Clinicopathological features and prognoses of very young patients (≤35 years) with breast cancer: a retrospective population-based study in China

To the Editor: In China, very young breast cancer patients (≤35-year-old) make up approximately 10% of all breast cancer cases, compared to 2% in Western countries. This suggests that different morbidity may be caused by different geographic regions and ethnicities, even leading to different clinicopathological characteristics and prognoses. Tang et al^[1] reported that very young breast cancer patients had poor disease-free survival (DFS), and the risk of disease progression was 1.557-fold higher than that for the elderly patients, but no difference was observed in overall survival (OS). However, few studies have focused on very young patients with breast cancer in China. Therefore, we conducted a retrospective population-based study to investigate the oncological outcomes of very young breast cancer patients. The studies involving human participants were reviewed and approved by the Ethics Committee of the International Peace Maternity and Child Health Hospital ([No. GKLW] 2021-37).

Data was obtained from Shanghai Jiao Tong University Breast Cancer Database, and we first identified patients with Stage I–III who were first treated with surgery between January 1, 2010 and December 31, 2017 (n = 17,599). The pathological type of invasive ductal carcinoma was selected. The inclusion criteria were as follows: premenopausal women aged ≤50 years; complete data of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2); and complete informaiton of survival outcomes. Finally, 3443 patients were included. Patients with lymph node metastasis received chemotherapy. Chemotherapy for patients without lymph node metastasis was decided by the doctors. Patients with lymph node metastasis and patients undergoing breast conserving surgery received radiotherapy. Patients with ER- or PR-positive tumors received endocrine therapy. Patients with HER2-positive tumors received trastuzumab. Immunohistochemistry was used to analyze the expression of ER, PR, Ki67, and HER2 proteins. An ER and PR expression of >1% was considered positive, and PR >20% was classified as high expression. The HER2 status was classified as follows by scoring the tumors according to the intensity and completeness of the cell membrane staining using a four-tier scale: 0 for no immunoreactivity, 1+ for weak and incomplete membrane staining, 2+ for weak/moderate and complete membrane staining, and 3+ for strong and complete membrane staining. A 3+ tumor was considered HER2-positive, whereas 1+ and 0 tumors were considered HER2-negative. For tumors scoring 2+, fluorescent in situ hybridization (FISH) result was used. HER2-positive was considered if FISH result was positive, otherwise the HER2-negative was considered. We defined Ki67 >14% as high level according to the highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer. Similarly, the classification of molecular subtypes was based on St. Gallen highlights as follows: Luminal A was ER-positive and PR high expression with HER2-negative and low Ki67 level; Luminal B (HER2-) was ER-positive and HER2-negative with either PR low expression or high Ki67 level; Luminal B (HER2+) was ER-positive and HER2-positive; HER2 overexpression (HER2+) was ER-negative, PR-negative, and HER2-positive; triple-negative was ER-negative, PR-negative, and HER2-negative.

Statistical analyses were conducted using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). Categorical data and continuous data were presented as frequency (percentages) and mean ± standard deviation/median, respectively. DFS1 was defined as the time from diagnosis to the detection of locoregional recurrence, distant metastasis, death due to any cause, and secondary primary cancer excluding secondary primary breast cancer. DFS2 was defined as both DFS1 and secondary primary breast cancer. Distant metastasis-free survival (DMFS) was defined as the time from diagnosis to the appearance of any distant metastasis. Breast cancer-specific survival (BCSS) was defined as the time from diagnosis to death due to breast cancer. OS was defined as the time from diagnosis to death due to any cause. We stratified by age at diagnosis (≤35 years, 36–39 years, and 40–50 years), and the 36–39 years age group acted as the reference group. The differences in the distribution of clinical indicators among different age-groups were explored using the chi-squared test for categorical variables. Kaplan–Meier method was employed to calculate the survival rate, and the differences among various subgroups were assessed using the log-rank tests. Cox regression analyses were carried out to explore the effects of various factors on survival time. The estimates derived from Cox regressions were presented as hazard ratio (HR) and 95% confidence interval (CI). A two-sided P-value <0.05 indicated a statistically significant difference.

The three age-groups comprised 13.5% (463/3443), 18.1% (622/3443), and 68.4% (2358/3443) of patients, respectively. Very young patients showed a significant association with histological grade III, less ratios of ER-positive expression, less ratios of PR-positive expression, and high Ki-67 level (all P <0.05). The most prevalent molecular subtypes in very young patients were luminal B (HER2–) and luminal B (HER2+) [Supplementary Table 1, http://links.lww.com/CM9/B469].

The median follow-up was 54.6 months. Compared to the 36–39 years age group, the very young patients showed an inferior 5-year DFS1, 5-year DFS2, 5-year OS, 5-year DMFS, and 5-year BCSS. No significant differences were observed between women aged 36–39 years and those aged 40–50 years. The 5-year DFS1 of the three age-groups were 85.4%, 93.8%, and 93.1%, respectively. The risk of disease progression in very young patients was 1.846-fold higher than that in the 36–39 years age group. Moreover, the 5-year OS was 95.7% in the very young patients, which was a worse outcome in contrast to the 36–39 yeas and 40–50 years age groups (98.9% and 98.0%, respectively). The 5-year risk of death in very young patients was 3.205-fold higher than that in the 36–39 years age group [Table 1]. Next, we investigated the impact of age on molecular subtypes, and did not find any significant difference in any prognostic indicator of patients with Luminal A and HER2+ disease among the three age-groups. In the Luminal B (HER2+) subgroup, very young patients showed a worse 5-year OS and 5-year BCSS than the 36–39 years age group. No significant difference was detected between the 36–39 years age group and the 40–50 years age group in any prognostic indicator. In the Luminal B (HER2–) subgroup, very young patients exhibited higher risks of recurrence and death than the 36–39 years age group in 5-year DFS1, 5-year DFS2, 5-year OS, and 5-year BCSS [Supplementary Table 2, http://links.lww.com/CM9/B469].

Table 1.

HRs and 95% CIs derived from Cox regression analysis for 5-year DFS1, 5-year DFS2, 5-year OS, 5-year DMFS and 5-year BCSS by age group.

Age group (years)	Patients	5-year DFS1	HR (95% CI)*	5-year DFS2	HR (95% CI)*	5-year OS	HR (95% CI)*	5-year DMFS	HR (95% CI)*	5-year BCSS	HR (95% CI)*
≤35	463 (13.4)	396 (85.5)	1.846 (1.240, 2.747)	393 (84.8)	1.855 (1.263, 2.724)	443 (95.7)	3.205 (1.359, 7.556)	420 (90.7)	1.956 (1.183, 3.235)	443 (95.7)	3.189 (1.351, 7.523)
36–39	622 (18.1)	583 (93.8)	1.000 (REF)	580 (93.3)	1.000 (REF)	615 (98.9)	1.000 (REF)	598 (96.2)	1.000 (REF)	615(98.9)	1.000 (REF)
40–50	2358 (68.5)	2196 (93.1)	1.020 (0.728, 1.430)	2189 (92.8)	1.019 (0.735, 1.413)	2311 (98.0)	1.906 (0.898, 4.044)	2254 (95.6)	1.045 (0.679, 1.607)	2311 (98.0)	1.805 (0.847, 3.845)

Data are presented as n (%). ^*Adjusted for histological grade, pathologic TNM (pTNM), chemotherapy, radiotherapy, endocrine therapy, trastuzumab administration, and molecular subtype. BCSS: Breast cancer special-survival; CI: Confidence interval; DFS: Disease-free survival; DMFS: Distant metastasis-free survival; HR: Hazard ratio; OS: Overall survival; REF: Reference.

Several studies have suggested that young age is an independent risk factor for poor DFS and death of breast cancer patients. Recently, there is a consensus that young breast cancer patients are defined as those of an age <40 years, and very young breast cancer patients of an age ≤35 years, according to the European School of Oncology and the European Society of Medical Oncology 4th International Consensus Guidelines for Breast Cancer in Young Women.^[2] Tang et al^[3] demonstrated that young Chinese patients had poor survival rates in patients aged ≤50 years, irrespective of the cutoff age was 35 or 40 years old. Lian et al^[4] reported that age between 36 years and 40 years was also a risk factor for poor prognoses in Chinese patients. Nevertheless, the result was based on a small sample. Based on our large cohort study, the very young patients had worse outcomes among patients aged ≤50 years.

Breast cancer in very young patients presented mainly the Luminal B subtype, while few of them presented the Luminal A subtype. It was consistent with previous reports in Asian populations that the proportion of Luminal B disease in patients aged ≤35 years was preponderant over that in middle-aged or elderly patients.^[1,3] Our study finding was different from the previous results that patients aged ≤40 years with Luminal A disease exhibited a poorer DFS, DMFS, and BCSS compared with middle-aged and elderly patients.^[3–5] The result in our study was that no difference was observed among the three age groups in prognoses. There were only 36 and 91 patients with Luminal A tumors who were very young and aged 36–39 years. The small sample size might cause bias. The present study showed that very young patients with the Luminal B (HER2+) and Luminal B (HER2–) subtypes all exhibited poor prognoses in accordance with the previous studies.^[3–5] The inferior outcomes of younger women with the Luminal B subtype may result from tamoxifen resistance. In 2015, the results of the combined analysis of the tamoxifen and exemestane trial and the Suppression of Ovarian Function Trial suggested that tamoxifen or exemestane plus ovarian function suppression (OFS) significantly reduced the risk of recurrence compared to tamoxifen alone for premenopausal women with hormone receptor-positive tumors, especially for those aged ≤35 years.^[6] However, no benefit was observed from OFS for Luminal A disease in patients, and only Luminal B (HER2–) cases receiving chemotherapy benefited from exemestane plus OFS.^[7] Cancello et al^[8] also demonstrated that combination therapy using OFS and tamoxifen was significantly correlated with improving DFS compared to tamoxifen alone for very young patients. However, the benefit of the combination was restricted to patients with Luminal B disease. The tamoxifen resistance of the Luminal B subtype might explain the benefits from combination therapy of OFS and exemestane or tamoxifen. Since our study included the patients diagnosed during 2010–2017, the combining endocrine therapy with OFS was not a routine regimen for the patients with high-recurrence-risk Luminal tumors. A follow-up study should address the appropriate combination endocrine therapy which would improve the prognoses in very young patients with Luminal B tumors. The recurrence and metastasis mechanisms of the Luminal B (HER2+) subtype are complex owing to the crosstalk between hormone receptor and HER2 receptor pathway. Cross-talk has been reported by several investigators, with HER2 over-amplification, resulting in resistance to estrogen-deprivation therapies. The APHINITY trial was first reported in 2017 and showed that combination therapy using trastuzumab and pertuzumab improved the 3-year invasive DFS for HER2-postive breast cancer patients compared to using trastuzumab only. This trial also showed that combination therapy improved invasive DFS of hormone receptor-positive and HER2-positive disease, and did not have an impact on hormone receptor-negative and HER2-positve disease with 6 years' follow-up.^[9] Thus, dual blockade HER2 signaling could induce ER function in Luminal B (HER2 +) cell lines. Therefore, intensive treatment for anti-HER2 receptor might present a therapeutic option for patients with Luminal B (HER2+) tumors, including very young patients. In our study, the patients with HER2-positve tumors were treated with trastuzumab only, because the evidence of efficacy of dual blockade HER2 signaling therapy was limited before 2017. Above all, further studies are needed to better understand the impact of younger age on recurrence and metastasis mechanism of luminal B (HER2+) patients.

The present study has some limitations. First, all enrolled patients were selected from an ethnically homogeneous population, and results may not be generalizable to other ethnic groups. Second, we did not have details of the components and regimens of chemotherapy, and failed to collect information about chemotherapy-induced amenorrhea and application of OFS, and the results may be influenced by these residual confounding factors.

In conclusion, the present study suggested that breast cancers in very young patients in China were more likely to present advanced disease with high histological grade and high Ki-67 level, and to exhibit Luminal B tumors predominantly. Very young breast cancer patients had poorer prognoses among patients aged ≤50 years. Luminal B (HER2+) tumors were associated with a poor 5-year OS and 5-year BCSS, and Luminal B (HER2–) tumors showed an inferior 5-year DFS, 5-year OS, and 5-year BCSS in very young patients.

Acknowledgments

The authors acknowledge the efforts of the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB).

Funding

This study was supported by the Shanghai Municipal Key Clinical Specialty (No. shslczdzk06302).

Conflicts of interest

None.

Supplementary Material

cm9-136-1488-s001.doc ^{(175.5KB, doc)}