Long-term outcomes of non-metastatic breast cancer patients by molecular subtypes | BMC Women’s Health | Full Text
A total of 1287 women with non-metastatic breast cancer aged 21 to 87 years have entered the study, of whom 200 patients (15.5%) died, and 1087 cases (84.5%) were censored. The mean age of patients was 47.00 ± 10.72 years, 62% of patients were < 50 and 25.9% were < 40 years old. The characteristics of patients and differences in clinicopathologic and treatment features grouped by various molecular subtypes have been summarized in Table 1. In 64% of cases, the lymph nodes showed a positive result and in 68%, patients were diagnosed in early-stages (stages I and II). Patients with available chemotherapy information included 842 patients received adjuvant chemotherapy, 259 patients received Neoadjuvant chemotherapy, 99 patients received both, and 8 patients received no chemotherapy. So, we divided patients into those received and those not received adjuvant chemotherapy. All of the patients underwent surgery, and most patients received adjuvant chemotherapy (73%), radiotherapy (90%), and hormone therapy (80%). Proportions of patients by tumor subtype were 20%, 52%, 12% and 16% for HR+/Her2+, HR+/Her2−, HR−/Her2+ and HR−/Her2− respectively.
As demonstrated in Table 1, clinicopathologic and treatment patterns differed by molecular subtypes. Patients with HR−/HER2+ status tended to have larger tumor size (P = 0.001), higher histologic grade (P < 0.001), higher stage (P = 0.038) and positive lymph node (P < 0.001). In contrast, smaller tumor size (P = 0.001), lower stage (P = 0.038) and lower grade (P < 0.001), were more common in HR+/HER2− patients. The lowest positive lymph nodes rate (about 50%) was also observed in triple-negative breast cancer (TNBC) patients (P < 0.001).
Almost half of women were treated by BCS; however, in HR−/HER2+ patients, MRM was the more prevalent procedure (P = 0.001). Hormone therapy differed significantly between subtypes. Virtually all HR-positive patients received hormone therapy compared with less than 40% of HR-negative patients. In addition, nearly all of the patients received radiotherapy and adjuvant chemotherapy, although in HER2− patients, adjuvant chemotherapy was more common (P = 0.022).
Figure 1 shows recurrence, metastasis and mortality rates by molecular subtypes according to treatment types. In all subgroups, patients who had MRM surgery experienced higher rate of mortality, metastasis, and recurrence than those who undergo BCS surgery (Fig. 1.a). Furthermore, patients who received hormone therapy, particularly HR+/HER2+ tumors, had lower mortality and metastasis rates, while HR−/HER2+ tumors had higher mortality rate (Fig. 1.b). The mortality rates of patients who received radiation therapy and/or adjuvant chemotherapy were nearly identical to those of other patients, as shown in Fig. 1.c and d. Patients with negative HR who received radiation therapy had a lower recurrence and metastasis rates, and those who received adjuvant chemotherapy had a greater recurrence and metastasis rate.
Recurrence, metastasis and mortality rates of breast cancer patients according to a type of surgery, b hormone therapy, c radiotherapy, d adjuvant chemotherapy
Recurrence, metastasis and mortality rates of breast cancer patients according to a type of surgery, b hormone therapy, c radiotherapy, d adjuvant chemotherapy
The Kaplan–Meier method estimated 170.09 ± 3.11 months for mean OS and 155.2 ± 3.32 months for mean DFS. In addition, 1, 5, 7, 10, and 15-year OS rate was calculated 98%, 86%, 79%, 72%, and 67%, respectively. The Kaplan Meyer DFS curve with the 95% confidence interval is shown in Fig. 2.
Kaplan–Meier disease-free survival curve with 95% CL in the month for breast cancer patient
Kaplan–Meier disease-free survival curve with 95% CL in the month for breast cancer patient
The survival plot is almost flat after about 150 months. The cure fraction is estimated about 60% (the difference between the smooth sequence of the chart and the zero value on the survival probability axis). Patients who survived longer than 150 months were intuitively considered as cured or long-term survivors.
The 5-year DFS was 77.3% in HR+/Her2+, 84.2% in HR+/Her2−, 62.3% in HR−/Her2+, and 76.5% in TNBC (Table 2). In general, DFS of breast cancer subtypes were associated with tumor stage (Fig. 3). The DFS was not significantly different among molecular subtypes in stages I and III breast cancer (Fig. 3a and c). By contrast, in stage II, HR−/HER2+ patients had worst prognosis with 5-year DFS of 57.4% and HR+/HER2− patients had best DFS of 87.3%. The 5-year DFS estimated in stage II TNBC was 79.2%, which was lower than DFS estimated in the HR+/HER2− group (Table 2).
DFS of a stage I; b stage II; c stage III breast cancer by different molecular subtype
Prognostic factors of DFS survival
We performed the univariate and multivariate Cox mixture cure model to analyze the prognostic factors for short-term and long-term DFS of breast cancer patients, as shown in Table 3.
The effect of factors on survival time and cure probability of patients were indicated by HR and OR, respectively. If the HR is more/less than one, it means that the variable is a risk/protective factor for survival. Whereas the OR more/less than one means that the variable is a protective/risk factor for odds of cure. The greater distance from one, the greater effect.
In univariate analysis, the hazard ratio of DFS in the TNBC, HR+/HER2+, and HR−/HER2+ were 1.78, 1.53 and 1.38 compared to HR+/HER2 as the reference subtype. However, only the HR−/Her2+ subtype was associated significantly with the cure probability (OR = 0.38). On the other hand, after adjusting for demographic and clinical factors, the risk of mortality, metastasis, and recurrence was not significantly associated with molecular subtype in the short-term. Still, the cure probability of HR−/Her2+ patients was significantly lower than HR+/HER2− patients (OR = 0.22).
Other associated factors with worse short-term DFS included larger tumor size (HR = 1.99) and positive lymph nodes (HR = 1.58). Furthermore, high-level of education (HR = 0.7), BCS surgery (HR = 0.55), and adjuvant chemotherapy (HR = 0.55) had a protective effect on DFS.
In the long-term, married women were more likely to be cured (OR = 1.62). Regardless, the cure probability of the women with obesity (OR = 0.41), postmenopausal status (OR = 0.63), family history of cancer (OR = 0.66), IDC pathology (OR = 0.26), and advanced tumor stage (OR = 0.21) was significantly lower than the others.
The 5-year OS rate was 86.3% for all patients. Before 2000, the survival rate of Japanese, Korean, Turkish, and Arab females was 88.1%, 83.7%, 76.7%, and 64.5%, respectively [32]. Moreover, it is slightly lower than the 5-year OS of 91% in the USA [33] and 89.7% in Brazil [34]. Considering breast cancer research center as a referral center in Iran, it seems that the 5-year survival rate in Iran is higher than it in many Asian counterparts but lower than in American countries. It can be concluded that even without a national screening policy and lack of availability to some new therapeutic modalities, our survival rate is within an acceptable limit, so it is expected to improve soon.
This research revealed that the tumor characteristics and survival rates varied with the molecular subtype. Like other studies, more proportion of tumors under 2 cm, stage I, and low histologic grade were in HR+/HER2− patients [30, 31]. By contrast, HR−/HER2+ tumors tended to be larger in size, higher stage, higher histologic grade, and positive lymph nodes. Even though these results differ from some earlier studies that reported worse tumor features in TNBC [38, 41], they are consistent with those of Chinese [30] and Canadians [12] that observed the worst tumors in HR−/HER+ patients. As suggested in the literature [31, 42], breast cancer patients with TNBC have fewer positive lymph nodes, increasing the possibility of blood spreading of this cancer than lymphocytes. Future researches are needed to clarify this molecular subtypes’ mechanism.
After adjusting for pathological and demographic variables, short-term survival was not significantly different between the molecular subtypes, but in the long-term, the cure probability of HR−/HER2+ patients was much lower than the others. In other words, the short-term survival differences between subtypes are mostly due to pathological and demographic variables. However, even after adjusting for these variables, HR−/HER2+ patients still are less likely to be cured in the long-term.
The current study represents the biomarker analysis of DMR and RR in breast cancer by molecular subtype. For both DMR and RR, patients with HR+/HER2− tumors had the most favorable prognosis, with DMR and RR of only 7.1% and 2.6% at 5 years. Conversely, HER2 positive and TNBC exhibited the highest rates of DMR (14.1% and 9.3%) and RR (10.4% and 4.9%). Our results have several similarities with a retrospective cohort study of Asian young breast cancer patients that found HR−/HER2+ tumors had the highest recurrence and metastasis rates. In contrast, HR+/HER2− tumors displayed the lowest LRR [30]. Another study of 10-year recurrence in European breast cancer patients announced that those with HR−/HER2+ and TNBC had a significantly higher recurrence and metastasis rate than HR-positive profiles, which was in agreement with our findings [22]. A Canadian study showed that, after a median follow-up of 6.9 years, 8% of HER2-positive cancers had a local recurrence, compared to 12% in TNBC. Moreover, they showed that distant metastases occurred in 19.2% of HER2-positive and 27.4% of TNBC. They also noted that the HR+ patients had the best prognosis of local recurrence and distant metastasis [43].
In this study, we tried to predict breast cancer patients’ short- and long-term survival with robust statistical methods. We have some limitations in our study. First, we classified molecular subtypes based on HR and HER2 status without additional biomarkers, including Ki-67 and cytokeratin levels. Second, the medical records we used did not include detailed information on different therapies, such as endocrine therapies, HER2-directed therapies, or chemotherapy. By adjusting for these factors, we might reduce confounding effects and improve our knowledge about the survival of breast cancer molecular subtypes. Third, since there was a large amount of missing data, especially for ER, PR and HER2, we had to use the limited number of data available. So, the results should be interpreted with caution.