TURKISH JOURNAL OF ONCOLOGY

Summary

OBJECTIVE
Breast cancer incidence increases with age, and elderly patients are frequently underrepresented in clinical trials. This study aimed to show the tumor and treatment characteristics, toxicity and survival differences in the groups under and over 65 years who received adjuvant radiotherapy.

METHODS
Between 2010-2023, 1265 patients who underwent adjuvant radiotherapy were retrospectively evaluated. Patients were categorized into <65 years and ≥65 years. Demographic characteristics, treatment modalities and treatment outcomes were compared between the groups.

RESULTS
Of all patients, 14.7% were aged 65 years and older. Median overall survival (OS) was 158.4 months in patients younger than 65 years and 122.7 months in those aged 65 years and older (p<0.001). Age ≥65 years was identified as an independent prognostic factor for both OS and disease-free survival (DFS). Elderly patients received chemotherapy less frequently and were more often treated with hypofractionated radiotherapy. Mortality rates were significantly higher in the ≥65 age group.

CONCLUSION
Patients aged 65 years and older had worse DFS and OS compared with younger patients. Elderly patients were less likely to receive chemotherapy and more likely to receive hypofractionated radiotherapy. Treatment decisions should be individualized, and chronological age alone should not be the sole determinant in therapeutic planning.

Summary

Introduction

Breast cancer is the most common cancer in women and the second most common cause of cancer-related deaths.[1] The mean age at diagnosis is 63 years, and its frequency increases with age.[2] 46.3% of new cases are seen in patients over 65 years of age.[3] Age is an increasing risk factor for breast cancer.[4] When the mortality rates due to breast cancer are evaluated in the SEER database, most deaths occur in the 65-74 age range, and the median age at death is 74 years.[3] While survival was worse in the younger patient group in some studies, survival was observed to be lower in older patients in some studies.[5-7] Higher mortality and treatment-related morbidity have been reported in older women compared to young women.[8] This may be related to detecting the disease at more advanced stages, delayed diagnosis, comorbidities, and deterioration of organ functions.[9]

Patient management at the same stage differs according to the patient's physical functions. Elderly patients receive less treatment even if they are in the early stages, and recurrence increases while overall survival is observed to be lower.[5] Age should not be the only determinant in treatment decision-making. The patient's performance, stage of the disease, life expectancy, comorbidities and tumor characteristics should be taken into consideration when making treatment decisions.[5] Under-treatment while trying to avoid over-treatment may be a reason for different outcomes due to age.[10] Geriatric comprehensive evaluation is important to avoid unnecessary or excessive treatment in patients, but its use in routine is still incomplete.[2] Healthy elderly patients can be treated in the same way as younger patients.[11] According to the literature, elderly patients receive inadequate adjuvant treatment. Only 3% of patients participating in clinical trials for breast cancer are aged 70 years and older.[11]

Advanced age at diagnosis is associated with different clinical and pathologic features and differences in treatment patterns.[4] With the increase in the elderly population, it is important to know the prognostic features in this group, which will be more common in our daily practice in the future, and to identify the patient group that receives less treatment. In this study, we aimed to compare the treatment and survival results of elderly patients with patients under 65 years of age and to determine the differences in patient and tumor characteristics between the groups.

Introduction

Methods

Patient Selection
The data of 1265 patients who received adjuvant radiotherapy for breast cancer in our clinic between January 2010 and November 2023 were retrospectively evaluated. Female patients over 18 years of age, pathologically diagnosed with invasive carcinoma, without metastasis, who completed radiotherapy treatment and who had at least one year of follow-up were included in the study. Patients with metastasis, second primary cancer and bilateral breast cancer at the time of diagnosis were excluded. Patients were staged according to the American Joint Committee on Cancer (AJCC) 8th version.[12] Patients who received neoadjuvant treatment were staged according to pre-treatment radiologic imaging, and patients who received adjuvant treatment were staged according to postoperative pathology results.

Patients were divided into two groups as under and over 65 years of age, since the World Health Organization considers people over 65 years of age as elderly. Clinicopathologic features, treatment modalities and treatment outcomes were compared between the groups. This study was performed in line with the principles of the Declaration of Helsinki. Approval for this study was granted by the Ethics Committee of Necmettin Erbakan University (No: 2023/4555, Date: 06/10/2023). Due to the nature of the study, informed consent was not obtained from the patients.

Treatment
Surgery: Patients underwent modified radical mastectomy (MRM) or breast-conserving surgery (BCS). A sentinel lymph node biopsy (SLNB) or axillary dissection (AD) performed axillary sampling.

Chemotherapy: Patients received adjuvant or neoadjuvant chemotherapy according to their stage and hormone status. Chemotherapy was given as four cycles of cyclophosphamide and doxorubicin +/- 12 weeks or four cycles of the taxane group.

Radiotherapy (RT): After MRM, RT was applied according to the presence of T3-4 tumor, lymph node positivity, lymphovascular invasion (LVI), and extracapsular extension (ECE), and RT was applied to all cases after BCS. In patients with regional lymphatic irradiation, supraclavicular region irradiation was added to the treatment. In inner quadrant tumors and patients with a high number of involved lymph nodes, mammary internal irradiation was also added. Standard two parallel opposing tangential fields and 3-dimensional conformal RT techniques were applied for 50 Gy. A 10-16 Gy boost dose was added in patients who underwent BCS. All patients were treated with the Eclipse treatment planning system (Varian Medical Systems Inc., Palo Alto, CA).

Survival
The primary endpoint of this study was to analyze survival outcomes in elderly patients, and the secondary endpoint was to determine the factors affecting survival. The follow-up period was calculated as the time from the date of diagnosis to the last follow-up visit or death. Overall survival (OS) was defined as the time from the time of diagnosis until death or last follow-up; disease-free survival (DFS) was defined as the time from the time of diagnosis until distant metastasis/recurrence/death. Patients were followed up until death or until November 2024. Routine follow-ups were performed every 3 months for the first 2 years, every 6 months until 5 years and then annually.

Statistics
Statistical analysis was performed with SPSS (Statistical Package for Social Sciences) version 13. P<0.05 was considered statistically significant. Patient characteristics were summarized as n (%) for categorical variables and median for continuous variables. Patient and tumor characteristics between both groups were evaluated with the chi-square test and the Mann Whitney U test. Survival rates were evaluated using the Kaplan-Meier method. Differences in survival between the two groups were evaluated by a log-rank test. Statistically significant values in univariate analysis were included in multivariate analysis. Cox proportional hazard models were used in univariate and multivariate analyses.

Methods

Results

Patient and Tumor Characteristics
14.7% of the patients were 65 years and older. The median age was 51 years, and the median follow-up was 81 months. Patient and treatment characteristics are shown in Table 1. Comparing the under-65 and over-65 age groups, it was observed that older patients received less chemotherapy (p<0.001), received more hypofractionated radiotherapy (p<0.001) and had more deaths (p<0.001). Although not statistically significant, more MRM was administered (p=0.054). No difference was observed regarding other treatments, side effects and tumor characteristics.

Table 1: Characteristics of the patient and treatment with respect to age group

Survival
In patients under 65 years of age, overall survival (OS) was 158.4 months, while it was 122.7 months in the group over 65 years of age (p<0.001). The 5, 10 and 15-year survival rates were 83.9%, 51.9%, 36% and 90.9%, 81.7%, 75.5% in the over-65 and under-65 groups, respectively (Fig. 1). In the whole group, being over 65 years of age was shown to be a factor affecting OS and DFS in both univariate and multivariate analyses.

Fig 1: Overall survival (a) and disease-free survival (b) by age groups: <65 vs ≥65.

In univariate analysis, when the factors affecting OS in the whole group were evaluated, receiving neoadjuvant CT (p<0.001), being triple negative (p<0.001), being over 65 years of age (p<0.001), being advanced stage (p<0.001), being grade 2-3 (p=0.002), presence of ECE (p<0.001), presence of LVI (p<0.001) and presence of metastasis (p<0.001) were found to be negatively effective. In the under 65 age group, receiving neoadjuvant CT (p<0.001), being triple negative (p<0.001), advanced stage (p<0.001), grade 2-3 (p=0.003), presence of ECE (p<0.001), presence of LVI (p<0.001), presence of metastasis (p<0.001); in the group older than 65 years, advanced stage (p=0.021) and presence of metastasis (p<0.001) had a negative effect on OS. Multivariate analysis results in all three groups are summarized in Tables 2-4. In the group over 65 years of age, advanced stage and the presence of metastasis were found to be the parameters affecting OS.

Table 2: Multivariate analysis of overall survival and disease-free survival in patients <65 years

Table 3: Multivariate analysis of overall survival and disease-free survival in patients ≥65 years

Table 4: Multivariate analysis of overall survival and disease-free survival in all population

The 5, 10 and 15-year DFS rates were 82.3%, 53.8%, 37.4% and 87.4%, 81.7% and 80.8% in the over-65 and under-65 groups, respectively. When the factors affecting DFS were evaluated, receiving neoadjuvant CT (p=0.004), being triple negative (p<0.001), being over 65 years of age (p<0.001), being advanced stage (p<0.001), being grade 2-3 (p=0.002), ECE positivity (p<0.001), LVI positivity (p<0.001) in the whole group; and being advanced stage in the group over 65 years of age had a negative effect. Multivariate analysis was not performed in the group over 65 years of age because it was a single factor.

Results

Discussion

According to 2024 statistics, the probability of developing invasive breast cancer in women over 65 years of age is 1 in 14 women (7.2%).[1] Breast cancer is a serious cause of mortality and morbidity, with 64.1% of deaths in patients with breast cancer occurring in the 65 years and older group.[3] Although older patients have less aggressive tumor characteristics, survival has been found to be shorter.[5] This may be related to patients being diagnosed at a more advanced stage, having comorbidities and receiving less treatment than necessary.[13] In our study, survival was 30.1% and 14.6% (p<0.001) in the groups below and above 65 years of age. No difference was observed between both groups in terms of stage. However, it was observed that patients received less chemotherapy, more hypofractionated RT and more MRM. However, when the patient groups aged 65 and 75 years were compared among themselves, it was observed that patients aged 75 years and older were diagnosed at more advanced stages. In the 65-74 age group, 16.4% of the patients were stage 1, whereas 2.9% in the 75 years and older group (p=0.040). Women over 75 years of age are not included in routine screening programs because there is insufficient evidence for the routine use of screening mammography.[14] This difference may be explained by the decrease in screening in this age group.

Age-related differences have been shown in the biological and molecular characteristics of breast cancer with advanced age. More hormone-positive and more favorable features are observed.[10] In a study evaluating 1,201,252 patients, hormone positivity and HER-2 negativity were more frequent in patients older than 75 years.[15] However, no difference was observed in our study in hormone profile or pathologic features such as LVI, PNI, LVI, or grade.

Breast cancer treatment includes surgery, chemotherapy, radiotherapy and hormonal treatment options. Treatment is based on the patient's stage, functional status, comorbidities and tumor characteristics. Although elderly patients are diagnosed at advanced stages compared to younger patients, they receive primary surgery less frequently, less axillary dissection and less adjuvant treatment.[16] In the elderly patient group, less invasive surgical options are evaluated. Surgery is a standard and safe treatment in the non-metastatic group. Less invasive approaches to the axilla are preferred, especially in the node-negative patient group.[9] It has been shown that surgical approaches in elderly patients are similar to those in younger patients in terms of survival, side effects, and quality of life.[8] Morgan et al.[17] reported a higher tendency for mastectomy in elderly patients. In our study, no difference between axillary dissection and SLNB was observed between the groups. However, mastectomy was more frequently performed in the elderly group. This may be related to patient preference, surgeon preference or more advanced stage diagnosis.

It was observed that the elderly patient group received less chemotherapy in our study. 24.7% of patients over 65 years of age did not receive CT. CT reduces breast cancer-related mortality in patients with breast cancer.[18] Although a decrease in cancer mortality and recurrences has been demonstrated in elderly patients with good general conditions with CT, treatment-related toxicity is more common in this group.[19] CT may have been administered less frequently, especially in the patient group with comorbidities, due to its serious side effects. However, chemotherapy regimens similar to those in young patients should be recommended in patients with good general conditions. Age should not be the only limitation in this group.

Hypofractionated RT has efficacy and safety similar to conventional RT.[20,21] Randomized controlled trials have demonstrated equal local recurrence rates, toxicities, and cosmetic results.[22] Hypofractionated RT may be a suitable option, especially in elderly patients, because of its lower fraction number and effective results. In our study, hypofractionated RT was performed more frequently in elderly patients compared to younger patients (4.8% vs. 0.2%; p<0.001). Hypofractionated RT was not effective on OS and DFS.

The stage is one of the most important prognostic factors. The 5-year relative survival rate is 99% for localized disease, 86% for regional disease, and 31% for metastatic disease.[1] In our study, 5-year survival was 98.8% in stage I and 88.5% in stage II-III disease. Being in the advanced stage had a negative effect on OS and DFS in the over-65 and under-65 age groups. In the over-65 group, being in the advanced stage was the only statistically significant factor; therefore, multivariate analysis could not be performed.

A comprehensive geriatric assessment is an objective resource that evaluates patients' comorbidities, cognitive functions, socioeconomic and nutritional status and functional status.[23] Understanding the relationship between comorbidities and susceptibility to adverse effects is important to maintaining quality of life.[24] ASCO recommends geriatric evaluation before CT in patients over 65 years of age.[25] Although geriatric evaluation is recommended, it is a time-consuming method. However, it is important to individualize treatment.

Limitations of Our Study
The most important limiting feature of our study was its retrospective nature. Geriatric evaluation was not performed. However, the strengths were the treatment of the patient group in a single center with the same treatment protocol and a long follow-up period.

Discussion

Conclusion

Being over 65 years of age was found to be a parameter affecting disease-free survival and overall survival. Compared to patients under 65 years of age, mortality and disease-free survival rates were worse in women over 65 years of age. The elderly patient group received less chemotherapy, more hypofractionated radiotherapy and more metastases. Treatment was well tolerated in this group, which received curative treatment. No difference in toxicity was observed. Age should not be the only determining factor in treatment decision-making. It should be recommended that geriatric evaluation be routinely performed, and treatment protocols similar to those of younger people should be applied to the elderly group, which can tolerate treatment.

Conclusion