Histo-Phenotypic Aspects of Breast Cancer in Women under 40 Years Old, in Yaoundé ()
1. Introduction
Breast cancer is the most common cancer and the leading cause of cancer death among women worldwide [1] . In Cameroon, there were approximately 4170 new cases of breast cancer (20.1%) recorded in 2020, with 2108 deaths [2] . In young women, the definition of breast cancer has been controversial. A “young” woman is considered to be under 35, under 40, or simply premenopausal [3] . Globally, breast cancer in young women accounts for 7% of cases [4] . In Africa, studies have found 18.46%, 8% - 12%, and 18.2% of breast cancer cases in women under 40 in Morocco, Tunisia, and Mali respectively [5] [6] [7] . Although it is rare and little studied in this population, the histological and biological characteristics of infiltrative breast cancers in young women had a worse prognosis: grade 3, hormone receptor negative, Her 2 positive, triple negative compared to the rest of the population [8] . Overall survival was significantly lower in young patients, as were relapse-free survival, locoregional recurrence-free survival and metastasis-free survival [8] . Faced with this growing proportion of breast cancer and its severity in the world, particularly in our environment, we proposed to improve Cameroonian data by conducting this study whose objective was to determine the histological and phenotypic aspects of breast cancer in young woman.
2. Materials and method
Ethical considerations: The study was conducted following the fundamental principles of research as per the Declaration of Helsinki. We obtained ethical clearances from the Institutional Ethics Committee of the University of Douala and the Gynecological-Obstetric and Pediatric Hospital of Yaoundé, as well as a research authorization from the General Hospital of Yaoundé.
Data collection and analysis: We conducted a cross-sectional and analytical study with retrospective data collection over a period of 6 months from January 1 to June 30, 2023. The recruitment period lasted for 5 years from January 1, 2018, to December 31, 2022. We recruited records from the registries of oncological and gynecological consultations and hospitalization reports at the General Hospital and the Gynecological-Obstetric and Pediatric Hospital in Yaoundé. All records of women with breast cancer were included. The diagnosis of breast cancer was confirmed through histopathology and immunohistochemistry. Data were collected using pre-established and pre-texted technical sheets. The variables included sociodemographic data of the population, personal and family history of patients, clinical characteristics of the tumor, anatomopathological characteristics, treatment modalities, and disease progression. The collected data were recorded on a specific technical sheet and then entered. The data were analyzed using the SPSS (Statistical Package for Social Sciences) software version 23.0. The study population was divided into 2 age groups: Under 40 years and Over 40 years. Qualitative variables were presented in terms of frequencies and percentages and compared using the Chi-square test or Fisher’s exact test, with a 95% confidence level (Odds ratio). A p-value < 0.05 was indicative of a statistically significant result. The results were presented in tables generated using Microsoft® Office.
3. Results
Over a period of 5 years, we recruited 89 patients aged under 40 and 107 patients over 40; for a total of 196 cases.
The average age of patients in the 40 and under group was 34.96 ± 4.23 years, ranging from 25 to 40 years; while those over 40 had an average age of 53.66 ± 9.02 years, ranging from 41 to 77 years (Table 1). History of mastopathies was more common in women over 40 (6.54% vs 4.49%) without significant difference. Menopause was found in 3.4% of women under 40, compared to 40.2% in women over 40 (p < 0.001). Comorbidities were mainly dominated by hypertension, less common in those under 40 (6.7%) compared to women over 40 (22.4%) (p = 0.002). Women under 40 had, non-significantly, fewer family history of breast cancer compared to their counterparts, with respective frequencies of 12.2% and 17.8% (Table 2).
The two main reasons for consultation were breast nodules (83.1% vs 75.7%; p = 0.136) and breast pain (21.3% vs 15.9%; p = 0.212) in both study groups. (Table 2). Breast size increase (70.8% vs 61.7%; p = 0.118) and orange peel skin appearance (44.9% vs 33.6%; p = 0.071) were the main physical signs identified and were more common in those under 40 years old. Ulcerations and breast retraction were significantly more frequent in those under 40 years old, with a risk multiplied by 2.7 (p < 0.05) (Table 3).
The involvement was unilateral in most cases, with a preferential involvement of the left breast in those under 40 years old, with respective frequencies of 60.7% and 54.2% for those over 40 years old. However, bilaterality was significantly more common in women under 40 years old (p < 0.05) (Table 4). As for the location, the supero-external (68.5% vs 56.1%; p = 0.050) and infero-external quadrants (34.8% vs 29.0%) were the most affected. Tumors classified as T4 were the most common: 46.1% vs 40.2% respectively in each group. Lymph node involvement was higher in women under 40 years old with a frequency of 69.6% compared to women over 40 years old, which was 53.2%. Women under 40 years old had a higher percentage of metastases at 24.7%. Stage 4 of the disease was the most represented, at 48.3% and 47.7% respectively. However, the difference observed in the various groups was not significant (Table 4).
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Table 1. Distribution of women with breast cancer according to age.
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Table 2. Distribution of women with breast cancer according to personal past history.
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Table 3. Distribution of women with breast cancer according to reason for consultation and physical signs.
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Table 4. Distribution of women with breast cancer according to laterality and clinical stage.
The invasive ductal carcinoma was the most represented regardless of the group, with a frequency of 96.6% in those under 40 years old versus 94.4% for the rest of the population. The other cancers consisted of lobular carcinoma in situ, invasive lobular carcinoma, mucinous, and cribriform (Table 5). Most patients were classified as SBR 2, with 43.8% in those under 40 years old, compared to 57% in those over 40 years old. However, 39.3% of patients under 40 years old presented significantly (p = 0.008) with a grade 3 higher than patients over 40 years old (22.4%), with a confidence interval (OR = 2.24 [1.20 - 4.17]) (Table 5). Hormone receptor positivity was significantly lower in those under 40 years old than in those over 40 years old, at 38.2% and 53.3% (OR: 0.542 [0.3 - 0.96]; p = 0.018). Her 2 was overexpressed in 39.32% and 25.23% of cases, respectively, in each group, a significant difference. The Ki67 rate was more significant in those under 40 years old compared to those over 40 years old (30.3% vs. 2.8%), with a risk multiplied by 15 (OR: 15.09 [4.39 - 5.83]; p < 0.001) (Table 5). The most common molecular type was Triple Negative (48.3% vs. 36.4%), Her-2 positive tumors were more common in young women (17.97% vs. 10.3%), without significant difference (Table 5).
According to therapeutic modalities, chemotherapy was observed in all cases. Concerning surgery, it was frequent in 62.9% vs 68.2% (p = 0.265). Hormone therapy was more practiced among women over 40, 32.7% compared to 23.6%. No statistically significant difference was observed between these two groups therapeutically (Table 6).
In terms of survival, overall, patients under 40 years old had 3 times the risk of dying with a higher mortality rate compared to patients over 40 years old, 48.3% and 22.4% respectively (OR: 3.23 [1.74 - 5.98]; p < 0.001). Likewise, they had a significantly lower survival rate compared to those over 40 years old (40.4% vs 57%) p = 0.015 (Table 7). The median survival time of those under 40 was lower, 83 months, compared to those over 40, which was 120 months. The difference in survival observed in the two groups was statistically significant according to the Log Rank test or Mantel-Cox test (p < 0.018) (Figure 1).
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Table 5. Distribution of women with breast cancer according to anatomopathological and immunohistochemical characteristics.
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Table 6. Distribution of the population according totherapeutic modalities.
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Table 7. Distribution of women with breast cancer according to outcome.
4. Discussion
Breast cancer in young women is a public health issue in Cameroon as well as worldwide. It presents different characteristics and often appears more aggressive due to their complex histological and biological aspects [9] . In our series, women under 40 years old had higher percentages in terms of tumor size, lymph node involvement, and metastases compared to those over 40. This could be explained by the more intense hormonal action in young women leading to rapid invasion of tumor cells and rapid progression of the disease, compared to those over 40 who are sometimes in premenopausal or menopausal phase. Stage 4 of the disease was the most common, at 48.3% and 47.7% respectively (p = 0.521). These results are similar to those found in Congo in 2020 by Ndounga et al., who also found the disease at late stages in young women [3] . But they differ from those of Eric et al. in Croatia in 2018 and Alzaman et al. in Saudi Arabia in 2016, who found a predominance of T2 classified tumors in patients under 40 [10] [11] . Furthermore, stage II of the disease was the most frequent in the study groups [11] . These observed differences could be explained by the delayed consultation of women with breast cancer in our context.
According to the literature data, infiltrating ductal carcinoma represents the most common form of breast cancer (70%) and can occur in both pre- and post-menopausal women. In fact, infiltrating ductal carcinoma was the most represented in our 02 study groups with no significant difference, respectively 96.6% versus 94.4% (p = 0.348).
In our study, patients under 40 years old had a higher grade III compared to those over 40 years old: 39.3% versus 22.4%, the difference observed between the two was significant (OR = 2.24 [1.20 - 4.17]; p = 0.008). This is consistent with the results of Fleurier et al. in France, who found a significantly higher grade III in those under 40 years old compared to those over 40 years old (49% and 26%); p < 0.001 [8] . This trend was also observed by Eric et al. in Croatia and Alzaman et al. in Saudi Arabia, who found, respectively, in the different study groups (29.1% versus 17.9%); p = 0.004 [10] and (53.2% versus 33.9%); p = 0.031 [11] .
The most frequent molecular type in both study groups was triple negative, which was more common in women under 40 years old (48.3% vs. 36.4%) with no significant difference [12] . These results are consistent with those found in Croatia (32% vs. 10%) p = 0.001 and in several studies conducted in young African women: for example, in Mali, it represented 45.9%; in Togo, it was present in 57.2% in the study by Toukilnan et al. [13] and in 37.9% in Cameroon according to a study by Atangana et al. on the entire population [14] . The high frequency of triple negative in women under 40 years old could be explained by their young age. Indeed, it has been described in the literature that the young age of patients is a risk factor for aggressive forms of breast cancer. In their study, Schmadeka et al. found the same result [15] . However, in some European studies, luminal B and luminal A were more common [8] [9] [10] [11] , although triple negative tumors were much higher in young women, 28% vs. 10% (p = 0.002) in France [8] and 21.3% vs. 8.1% in Saudi Arabia (p = 0.046) [11] . This difference could be attributed to race: black women may have a higher risk of presenting more aggressive tumors compared to white women due to the high frequency of BRCA1 and BRCA2 mutations in the black population.
At the same time, Her-2 tumors were more common in the young population at 17.97% compared to 10.3%. Similar trends had been observed by Ndounga et al. (6% versus 0%) [3] , Fleurier et al. (7% versus 5%; p < 0.05) [15] , and Alzaman et al. (27.7% versus 19.4%; p = 0.04) [11] . Young women significantly had a lower percentage of positive hormone receptors (38.2%) compared to women over 40 years old (54.2%). There was a significant difference in the Ki67 proliferation index between young and older women. The rate was higher in patients under 40 years old compared to those over 40 (30.3% versus 2.8%) with a risk multiplied by 15 (OR = 15.09 [4.39 - 5.83]; p < 0.001). All these differences could indicate the aggressiveness of breast cancer in young women.
In terms of survival, there was a significant difference between our two groups. The survival of young women was lower compared to the rest of the population with an overall survival rate of 40.4% compared to 57%. This rate was lower than that observed in a study carried out in France, where it was 87.7% as compared to 93.4% [8] . This could be due to, first the difference in the technical platform which is more developed in western countries, and also due to diagnosis at the late stage of the disease in our context. Women under 40 had a mortality rate of 48.3%, higher than that of women over 40 (22.4%). The mortality rate was identical to that of Ndounga et al. [3] in Congo, 47% in young women compared to 18.2%. This high rate in women under 40 years of age could be due to late diagnosis, absence of hormone receptors making them refractory to endocrine treatment, high histological grade, Her2 overexpression with significant Ki67, more aggressive molecular type.
Limitations: These were mainly due to missing data, either due to incomplete or unfound files, or to patient loss to follow-up.
5. Conclusion
Breast cancer has become a global scourge and represents a public health problem in our environment. It remains more aggressive with a higher mortality rate in women under 40, among whom this cancer is dominated by high-grade infiltrating ductal carcinomas and triple-negative and Her-2 phenotypes.
Appendix: Data Collection Form
Data collection form number: ______________/
- Patient File number: __________________/
- Study Group |__________|: 1) Under 40 years 2) 40 years and older
- Health facility of follow up |__________|: 1 = HGY; 2 = HGOPY
A. Socio-Demographic Characteristics
1. Age at diagnosis (years): ____________________
2. Education Level |________|: 1 = None; 2 = Primary; 3 = Secondary; 4 = Superior
3. Marital status |________|: 1 = married; 2 = Single; 3 = Divorced; 4 = Widow
4. Weight (kg): ___________________
5. Size (cm): ___________________
6. BMI (kg/m2) :__________________
B. Clinical Characteristics
7. Reason(s) for Consultation
- Routine screening (campaign and others) |________|: 1) Yes; 2) No
- Breast nodule or swelling |________|: 1) Yes; 2) No
- Deformity of the skin or nipple |________|: 1) Yes; 2) No
- Breast discharge |________|: 1) Yes; 2) No
- Breast pain |________|: 1) Yes; 2) No
- Axillary nodule |________|: 1) Yes; 2) No
- Vegetative Ulceration |________|: 1) Yes; 2) No
- Others (to be specified): _____________________________________
- Date of onset of first symptoms: _____________________/
8. Date of first consultation: _____________________/
Time lapse between both dates (days): _____________________/
C. Past History
9. Comorbidities
- HTN |________|: 1) Yes; 2) No
- Diabetes |________|: 1) Yes; 2) No
- HIV infection|________|: 1) Yes; 2) No
- Viral Liver Infection |________|: 1) Yes; 2) No
- Heart failure |________|: 1) Yes; 2) No
- Stroke |________|: 1) Yes; 2) No
- Other comorbidities______________________________________________
10. Age of first menstruation: _____________/
11. Age of first pregnancy: ___________/
12. Total number of pregnancies: _______________
13. Parity:_____________________
14. Number of preterm babies________________________________
15. Number of abortions_______________________________
16. Number of living children ___________________________
17. Personal history of mastopathies
- None |________|: 1) Yes; 2) No
- Fibroadenoma |________|: 1) Yes; 2) No
- Mastitis |________|: 1) Yes; 2) No
- Fibrocystic Disease |________|: 1) Yes; 2) No
- Cyst |________|: 1) Yes; 2) No
- Other_______________________________________________
18. Menopause |________|: 1) Yes; 2) No
19. Contraception |________|: 1= None; 2 = Oral; 3 = Injectable; 4 = Implant; 5 = Patch; 6 = IUD
If contraception, duration of use (years): _____________________
20. Breastfeeding |___________| 1) Never; 2) Exclusive; 3) Mixed
If breastfeeding, duration of breastfeeding (in years): __________________
21. Personal history of other cancer |_________|: 1 = None; 2 = Cervix; 3 =Ovaries; 4 =Stomach; 5 = Other (to be specified) _________________________
22. Family history of breast cancer |________|: 1) Yes; 2) No
If yes, degree of kinship |_________|: 1 = 1st degree; 2 = 2nd degree; 3 = 3rd degree; 4 = Other
23. Family history of other cancers |________|: 1) Yes; 2) No
If yes, degree of kinship |_________|: 1 = 1st degree; 2 = 2nd degree; 3 = 3rd degree; 4 = Other
D. Clinical
Date of diagnosis: ____________________
Diagnostic time_____________________
24. General signs |_______|: 1 = Stage 0; 2 = Stage 1; 3 = stage 2; 4 = stage 3; 5 = stage 4
25. Affected breast(s) |______________|: 1 = Left breast; 2 = Right breast; 3 = Bilateral
26. Location of the tumor:
- Upper outer Quadrant |________|: 1) Yes ; 2) No
- Upper inner Quadrant |________|: 1) Yes ; 2) No
- Lower Outer Quadrant |________|: 1) Yes ; 2) No
- Lower inner Quadrant |________|: 1) Yes ; 2) No
- Nipple |________|: 1) Yes; 2) No
- Other_____________________________________
27. Skin signs
- No Signs |________|: 1) Yes; 2) No
- Swelling |________|: 1) Yes; 2) No
- Orange peel |________|: 1) Yes; 2) No
- Ulceration |________|: 1) Yes; 2) No
- Retraction |________|: 1) Yes; 2) No
- Other skin signs (to be specified) ________________________
28. Histological type: |________________|: 1 = ductal carcinoma in situ; 2 = lobular carcinoma in situ; 3 = invasive ductal carcinoma; 4 = invasive lobular carcinoma; 5 = tubular carcinoma; 6 = medullary carcinoma; 7 = mucinous carcinoma; 8 = invasive cribriform carcinoma; 9 = endocrine carcinoma of the breast; 10 = metaplastic carcinoma; 11 = apocrine carcinoma; 12 = adenoid cystic carcinoma; 13 = mucoepidermoid carcinoma; 14 = secretory carcinoma; 15 = invasive micropappillary carcinoma; 16 = malignant phyllode tumor; 17 = scirrhous breast carcinoma; 18 = colloid adenocarcinoma
29. Classification |______________| 1 = clinical 2 = pathological
30. Tumor size |______________|: 1 = T0 (no palpable tumor); 2 = T1 (tumor ≤ size 2 cm in diameter); 3 = T2 (2 cm
size 5 cm in diameter); 5 = T4 (tumor with extension to the wall and/or skin); 6 = Tx (undetermined)
31. Lymph node involvement |______________|: 1 = Absence of lateral lymph nodes (N0); 2 = Presence of motile ipsilateral axillary lymph nodes (N1); 3 = Presence of fixed ipsilateral axillary lymph nodes or subclavicular lymph nodes (N2); 4 = Presence of ipsilateral sus clavicular lymph nodes (N3); 5 = Nx (Undetermined)
32. Metastasis |_________|: 1 = Yes ; 2 = No 3 = undetermined
33. Clinical stage of breast cancer at diagnosis |_____________|: 1 = Stage 1 (T1N0M0); 2 = Stage 2 (T2N0M0); 3 = Stage 3 (T3N0M0-T4N1M0); 4 = Stage 4 (T4N2M1)
E. Paraclinical Workup
34. Mammography |_________|: 1 = ACR 1; 2 = ACR 2; 3 = ACR 3; 4 = ACR 4; 5 = ACR 5; 6 = ACR 6; 7 = Not done
35. Ultrasound |_________|: 1 = BI-RADS 0 ; 2 = BI-RADS 1; 3 = BI-RADS 2; 4 = BI-RADS 3; 5 = BI-RADS 4; 6 = BI-RADS 5; 7 = BI-RADS 6; 8 = Not done
36. Nature of biopsy sent for pathological examination |___________|: 1 = Breast biopsy; 2 = Lumpectomy; 3 = Mastectomy; 4 = Lymph node dissection; 5 = 3 + 4; 6 = Cytopuncture
37. SBR Classification |_________|: 1 = Grade I 2 = Grade II 3 = Grade III
38. Guildford grading system ------- 1 = grade I 2 = grade II 3 = Grade III
39. Hormone receptors:
- Progesterone |________|: 1) Present; 2) Absent; 3) Not done
-Estrogen |________|: 1) Present; 2) Absent; 3) Not done
-Her-2 I-------------I: 1) Positive; 2) negative; 3) Not done
-Ki67 |________|: 1) ]0 ; 14%]; 2) ]14% ; 30%] ; 3) [ 30% ; 100%[
40. Molecular Types: __________|: 1 = luminal A; 2 = luminal B; 3 = Her-2; 4 = triple negative
41. Treatment |_______________________|:
1 = Chemotherapy 4 = Hormone therapy 7 = 2 + 3
2 = surgery 5 = 1 + 2
3 = Radiation therapy 6 = 1 + 2 + 3
If surgery, specify |____________|: 1) Conservative; 2) Radical
If chemotherapy, specify |____________| 1) neoadjuvant 2) adjuvant
F. Follow Up
42. 1-year follow up |__________| A: 1) Complete remission; 2) Partial remission; 3) Progression; 4) Stationary; 5) Lost to follow-up (undetermined); 6) Death
43. Follow up at 2 years |__________| A: 1) Complete remission; 2) Partial remission; 3) Progression; 4) Stationary; 5) Relapse; 6) Lost to follow-up (undetermined); 7) Death
44. Follow up at 3 years |__________| A: 1) Complete remission; 2) Partial remission; 3) Progression; 4) Stationary; 5) Relapse; 6) Lost to follow-up (undetermined); 7) Death
45. Follow up at 4 years |__________| A: 1) Complete remission; 2) Partial remission; 3) Progression; 4) Stationary; 5) Relapse; 6) Lost to follow-up (undetermined); 7) Death
46. Follow up at 5 years |__________| A: 1) Complete remission; 2) Partial remission; 3) Progression; 4) Stationary; 5) Relapse; 6) Lost to follow-up (undetermined); 7) Death
Global Evolution
47. Death |__________|: 1) Yes; 2) No; If deceased, date of death___________
48. Relapse |__________|: 1) Yes; 2) No; If relapsed, date _________
49. Date patient was last seen |__________|