breast cancer, prognostic factors, younger patients Prognostic factors and survival of women with breast cancer under 40 years old: A single-centre experience

Objective: This retrospective research aimed to evaluate the results of treatment outcome and clinicopathological features of breast cancer patients under 40 years old. Material and methods: A total of 80 patients who were receiving radiotherapy and/or chemotherapy treatment for breast cancer (<40 years old) were included in the study. Results: First-degree relatives with breast cancer history (p=0.028), oestrogen receptor positivity (p=0.012) and progesterone receptor positivity (p=0.017) were associated with overall survival. No prognostic factors were found in the multivariate Cox regression analysis for overall survival. In multivariate Cox regression analysis, we found breast-conserving surgery type (hazard ratio = 6.104. 95% confidence interval = 1.037–53.928, p=0.045), lymphovascular invasion presence (hazard ratio = 0.127, 95% confidence interval = 0.016– 1.025, p=0.005) and curative radiotherapy doses (hazard ratio = 185.976, 95% confidence interval = 5.342–6474.1, p=0.004) as independent prognostic factors for disease-free survival. Overall, survival of 1, 3 and 5 years was 88%, 74% and 65%, respectively. Median was 48±2.6 (42.8–53.19) months. Also, 1-, 3- and 5-year disease-free survival was 85%, 67% and 27%, respectively. Median was 30±1.8 (27.4–32.5) months. Conclusion: Breast cancer patients under the age of 40 years are highly heterogeneous and are a complex patient group. The prognosis is worse in these patients, and prognostic factors and pathological subtypes should be taken into consideration when making treatment decisions.


Introduction
Breast cancer is the most common malignancy in women and the most common cause of death after lung cancer [1]. The treatments for invasive and non-invasive breast cancer are different and complex. Invasive breast cancer is the most common type in the world and in Turkey. Although its frequency increases with age, it is more common in Asia at the age of 50 years [2]. Breast cancer, especially under the age of 40 years, is more heterogeneous and has many subtypes, and treatment is complicated.
Although there are standards related to the treatment of breast cancer, molecular subtypes are defined every year, and treatments change accordingly. Treatment response and disease-free survival (DFS) are different compared with elderly patients, especially in women with breast cancer under the age of 40 years [3,4]. In young breast cancer patients, the disease is more aggressive, and the treatment response is less likely. The personalisation of treatment decisions according to clinical and biological subtypes has become prominent in recent years. Therefore, family history and clinicopathological factors such as tumour size, lymph node, histologic type, grade, lymphovascular invasion (LVI) vs. molecular subtypes and hormone receptor expression play key roles in the treatment decision.
In this study, we aimed to evaluate the clinicopathological features and treatment response of patients with breast cancer under 40 years old and discuss which subgroups may further benefit from treatment.

Material and methods
In this retrospective study, we evaluated 80 patients under 40 years old who were diagnosed with invasive breast cancer. Patients' records were evaluated between 2012 and 2018. Although all related pathology results were obtained from hospital data, information about treatment follow-up was obtained from clinical files. Patients with ductal carcinoma in situ, insufficient record information, male sex and age >40 years were excluded.
This study examined the mean age, family history, pathology, tumour size, surgery type, adjuvant or neoadjuvant chemotherapy, tumour stage, nodal stage, histologic and nuclear grades, LVI, perineural invasion (PNI), adjuvant radiotherapy doses and hormone receptor status.
Overall survival (OS) was defined as the time between the date of diagnosis and the last contact or death. DFS was the period between the date of diagnosis and the time of local tumour recurrence and metastasis.
For DFS, the univariate analysis showed that surgery type, adjuvant radiotherapy doses and positive ER and PR were statistically significant (p<0.05). The multivariate analysis revealed that surgery type (breast-conserving vs mastectomy), LVI and radiotherapy doses (curative vs palliative and curative vs oligometastatic and received curative radiotherapy) were independent prognostic factors (Table 3). ER positivity is statistically close to the meaning and can be considered statistically significant (p=0.057).

Discussion
Breast cancer is still the leading cause of death in women in the world. It is a histologically and clinically heterogeneous and complex disease, especially in young patients. Identifying prognostic factors in young patients can make treatments more successful. In our hospital, we tried to determine subtypes that benefited from the treatment by examining our breast cancer patients under 40 years of age. Moreover, we tried to identify prognostic factors.
Young age in breast cancer is an independent risk factor for survival in many studies [5][6][7]. We did not find this difference in patients between 20-30 and 31-40 years old. The most important prognostic factor in young patients is having a history of breast cancer in their first-degree relatives. Brewer et al. showed that first-degree relatives with a history of breast cancer and the risk of breast cancer increased in young patients [8]. Similarly, in our study, although it was significant in univariate analysis for OS, it was not significant for DFS.
Many studies have shown that OS is the same in patients undergoing mastectomy and breast-conserving surgery [9,10]. In terms of OS, this study did not find any difference between the two surgery types, but breast-conserving surgery was found to be a prognostic factor in terms of DFS in multivariate analysis. The reason for this is that most of the patients undergoing mastectomy were from locally advanced patients who had previously received neoadjuvant chemotherapy.
The presence of LVI has been associated with distant metastasis and axillary lymph node involvement in patients with breast cancer [11]. In many studies, the presence of LVI affects OS and DFS in young breast cancer patients [11,12]. The presence of LVI was found to be an independent risk factor. In our study, the presence of LVI was found to be an independent prognostic factor for DFS (p=0.05).
Adjuvant chemotherapy and radiotherapy are known to increase OS and DFS in young breast cancer patients. Adjuvant radiotherapy is especially important in preventing local recurrence for patients under 60 years old [13,14]. Similarly, curative radiotherapy application was found to be statistically significant in our study according to both palliative radiotherapy and radiotherapy dose applied in oligometastatic disease (p=0.004 and 0.002, respectively). The adjuvant curative dose of radiotherapy (50Gy and/or 60Gy) is an independent prognostic factor in multivariate analysis.
Approximately 80% of patients with breast cancer are ERpositive patients. In these patients, endocrine therapy is added to adjuvant therapy after surgery. Endocrine therapy causes prolonged DFS and OS and decreases the risk of recurrence in patients with breast cancer, both early and advance [15,16]. In our study, although ER and PR positivity were found to be statistically significant in univariate analysis for OS, this could not be demonstrated in multivariate analysis. However, ER positivity can be evaluated as a prognostic factor in multivariate analysis for DFS (p=0.057). This may be because our patients' follow-up is short. In our hospital, endocrine therapy (Tamoxifen 10mg × 2) was initiated in all patients with hormone receptor positivity, and endocrine therapy was not given in hormonenegative patients.
Another important problem is the triple-negative patient group (negative ER, PR and HER-2), which accounts for about 15-20% of all breast cancers. The prognosis of patients in this group is poor because of early recurrence and distant metastases [17,18]. In addition, triple-negative patients are generally those with young patients with breast cancer [19]. Although our study was a group of young breast cancer patients, it was not found to be statistically significant for OS and DFS as our number of triple-negative patients was low, and our follow-up time was short.
This study has three important limitations. Firstly, the most important prognostic factor in the young patient group is the absence of breast cancer BRCA-1 and BRCA-2 results. Secondly, patient follow-up is short. Thirdly, this group of patients should be evaluated separately in patients who were originally oligometastatic.

Conclusion
In young breast cancer patients, OS and DFS are shorter than the elderly group, and their treatment varies according to complex and subgroups. When making a treatment decision, prognostic factors and molecular subtypes should be taken into consideration. According to the results of the study, there are numerous prognostic predictors of a worse DFS, and the most important were operation type, LVI presence and radiation doses. The most important prognosis factor for OS was a family history of first-degree breast cancer.

Disclosures:
There is no conflict of interest for all authors.