000 population) [17]. In this study, the vast majority of cases included breast cancer (79.5%) and reproductive system cancer (12.3%). Among SBCs patients, SMPMNs were observed in 60 cases.
Causes of MPMNs has not been studied, however, causal relationships with the following factors are possible. Firstly, with endogenous factors: abnormal embryonic development, immunity-related and endocrine diseases affecting sensitivity to carcinogens [18].
The second cause is linked with environmental and lifestyle exposures, including long-term effects of radiation and industrial pollution. The study statistically proves the possible impact of radioactive contamination following the Chernobyl accident on possible MPMNs development. However, no difference was identified in the incidence of MPMNs among the urban and rural population.
Thirdly, genetic determinants may influence MPMN occurrence. In patients with breast cancer and ovarian cancer, positive family history is observed, which is transmitted through autosomal dominant inheritance [19]. In the study, only 9 patients had a family history of breast and ovarian cancer. Thus, the presence of BRCA 1/2 mutations in young patients with simultaneous breast cancer was proved [20].
Finally, MPMN is caused by iatrogenic effect, especially radiation therapy and drug therapy. Carcinogenic effect of radiation therapy can be produced by DNA damage and oncogene activation. Thus, patients with BC are continuously treated with polychemotherapy and hormone therapy that suppress the immune system thereby increasing the probability of cancer occurrence [21]. The study did not reliably prove the increased overall survival from radiation therapy and drug therapy, especially in patients with SMPMNs.
There is currently no consensus for the method of calculating the survival rate of MPMN. Many researchers recommend basing the rate from the final diagnosis of the malignancy tumour, while others suggest calculating survival from the diagnosis of the first tumour in order to take into account the increased risk of malignancy tumour occurrence during the prolonged survival period. We recommend using the last cancer diagnosis to calculate the survival rate for determining the prognosis of MPMN. Because MMPMN has a relatively longer interval, which can possibly result in a bias, it is suggested that the calculation of survival time that is based on the last tumour diagnosis is more reasonable. In a study of the survival time of MPMN, second primary small cell lung cancer (SCLC) was compared to first primary SCLC and no significant differences were found in efficacy and median survival time [22,23].
Although there is not yet a consensus of prognostic factors of MPMN, several studies have shown consistent prognostic factors, including: the MPMN occurrence interval, earlier or later stage of the disease and tumour type, biological characteristics, and whether or not diagnosis and correct treatment are applied in a timely manner, including radical surgery, adjuvant chemotherapy, and radiotherapy. The definition of SMPMN and MMPMN is the starting point to achieve accurate comparisons, and 6 months is the standard criterion used in most previous studies. According to the biological characteristics of tumours, malignant tumours must be present for a certain period of time before showing clinical manifestations; therefore, if the interval time between tumours is too short, MMPMN might be equivalent to SMPMN, so that the designation of simultaneous or metachronous is merely relative.
The SMPMNs survival rate was lower compared with those of MMPMNs and unilateral breast cancer, and SMPMNs was also associated with a higher risk of distant metastasis. In this study, overall survival in patients with SMPMNs was lower than in patients with MMPMNs being 0.73 and 0.92, respectively; similar results were obtained by British researchers [24].
At present, reconstructive and oncoplastic surgery are an integral part of surgical treatment. However, many unresolved issues remain with regard to the choice of a particular type of surgery, and in patients with MPMN this issue was never studied. The data obtained that are based on large clinical material prove the need to implement modern approaches in this patient population. Thus, using BCS is more appropriate in patients with MBCs, and in patients with SBCs mastectomy with simultaneous breast reconstruction is deemed more preferable.
Conclusions
A more aggressive course of BC is observed in patients exposed to radiation from the Chernobyl accident under the age of 30 (p = 0.000798). The clinical course of disease in patients with SMPMNs is worse and prognostically unfavourable as compared to MMPMNs (p = 0.00162). The influence on clinical course of disease of primary localization, type of settlement, blood group and Rh factor, type of special treatment, and age in patients with SMPMNs and MMPMNs was not statistically proven. The impact of operative intervention scope in patients with SMPMNs compared to patients with MMPMNs was statistically proven, i.e. the course of the underlying disease in patients who underwent mastectomy is three times worse compared to patients who underwent BCS (p = 0.00048). Plastic and reconstructive surgery in patients with SMPMNs was statistically proven in this study as reasonable, increasing overall survival by 29% (p = 0.015). The influence of local recurrence on overall survival in patients with SMPMNs was proven, i.e. reduction in overall survival by 71% (p = 0.033). However, the influence of local recurrence in patients with MMPMNs was not statistically proven.
In summary, sufficient clinical attention should be paid to MPMN to avoid misdiagnosis and missed diagnosis, and the difference between metastasis and recurrence of carcinomas and MPMN should be established. In addition, early detection, early diagnosis, and radical treatment are all essential for efficient treatment of MPMN. The stage of disease and site selection should be used to determine surgically based treatment options, combined with chemotherapy, radiotherapy, biological therapy, and other methods to improve survival.