Our findings from the retrospective study at Pauls Stradins Clinical University Hospital suggested that BRCA pathogenic variants and high Ki67 expression are associated with a higher incidence of complete pathological response after neoadjuvant chemotherapy.

As one of the prognostic biomarkers in the treatment of breast cancer, the Ki-67 index has been demonstrated to be associated with tumour chemosensitivity and associated with a more frequent pCR, while pCR improves patient survival [2]. In a study by Nakashoji, a high Ki67 score was observed in 83% of patients in the pCR group vs. 46% in the non-pCR group [7]. In this study, 50% of patients receiving neoadjuvant chemotherapy had a Ki-67 index above 50%, and 47.5% of these patients achieved a pCR. Additionally, pCR was observed more frequently in patients with BRCA 1 or 2 pathogenic variants (57.7%).

The addition of platinum to NAC regimens showed promising results, but their use remains controversial. The meta-analysis performed by Li and his colleagues shows that the addition of platinum to standard chemotherapy increases the probability of pCR by 13.2% (49.1% in the platinum-based NAC group vs. 35.9% in the standard NAC group) [8], but in a study published in 2018 by Gass and colleagues, pCR reached 50% after platinum/taxane treatment (vs. 41.8% after anthracycline/taxane treatment) [9]. Similarly, in the GeparSixto trial, carboplatin-based NACT increased pCR rates – 53.2% vs. 36.9% (p = 0.005) [4], while our analysis failed to support these findings in this retrospective cohort – 40.4% in platinum-based NAC vs. 21.2% in nonplatinum-based NAC, but this was not statistically significant in the adjusted analysis.

In patients with TNBC, a pCR has been observed to be a strong indicator for better outcome. If pCR is achieved as a result of NAC, survival is similar to survival in other, more favourable, molecular subtypes of BC, but in the case of a partial response to NAC, short survival and fast recurrence are commonly observed [9]. In a study by Gass and colleagues, pCR was significantly related to increased RFS and OS [10]. Two other randomized trials, the CALB40603 trial and BrighTNess study, demonstrated significant increases in pCR rates and relapse-free survival in TNBC with the addition of carboplatin to taxane- and anthracycline-containing NACT [11, 12]. The BrighTNess study identified significant improvements in RFS for patients with pCR vs. non-pCR both in patients with an identified germline pathogenic variant in BRCA1 or BRCA2 (HR 0.14) and in BRCA wildtype patients (HR 0.29) [12]. Our study confirmed these data – patients with pCR experienced increased RFS (7.7% relapsed in pCR vs. 24.1% in non-pCR) and OS (3.8% died in pCR vs. 14.8% in non-pCR) than patients with partial response, but the result was not statistically significant, which may be based on the low number of patients in the study group.

Regarding decreased survival rates, patients with incomplete response to NAC are candidates for postoperative systemic treatment, such as chemotherapy or innovative drugs, to improve disease control and survival. Since 2017, when Masud and colleagues published results from the CREATE-X study with colleagues, it is known that patients with residual disease following NAC and surgery may benefit from adjuvant chemotherapy with capecitabine [13]. Capecitabine was not reimbursed in Latvia in the current time period, and only 4 patients received adjuvant treatment in the non-pCR group.

In our study, a comparison between TNBC patients with BRCA pathogenic variants and sporadic cancer patients was also performed. As expected, patients with BRCA pathogenic variants were significantly younger, and increased pathological response to NAC was observed. According to the Miller-Payne grading system, grade I-II response (no response or weak response to NAC) was not observed (0%) in the BRCA-mutated group compared to 34.7% in the sporadic TNBC group, but pCR was observed in 57.7% vs. 20.4%, respectively. Patients with BRCA-mutated TNBC were more often treated with platinum-based NAC, and the mastectomy rate was significantly higher. Similar findings were published by Kedzierawski and colleagues – the rate of pCR in BRCA-mutated TNBC was 54.2% vs. 40.3% [14].

This study has limitations that should be mentioned. First, it was a retrospective study with a relative deficiency of patients in subgroups, which could have influenced the bias of the obtained results. The collected sample size in two years was small, which could be improved in further studies by adding patients from the next years. Second, the study group was heterogeneous – different chemotherapy regimens used, clinical and pathological findings, surgery types, and BRCA status (mutated, wild type or unknown) could also impact the results. In our study, ten different platinum-based chemotherapy regimens with different counts of chemotherapy agents were used. In such a small study, it is difficult to refer to the results, but we observed a benefit of adding platinum salts in patients with BRCA1/2 pathogenic variants. Larger randomized trials have already been published addressing the efficacy of platinum-based NAC and its correlation with pCR and survival in TNBC; therefore, our retrospective study adds real-life experience from a single university hospital to the current knowledge despite its limitations. Further studies are needed to confirm the current results.