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Neoadjuvant chemotherapy of capecitabine + epirubicin + cyclophosphamide combination therapy (‘CEX’ therapy) for HER-2 negative breast cancer, as retrospective study in our institute.

Background: We have modified and performed neoadjuvant chemotherapy (NAC) using capecitabine + epirubicin + cyclophosphamide combination therapy (‘CEX’) for HER-2 negative breast cancer. In this study, we investigate the outcomes achieved in our institute and report the effectiveness and tolerability of this therapy, retrospectively. Methods: The patients included in this study had breast cancer that was negative for HER-2 and positive for lymph node metastasis or negative for lymph node metastasis with a tumor diameter of 20 mm or greater without any distant metastasis. Additionally, groups with performance status (PS) 0-1, aged 75 or less, and with an EF > 60% were targeted. Clinical evaluations were made after a total of 4 courses of epirubicin: 80 mg/m 2 , cyclophosphamide: 500 mg/m 2 (administered every 3 weeks) and capecitabine: 1500 mg/m 2 (administered for 2 weeks and withdrawn for 1 week). Results: Eighteen patients received treatments between 2009 and 2013. All patients achieved clinical benefits. The clinical response rates (CRR) were 83.3% (15/18) and 50% for clinical complete response (cCR). All patients achieved positive aesthetic outcome with breast-conserving surgery. Those patients had satisfactory outcomes, with pathological complete response (pCR) in 33.3% (triple negative (TN): 6, luminal: 0) and n0 in 68.8% (TN: 8, luminal: 3). All patients with pCR are in a relapse-free survival state and are still under observation. The adverse events were grade 2 or lower for all patients. Conclusions: This study suggested that ‘CEX’ therapy as NAC could be an important option for individualized treatment. In particular, it was effective for TN breast cancer.

However, we believe that the outcomes of this standard treatment are still controversial 15,17,19 . For the outcome of pCR rate at 20-30%, there is a concern that target patients who have experienced high-grade adverse events for nearly 6 months would be discouraged from receiving further treatments or restarting the treatments when recurrence occurs. Therefore, for this type of breast cancer, it is crucial to establish a NAC regimen that can yield both high response rates and high tolerability in a short period of time, assuming preoperatively that AT would be performed [20][21][22][23][24][25][26][27][28][29][30][31][32][33] .
Since 2009, we have modified and performed NAC using 'CEX' therapy for HER-2 negative breast cancer without any distant metastasis. In this study, we investigate the outcomes achieved in our institute and report on the effectiveness and tolerability of this therapy. In addition, this report will be described retrospectively.

Patients and eligibility criteria
The patients included the following: all of patients who had histologically demonstrated evidence of invasive breast cancer with negative for HER-2, and, positive for lymph node metastasis or patients with primary breast cancer that was negative for lymph node metastasis with a tumor diameter of 20 mm or greater without any distant metastases; patients younger than 75 years old, not complicated by other tumors at the time of starting the treatments, and who had never received preoperative treatments; patients with white blood cell count >3,000/ (neutrophil count >1,000), hemoglobin>10.0, Plt >100,000, EF >60% for cardiac functions, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, and patients who did not have any social or economic restrictions. And, patients who were adequately informed of this clinical trial and submitted a consent form.
Excluded criteria for this study were as follows, 1) in cases there were judged impossible to continue the survey after that due to reasons such as a transfer, 2) withdrawing consents, 3) in cases that did not correspond to the eligibility criteria, 4) others; in cases judged as impossible to continue this study.
The primary endpoint was the pCR rate, and the secondary endpoints were (1) breast-conserving surgery rate, (2) clinical response rate, and (3) safety (the level of adverse events). The anti-tumor evaluation was made by RECIST guideline, and be expressed as follows: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and, from clinical-pathological aspects, clinical CR (cCR) and pathological CR (pCR).
The medications to be administered in this study were approved domestically and internationally and can usually be carried out in clinical practice. Evaluation on adverse events and countermeasures can also be handled with daily practice. The adverse events were evaluated by scores based on Common Terminology Criteria for Adverse Events (CTCAE) ver.

4.0.
As in previous studies, the treatment was discontinued or switched to another treatment when (1) the disease progressed without showing any response, (2) adverse events of grade 4 continued, or (3) the patient did not agree to the treatment or requested to discontinue the treatment.
This clinical study was analized retrospectively, and the design and conduct of this study were applied to the ethics community of our institute (the approval number; 591).

Regimen management ('CEX'-NAC)
Clinical evaluations (computed tomography (CT), ultrasonography (US), magnetic resonance imaging (MRI), etc.) were made after a total of 4 courses of epirubicin: 80 mg/m 2 + cyclophosphamide: 500 mg/m 2 (administered every 3 weeks) and capecitabine: 1500 mg/m 2 (administered for 2 weeks and withdrawn for 1 week). We tried to reduce the dose of this regimen below the usual dose level, and it was expected both high response and high tolerability would be obtained. When the hematological adverse events of grade 3 were occurred, we planned to reduce to 85% of the initial dose of the chemotherapeutic agents and to change the interval of this chemotherapy administration (postponed by 1 week). And, Based on the results of previous studies, we expected that The clinical response rates (CRR) and pCR rate in this regimen were 70% and 20%, respectively. We have demonstrated the clinical findings of a patients who was treated by 'CEX'-NAC (Fig. 1), (Fig. 2), (Fig. 3).

Results
For all patients who did not obtain pCR, and adjuvant chemotherapy using taxane agents were performed especially for the patients with node positive after 'CEX-NAC'. The treatment plan and schedule were performed by the doctors in charge, and there were no strict rules (Table. 1).
As of 2018, the average prognostic period for patients enrolled in this study is 83.6 months (3 -9year). All patients with pCR are in a relapse-free survival state and are still under observation (Table. 1).
The adverse events were grade 2 or lower for all patients in terms of both hematologic and non-hematologic toxicity (Table. 2).

Discussion
Recently, the standard strategy for locally breast cancer has been to select either adjuvant therapy or neoadjuvant chemotherapy (NAC) after surgery; histological subtypes and growth markers, which are evaluated for tumor characteristics (current status) 1-14, 16-19, 39 . It is known that there is no difference in terms of prognosis between these two therapies 1-14, 16-19, 39 .
However, there are also many reports stating that patients who could eventually achieve pathological complete response (pCR) with NAC had a satisfactory prognosis 1-14, 16-19, 39 .
In cases breast-conserving surgery is considered for a tumor of cT2 or above, it is significantly beneficial for the patients if the suitable and reasonable surgery is successfully performed after NAC.
Capecitabine (X), a constitutional isomer of 5-FU, is a type of oral pyrimidine fluoride agent that induces anti-tumor effects by using thymidine phosphorylase during the metabolic process and not taking the form of 5-FU inside the intestinal tract or in the blood; hence, theoretically, it induces less toxicity in the blood or in the digestive tract 20-25, 27-28, 30-31 . It was reported that concomitant use of X with various agents, such as cyclophosphamide, yields higher chemical modulation than monotherapy 20-21, 25, 27 . Moreover, there were also reported in some studies that concomitant therapy was more clinically effective compared to monotherapy 22-24, 26, 30-33 .
'CEX' therapy is a regimen in which 5-FU of FEC is replaced by X 30,34,36 .
Its effectiveness were reported in a FinXX trial conducted by a European group of medical professionals in Finland [34][35]37 . Saji et al. also reported its benefits in Japan 30,38 . In this study, we administered a total of 4 courses of 'CEX' as NAC in our hospital. According to the results, RR was achieved in 83.3% and pCR rate in 33.8%. In particular, pCR rate was achieved in 44.4% of TN or solid type of invasive ductal carcinoma patients, suggesting that it yielded outcomes that were comparable to those of FEC or other regimens 15 .
Follow-up investigations have been made for all patients; some of which have been observed for 8 years as of 2018. All patients who achieved 'pCR and node negative in PR' have maintained a relapse-free survival state. These results are suggested that control of lymph node metastasis will be an important prognostic factor.
Moreover, it was also revealed in this study that treatment without taxane or a 4-course treatment with anthracycline could be adequate for some patients by taking subtypes and histological characteristics into consideration. The outcomes obtained in this trial also suggest that concomitant use of capecitabine yielded synergistic effects 20-28, 30-33, 35-38 . On the other hand, except for some subtypes, pCR is a good prognostic predictor.
However, it has been stated that pCR has not been established as an alternative endpoint for recurrence-free survival or overall survival in evaluating drug efficacy 40 . Long-term observation and careful evaluation of the outcome of this regimen are also considered necessary. For adverse events, neutropenia was observed as hematologic toxicity, as with FEC, but it could be resolved with G-CSF in all 'grade 2'. The onset of FN was only observed in 3 patients. Non-hematologic toxicity, including digestive tract toxicity, such as nausea and vomiting, remained at Grade 2. Hand-and-foot syndrome also remained at Grade 1 due to the preset value of X and its schedule. Moreover, peripheral nerve disorders hardly developed, as taxane was not used.
These contributed to the outcome that all patients who had been treated with this regimen could complete 4 courses, suggesting that 'CEX' therapy is a regimen that can contribute to the maintenance of QOL.

Conclusions
Unfortunately, this study was a report by our single institute, and its study design may have had to be considered for a while, so we thought weakness of the accuracy as a clinical trial. Therefore, we believe that further adjustments to the regimen, such as the selection of indicated cases, an optimal administration period, and administration of taxane agents one after another, as well as the accumulation of cases and multicenter collaborative clinical studies, will be necessary in the future to conduct highly accurate clinical studies.
It is expected that further improvement of genetic examinations will enable us to provide individualized treatment via appropriate drug selection in breast cancer treatment. The findings we obtained in this study suggest that 'CEX' therapy as NAC could be one of the important options for individualized treatment. In particular, it was effective for TN breast cancer.
However, the same benefits were not achieved for the patients of luminal type.

Declaration of conflict of interest
The author have no conflicts of interests to declare.

Ethical approval
This study was conducted in accordance with the principles laid down in the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Nippon Medical School, Tama-Nagayama Hospital (the approval number; 591).   The primary breast tumor and the axillary swelling of lymph nodes were not detected on CT (3a, 3c) and ultrasonography (3b); as clincal complete response (cCR), and, microscopic view of the resected specimen with hematoxylin-eosin staining; no remaining cancer was found (3d; ×400) ; as pathological complete response (pCR), and equivalent to Grade 3 of Evans's criteria as therapeutic effect.