In 2020, there were 2.3 million women diagnosed with breast cancer and 685 000 deaths globally. According to statistical data, approximately 54% of these patients are locally advanced [9]. Neoadjuvant chemotherapy is the standard treatment for locally advanced breast cancer. It is also recommended for breast-conserving surgery and minimal axillary lymph node dissection in early-stage breast cancer[10]. However, the first aim of neoadjuvant treatment is to downstage the disease and render in-operable tumors resectable. The pathological target in neoadjuvant therapy is the complete pathological response(pCR) [11]. pCR is a prognostic factor and linked to a better overall survival (OS) and event-free survival (EFS)[12]. The most important factor affecting the complete pathological response is the affinity of the tumor to neoadjuvant therapy. The neoadjuvant chemotherapy sensitivity of the tumor is different in molecular subtypes[13]. Molecular subtypes are divided into five main groups depending on the presence or absence of estrogen, progesterone, HER2 receptor, and the percentage of Ki-67[14]: Luminal A, Luminal B HER2-negative, Luminal B HER2-positive, Pure HER2-positive, Triple-negative or basal-like. Luminal A tumors are represented in 30-40%, luminal B HER2-negative tumors 20-30%, HER2-positive tumors (pure HER2-positive and Luminal B) 15-20%, and triple-negative tumors 15-20%. In our data, the incidence of subtypes was similar. However, luminal A tumor was less than the literature, with a rate of 27.7%.
Pathologic responses of primary breast tumor were evaluated according to the Miller-Payne grading system, which defines pCR as the absence of invasive and in situ carcinoma in the breast and axillary nodes (ypT0/ypN0) [15]. The clinical trials have shown that the complete pathological response is related to good treatment results[16]. In recent years, factors predicting complete pathological response were investigated. ER, PR levels, HER2 status, tumor grade, molecular subtype, perineural invasion, vascular invasion, Ki-67, and tumor size could not be fully correlated with pathological response[17]. Grade 5 in the MPG system was considered to complete pathological response. In our study, the number of patients with complete pathological responses was 35. (34.7%). In the 101 patients, pathological complete response rates for primary tumour in luminal A, luminal B/HER2-, luminal B/HER2+, pure HER2-positive, and triple-negative disease were 7.1%, 44.0%, 57.8%, 60.0%, and 21.0%, respectively. In other words, the group with the highest pathological response rate was pure HER2 positive, and the group with the lowest was luminal A (%7,1). pCR rate was significantly lower for luminal A tumor (P=0.001). Even if the pathological complete response rate of luminal A tumors is low, survival rates are high. No local recurrence or death was observed in any of the Luminal A tumors in our data. Although luminal A tumors respond less to chemotherapy, the positivity of ER, PR, and low Ki-67 level is associated with a good prognosis [18]
The pathological complete response rates in lymph nodes of luminal A, luminal B/HER2-, luminal B/HER2+, pure HER2-positive, and triple-negative disease were 14.3%, 52.0%, 89.5%, 60.0%, and 47.4%, respectively. There was a statistically significant difference in axillary response rates in the molecular subtype groups(p<0.001).
HER2-positive tumors are known for their aggressive behavior. In the study of Buzdar et al., the pCR rate for HER2-positive tumors was given as 66.7%[19]. Our study examined the HER2-positive tumors in 2 categories: Luminal B HER2-positive and pure HER2-positive. Pathological complete responses of these two subgroups were compatible with the literature, 57.8%, and 60%, respectively. When the patients with a pathologically complete response and those who did not were compared, a significantly higher HER2-positivity was found at complete responders (p = 0.017). Anti-HER2 treatments contributed to this critical response in neoadjuvant therapies. In a meta-analysis by Antonis et al., they determined that the addition of trastuzumab in HER2-positive breast cancer in the neoadjuvant setting improves the probability of achieving higher pCR[20]. In addition, clinical studies have shown that the use of dual HER2 blockade (pertuzumab + trastuzumab) in neoadjuvant therapy further increases the pCR rate[21]. Clinical studies have shown that neoadjuvant chemotherapy with trastuzumab plus pertuzumab increases the pCR rate compared with trastuzumab alone, resulting in about 50-70% pCR rate[22]. In our data, pCR was observed in all six patients who received dual HER2 blockade. The low number of patients given pertuzumab is that it was not paid by health insurance before 2019.
Triple-negative tumors are also tumors with an aggressive course. However, it has a high sensitivity to chemotherapy. Neoadjuvant chemotherapy is seen as the standard treatment for triple-negative and HER2-positive tumors. In the study of Sharma et al., 35-55% pCR was seen with neoadjuvant cytotoxic chemotherapy in triple-negative tumors[23,24]. In the GeparSixto study, 53.2% pCR was obtained by adding carboplatin to neoadjuvant therapy in triple-negative tumors[25]. In our study, the rate of pCR in triple-negative tumors was much lower than in the literature (21%, n:5). The neoadjuvant treatment of patients with a complete response was combined-based therapy with anthracycline and a taxane (FEC, ACT, or FECT). Carboplatin was added to the treatment of only one of these patients. When all triple-negative patients were examined, there were already only two patients to whom carboplatin was added to their treatment. In other words, 50% of the patients who added carboplatin in our study gave a complete response.
Luminal A tumor is the least chemosensitive; our study achieved pCR rates of 7,1% (n:2). In the study of Collins et al., 114 patients with Luminal A tumor had a pCR rate of 7.9%[26]. In Collins et al. study, patients with complete pathological responses were patients with high-grade tumors and weak PR expression. In our study, the tumor grade of 2 patients with complete pathological response was two, and the PR expression percentage was below 10%. Similar results were obtained for luminal A tumors in the 14000 diseases neoadjuvant study of Haque et al. The rate of pCR in patients with luminal A tumor was found to be 0.03%. However, in the 5-year overall survival analysis, Luminal A tumors are much better than other subtypes. (98.2%) [27]. This shows that the survival of luminal A tumors is quite good, although they do not give a complete pathological response. In our study, no recurrence was observed in any patient with luminal A tumor despite the low pCR rate.
In our data, the second-highest pCR rate was in Luminal B HER2-positive tumor (%57,8). In the study of Wang et al., The rate of pCR was 13.4% in patients with Luminal B tumors. However, Wang et al. showed that patients with a high Ki-67 index above 40% had a better pathological complete response and recurrence-free survival[28]. A meta-analysis of 6793 patients by Tao et al. showed Ki-67 labeling index is a predictive marker for a complete pathological response to neoadjuvant chemotherapy in breast cancer[29]. In our data, the median index of Ki-67 of all patients with a complete pathological response was 40% (30-65), and the median index of Ki-67 for those who did not have a complete pathological response was 30 (15-60). There was no statistically significant difference between the two groups (p:0.06). However, when patients with luminal B tumors were examined separately, the median index of Ki-67 was 41.7 (range 10-80). The high Ki-67 value of our patients with luminal B tumors may have contributed to a better response to neoadjuvant chemotherapy.
In our data, patients with complete pathological response had a high rate of clinical axilla positivity before neoadjuvant chemotherapy (88.6%, p: 0.043, OR: 3.69; 95% CI 1.0-13.1). Samiei et al. showed that, on the contrary, patients with clinically negative axilla achieved a higher rate of complete pathological response in ER+HER2+, ER-HER2+, and triple-negative subtypes[30]. All patients with clinically positive axilla were in the luminal B HER2-positive and pure HER2-positive groups in our study.
Patients with grade 3 tumor differentiation constituted 38.6% of the entire population (n:39). The grade 3 group had the highest rate of pCR (n:18, 46.2%). Diaz-Casas et al. reported the pCR rate as 21.3% in grade 3 tumors[31]. In the study of Jarzab et al., the pCR rate was reported as 30.9% in patients with grade 3 nuclear differentiation[32].
Pathological complete response is associated with the neoadjuvant chemotherapy regimen. Anthracycline-based chemotherapy regimens form the basis of treatment. ACT regimen achieved the highest pCR rate, 29.9% (n = 26), and ıt was similar to FEC and FETCH. In recent years, pertuzumab has been added to the treatment of HER2-positive tumors along with trastuzumab. In addition, carboplatin was added to the anthracycline and taxane regimen in triple-negative tumors. However, since the number of these patients was small in our study, the effects of pertuzumab and carboplatin on pCR could not be reported.
There was a significantly higher EFS and OS difference in the Luminal A subtype compared to the other molecular subtypes. (p < 0.001) However, the complete pathological response did not affect survival in Luminal A tumor. This can be explained by the low chemosensitivity of Luminal A tumors. Fortunately, long survivals have been achieved with the increase in hormone therapy options over the years. The HER2 positive group had a high pathological complete response. However, this situation was not reflected in EFS and OS in our patient population. Regardless of the subgroup, when the patients were divided into two groups as pathological complete response and non-responder and OS analysis was performed, there was no significant difference in survival between the two groups(p:0.06). However, the short follow-up period in our study may have prevented us from seeing a significant difference. We hope that with a larger patient group and a more extended follow-up period and with the use of new neoadjuvant treatment regimens we can distinguish between pathologically responding and non-pathological subgroups.