Although most patients with breast cancer show partial or complete response to NST, there is still a fraction of patients running into PD. The rate of PD in our centre was 1.6%, in accordance with the study by Leisha (1.9%) but lower than the previous data (3–7%)[8][9][11][15]. Due to emerging treatment options such as targeted therapy and immunotherapy, the survival outcomes of patients receiving neoadjuvant systematic therapy are constantly improving. However, considering the poor outcomes of PD, it is essential to identify these patients promptly and generate appropriate salvage treatment strategies. To our knowledge, this study represents the largest contemporary dataset of patients with PD in China, focusing on the survival outcomes and value of predictive factors.
Considering the limited clinical studies concerning PD and subsequent treatments, no standard ST protocol was established. Despite emerging new therapies, surgery has always played a vital role in treating breast cancer[16][17]. Overall, 80% (48/60) of patients received surgical management during this study, among whom 17 received direct surgery and 31 received delayed surgery in our centre. According to the univariate and multivariate analyses, not receiving direct surgery was statistically a predictor of poor clinical outcomes in our study (p = 0.013). Furthermore, patients who received delayed surgery after other nonsurgical ST modalities were noted to have worse survival outcomes than those who received surgery directly. Other neoadjuvant studies also suggested that switching to different chemotherapy regimens when PD occurred before surgery did not result in any improvement in pCR[18][19]. Similar suggestions were drawn in the study by Abigail S who concluded that early surgical referral is warranted when progression might jeopardize the operability of lesions[20]. Hence, we suggest that once PD occurs, direct surgery should be considered first instead of other regimens.
Concurrent radiation is one area of investigation that may hold promise for patients with PD. However, no difference in survival outcomes was detected between receiving radiation therapy or not from a statistical perspective due to the low number of events. Judging from our results, neoadjuvant radiation could in part convert a previously unresectable tumour to an operable tumour, thus leading to an increase in the number of surgeries in patients with PD. Numerically, 56.0% (14/25) of our patients receiving NAR successfully downstaged their tumours and underwent delayed surgery. Interestingly, we did not find any survival difference in those undergoing surgery compared with those not undergoing surgery (p = 0.82). Hence, for inoperable patients, neoadjuvant radiation may partly show signs of tumour downstaging but no improvement in survival outcomes. Historically, NAR is known as a local therapeutic method to increase the rate of breast-conserving surgery by tumour downstaging. However, the increase in the overall treatment time (OTT) and the higher risk of surgical morbidity caused by NAR cannot be neglected[21][22]. Recent studies have found that adjusting the frequency of NAR could provide a solution. A randomized pilot trial reported that accelerated NAR in 5 fractions with a simultaneously integrated boost is feasible and results in a shorter OTT without excess acute toxicity[23]. Other studies have also explored the role of radiation as a supplement to systemic therapy in this population, but there is still no consensus[10][24]. In general, the association between NAR and better survival outcomes remains uncertain, and further studies are needed.
As a clinically heterogeneous disease, different subsets of breast cancer show variable sensitivity to NST[25][26]. It is notable that in our study, a total of 53.5% of patients were diagnosed with TNBC, while the rate of TNBC for all breast cancer diagnoses was only 15–20%[27][28]. Compared with patients with HR-positive or HER2-positive disease, patients with TNBC were noted to have a poorer prognosis. TNBC was also proven to be independently associated with distant failure in our multivariate analysis. TNBC generally has a more aggressive biology, with earlier onset of metastatic disease, visceral metastases, and inferior survival outcomes, which could, in part, provide a biological explanation for the poor prognosis among this group of patients with PD, regardless of whether they receive NST[29][30][31]. The high proportion of TNBC (68.2%) of all patients with PD who developed distant metastasis suggested that more contemporary treatment of patients with TNBC should be utilized to improve their outcomes. Previous studies have demonstrated that triple-negative breast cancer cells are more likely to express proteins of programmed death ligand-1 (PD–L1) than other breast cancer subtypes. Several clinical trials of immune checkpoint inhibitors such as atezolizumab and avelumab have been conducted in neoadjuvant therapy for patients with TNBC (NeoTRIPaPDL1 Michelangelo study, KEYNOTE–173, KEYNOTE–522, etc.). Preliminary results have shown that immune checkpoint inhibitors combined with chemotherapy can improve the survival of patients with TNBC[32][33][34][35][36]. The results of studies concerning other supplementary therapies targeting the VEGF and PI3K pathways are also encouraging for improving the pCR rate[37][38][39]. Taken together, the results of these landmark trials demonstrate that other supplementary systemic therapies will play an important role in the treatment of patients with TNBC and may decrease the number of patients with PD while receiving NST.
Given the variability of salvage therapies for patients progressing on NST and the paucity of studies on predictors of distant failure after PD, it is necessary to identify these patients in a timely manner in order to optimize their subsequent treatments and outcomes. Approximately 36.7% of patients in the study population developed distant failure. Considering their poor prognosis, the identification of favourable features to identify patients in this subgroup warrants further attention. Thus, we summarized the characteristics of breast cancer patients treated with NST in our own centre who progressed and compared outcomes of patients using different ST strategies. The ultimate aim is to identify the best ST strategy to use and the clinical features of the patients with the highest risk of distant failure.
Our study had several potential limitations. First, as a retrospective study, selection bias was inevitable. Second, changes in systemic therapy and the emergence of biological therapies were dismissed in our analysis. Third, owing to some loss of follow-up data, it was difficult to collect all the events accurately which has underpowered our analysis. Finally, the low prevalence of PD and events may contribute negatively to detecting the significant difference between survival outcomes of each subgroup and the predicting factors. Therefore, our study can only put forward suggestions according to the outcomes of our patients with PD during NST. This result is insufficient to determine the standard ST for patients with PD. Prospective studies should be conducted to define the clinical utility of various ST strategies.