We found a statistically different decreasing trend in the LR and RR rates over time in this large retrospective cohort study of young women with operable invasive breast cancer. This research also revealed that the LR and DM rates varied with molecular subtype. Tumor size, lymph nodes metastases, and hormonal therapy were associated with LR, while lymph node metastases and suppression of ovarian function impacted RR based on the multivariate analysis. The 5-year OS of YBC patients was > 90%, with HR-/HER2 + tumors having the worst survival.
The overall 5-year rates of developing LR, RR, and DM were 6.7%, 5.1%, and 16.6%, respectively. Several studies have reported various rates of LRR of YBC patients. LR occurred in 5.4% of the entire population (7.6% of those who underwent breast-conserving surgery [BCS] and 2.6% of those who underwent a mastectomy). An RR of 0.6% after BCS versus 2.6% after mastectomy during 11 years of follow-up in women with breast cancer ≤ 35 of age were collected from the Ontario Cancer Registry between 1994 and 200313. A study conducted by Aalders et al.14 reported that young patients < 35 years of age with early-stage breast cancer had a 5-year cumulative incidence of LR, RR, and DM of 3.5%, 3.7%, and 13.9% between 2003 and 2008, respectively. Another study reported a cohort of 3024 patients 18–40 years of age diagnosed with breast cancer a 5-year LRR rate of 2.63% after mastectomy versus 5.33% after BCS (HR, 3.39; 95% CI, 2.03–5.66; P < 0.001)12. The previous studies likely showed lower rates of LRR because early-stage breast cancer accounted for a large proportion of the study subjects. Patients with stages I and II breast cancer made up 75% of the cohort in our study, while the percentage reached 95% in the study conducted by Aalders et al.14 .
The rates of LR and RR demonstrated a significant decreasing trend during the period of our study. The results of our research were consistent with previous studies14–16, 21,35. A study conducted by Cossetti et al.21 divided 7178 patients with biopsy-proven stage I-III breast cancer into cohort 1 (C1) and 2 (C2) who were diagnosed between 1986 and 1992, and mid-2004 and 2008, respectively. The authors demonstrated that the hazard rate of relapse was nearly halved in all yearly intervals to year 9 in C2 compared with C1 among the overall population21. The patients < 40 years of age in this research accounted for 13.2% of patients, and a subsequent study involving patients < 35 years of age showed overall 5-year rates for LR and RR decreased over time14. We studied the time trend of tumor characteristics per incidence year of patients and revealed that the proportion of stages I and II breast cancer increased, while stage III showed a downward trend over the 9 years. This finding might explain, in part, the decreasing trend of recurrence rates over time.
We observed a downtrend in the recurrence of DM over time, although the difference was not statistically significant. Previous studies have reported similar results14,17,36. Therefore, we suggest that the improvement in OS among patients with breast cancer is closely associated with the lower DM rates in recent years16,19,37,38.
Patients with HR-/HER2 + tumors (HER2 over-expressing tumors) had the highest LR rates, while HR+/HER2- tumors (luminal tumors) displayed the lowest LR rates among the entire cohort. A systematic review identifying patients from 15 studies appraised the effect of molecular subtype on LRR according to the type of surgery and the authors suggested patients with triple-negative and HER2 over-expressing subtypes were at high risk of developing LRR, and luminal tumors exhibited the lowest LRR rates25, which was in agreement with our findings. A cohort of 394 early-stage invasive breast cancer patients undergoing BCS were classified as luminal A, luminal B, HER-2, and basal phenotype. The reported crude LRR rates of the basal phenotype were highest (17.3%), followed by HER-2 (15.4%), luminal B (8.7%), and luminal A (5%)24. A five-biomarker panel (ER, PR, HRE-2, CK5/6, and EGFR) was used to categorize the tumors, which is not a commonly intrinsic molecular phenotype of breast cancer, and therefore it is not useful clinically. However, the results of our research differed slightly from those of published studies14,26,39. These studies reported no difference in LR among patients with various tumor subtypes. We found that molecular subtype was a prognostic factor for both LR and DM, but not an independent prognostic factor based on the Cox proportional hazard model.
We found the cumulative probability of 5- and 10-year OS was 91.9% and 86.2%, respectively, in YBC patients ≤ 35 years of age in our study. A population-based study of women diagnosed with breast cancer from 1992–2005 demonstrated that the breast cancer-specific survival of patients < 35 years of age was 69% at the 10-year follow-up evaluation27. Jacqueline et al.38 reported that the 5-year breast cancer net survival in females diagnosed between 2001 and 2009 was 88.2% independent of race and age, and the survival rates improved from the 2001 and 2003 to 2004 and 2009. Another study suggested that the 5-year breast cancer-specific survival increased from 74.0% during 1975–1979 to 88.5% during 2010–2015 in women diagnosed between ages 20 and 39 years from the SEER database20. The data obtained in our research were slightly higher than previous studies, which might be due to the recent study year accompanied by the improved treatment methods. In addition, the 10 years of follow-up data were not available for patients between 2010 and 2014. Lastly, our study might be limited by the single-center and retrospective nature. In short, the survival rate of YBC patients has improved in recent years.
Our findings demonstrated that the differences in prognosis among YBC patients varied with molecular subtype. Women with HR-/HER2 + had the worst LRFI, RRFI, DMFI, and OS compared to the other subtypes, which was consistent with previous articles33 24,29,30. Nevertheless, many studies have indicated that YBC patients with luminal B subtype had a worse prognosis27,28,31,32. The reason causing the discrepant results might be connected to the year of the study (i.e., there was no HER2-targeted therapy until 1998). After the development of HER2-targeted therapy, the survival of HER2-positive patients was greatly improved40. With the rapid development of HER2-targeted therapies, such as the combination of trastuzumab and pertuzumab, and neratinib and T-DM1, the outcomes of HER2-positive patients could be further improved41–43.
However, there were some limitations in our study. First, molecular subtypes were categorized according to HR and HER2 status without other marks, such as Ki-67, and analyses of HER2 status were limited by FISH testing that was not performed in some cases. Thus, we could not further subdivide the molecular subtypes. Second, information concerning adherence to adjuvant endocrine therapy and ovary function suppression, such as goserelin, was not available on medical records obtained through the subsequent follow-up. Therefore, the reliability of information might be affected by recall bias. Third, the median follow-up of 82 months was relatively short for YBC patients. Finally, the patients were collected in a large single center in northern China and is not population based. As a result, the experiences of patients in our study might not be generalizable to all young women with breast cancer.
In conclusion, the overall 5-year LR and RR rates with YBC patients were low and showed a decreasing trend and the proportion of early-stage breast cancer increased between 2006 and 2014. The highest LR rates and worst survival in this young population were associated with HR-/HER2 + tumors. We expect to develop more new treatments to prolong the survival time and improve the quality of life of young women with breast cancer in the near future.