Abstract
Background/Aim: To predict pCR during neoadjuvant chemotherapy is still difficult. The aim of this study was to evaluate the optimal tumor reduction rate and modalities for predicting pCR after two cycles of docetaxel. Patients and Methods: We analyzed 52 patients with HER2-positive or triple-negative breast cancer. The tumor reduction rate was evaluated after two 3-week cycles of docetaxel (plus trastuzumab for HER2-positive cancer patients). Patients without progression completed two additional cycles of docetaxel and four cycles of an anthracycline-containing regimen. Results: Twenty-eight patients achieved pCR. The optimal tumor reduction rates for predicting pCR were 23, 39, 32, and 40% for US, caliper, MMG, and MRI measurements, respectively. The AUC was highest for caliper measurements. The optimal modality for predicting pCR differed among subtypes. Conclusion: Although tumor reduction rate after two cycles of chemotherapy is highly predictive of pCR, the optimal cutoff value differed among the modalities and breast cancer subtype.
The age-adjusted prevalence of breast cancer among Japanese women is approximately one-half that of women in Western countries. However, examining annual trends, the prevalence has continued to increase in Japan, whereas a decreasing trend has been observed in Western countries. The estimated number of cancer cases in Japan in 2019 is predicted to exceed 90,000. Neoadjuvant chemotherapy (NAC) is administered to women with breast cancer to reduce tumor size for locally advanced tumors or to permit breast-conserving surgery. Patients achieving pathological complete response (pCR) had better prognoses than those who did not experience pCR. Therefore, pCR has been proposed as a surrogate endpoint for predicting disease-free and overall survival (1, 2).
In prior research, NAC did not improve prognosis compared with adjuvant treatment (3, 4). In addition, clinical studies have indicated that the administration of additional treatment to all patients without selecting high-risk patients may not be completely effective (5-7). Conversely, some studies have revealed that additional treatment in patients who did not experience pCR after neoadjuvant treatment improved prognosis (8-10). From these clinical studies, it can be concluded that appropriately identifying high- and low-risk patients according to treatment response is important for improving treatment efficacy.
Several studies have attempted to predict pCR by determining the optimal tumor reduction rate during NAC (11, 12). Tumor response was determined by palpation after two cycles of doxorubicin and cyclophosphamide (TAC) in the GeparTrio pilot study. Patients were defined as responders when the tumor size decreased less than 50% (11). The phase II JBCRG-03 clinical trial examined the pCR rate of docetaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) (13). Response was defined as a 30% reduction in tumor size after four cycles of docetaxel compared with that in non-responders, and this criterion marginally predicted pCR with an OR of 0.64. The most optimal modality for predicting pCR and the cutoff tumor reduction rate are unclear. The aim of this study was to prospectively evaluate the optimal tumor reduction rate and modalities for predicting pCR in patients with early breast cancer after two cycles of docetaxel.
Flow chart of participant enrollment.
Patients and Methods
Patients. Informed consent was obtained from all individual participants included in the study.
The eligible patients were women with breast cancer, aged 20-71 years, and with a performance status of 0-1 who were scheduled to receive docetaxel and FEC or epirubicin and cyclophosphamide (EC). The following breast cancer subtypes were eligible: luminal human epidermal growth factor receptor 2 (HER2)-positive breast cancer [BC; hormone receptor (HR)-positive and HER2-positive], HER2-enriched BC (HR-negative and HER2-positive), and triple-negative breast cancer (TNBC; HR-negative and HER2-negative). Patients with distant metastasis, those who had received prior treatment for breast cancer, or those who were pregnant or breastfeeding were excluded.
Study design. This was a prospective, multicenter, observational study. This study was approved by our institutional review board (14082524). All procedures were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Patients were recruited at Nagasaki University, National Hospital Organization Nagasaki Medical Center, and Nagasaki Rosai Hospital from September 2014 to December 2018. All patients were scheduled to receive two 3-week cycles of docetaxel (75 mg/m2), and trastuzumab was added to patients with HER2-positive cancer. Tumor size was measured using calipers, mammography (MMG), US, and magnetic resonance imaging (MRI) during the third week of the second cycle. We calculated the tumor reduction rate for each modality. Caliper, MMG, and MRI measurements were performed by the same doctor for each patient. US was performed by technicians in the same laboratory for each patient. We calculated the tumor reduction rate as the difference between the size of the tumor before treatment and after 2 cycles of chemotherapy divided by the size of the tumor before treatment. Patients with disease progression, as defined using RECIST guideline ver. 1.1, switched chemotherapy regimens or underwent surgery. Patients without disease progression completed the rest of the second cycle of docetaxel (plus trastuzumab for patients with HER2-positive cancer) followed by four 3-week cycles of FEC/EC. After treatment, patients underwent surgery. We evaluated complete remission pathologically. We defined pCR as the absence of invasive carcinoma in both breast and lymph nodes. Each investigator recorded patients' clinicopathological characteristics, tumor size by modality, and pathological findings prospectively and delivered them to Nagasaki University.
Clinicopathological factors of all patients.
Study endpoint. The primary endpoint was the optimal tumor reduction rate as determined using US for predicting pCR after two cycles of docetaxel. The secondary endpoint was the utility of caliper, MMG, US, and MRI measurements for predicting pCR across all cohorts and subtypes. The treatment discontinuation rate was evaluated after two cycles of treatment.
Sample size. In GeparTrio, the ratio of responders to non-responders in the US after two cycles was 4:6. We assumed that the probability of a non-responder and of a positive pCR was 0.1 and the OR used to predict response vs. no response was 8.0. The target number of sample size was set to 60 in consideration of a 10% dropout proportion.
Statistical analysis. Patients' clinicopathological features and tumor reduction rates were compared between the pCR and non-pCR groups. Variables were presented as frequencies for categorical variables and medians and interquartile ranges for quantitative variables. Associations between variables were assessed using Fisher's exact test for categorical variables and the Mann–Whitney U-test for quantitative variables. The cutoff for predicting pCR was defined via receiver operating characteristic (ROC) analysis. All statistical analyses were performed using EZR software and MEDCALC. p<0.05 was considered statistically significant.
Comparison of clinicopathological factors between the pCR and non-pCR groups.
Results
Patients. In total, 54 female patients with breast cancer were recruited into the trial. One patient was excluded because she had the luminal subtype, and one patient withdrew consent, leaving 52 patients in the final analysis (Figure 1). The patient characteristics are shown in Table I. Patent age ranged from 48 to 65 years (median: 53.5 years). The numbers of patients with various BC subtypes were as follows: luminal HER2-positive BC, 11; HER2-enriched BC, 22; and TNBC, 19. The numbers of patients with various pretreatment tumor types were as follows: T1, 10; T2, 34; T3, 6; and T4, 2. Twenty-six patients were positive for pretreatment axillary lymph node metastasis. Tumor size could not be measured in some cases, and the numbers of patients who underwent tumor size measurements were 40, 38, 49, and 47 for calipers, MMG, US, and MRI, respectively.
Relationships of pCR with clinicopathological factors and tumor reduction rates after two cycles of docetaxel. Of the 52 patients, 48 completed chemotherapy. Three patients discontinued chemotherapy because of side effects, whereas treatment was discontinued in one patient who experienced progression, with this patient undergoing surgery (Figure 1). Twenty-eight patients (54%) achieved pCR (Table II). Patients who achieved pCR had a larger tumor reduction rate after two cycles of docetaxel than those without pCR, as measured using calipers (62% vs. 25%; p=0.0002), MMG (40% vs. 19%; p=0.01), US (35% vs. 14%; p=0.001), and MRI (47% vs. 19%; p=0.0002). Patients who achieved pCR were more likely to have HER2-enriched BC (57% vs. 25%, p=0.03) and lymph node metastasis (64% vs. 33%, p=0.05). HER2-enriched BC was associated with a higher frequency of lymph node metastasis than the other subtypes (68% vs. 37%, p=0.05). There was no significant difference among the groups in terms of age, body mass index, and cStage.
Optimal tumor reduction rate for predicting pCR. The primary endpoint, the optimal tumor reduction rate for predicting pCR using US, was 23% (Figure 2). The area under the curve (AUC) for US was 0.803 [95% confidence interval (CI)=0.674-0.932]. The optimal tumor reduction rates for predicting pCR using calipers, MMG, and MRI were 39, 32, and 43%, respectively, and the AUCs for these modalities were 0.853 (95%CI=0.735-0.971), 0.746 (95%CI=0.584-0.908), and 0.817 (95%CI=0.694-0.939), respectively. Using these cutoff values, the utility of the modalities for predicting pCR was analyzed via univariate analysis (Table III). The highest OR was obtained for caliper measurements (OR=20.9, p<0.0001). The optimal modalities for predicting pCR differed among the subtypes, although the number of cases was small (Table III). MMG and US measurements were predictive of pCR with statistical significance among patients with luminal HER2 BC, whereas caliper and MRI measurements were predictive of pCR with statistical significance for patients with HER2-enriched BC and TNBC. MRI measurement was predictive of pCR with statistical significance among patients with TNBC, whereas a positive trend was noted for patients with HER2-enriched BC.
Discussion
We performed a prospective observational study to evaluate the optimal modalities and the cutoff tumor reduction rate after two cycles of docetaxel for predicting pCR in patients with early breast cancer undergoing surgery after neoadjuvant chemotherapy. We found that the optimal tumor reduction rate as measured using US for predicting pCR was 23%. Although all modalities could accurately predict pCR, caliper measurement had the highest AUC in ROC analysis. The optimal modalities for predicting pCR differed among subtypes, although the number of cases was small.
Receiver operating characteristic curve for each modality. a: Caliper. b: Mammography (MMG). c: Ultrasonography (US). d: Magnetic resonance imaging (MRI).
To perform NAC to determine whether a patient will achieve pCR or not is important for selecting high risk breast cancer. Some clinical trials identified high-risk patients and administered additional treatment after NAC and surgery. Masuda et al. reported that adjuvant capecitabine therapy after NAC was effective for prolonging overall survival and disease-free among patients with HER2-negative breast cancer who did not achieve pCR (9). In the KATHERINE trial, among patients with HER2-positive breast cancer who did not achieve pCR after neoadjuvant therapy, T-DM1 reduced the risk of recurrence of breast cancer and death compared with using trastuzumab alone as the usual treatment (10). Other clinical trials have attempted to change the treatment by judging treatment effect during neoadjuvant chemotherapy. In the GeparTrio trial of patients treated with TAC, early responders were randomly assigned to receive four or six additional cycles of TAC cycles (conventional chemotherapy group and response-guided chemotherapy group, respectively), whereas early non-responders received four cycles of TAC or switched to vinorelbine and capecitabine (conventional chemotherapy group and response-guided chemotherapy group, respectively) (14). In that trial, disease-free and overall survival were significantly longer after response-guided chemotherapy than after conventional chemotherapy (8). Thus, evaluating risk during treatment could help avoid the administration of ineffective treatment and improve prognosis.
Univariate analysis of the prediction of pathological complete response by modality.
There is no consensus concerning the optimal timing and modality for evaluating response to NAC. We decided to evaluate tumor size after two cycles of docetaxel because docetaxel can be combined with another chemotherapy when the treatment response is poor. Some studies have reported that MRI during NAC to monitor response is accurate for patients with TNBC or HER2-positive breast, but is inaccurate for those with estrogen receptor-positive/HER2-negative breast cancer (15, 16). Similarly, in the BrighTNess trial, complete response on mid-treatment MRI had a high positive prediction value for pCR after the completion of NAC in patients with TNBC. However, in addition to patients with ≥50% tumor reduction, a substantial proportion of patients with <50% tumor reduction and an increase in the largest tumor diameter also achieved pCR (12). Many attempts have been made to determine the early effects of chemotherapy using fluorodeoxyglucose-positron emission tomography (FDG-PET). FDG PET/CT has considerable potential for the early prediction of pCR to NAC in aggressive subtypes such as TNBC or HER2-positive breast cancer (17). Despite its efficacy, FDG PET/CT is extremely expensive, and it is not available at all facilities. Our primary endpoint was the optimal tumor reduction rate as identified using US, because US is convenient and inexpensive and it can be performed at any facility. US has problems such as measurement errors and reproducibility between inspectors. Some patients had dense breasts or non-massogenic lesions, and they could not be evaluated using MMG. MRI is reproducible and objective, but it cannot be performed in patients with asthma or claustrophobia. Measurements using calipers reflect the relative hardness of the surrounding tissue. For this reason, calipers can be used to examine histological changes opposed to the evaluation of images obtained via US and MRI. As previously reported, we will need to determine the effect of using the most appropriate modality for each subtype.
This study had several limitations. First, the number of cases was calculated by combining multiple subtypes; therefore, it may be possible to analyze a heterogeneous population together. In addition, analysis by subtype resulted in small numbers of cases. Second, the sample target was not reached because of delayed case accumulation.
In conclusion, the optimal reduction rate for predicting pCR was 23% on US, 39% using calipers, 32% on MMG, and 43% on MRI. Caliper measurement had the highest AUC among the modalities. Therefore, the optimal modality for predicting pCR might differ among tumor subtypes, and thus, efforts should be made to select the best modality for each individual subtype.
Acknowledgements
The Authors thank Ms Yamamura and Ms Haraguchi for creating and managing the database. The Authors also thank Joe Barber Jr., PhD, from Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.
Footnotes
Authors' Contributions
SK, SM, KY were responsible for conceiving and designing the trial, planning data analysis and collecting data, and are in charge of patient recruitment and treatment. Megumi M, Michi M, TI, CS, RO and HY participated in data collection and were in charge of patient recruitment and treatment. SS were responsible for the sample size and allocation. KK, TN and SE are responsible for planning the data analysis and analysing the data resulting from the trial. SK accessed the final trial dataset and analyse the data. All Authors have contributed to and approved the final version of this manuscript for publication.
Conflicts of Interest
The Authors have no conflicts of interest to declare regarding this study.
- Received February 10, 2020.
- Revision received March 4, 2020.
- Accepted March 5, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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