In spite of the dramatic increase in the number of EBC patients,3–5, 16 chemotherapy for T1 pN0M0 breast cancer remains controversial. Therefore, it is imperative to establish a safe, specific, and effective chemotherapy strategy to guide treatment and improve the prognosis of these patients.
In addition to creating the strategy, we utilized PSM and external validation to verify the association between chemotherapy and significant survival advantages obtained by breast cancer patients with T1 pN0M0.
Chemotherapy is recognized as a primary systematic adjuvant modality; however, it negatively influences survival and reduces the quality of life because of its short-term toxicities, including alopecia, nausea, vomiting, and fatigue, and potential long-term effects, including myelosuppression, cardiovascular toxicity, neurotoxicity, marrow neoplasm, and cessation of menses and fertility.17–20 EBC patients are expected to survive their cancer diagnosis; however, it is not appropriate to select breast cancer-specific mortality as an endpoint. Therefore, adjuvant therapy has been crucial for observing improvements in the OS of breast cancer patients.21, 22 Mortality should be considered because it can be caused by toxicities related to chemotherapy. Furthermore, our study suggests that chemotherapy possibly accelerates death for some HR+/HER2- T1ab pN0M0 patients.
Postmastectomy radiation therapy is widely considered to reduce the risk of local recurrence and breast cancer mortality, especially for patients with locally advanced breast cancer who are at high risk because of large tumors and axillary lymph node involvement.23 However, the majority of T1 pN0M0 breast cancer patients prefer to undergo breast-conserving surgery instead of mastectomy, and adjuvant radiotherapy is an indivisible locoregional treatment for breast-conserving surgery that achieves local control benefits and OS advantages.24–29 These results are consistent with the results of our study.
There was an obvious contradiction in the results obtained using the SEER database and those of external validation. The external validation results indicated that patients with grade II T1b pN0M0 can acquire survival benefit from chemotherapy, but the SEER database results did not. There are two interpretations of this phenomenon. First, the data used for external validation are relatively limited; therefore, inevitable deviations may have occurred during statistical analyses. Second, the two cohorts of data were derived from China and the United States. Admittedly, the factors that affect a patient’s lifetime vary from country to country and include cultural barriers, ethnic differences, and genetics.30 Consequently, the final conclusions refer to the results obtained using the SEER database.
Our research results, the guidelines of the National Comprehensive Cancer Network (NCCN), and the guidelines of the St. Gallen International Breast Cancer Conference (BCC) are nearly identical.31, 32 The NCCN suggests the following:
1. For node-negative HR+/HER2- breast cancer, if the tumor is 0.5 cm or smaller, chemotherapy is not recommended. If the tumor is larger than 0.5 cm, then performing a 21-gene reverse-transcription polymerase chain reaction assay (Oncotype DX) is strongly considered.33–35
a. If the recurrence score is ≥ 31, the risk of recurrence is high and chemotherapy is recommended.
b. If the recurrence score is 26–30, the risk of recurrence is moderate and the decision to perform chemotherapy is based on other clinical factors.
c. If the recurrence score is < 26, the risk of recurrence is low and chemotherapy is not recommended.
2. For node-negative HR+/HER2 + breast cancer, if the tumor is 1.0 cm or smaller, it is uncertain whether chemotherapy is required. However, chemotherapy is recommended for T1a category 2B, which means that there is an NCCN consensus that intervention is appropriate based on lower-level evidence. If the tumor is larger than 1.0 cm, chemotherapy is recommended.
3. For node-negative HR-/HER2 + breast cancer, chemotherapy is recommended. However, chemotherapy is recommended for category 2B when the tumor is smaller than 0.5 cm.
4. For node-negative HR-/HER2- breast cancer, if the tumor is smaller than 0.5 cm, chemotherapy is not recommended. However, chemotherapy is necessary for any other case.
The BCC guidelines are different but somewhat similar to the NCCN guidelines.32 Routine adjuvant chemotherapy is not recommended for T1a pN0 breast cancer; this is identical to our research results. The BCC panel recommends adjuvant chemotherapy for HER2-positive and triple-negative breast cancer (TNBC) stage T1b pN0 and higher. For ER+/HER2- T1pN0 breast cancer, regardless of luminal-A-like qualities (strongly ER-positive and PR-positive, HER2-negative, with lower grade and proliferation markers) or luminal-B-like tumors, the BCC panel does not recommend adjuvant chemotherapy for patients with low genomic risk scores according to the Oncotype DX and 70-gene signature tests (MammaPrint).36–38 Additionally, the European Society for Medical Oncology guidelines are in agreement with the St. Gallen guidelines regarding chemotherapy for EBC.39
In our opinion, which is supported by the St. Gallen guidelines, adjuvant chemotherapy should not be performed for T1a pN0 breast cancer.
For HR+/HER2- T1bc pN0 breast cancer, chemotherapy is recommended for grade II and grade III T1c pN0 breast cancer if no genetic signature test has been performed or if the 21-gene assay indicates a medium risk. If the conditions are suitable, then we propose following the guidelines to accomplish genetic testing for these patients. For the other three molecular subtypes, chemotherapy is recommended for stage T1b pN0 and higher; this is also mentioned in the St. Gallen guidelines. Some retrospective studies demonstrated the survival benefits of adjuvant chemotherapy for patients with T1c N0M0 TNBC.40, 41 We incorporated tumor grade, which is an independent prognostic indicator, to assess the effects of chemotherapy.42–44 Patients, including those with TNBC, can be exempt from adjuvant chemotherapy if they have grade I/II T1b pN0 and grade I T1c pN0 breast cancer.
There were several limitations to our study. First, the SEER database was devoid of variables for genes and therapies, such as the 21-gene assay and schemes and dosages of chemotherapy and endocrine therapies. Second, because the endpoint was OS, age was a significant factor that could not be included to evaluate the effects of chemotherapy. Third, because we used a retrospective cohort population, inevitable selection bias might have affected the conclusions. Further large-scale, prospective, randomized, controlled trials are warranted to accurately identify the outcomes.