Determinants of Early Survival of Breast Cancer Patients in Yaoundé-Cameroon ()
1. Introduction
Breast cancer is the most common cancer in the world with a global prevalence of 7.79 million. There were 2.26 million new cases (11.7%) and 684,996 deaths (6.6%) in 2020 [1] . Breast cancer is a multifactorial disease with diverse risk factors. Its global incidence, mortality and survival rates are variable [2] . From 2008 to 2020, we note an increase of more than 50% in the number of new cases in the world due to improvements of screening techniques, diagnosis and treatment methods on the one hand, and the increase in life expectancy, demographic growth, urbanization, and the adoption of predisposing lifestyles on the other hand. Accordingly, global mortality due to breast cancer has increased over the last ten years, from 458,000 deaths in 2008 to 684,996 deaths in 2020 [1] [3] .
In Africa, despite the fact that screening, diagnosis and treatment resources are limited, the incidence of breast cancer has practically doubled; from 92,600 new cases in 2008 to 186,598 new cases in 2020 [1] [4] . This cancer, just like in the world, occupies first place in Africa with a prevalence of 429,220 cases and a mortality of 85,787 deaths in 2020 [1] . In Cameroon, the global trend is seen, with increasing incidence. Some 4,170 new cases of breast cancer (20.1%) were recorded in 2020, with a mortality of 2,108 deaths (16.9%) and a prevalence of 8,150 over five years [1] .
Despite the increasing incidence and mortality of breast cancer, overall survival has significantly improved due to early diagnosis and constant improvement in therapeutic strategies [5] [6] . However, 5-year survival varies considerably around the world, with better figures reported in developed countries. In Cameroon in 2022, Noa et al. reported the overall survival at two, three and five years of 79.4%, 73.4% and 62% respectively [7] . Additionally, a recent study, conducted by Mapoko et al. on the determinants of prolonged survival after diagnosis of breast cancer at the Yaoundé General Hospital, estimated the survival rate at 3 years, 5 years and 9 years, respectively at 65.11%; 58.6% and 39% [8] . As determinants of survival, the completion of chemotherapy and hormone therapy was associated with prolonged survival, while the occurrence of disease progression with this treatment was associated with a reduction in survival. These two studies give us better results than figures reported from other countries in sub-Saharan Africa. This could be the impact of several measures taken to fight against cancer, and breast cancer in particular. These include the creation of a national committee for the fight against cancer and cancer care services, the training of health personnel in the fight against cancer, the setting up of screening activities, early treatment and curative care; and the establishment of research activities.
Although efforts have been made by the Cameroonian State, breast cancer remains a real public health problem [1] [7] [8] . From the two recent studies by Mapoko et al, and Noa Ndoua et al, it appeared that mortality was higher in the first three years despite early treatment of cases, including after surgery. This is why we decided to study the determinants of early survival during the first five years following the diagnosis of breast cancer.
2. Methodology
2.1. Study Design and Framework
The study was cross-sectional and analytical, with retrospective and prospective data collection at the oncology departments of the Yaoundé Gyneco-Obstetric and Pediatric Hospital (YGOPH), and the Yaoundé General Hospital (YGH). The study lasted 7 months. The period of study was 06 years, from January 2017 to December 2022.
2.2. Study Population
The study population consisted of patients with breast cancer at the YGOPH and the YGH during the period of study. We consulted the files of these patients and included all cases (non-probabilistic sampling) meeting the inclusion criteria. We excluded patients whose files did not contain the diagnosis, and for whom latest news could not be obtained, because they did not allow survival calculations. We calculated the minimum sample size using the Lorentz formula, considering as the prevalence of the event studied (5-year survival) to be 62%, according to a previous study done in Cameroon in 2022 by Noa et al. [7] . This gave us a sample size of 362.
2.3. Data Collection
We used data from all YGOPH and YGH outpatient oncology registers from 2017 to 2022, to have a database of all breast cancer patients seen during this period. Secondly, we keenly searched the archives of the Gynecology-Obstetrics and Oncology departments for the medical files of these patients with breast cancer in order to collect data. We completed the missing information, and data relating to survival, which did not appear in the files, directly from the patients or their relatives through a telephone conversation. Data collected included sociodemographic/epidemiological, clinical, paraclinical, and therapeutic variables, and data relating to follow-up and survival.
2.4. Definitions
We chose as the original date, the date of diagnosis of breast cancer and as the point date, the end date of the study, that is, May 6, 2023. The date of the latest news was the date on which we last heard from the patient. This date could be the date of death or the date of the last consultation, if the patient did not present the event studied (death), or if the subject was lost to follow-up, and the point date for those who were alive (dated May 6, 2023). The latest news was that the patient could be dead, alive, or lost to follow-up. The follow-up is the time that elapsed between the start date of the study and the end date. Participation time is the time between the original date and the latest news date. If the patient was lost to follow-up at the time point, she was right censored when determining the survival curve.
2.5. Ethical Considerations
We obtained authorization from the YGH(N˚ 137-23/HGY/DG/DPM/APM-TR of February 13, 2023), and from the Institutional Research Ethics Committee for the Human Health (CIERSH) of YGOPH (N˚ 406/CIERSH/DM/2023 of March 3, 2023).We also had ethical clearance from the Institutional Ethics and Research Committee (CIER) of the Faculty of Medicine and Biomedical Sciences of the University of Yaoundé I (N˚ 0061/UYI/FMSB/VDRC/DAASR/CSD of February 6, 2023).
2.6. Statistical Analyses
We used SPSS software version 23.0 (Statistical Package for Social Sciences) for analyses. Quantitative variables were expressed by the median followed by the range, and the mean followed by the standard deviation. Survival analysis was done with estimated survival curves using the Kaplan-Meier method. Survival curves were compared using the Log Rank test. Factors influencing survival were evaluated using the Cox model, through multivariate analysis. The statistical significance threshold was set at 0.05 and the confidence interval at 95%.
3. Results
From 2017 to 2022, we recorded 1,610 files of patients with breast cancer at the YGH and the YGOPH. Among these files, 539 corresponded to our study period, while 39 files were unusable for our study. We thus retained 500 files for the study. During the follow-up, 98 patients died, 168 were lost to follow-up, and 234 were alive at the closing date of the study.
3.1. Sociodemographic Characteristics
The ages of the 500 patients studied ranged from 22 to 83 years with a mean age of 47.19 ± 11.61 years. The most represented age group was 30 to 45 years old (45.8%) and the median was 46 years. More than half of the patients were single (51.4%) and had attained a higher education level (57.2%). The informal sector of the economy had a high representation (43.6%), while the majority resided in the urban setting (53.8%), and were Christians (94%). The highest presence, with respect to region of origin, was the West (37.4%), followed by the Center (27.8%) regions. We also recorded 29 participants from Chad and Gabon (5.8%).
3.2. Clinical Characteristics of the Study Participants
The average consultation time (between the appearance of the first symptoms and the first consultation) was 10.26 ± 10.62 months with extremes of 1 month and 61 months. In our study population, only 3.8% were diagnosed during a screening campaign or routine visit. The remaining 96.2% were diagnosed following a consultation for symptoms. The most frequent reasons for consultation were the perception of a breast nodule or mass (79.9%) followed by breast pain (14.8%) and skin or nipple abnormalities (4.7%).
The majority of women had had more than 02 pregnancies (57.4%), and were multiparous (47.4%). Sixteen percent (16%) of women used a modern method of contraception with a predominance of combined oral contraceptives. The average age of first period was 14 ± 1.70 years with extremes of 9 years and 18 years. The most common age group for first pregnancy was 18 to 30 years (74.5%), the average being 22 years. Forty-one percent (41%) of women had reached menopause at the time of diagnosis. In our study population, 17.4% had comorbidities, the most common being hypertension (62.1%). Eight-point six percent of patients had a past history of breast disease, mainly fibrocystic mastopathy. The notion of a history of cancer in a family member was found in 39 patients (7.9%), mainly first degree, and 57 patients had familial breast cancers (11.5%). The nodule was located in the left breast in 58.6%, preferentially in the QSE (58%). The majority of patients were classified as stage 3 at the time of diagnosis (47.6%).
3.3. Paraclinical Characteristics of the Study Population
Infiltrating ductal carcinoma was the most represented histological type (84.7%), while grade 2 of the SBR classification, was the most represented histo-prognostic category (40.2%). Immunohistochemistry was performed by 34.20% of patients and the most represented molecular subtype was triple negative (41.8%) followed by Luminal A (30%). On imaging, the ACR 4 finding was the most common (59.6%) (Table 1).
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Table 1. Distribution of the study population with respect to histology, immunohistochemistry and imaging.
3.4. Therapeutic Characteristics of the Study Population
Surgery was performed in 45% of cases and the majority of operated patients received radical treatment (88.4%). Chemotherapy was administered in 79.4% of cases; the most frequently used chemotherapy regimen was regimen D (1st line FAC/AC, 2nd and 3rd line not received) in 35.5% of cases. Hormone therapy was prescribed in 34.2% of patients while 14.6%received radiotherapy. Of all 500 patients retained, 17.2% received no treatment. In patients, whose assessment was known, partial response was observed in 42.1%, and complete response in 35.4% (Table 2).
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Table 2. Distribution of the study population with respect to treatment modalities.
Regimen A: 1st line (FAC/AC), 2nd line (Taxol/Taxotere), 3rd line (Capecitabine);
Regimen B: 1st line (FAC/AC), 2nd line (Carboplatine + Taxol), 3rd line: (Capecitabine);
Regimen C: 1st line (FAC/AC), 2nd line: (Taxol/Taxotere/Carboplatine + Taxol), 3rd line: not received;
Regimen D: 1st line (FAC/AC), 2nd line: not received/ not known, 3rd line: not received;
Unknown: treatment not initiated or undocumented.
3.5. Evaluation of Survival
The survival of patients with breast cancer at 1, 2, 3, 4, and 5 years was, respectively, 90.6%, 83.1%, 74.2%, 69.8%, and 59.2%. The slope of the survival curve reveals that mortality was higher in the first 40 months (the first three and a half years), before stabilizing and remaining constant after the fifth year. The median survival time was not reached. However, the first quartile (Q1) was 36.00 months (3 years). However, the average survival time of our study sample was 56.91 months (4.74 years). The minimum survival time was 0.73 months (22 days), while the maximum survival time was 76 months or 6.33 years (Figure 1).
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Figure 1. Survival curve of population according to the Kaplan Meier method.
3.6. Factors Associated with Survival
Identification of factors associated with the death of patients with breast cancer was sought through univariate analysis among epidemiological factors (age, level of education, profession, marital status, religion), clinical factors (reasons for consultations, clinical signs, tumor location, clinical stage), paraclinical characteristics (histological type, differentiation grade, hormonal receptors, Her-2) and therapeutic variables (type of surgery, chemotherapy, radiotherapy, hormonal therapy). Multivariate analysis of the determinants of survival of patients with breast cancer, according to the Cox model, made it possible to identify independent factors associated with a reduction in survival. These include breast ulceration, presence of bilateral tumor, and clinical stage 3 disease. Meanwhile, the ACR3 classification on imaging was associated with improved patient survival.
Table 3 reveals that patients with ulcerated cancer are three times more likely
Table 3. Multivariate analysisof factors associated with survival following the Cox model.
Variables
Death
Adjusted P value
Adjusted HR
(95% CI)
Yes
No
Married
59 (11.8)
197 (39.4)
0.365
1.57 ( 0.91 - 2.47 )
Diabetes
7 (1.4)
8 (1.6)
0.129
3.74 ( 0.70 - 10.58)
Breast pain
22 (4.5)
51 (10.3)
0.071
1.95 (0.99 - 3.41)
Vegetative ulceration
8 (1.6)
9 (1.8)
0.002
3.23 (1.51 - 6.89)
Bilateral breast lesion
5 (1.0)
4 (0.8)
0.001
9.152 (3.52 - 23.85)
Stage 3
58 (11.6)
180 (36.0)
0.010
1.72 (1.14 - 2.56)
ACR3
3 (0.6)
44 (8.8)
0.005
0.19 (0.59 - 5.98)
CIS carcinoma
0
29 (5.8)
0.955
0.79 ( 0.76 - 1.83)
Luminal A
4 (0.8)
47 (9.4)
0.078
0.32 (0.11 - 1.92)
to die early (aHR = 3.23; p = 0.002). Mortality is nine times higher in breast cancer patients with bilateral involvement (aHR = 9.2; p<0.001). Mortality is twice as high (1.72 times) in the group presenting clinical stage 3, in a statistically significant manner (aHR = 1.72; p = 0.010). On the other hand, the survival of patients with breast cancer is significantly improved for those whose imaging results classified their lesion as ACR 3 (aHR = 0.19; p = 0.005).
4. Discussion
4.1. Epidemiological, Clinical and Paraclinical Characteristics
4.1.1. Age
The ages of patients in our sample ranged from 22 to 83 years with a mean age of 47.19 ± 11.61 years. These results corroborate finding in Cameroon by Kemfang et al. in 2020, and Kodoume et al. in 2023, which were 48.62 and 48.27 years, respectively [9] [10] . This mean age is also close to the 48 years average reported by Diallo et al. (2022) in Senegal [11] . However, our results contrast with those reported in South Africa, in Soweto, and in England by Morra et al. where the average age at diagnosis was 54.4 years [12] and 57 years [13] respectively. This can be due to the higher life expectancy in the latter settings, but may also suggest an earlier occurrence of breast cancer in our setting.
4.1.2. Parity
Most of the participants had had more than 02 pregnancies (57.4%), and 47.4% were multiparous. These values are comparable to those obtained by Kodoume et al in 2023 [10] , who found that 53.0% of breast cancer patients were multiparous, with an average parity of 3.9 ± 2.1 children [14] . This result is slightly higher than that of Ogundiran et al. in Nigeria where the average parity among women was 3 children [15] . In Eastern Indonesia, a study found that 87% were multiparous or had given birth at least once [16] . However, nulliparity is a recognized risk factor for breast cancer.
4.1.3. Menstruation Status
The 41.6% proportion of postmenopausal women is similar to the 43.16% reported by Kemfang et al. in the same setting [17] , and the 42.4% reported by Ogundiran et al. in Nigeria. It is also only slightly higher than the 39% reported in 2021 in Madagascar by Ranaivomanana [18] . This further suggests that in Africa breast cancer affects younger women.
4.1.4. Time Taken to Consult
A delay in consultation was observed in our study population. The average time to the first gynecology consultation was 10.26 months. This result is similar to the 9.9 months reported by Mapoko et al. in 2023 [8] . However, these values are higher than that reported in Morocco by 6 months [19] . This can be explained by the fact that many patients in our setting seek care from alternative medicine first before they consult providers of modern medicine.
4.1.5. Presenting Complaint
The most frequent reasons for consultation were the perception of a breast lump (79.9%), and breast pain (14.8%). This is also reported in the Cameroonian literature [10] [14] [17] . In contrast, in Mali, Togo et al. found breast pruritus as the most frequent reason for consultation (35%), followed by pain and breast discharge [20] .
4.1.6. Presence of Comorbidities
The 17.4% prevalence of comorbidities (62.1% due to high blood pressure, and 29.9% due to HIV), is only slightly lower than the 24% reported by Mapoko et al., in the same setting. High blood pressure was also the most common comorbidity, followed by HIV and diabetes in the latter study [8] . Cubash et al. reported that 15-20% of breast cancer patients were HIV positive in South Africa [12] .
4.1.7. Clinical Stage of Breast Cancer
Stage 3 was the most observed clinical stage (47.6%) [21] . This is similar to the figures of Ranaivomanana et al. in 2021 in Madagascar [18] , and Galukande et al [22] where stage 3 represented 40.1%. On the other hand, the study carried out by Balawardena et al in India [23] found that stage 2 was in the majority (56%). This further suggests that our patients report later for consultation.
4.1.8. Paraclinical Characteristics
The most common histological type was invasive ductal carcinoma (84.8%), while grade II was the most represented (40.2%) as described in the literature [10] [11] [19] [24] [25] . Approximately 34.20% of patients performed immunohistochemistry, and the most represented molecular subtype was triple negative (41.8%), followed by Luminal A (30%). This frequency of triple negative is close to the 37.98% reported by Atangana et al. in 2017 in the cities of Douala and Yaoundé [26] .
4.2. Treatment modalities
4.2.1. Surgery
Conservative surgery was adopted in 11.6% of patients and in 88.4% the surgery was radical. This is similar to the proportions of radical surgery of 88.08% and 92% observed by Kemfang et al. in 2020 [9] , and Noa et al. in 2022 [7] , respectively. Other studies have found a slightly higher prevalence of conservative treatments in developed countries. This could be due to late presentation and poor availability of radiotherapy in poorer settings.
4.2.2. Chemotherapy
The majority of patients in our study (79.4%) had received chemotherapy because advanced stages were more common. However, our result is lower than 97% chemotherapy rate reported by Noa et al. [7] at YGOPH and it is lower than 97.5% reported by Mapoko et al. [8] at YGH. These studies had smaller sample sizes, 204 and 166 patients, respectively. However, the difference could also translate an improvement stage of disease at presentation. In Ethiopia this value was 83% [27] .
4.2.3. Hormone Therapy
Hormone therapy was prescribed in 34.2% of cases, a figure similar to that reported in 2022 by Noa et al. (37.3%). However, a much lower figure (19.9%) was observed by Kemfang et al. in 2015 in a survival cohort [9] . This could be explained by the fact that our studies are more recent, with the popularization of hormone therapy.
4.2.4. Radiotherapy
Radiotherapy sessions were completed in 14.6% of cases. Our results are lower than the 62% of patients who underwent radiotherapy sessions in the study by Noa et al. [7] . This difference could be explained by the fact that they had studied operated patients, among whom those presenting at stages T4 and T3, with lymph node involvement, were the majority and therefore eligible for radiotherapy.
4.3. Evaluation of Survival
The survival of patients with breast cancer at 1, 2, 3, 4 and 5 years was respectively 90.6%, 83.1%, 74.2%, 69.8, and 59.2%. Mortality was higher in the first three years. The median survival in our study population was not reached. However, the first quartile was Q1 = 36 months (or 3 years). This means that the death rate in our population did not reach 50% during the follow-up period. However, 25% of patients died before 3 years. These results are similar to those observed in Cameroon by Noa et al. and Mapoko et al. The study conducted by Noa et al. in 2022 [7] showed 2, 3 and 5 year survival of 79.4%, 73.3% and 62% of patients operated on for breast cancer. In 2023, Mapoko et al. had found respectively at 3 and 5 years 65.11% and 58.6% [8] . In Africa, in general, and sub-Saharan Africa in particular, low 5-year survival rates close to 50% have been reported. South Africa in 2018 reported a 5-year survival of 61%. On the other hand, this rate is twice higher than that found by Kemfang et al in 2015 in Cameroon, in a study carried out over the period from 1995 to 2007, where 5-year survival was 30% [9] . This difference could be explained by the fact that our study focused on patients whose follow-up is recent from 2017 to 2022, and suggests that therapeutic advances have improved survival. However, our 5-year survival is still low compared to those observed in Japan and Sweden, where survival rates of around 80% are reported for women with breast cancer [28] . The 5-year survival was 73% and 85% in African American and White American women respectively [29] . In 2016 in France, the 5-year survival rate for breast cancer was 88% [30] . These variabilities in survival observed in Africa and elsewhere could be explained by the fact that in African countries, more than half of the patients had advanced stages at diagnosis, as in our study population. Furthermore, financial, geographical and therapeutic accessibility are limited, and the use of alternative therapies and problems with therapeutic compliance are significant [17] .
4.4. Factors Associated with Survival
After multivariate analysis, the independent factors associated with a reduction in survival were breast ulceration (aHR = 3.23; p = 0.002), bilateral location of the tumor (aHR = 9.2; p < 0.001) and clinical stage 3 (aHR = 1.72; p = 0.010) while ACR3 classification on imaging (aHR = 0.19; p = 0.005) improves patient survival. However, many other factors were not associated with survival despite the fact that they were shown to be in many other studies. These include age, histological type, receptor expression, hormonal and Her-2 receptors, and treatment modalities.
· Breast ulceration: Breast ulceration (aHR = 3.23; p = 0.002) reduced survival. This is explained by the fact that skin involvement in breast cancer classifies the lesion as stage T4b. This underscores why the ulcerated state is considered an indication of advanced disease.
· Bilateral location of the lesion: It was associated with poor survival (aHR = 9.2; p < 0.001). As observed in a study conducted in China in 2021 by Haaron et al, the bilaterality of the breast lesion (p = 0.01) was a significant prognostic parameter reducing the overall survival of breast cancer [31] .
· Clinical stage 3: It was associated with reduced survival (aHR = 1.72; p = 0.010). These results are similar to those observed in Tunisia in 2021 where clinical stage 3 (p=0.016) was associated with a reduction in survival [25] .
· The ACR 3 classification: Patients whose imaging classification ACR3 (aHR = 0.19; p = 0.005) had better survival. This could be explained by the fact that they were going to consult early and that the diagnosis could have been made early during the monitoring of the ACR3 lesion and treatment accordingly started earlier.
4.5. Limitations
These were mainly due to missing data, either due to incomplete or unfound files, or to patient loss to follow-up.
5. Conclusions
Our study population consisted of 500 patients and was young. Most of the cancers were diagnosed at an advanced stage. The most frequent histological type was invasive ductal carcinoma, grade II was the most represented, while the triple negative was the predominant molecular subtype. Surgery was done in 45% of cases, chemotherapy in 79.4%, hormone therapy in 37.3%, and radiotherapy in 14.6%. The survival of patients with breast cancer at 1, 2, 3, 4 and 5 years was 90.6%, 83.1%, 74.2%, 69.8%, and 59.2%, respectively.
Mortality was higher in the first three years and independent factors associated with reduced survival were breast ulceration, bilateral tumor location and clinical stage 3, while absence of pain and ACR3 classification on imaging were associated with improved patient survival.