After screening and analyzing the data from SEER database, eight independent prognostic factors (age, race, marital, grade, tumor size, number of positive nodes, breast surgery type, radiation) were included to build the nomogram to predict patients’ BCSS. Then, X-tile was used to find a binary critical point of risk model which could help T1-3N0-1 breast cancer patients with HR+, HER2- judge whether CHT is necessary. We were surprised to find that CHT should be recommended for the high-risk patients but patients in the low-risk group may receive endocrine monotherapy because no benefit was gained from CHT, which is of great significance for clinical practice. It means that we can divide people into two groups: those who need CHT or do not, without intermediate risk group. For low-risk patients, CHT may not improve survival but increase the burden of patients and is more likely to bring CHT-related complications and side effects; for high-risk patients, CHT can bring survival benefits.
The risk model provides an objective and clear method for clinicians and patients and it is the largest retrospective analysis of early breast cancer population with T1-3N0-1, HR+, HER2-. In recent years, there have been a number of single-center and multi-center retrospective analyses to discuss whether patients with HR+, HER2- early breast cancer need adjuvant CHT according to the clinicopathological factors.(14, 19, 20) In a population-based study from British Columbia, most of the 1 187 T1–2N0 early breast cancer patients without adjuvant systemic therapies (> 70%) did not recur locoregionally or distantly within 10 years after diagnosis,(20) which meant that a considerable proportion of patients with HR+, HER2- early breast cancer can avoid CHT without sacrificing the curative effect. Another study combined clinicopathological factors with gene test results to determine whether CHT is necessary,(21) which showed that the two methods had their own advantages and perfected each other. There are also some studies hoping to replace Oncotype DX by constructing imaging or clinical indicators model equations.(10, 22) However, most of them are single-center studies and limited by the sample size and follow-up time so the results were somewhat inconsistent and unreliable.
In this study, before PSM, the OS of CHT group is better than that of no CHT group. The possible reasons are as follows: first of all, the underlying diseases and baseline of the two groups are inconsistent (the no CHT group had more patients > 60 years old); secondly, compared with patients without CHT, CHT group patients may have fewer underlying diseases, so the better OS of CHT group may not be completely attributed to the effect of CHT. The BCSS of CHT group is worse than that of no CHT group and the reason may be that patients in the CHT group had larger tumors and a higher stage. After PSM, the CHT group had better OS benefit when the baseline (demographic and clinical characteristics) of the two group was well-balanced but BCSS had no difference between the two groups. However, the underlying diseases of patients in this study could not be obtained from the database.
CHT cannot improve the BCSS of this population, does it mean that these people do not need CHT? The answer is clearly No. Many clinical trials and retrospective analyses have confirmed that some of the patients with HR+, HER2- early breast cancer can benefit from CHT.(23–25) For instance, the ongoing Southwest Oncology Group (SWOG) S1007 RxPONDER trial (26) assigned women with 1–3 lymph node-positive nodes, HR+, HER2- breast cancer and a RS ≤ 25 to standard endocrine therapy with or without adjuvant CHT. This trial expects to determine the benefit (if any) of CHT for patients in this cohort. Based on the results of our study that there is no difference in BCSS between CHT and no CHT groups, we speculate that CHT can make some high-risk patients get better BCSS, but not benefit the low-risk groups.
In order to identify precisely who can benefit from CHT, we have teamed up with nomogram and X-tile to identify low- /high-risk groups in this study. The results showed that CHT did not improve survival of low-risk patients, and BCSS was slightly damaged. We speculated that breast cancer-related death may be caused by CHT-related injuries (such as CHT-related pneumonia, CHT-related myelosuppression), so such patients should give up CHT. For high-risk patients, CHT can bring obvious BCSS benefit and OS benefit is further increased (HR decreased from 0.663 to 0.583) so from another point of view, CHT is necessary for these people.
This study also had some limitations. For example, we could not get the information of endocrine therapy and CHT regimen from SEER database. Although the baseline of the two groups was balanced by PSM, the retrospective study could not replace the RCT study. It is worth noting that the nomogram and risk model constructed in this study have been verified by survival analysis, which played an effective role in deciding whether to undergo CHT or not for HR+, HER2- early breast cancer patients, and we expect it could be useful for the design of future RCT experiments.