Abstract
Breast cancer is the most common cancer in women globally(1). It is usually a disease of old age. The incidence of breast cancer in females younger than 40 years is as low as 0.5%. Disease in patients with age less than or equal to 40 years at diagnosis is usually considered a young breast cancer(2). Occurrence of more adverse pathological features like triple negative and Her2 positive breast cancer as well as lacking reliable screening methods in young women leads to the poor prognosis in this group of patients(3). In the present study we aim to find the clinical and pathological characteristics of breast cancer in young women and their survival outcome for 5 years comparing the same with those characteristics of the older patients. Patients with nonmetastatic carcinoma breast who had registered at Regional Cancer Centre, Trivandrum, during the year 2012 were selected for the study. Patient’s details including the clinicopathological features, treatment details, oncologic outcomes including recurrence, and survival data until 31 July 2019 were collected from treatment files kept in the hospital and via telephonic interview. Kaplan–Meier method was employed for survival analysis. Survival comparison was done using the log-rank test. Cox proportional hazards regression analysis was done for assessing the risk. Out of 1611 curatively treated patients with carcinoma breast, 281 (17.44%) were young breast cancer (equal to or less than 40 years). The median follow-up period was 82 months. Median age of diagnosis was 51.3 years. Young patients presented with larger tumour size, but nodal stage and composite stage, were not different. They had more TNBC status, 35% vs. 24%, p = 0.001. Young patient group had a drop in 5-year OS but statistically insignificant (75.9% vs. 82.5%, p = 0.179) and marginally significant drop in DFS (68.1% vs. 73.8%, p = 0.064). The proportion of young breast cancer is very high in the Indian population. Age is not an independent risk factor for worse prognosis. T and N stage, Her2nue status, and adequacy of nodal clearance are the most important independent risk factors deciding the 5-year OS.
Keywords: Young breast cancer, TNBC, Nodal yield, Molecular subtype
Introduction
Breast cancer is the most common cancer in women globally [1], with more than 2 million new cases diagnosed in 2018, accounting for 24.2% of all new cases in women. Patients younger than 40 years old at diagnosis are usually considered a young population[2]. The incidence of breast cancer is as low as 0.50% in females younger than 40 years old. Although young patients with breast cancers were thought to be associated with poor prognosis, the reason is not well defined. Several reports suggested that many factors such as the adverse pathological features [3, 4] and delay in diagnosis as well as lacking reliable screening methods in young women probably lead to the poor prognosis in this group of patients. Survival analysis also demonstrated that young breast cancer patients have early recurrence with shorter disease-free survival (DFS) and overall survival (OS) [5]. These findings suggest that the patients with young age should be treated with more intense therapeutic strategies.
In the present study we aim to find the clinical and pathological characteristics of breast cancer in young women and their survival outcome for 5 years comparing the same with those characteristics of the older patients.
Aim of the Study
This study aims to analyse whether young age is an independent adverse factor for breast cancer prognosis.
Primary Objective
The primary objective of this study is to find the incidence and pattern of recurrence and 5-year survival outcome in patients with carcinoma breast diagnosed at or less than 40 years of age.
Secondary Objectives
To evaluate the clinico-pathological profile of breast cancer in patients with diagnosis at or less than 40 years.
To correlate these parameters with 5-year survival outcome and to compare the same with patients who are more than 40 years of age at diagnosis.
Materials and Methods
Patients with nonmetastatic carcinoma breast who had registered at Regional Cancer Centre, Trivandrum, during the year 2012 were selected for the study. Patient’s details including the clinicopathological features, treatment details, oncologic outcomes including recurrence, and survival data until 31 July 2019 were collected from treatment files kept in the hospital and via telephonic interview. Patients were grouped into two based on the age at diagnosis. Young age at diagnosis was defined as age 40 or younger. All curatively treated young breast cancer was taken for analysis and compared with double the number (1:2 ratio) of older patients (consecutively registered).
Patients with a past history of other malignancy or those patients who have registered in RCC, but had not taken any curative treatment from RCC, were excluded.
Study Design
Retrospective observational study.
Study Settings
Division of Breast Oncology, Regional Cancer Center, Thiruvananthapuram, Kerala, India.
Statistical Analysis
Categorical summary measures were analysed by frequency/proportion and continuous variables by mean and standard deviation. The overall survival was calculated from the date of pathological diagnosis of malignancy or the date of registration in RCC if date of diagnosis is not available, until death. DFS was calculated from the date of diagnosis to the recurrence or death. SPSS software version 11 was used for statistical analysis. Kaplan–Meier method was employed for survival analysis. Survival comparison was done using the log-rank test. Univariate and multivariate Cox proportional hazards regression analysis was done for assessing the risk.
Results
In the year 2012, a total of 1909 patients with carcinoma breast were registered in Regional Cancer Center, Thiruvananthapuram, of which 189 were metastatic at presentation and 109 patients had not taken any treatment from RCC. The remaining 1611 patients were curatively treated. Median age at diagnosis was 51.3 years ranging from 18 to 90 years. Of the 1611 curatively treated patients, 281 were diagnosed to have carcinoma breast at or before the age of 40 years (17.44%), 92 patients were at or before 35 years (5.7%), and 31 patients were at or before 30 years of age (1.9%) (Fig. 1). Maximum incidence was in the age group 41–60 (63%). Twenty patients in the young group (8.2%) had a family history of breast cancer in 1st- or 2nd-degree relatives. Among the 281 young patients, 36 patients were not able to be contacted for follow-up. Final analysis included 245 young patients (age 40 or lesser) and 490 older patients constituting a total of 735 patients. Median follow-up period was 82 months, ranging from 0 to 92 months.
Fig. 1.
Pie chart for age distribution
Young patients had larger tumour at presentation, i.e. more T3/T4 disease than the older group (28% vs. 15%, p = 0.001). Nodal status was not different among the groups (p = 0.644). A total 52.5% young and 53.4% older patients were node positive. Composite stage also was similar between groups. A total of 56.4% of patients in the younger group and 63.4% in the older group had early breast cancer (stage I/II) (p = 0.174). No statistical difference was observed in the grade of the tumour, LVI/ECS status, hormone receptor, and Her2nue status among the groups. But the younger group had more TNBC and was statistically significant (35.4% vs. 23.5%, p = 0.001) (Table 1). A total of 31.3% patients in the young group and 37% patients in the older group had received NACT (p = 0.63). PCR rate was 28.5% in YBC and 37.2% in the older group (p = 0.588. BCS rate was high in younger patients (23.7% vs. 9.4%, p = 0.001). Adequacy of nodal yield (which was defined as nodal count of minimum 10) was not different between the groups.
Table 1.
Clinical and pathological characteristics in both age groups
| Age group | < 40 | > 40 | Total | P value |
|---|---|---|---|---|
| T1 | 47 (22%) | 78 (23%) | 125 (22.6%) | 0.001 |
| T2 | 108 (50%) | 210 (62%) | 316 (57.1%) | |
| T3 | 51 (23.7%) | 31 (9.1%) | 82 (14.8%) | |
| T4 | 9 (4.2) | 21 (6.1%) | 30 (5.4%) | |
| N0 | 104 (47.5%) | 157 (46.6%) | 260 (46.9%) | 0.644 |
| N1 | 53 (24.2%) | 88 (26.1%) | 141 (25.4%) | |
| N2 | 37 (16.9%) | 46 (13.6%) | 83 (14.9%) | |
| N3 | 25 (11.4%) | 46 (13.6%) | 70 (12.6%) | |
| Grade 1 | 2 (0.8%) | 4 (1%) | 6 (0.9%) | 0.093 |
| Grade 2 | 32 (14.2%) | 70 (15.5%) | 102 (15%) | |
| Grade 3 | 192 (85%) | 379 (83.7%) | 571 (84.1%) | |
| LVI | 16 (9.1%) | 38 (11.3%) | 54 (10.6%) | 0.431 |
| ECS | 32 (18.0%) | 84 (25.1%) | 116 (22.7%) | 0.065 |
| AJCC 7 stage 1 | 11 (5%) | 27 (8.1%) | 38 (6.9%) | 0.174 |
| Stage 2 | 113 (51.4%) | 184 (55.3%) | 297 (53.6%) | |
| Stage 3 | 96 (43.6%) | 122 (36.6%) | 218 (39.4%) | |
| NACT | 68 (31.3%) | 125 (37%) | 196 (34.7%) | 0.63 |
| PCR | 21 (30.9%) | 34 (37.2%) | 55 (28.5%) | 0.588 |
| BCS | 53 (23.7%) | 34 (9.4%) | 87 (14.9%) | 0.001 |
| ER positive | 112 (48.5%) | 229 (52.5%) | 341 (51.1%) | 0.321 |
| PR positive | 105 (45.5%) | 217 (47.3%) | 322 (46.7%) | 0.616 |
| HR neg | 110 (47.6%) | 196 (42.6%) | 306 (41.9%) | 0.211 |
| Her 2 positive | 50 (21.8%0 | 111 (24.3%) | 161 (23.5%) | 0.199 |
| Luminal | 121 (49.4%) | 241 (49.6%) | 362 (49.5%) | 0.959 |
| Her 2 enriched | 27 (11%) | 64 (13.2%) | 91 (12.4%) | 0.406 |
| TNBC | 81 (35.4%) | 114 (23.5%) | 195 (27.3%) | 0.001 |
| Nodal yield > 10 | 80.1% | 82.2% | 81.48% | 0.546 |
Locoregional recurrence was similar between the two age groups. No difference in local recurrence after BCS was observed between the groups, and there was one post-BCS breast recurrence in both groups. Distant metastasis was high among young patients but it was not significant (30.2% vs. 25.3%, p = 0.204). Most common site of metastasis was bone in the young group and lung in the older group, but the difference was not statistically significant. Incidence of contralateral breast cancer was 4.9% (10 cases) in YBC vs. 2.6% (8 cases) in older patients, which was not statistically significant (p = 0.119). A total of 75.2% of young patients and 80.5% of older patients were alive at the time of analysis (p = 0.126) (Table 2). Effect of PCR on betterment of OS was more among young patients. BCS found to have no added chance of loco regional or distant recurrence among young patients compared to older patients.
Table 2.
Oncologic outcomes after treatment in both age groups
| Age group | < 40 | > 40 | Total | P value |
|---|---|---|---|---|
| Recurrence | 76 (31.0%) | 119 (25.5%) | 195 (27.7%) | 0.059 |
| Local | 8 (2.9%) | 18 (4.2%) | 26 (4.1%) | 0.232 |
| Regional | 13 (5.3%) | 22 (5.2%) | 35 (5.3%) | 0.964 |
| Distant | 74 (30.2%) | 108 (25.3%) | 182 (27.3%) | 0.204 |
| 2nd primary | 12 (4.9%) | 11 (2.6%) | 23 (3.5%) | 0.119 |
| Alive with no disease | 151 (63.7%) | 273 (57.2%) | 424 (59.1%) | 0.126 |
| Alive with disease | 24 (10%) | 35 (7.3%) | 59 (8.2%) | |
| Died due to disease | 61 (24.8%) | 94 (19.5%%) | 155 (21.3%) |
The 5-year OS was lower in YBC compared to older patients (75.9% vs. 82.6%, p = 0.179), but statistical significance was not observed (Fig. 2). Marginally significant drop in 5-year DFS was observed among young patients (67.9% vs. 78.3%, p = 0.056). When the analysis was done with age cut-off of 35 to define the ‘the young”, OS was 73.5% vs. 80.7%, p = 0.239, difference was not significant. The difference in OS became statistically significant when the age cut-off was fixed as 30 years (52.9% vs. 81.2%, p = 0.001) (Table 3).
Fig. 2.
K–M plot of 5-year OS for different age groups
Table 3.
Five-year OS in subgroup analysis of each clinicopathologic variable
| 5-year OS | SE | P value | ||
|---|---|---|---|---|
| Age | All patients | 80.2% | 1.6% | |
| < 40 | 75.9% | 2.8% | 0.179 | |
| > 40 | 82.6% | 1.9% | ||
| AJCC 7 stage | I | 100 | 0.001 | |
| II | 93.0 | 1.5 | ||
| III | 68.2 | 1.4 | ||
| PCR | Achieved | 90.5% | 4.1 | 0.010 |
| No PCR | 76.8% | 3.8 | ||
| HR status | Negative | 77.2% | 2.6 | 0.040 |
| Positive | 85% | 1.9 | ||
| HER2nue status | Negative | 85.5% | 1.7 | 0.001 |
| Positive | 70.7% | 4.0 | ||
| Molecular subtypes | Luminal | 85.0 | 2.0 | 0.005 |
| HER 2 enriched | 68.6 | 5.6 | ||
| TNBC | 81.2 | 3.0 | ||
| Nodal yield | < 10 | 77.3 | 4.6 | 0.038 |
| > 11 | 85.6 | 1.7 |
The average number of years lost due to the carcinoma breast was 17.83 years for older patients and 36.98 years for younger patients (age less than or equal to 40 at diagnosis). Young patients with a strong family history of breast cancer had OS 83.8% and without family history had 89.2%, p = 0.841. Among Her2-positive young patients, OS in those who had received Trastuzumab was 87.5% and not received was 58.2%, p = 0.065. The Trastuzumab-received group had a trend towards improved survival.
OS for stage I was 100% for both groups, for stage II was 90.1% in young and 94.8% in old, and for stage III it was 64% in young and 72% in older group. OS in Luminal type was 83.9% in young and 85.6% in older, OS in Her2-enriched group was 54.1% in young and 77.2% in older, and OS for TNBC was 79.3% in young and 82.6% in older patients. If the patient did not have any recurrence, 5-year OS was 96.2% and 97.8% in young and older patients, respectively, which dropped to 32.4% and 39.2% if they had developed distant metastasis. None of them showed any statistical significance between the young and older patients. In patients who achieved PCR, the 5-year OS was 84% in young patients and 94% in older patients. In patients who had not achieved PCR, OS was 60% in young patients and 96% in older patients. The impact of PCR in OS was found to be more obvious in younger patients (p = 0.004).
Univariate analysis for OS has shown that T stage, N stage, composite stage, grade, LVI, ECS, hormone receptor status, Her2nue status, molecular subtype, PCR.
rate, nodal yield, distant recurrence, and contralateral second primary cancer are the significant variables determining the overall survival. In multivariate analysis only T stage, N stage, Her2nue positivity, and nodal yield were found to be significant for OS (Table 4). Nodal stage and molecular subtypes were the significant variables found in multivariate analysis for 5-year disease-free survival.
Table 4.
Multivariate Cox regression for overall survival
| Variables | P value | HR | 95.0% CI for HR | |
|---|---|---|---|---|
| Lower | Upper | |||
| T stage | 0.013 | |||
| N stage | 0.000 | |||
| Her2nue status | 0.019 | 0.349 | 0.145 | 0.840 |
| Nodal yield (> 10 vs. ≤ 10) | 0.041 | 0.316 | 0.105 | 0.955 |
| Age (> 40 vs. ≤ 40) | 0.045 | 0.383 | 0.150 | 0.979 |
Discussion
Breast cancer is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases diagnosed in 2018, accounting for 24.2% of all new cases in women. A total of 44% of these cases occur in very high-HDI (Human Development Index) countries, which represent about 19% of the world’s female population. When both sexes are considered together, breast cancer contributes to 11.6% of cases worldwide and ranks next to lung cancer. Breast cancer is the leading cause of cancer death also among women worldwide. It accounts for 15% of cancer-related deaths. In India, breast cancer contributes to 27.7% of total cancer in women and it accounts for 15.76% of cancer-related deaths. The age-standardized incidence ratio of breast cancer worldwide is 46.3 and the mortality rate is 13.0%. But in India it is 25.8 and mortality is 12.8, which indicates a high-mortality incidence ratio compared to the western world [6].
Breast cancer incidence increases with age, with the vast majority of women diagnosed after the age of 40 years [7]. Nevertheless, approximately 7% of women diagnosed with breast cancer are before the age of 40 [2]. The incidence of breast cancer in the young population in India is higher than the western population; multiple studies had reported incidence between 8 and 14%. A study from Ruby Hall Clinic, Pune, has reported a proportion of YBC (less than as 14.5%) [8]. The risk factors, clinical outcomes, and tumour biology are somewhat different in women below the age 40, suggesting that young breast cancer represents a distinct entity [2, 8–11]. The definition of a “young woman” in the field of breast oncology varies, with most articles referring to women under either age 35 or 40 years as “young”. In our study, we have taken 40 years as the cut-off to define “young age”. Foxcroft et al. in their series of 239 patients below 40 years of age reported 20% of young patients have BRCA 1 or 2 mutations [12]. In our study BRCA studies have not been carried out.
Current literature supports the hypothesis that breast cancer is generally more aggressive in younger women than older women due to larger tumour size, higher grade, higher lymph node positivity, and hormone receptor negativity with associated lymphovascular emboli [1–3, 11]. A total of 56% of young and 63% of older patients in our study were EBC, i.e. stage I or II. This difference was not statistically significant. In our series 85% of young patients had grade 3 tumour, 9.1% had LVI, and 18% had ECS; this was almost similar in older patients also. The presence of LVI and ECS was strongly associated with a worse prognosis in all age groups.
Estrogen and progesterone receptor status has been predominantly reported to be negative in younger patients [1, 13–15], in the present study 48% of young patients and 42% of older patients were hormone receptor negative, but the difference is not statistically significant. Difference in Her2 status also was not significant. But the proportion of TNBC was high in young patients (35% vs. 23%, p = 0.001). The incidence of triple negativity in some other Indian studies was up to 45.3% [16] (Table 1). This relatively high incidence of triple negative breast cancer in India may be partly explained by the fact that the risk factors for triple negativity are also commonly seen in Indian population, like high parity, young age at the time of first birth, younger age at diagnosis, and lower socio-economic status.
The 5-year overall survival for the whole group was 80.2%. OS for young patients less than 40 years was 75.9% and older patients was 82.6%, p = 0.179. When the age limit to define ‟young” was set at 35, OS was 73.5% vs. 80.7%, p = 0.238. When the comparison was done between 30 years and older patients, OS was 52.8% vs. 81.9%, p = 0.001, the difference became statistically significant. Five-year DFS in patients with less than 40 years was worse than older patients and the difference was marginally significant, 68% vs. 78%, p = 0.0568.
In a previous study by Krishnan nair et al. [17], from our institute, published in 1993, the 5-year OS for all ages together was 40% only. In their study the proportion of EBC was only 30% (in our study 61% were EBC). They also reported poor prognosis for older patients (age > 65 years). Other major studies published in recent years from India and the west have reported 5-year OS between 75 and 90%. Deshmukh et al. [8] in their study in 2014 have reported age is not an independent adverse prognostic factor in carcinoma breast. Nita nair et al. [18] also concluded in their study from TMH in 2018 that young age is not an independent adverse factor. But a major retrospective analysis from SEER data by Xiao Zhang et al. [19] in 2018 has clearly stated that carcinoma breast in patients with age less than 35 years has significantly lower 5-year overall survival (88.5% vs. 93.3%, p = 0.001) (Table 1).
When subgroup analysis was done after stratifying the patients based on AJCC stage, molecular subtype, nodal yield, LVI/ECS status, PCR rate, and distant recurrence, the 5-year OS and DFS were similar in both groups. So it is clear from the analysis that the observed non-significant drop in OS and DFS in young patients was due to the factor that young patients had presented with larger tumours, more TNBC, and more aggressive pathological factors like LVI and ECS and not just because of their “young” age.
Multivariate analysis also showed that only T stage, N stage, Her2nue positivity, and nodal yield were the significant variables determining OS. Age was not a significant risk factor in univariate or multivariate analysis.
In a similar study by Andersen et al. [5], they compared the microarray data of 140 young breast cancer (≤ 45 years old) and 252 older breast cancer (≥ 65 years old), and found that there was a greater proportion of aggressive intrinsic subtypes in young patients and leading to worse outcomes. They also concluded that young age is not an independent adverse factor apart from this bad biology.
Conclusions
The proportion of young patients (age less than 40 years) in the Indian population is higher than western data. There is a non-significant drop in survival in young patients with carcinoma breast, because of aggressive tumour biology, but the young age as itself is not an independent prognostic factor.
This study has several limitations, the most important is being a retrospective study with a small sample size from a single cancer centre. It also did not take into account the type of adjuvant treatment and compliance to the treatment. The risk factors for breast cancer in young patients including hereditary cancer syndromes were not analysed. However, it does give an outline about the disease profile of young patients with breast cancer in India, who are less extensively studied.
Declarations
Conflict of Interest
The authors declare no competing interests.
Footnotes
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Contributor Information
K. P. Abdulla, Email: abdullakp1987@gmail.com
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