Chemotherapy Choice in Neoadjuvant Dual Her2 Blockade; Is It Really Necessary to Add Anthracycline?


 1. BackgroundAddition of trastuzumab and pertuzumab to neoadjuvant chemotherapy in human epidermal growth factor receptor 2(HER-2) positive patients is the current clinical standard today. In studies on neoadjuvant chemotherapy, the primary endpoint is pathological complete response (pCR). More real-life data are needed to answer whether the presence of anthracycline in the chemotherapy regimen enhances complete response with neoadjuvant dual HER-2 blockade, and whether cardiotoxicity increases with dual HER-2 blockade after anthracycline.2. Methods52 patients with HER-2 positive breast cancer who received neoadjuvant chemotherapy were retrospectively evaluated. Three centers participated in the study (İzmir Kent Hospital, Manisa Celal Bayar University, Ege University). The effects of chemotherapy regimen and several other factors such as age, stage, menopause status, lymph node positivity, hormone receptor positivity on pCR were evaluated. Also presence of cardiotoxicity was evaluated.3. ResultsThe mean age of diagnosis was 46 ± 9 (range: 26-67), and 50% (26) of the patients were postmenopausal. The pCR rate was 71.2% (37) in the entire study group. In terms of pCR, there was no significant difference between those who use an anthracycline containing and non-anthracycline containing regimens (71.4% vs 70%, p=1.000), those with negative and positive hormone receptors (64.7% vs 74.3%, p=0.525), those with Ki67 levels of %20 or less and those over 20% (60% vs 73.8%, p=0.447), premenopausal and postmenopausal ones (76.9% vs 65.4%, p=0.054). 4. ConclusionsAs a result of the data we obtained, it was concluded that adding anthracycline regimen to dual HER-2 blockade in the neoadjuvant period did not bring additional benefits in terms of pCR. Additional studies are needed on whether the use of anthracycline-containing regimen contributes additionally in patients who will use the neoadjuvant pertuzumab-trastuzumab combination.


Introduction
Human epidermal growth factor receptor 2 (HER-2) is a tyrosine kinase transmembrane receptor and shows positivity in 15-20% of breast cancer cases. [1] HER-2 positivity is associated with aggressive course and poor prognosis. [2] Dual HER-2 blockade has proven its bene t rstly in metastatic HER-2 positive disease and then in the neoadjuvant stage. [3][4][5] The addition of trastuzumab and pertuzumab to neoadjuvant chemotherapy in HER-2 positive patients is now the clinical standard. The main purpose of neoadjuvant therapy is to increase breast protection rates by obtaining downstage in the tumor. [6] In studies on neoadjuvant chemotherapy, the primary endpoint is pathological complete response (pCR). Pathological complete response has a prognostic determinant role. [7] pCR was found to be associated with an increase in survival. [8] In neoadjuvant chemotherapy, dual HER-2 blockade led to an increased pathological complete response. [9] In the BERENICE study, dual HER-2 blokage with neoadjuvant chemotheraphy resulted in pCR rates up to 75% in HER-2 enriched group with. [3] The aim of our study is to answer the following questions: Does the anthracycline containing chemotherapy which will be used alongside dual HER-2 blockade in neoadjuvant treatment has additional bene t? Does cardiotoxicity increase with dual HER-2 blockade after anthracycline? To answer these questions, we retrospectively evaluated patients who received dual HER-2 blockade in neoadjuvant therapy and their responses according to the chemotherapy regimen they received.

Materials And Methods
The present study was approved by the Manisa Celal Bayar University Faculty of Medicine ethics committee board and was exempted from informed consent requirements owing to its retrospective design. After receiving the ethical approval from the Medical Research Ethics Committee of the Manisa Celal Bayar University Faculty of Medicine with the number 99 dated 24.08.2020, clinical characteristics, chemotherapy regimens, laboratory data, pCR rates and echocardiography results of 52 patients who were given pertuzumab-trastuzumab dual HER-2 blockades in neoadjuvant therapy in 3 clinical centers (Izmir City Hospital, Manisa Celal Bayar University, Ege University) in the last 3 years were examined retrospectively. All methods were performed in accordance with the relevant guidelines and regulations.
In the immunohistochemistry (IHC) analysis, those with estrogen reseptor (ER) or progestreone reseptor (PR) positivity were classi ed as hormone receptor positive. Tumors with ER and PR negativity were classi ed as hormone receptor negative. Those with +3 with HER-2 IHC analysis and those who tested positive for HER-2 Fluorescence in situ hybridization (FISH) were considered HER-2 positive.
Patient le scanning for neoadjuvant therapies revealed that 52 patients used 2 different chemotherapy regimens. 1st chemotherapy regimen: dose dense adriamisin-cyclophosphamide followed by weekly paclitaxel with trastuzumab-pertuzumab; (Anthracycline 60 mg/m2 and cyclophosphamide 600 mg/m2 were applied once in every 14 days for 4 cycles, then paclitaxel 80 mg/m2 was used for 12 weeks along with trastuzumab (6 mg/kg maintenance dose after 8 mg/kg loading dose) and pertuzumab(420 mg maintenance dose after 840 mg loading dose) which were used once in every 21 days), 2nd chemotherapy regimen: docetaksel-carboplatin-trastuzumab-pertuzumab (TCHP); Dosetaxel 75 mg/m2, carboplatin 6 AUC, trastuzumab (6 mg/kg maintenance dose after 8 mg/kg loading dose) and pertuzumab (420 mg maintenance dose after 840 mg loading dose); all of which were used once in every Page 4/12 21 days. Within the scope of the Turkish Health Ministry reimbursement, pertuzumab was used as only 4 cycles in both regimens.
Pathological complete response is considered ypT0/is,N0. Clinical and pathological staging was performed according to the American Joint Commitee of Cancer classi cation. [10] Statistical analysis Factors that may affect pCR (such as age, menopausal condition, clinical stage, histological grade, hormone receptor status, chemotherapy regimen) were examined by univariate logistic regression models. Odds ratio for all potential predictors was evaluated with a 95% safety interval and pCR response was evaluated. In multiple analyses, the p value below 0.050 was considered statistically signi cant. The distribution balance between groups was evaluated by skewnes method. SPSS 21 was used for statistical analysis.

Results
The height, weight and laboratory data of the patients at admission are shown in Table 1. The mean age of the included 52 patients at diagnosis was 46 ± 9 (range: 26-67).    The overall pCR rate was 71.2% (37) and pCR was 71.4% (30) in the group that used anthracycline containing regimen and 70% (7) in the group that used TCHP regimen(p=1.000). In patients with breast cancer who received dual HER-2 blockades, it was found that using a regimen containing anthracycline in addition to neoadjuvant therapy did not affect pCR. According to the TNM classi cation, the pCR was 94.7% in those with clinically N1 and 57.6% in those with N2-3 (p:0.004)( Table 3) 68.4% of N1 people received an anthracycline containing regimen, while 87.9% of N2-3 ones received regimen containing anthracycline(p=0.142).
In the group with a Ki67 index below 20%, the pCR was 60%, while in the group above 20%, the pCR was 73.8%(p=0.447).
In the group with negative hormone receptors, pCR was 64.7%, while pCR was 74.3% in the group with positive hormone receptor. The difference was not statistically signi cant. (p:0.525) pCR was 68.2% in those with stage 3 disease at the time of diagnosis, while pCR was 87.5% in those with stage 1-2 disease. The difference was not statistically signi cant (p=0.412). In those with stage 3 disease, regimens containing anthracycline were 81.8% and in those with stage 1-2 it was 75% (p=0.642).
While the rate of patients with cardiotoxicity with dual blockade was 5.8% (3), all these 3 patients were under 65 years of age and used anthracycline containing regimen as well as dual HER-2 blokage as adjuvant. HER-2 blockade was terminated in these patients as soon as the detection of cardiotoxicity.

Discussion
In HER-2 + Stage 4 breast cancer, higher pCR rates were reported with the use of double HER-2 blokage during the neoadjuvant period than previously achieved. [3,4] The pathological complete response obtained after neoadjuvant treatment has been shown to be a positive prognostic factor. [10,11] In the BERENICE study, in the HER2 enriched group, high pCR rates were obtained with the regime containing anthracycline followed by dual her2 blockade, which in turn caused the need to evaluate the additional advantages and possible side effects of anthracycline-containing regimens. [3] In the TRAIN 2 study, there was no signi cant difference between the regimen containing anthracyclines and the regimen that did not, and it was reported that it was preferable not to use anthracyclines. [13] The pathological complete response rates obtained in our study was found to be similar in anthracycline containing and not containing regimen groups. All patients with cardiotoxicity (5.8%) were patients who had received the treatment regimen containing anthracycline. The regimen containing the anthracyline preferred in the TRAIN 2 study was different from the one preferred in our study. In addition, in the TRAIN 2 study patients recieved 9 cycles of HER2 dual blockade, in our study it was limited to 4 cycles in accordance with the restriction of the Turkish Ministry of Health. In the TRAIN 2 study, pCR rates were 68% vs 67% in regimen-containing and non-containing anthracycline, while they were 70% vs 71.4% in our study. [12] Chemotherapy regimens containing and without anthracycline did not differ signi cantly in pCR in subgroup analyses, and considering that hematological and non-hematological toxicities are more common in anthracycline containing regimens, it is thought that anthracycline-free chemotherapy as neoadjuvant therapy would be an appropriate option.
In the metaanalysis performed by Ding and his colleagues, 7 randomized controlled trials were evaluated and patients who took and did not take anthracycline in early stage breast cancer were evaluated. As a result of metaanalysis, it has been suggested that opting for an anthracycline-free regimen leads to noninferior consequences. As expected, neutropenia and neutropenic fever were more common in patients who received an anthracycline-containing regimen. In addition, nonhematological side effects such as mucositis, nausea and vomiting were also detected more in the group containing anthracycline. [13] Conclusions One of the limitations of our study is that the number of patients is small. One of the reasons for this is that the use of neoadjuvant pertuzumab in our country can still be done with non-indication application approval. Another important limitation is that only cardiotoxicity is evaluated in the side effect pro le. However, the main purpose of our study was to show the effect of adding anthracycline regimen to pathological complete response and cardiotoxicity potential in those who used pertuzumab-trastuzumab during the neoadjuvant period.
As a result of the data we obtained, it was concluded that adding anthracycline regimen regimen to dual HER-2 blockade in the neoadjuvant period, regardless of subgroups such as age, stage, menopause status, lymph node positivity, hormone receptor positivity, did not bring additional bene ts. In this regard, it is necessary to support our data with studies carried out with larger patient numbers.