FEC 3 followed by docetaxel 3 had been one of representative preoperative/adjuvant chemotherapy regimens specified in the NCCN guidelines up to 2017.[13-17]. Notably however, the FEC regimen was excluded from the NCCN guidelines after the NSABP-B36 trial[18]. In that study, six cycles of an FEC regimen did not show a superior efficacy to four AC cycles, but did show a higher toxicity. In our present study, no reduction in toxicity was confirmed in the FEC3-D3 arm which was consistent with findings of NSABP-B36 study in which duration of cycles were addressed. Since the NSABP-B27 report, the AC4-D4 regimen has become widely used. However, the 8 cycles of treatment in this protocol requires 6 months to complete, and there have been concerns regarding the reduction in patient compliance that is commonly related to a longer treatment duration. In addition, there is a reported QoL decrease due to increased exposure to anthracycline and taxane in the AC4-D4 regimen. Strategies to reduce the number of chemotherapy cycles has also been explored in another study[19].
In our present study, we observed no significant difference between the two treatment arms in terms of the pCR rate, although a numerically higher pCR rate was noted among the AC4-D4 cases. The pCR rate in our study was low compared to the 26.1% level reported in the NSABP-B27[8]. The pCR rate is known to be higher after neoadjuvant chemotherapy in the absence of HER2, estrogen receptor (ER) positivity and a lack of lymph node metastasis[20-23]. The difference between the pCR rate in our study series and that in the NSABP-B27 trial may have been due to the greater number of lymph node metastases in our present cohort [Neo-Shorter vs. NSABP-B27, 247/247 (100%) vs. 244/805 (30.3%)] and also the higher ER positivity [Neo-Shorter vs. NSABP-B27, 153/247 (62.0%) vs. 319/805 (39.6%)]. In the NSABP-B27 study, the pCR rate in the AC followed by taxane treatment group with ER positivity was 14.1%, comparable to the 17.3% rate found in our present series. In addition, our observed pCR rate was low compared to a prior Indian study with a similar design concept[19]. The difference in the pCR rate between our present study and the prior Indian report may also have been affected by differences in the proportion of triple negative breast cancers (TNBCs) and HER2-positive tumors, even though they had a similar clinical stage (neo-shorter vs. India, 29.8% vs. 49%). Also, in the study cohort from India, unlike our present series, HER2 2+ was considered to be negative without further HER2 in situ hybridization being conducted, which may have affected the findings.
Similar to previous studies, the higher Ki67 level among patients with the luminal type breast tumors in our present cohort was associated with a higher pCR. There was no significant correlation found between Ki-67 and the pCR rate in previous TNBC studies, or among these cases in our present study, which might reflect the heterogeneity of this disease[24]. However, there was a significant correlation found in our current analyses, in both treatment arms, between the pCR and a Ki 67 index that was equal to or more than 55%.
There was no significant difference in the 3Y DFS between our two study arms and further subgroup analysis indicated that neither regimen was more favorable. Multivariate analysis revealed that a ³55% baseline Ki-67 labeling index (HR 2.1, 95% CI,1.03-4.40; P=0.04), and ³4 lymph node metastases at surgery (HR 1.9, 95% CI, 1.07-3.51; P=0.03) were independent predictive factors for the 3Y DFS outcome. A previous study found that an age >50, higher T and N clinical stage, or tumor size >5 cm were independent risk factors for distant metastasis in TNBC[25]. Additionally, in a previous meta-analysis study by Salvo et al of hormone receptor-positive and HER2-negative breast cancers, it was confirmed that lymph-node positivity was an important factor for recurrence[26]. Our present results were consistent with the previously reported criteria for high-risk recurrence in TNBCs or hormone receptor-positive breast cancers. In terms of the 3Y DFS, the difference between our current study findings and those of the PCAS01 trial appears be an effect of the inclusion ratio of stage I lesions (neo-shorter: stage I, 0%, 3Y DFS, 77.0% vs. PACS01: stage I, 10.4%, 3Y DFS, 84.5%). Similarly, the 3Y DFS in the NSABP-B27 trial (5Y DFS, 71%) was comparable to that of the Neo-Shorter subjects treated with AC4-D4 (74.9%). The difference may be due to the presence of higher-risk patients in our current series, including those with more than 4 LN metastases [≥4LN metastases: neo-shorter vs. NSABP-B27, 85/247 (34.4%) vs. 114/752 (15.2%)].
There was no significant difference in the toxicities between our present study arms. In our current cohort, febrile neutropenia was within the 11-34% range reported in previous studies[9, 19]. In terms of QoL outcomes, there was also no significant difference between our two study groups. The FACT-B score, including all subfactors, showed a gradual decrease during chemotherapy. These differences indicated that the chemotherapy affected the QoL. At the treatment baseline, the EWB had the lowest score whereas the FWB score was the lowest at the completion of the chemotherapy. The lowest sub-factor before the start of the chemotherapy was the EWB, and this was likely related to the previously described prevalence of depression in breast cancer patients[27]. That prior study reported that upon a diagnosis of breast cancer, uncertainty about future disease progress, imagining of a poor situation by the patient, and fear of physical changes following treatment can cause depression. In our current investigation, it appeared that the EWB level before the start of chemotherapy was also influenced by the abovementioned factors. The lowest subfactor at the completion of chemotherapy was the FWB, likely because of the toxicity effects after these treatments. Interestingly, at the midpoint of treatment, the FEC3-D3 cases had the lowest SWB and AC4-D4 patients had the lowest FWB. The FWB was thus not the lowest in the FEC3-D3 group even in the middle of the chemotherapy. The cause of this might be associated with the decrease in anthracycline administration but further research is warranted.
Limitations
Although the results of the TRYPHAENA trial were published in 2013[28], we were unable to use a HER2 blockade in our neoadjuvant setting, especially during study period, because of the reimbursement policy of the Korean National Health Insurance system for locally advanced breast cancer. Hence, 9.7% (24/247) of the cases included in our present study series had the HER2 subtype. In addition, only the 3Y DFS outcomes could be confirmed among our study patients because of the relatively short follow-up period. In this regard, continuous follow-up will be required to confirm any differences in the long-term outcomes in both arms.