Nowadays the widespread use of NACT in the treatment of breast cancer leads to the increase of breast conserving rate, reduction of recurrence rate and the appropriate use of drugs. Furthermore, robust evidence demonstrates achieving pCR after NACT indicates a good prognosis[5-7, 28]. As is known to us, ER+ breast cancer is insensitive to chemotherapeutics, thus, ER+ breast cancer patients have the larger possibility of suffering from side effects of NACT but without efficacy. It is imperative to establish a model to predict the sensitivity of neoadjuvant chemotherapy in ER+ breast cancer patients.
In our study, age, menstrual status and BMI were not independent influencing factors of achieving pCR after NACT in ER+ breast cancer patients. H J Choi et al[17] and S Yan et al[29] got a consistent conclusion. However, previous studies have shown that young breast cancer patients are more likely to achieve pCR after NACT[30]. Rong Guo et al thought age is an independent feature for predicting the probability of achieving an axillary pCR after NACT in patients with ER+ breast cancer[31]. The hypothesis demonstrated in premenopausal patient with high estrogen level chemotherapy can kill active tumor cells better because ER-positive breast cancer is estrogen dependent breast cancer[32]. Unfortunately, there is no reliable clinical evidence suggesting a significant correlation between menstrual status and the efficacy of NACT.
The tumor size and node status are important for the formulation of treatment strategy. Patients with large mass (> 5 cm) or axillary lymph node metastasis have necessary to do NACT[2-3]. Hwang et al[33] showed that patients with stage cN0-1 were more likely to achieve pCR than patients with stage cN2-3 (OR=2.93, 95%CI: 1.41~6.05, P=0.004). Nevertheless, some studies didn’t support this conclusion[17, 29]. Most researches demonstrated smaller tumor was more likely to achieve pCR after NACT in breast cancer patients[17, 29-30]. Although primary surgery is still recommended for early breast cancer, some studies proved that NACT has many advantages in the use of early breast cancer[34-36]. Furthermore, Ring[37] analyzed 453 patients who had a cCR after NACT and compared the prognosis of these patients with surgery and radiotherapy alone. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% vs 76%; 10-year, 60% vs 70%, P=0.9) between the two groups. The local recurrence rate of 8% in non-surgery group was higher than that in surgery group. With the development of medicine and radiotherapy, breast cancer avoiding surgery will become a reality.
In recent years, more and more studies have explored the correlation between PLR, NLR, FBG and other inflammatory indexes with NACT efficacy in breast cancer patients, but the conclusions dispute with each other[19-22]. In our study, we didn’t find the significant predictive value of the NLR, PLR and FBG for the efficacy of NACT in ER+ breast cancer patients. The level of inflammatory cells and mediators is not stable, so it is not accurate to predict the efficacy of chemotherapy.
Nowadays the expression levels of ER, PgR, HER2 and Ki-67 have become routine pathological indicators of breast cancer. By immunohistochemistry breast cancer can be quickly classified in five categories, and preliminarily judged the degree of malignancy. The result shows that the expression of ER and Ki-67 is an important factor to predict achieving pCR after NACT in ER+ breast cancer patients. The expression level of Ki-67 reflects the ability of tumor cell proliferation, which is closely related to the sensitivity of chemotherapy. Sueta[38] enrolled different subtypes of breast cancer patients and multivariate analysis showed that Ki-67 was an independent factor influencing the pCR of ER+ breast cancer patients after NACT(OR=6.24, 95%CI: 1.40~27.7, P=0.016). Wang [12] analyzed 188 ER+ patients and the overall pCR rate was 9.57%. The results consistent with our study showed that Ki-67 expression was significantly related to the efficacy of chemotherapy. Similar with the conclusion of previous studies, ER expression was negatively correlated with pCR rate in ER+ breast cancer[29, 31]. In addition, a meta analysis that included 20 studies on neoadjuvant endocrine therapy(NAET) for ER+ breast cancer showed that NAET has the same curative effect on ER+ breast cancer as NACT and that NAET has fewer adverse reactions[39]. It has been proved that HER2(+) breast cancer is more malignant than HER2(-) breast cancer and HER2(+) breast cancer patients have a later stage than HER2(-) when diagnosed,therefore, our study has the large percentage of HER2(+) patients, 36.7%[40]. The result showed the expression of HER2 has no relation with achieving pCR after NACT. The efficacy of neoadjuvant targeted therapy has been recognized in recent. In particularly, the combination of trastuzumab and patuzumab has a good performance in the treatment of advanced breast cancer[41-43]. However, In treatment of ER(+) breast cancer anthracycline combined with taxanes is still the main neoadjuvant chemotherapy strategy. Neoadjuvant targeted therapy may be helpful to the curative effect, but in clinical it is rarely used with anthracycline when considering the cardiotoxicity.
Here we developed and validated an easy-to-use nomogram to predict the pCR of thrice weekly standard NACT in ER+ breast cancer patients. Through this nomogram we can quickly understand the sensitivity of patients to chemotherapy and patient outcomes. The nomogram indicated that ER+ breast cancer patients with small tumor size, low ER expression, high Ki-67 index and histological grade Ⅲ were more likely to achieve a pCR after NACT. With an AUC of 0.774 and a C-index of 0.809 (95% CI: 0.751–0.867), the model exhibited sufficient ability.
Although the nomogram performed a sufficient level of accuracy for predicting achieving pCR in ER+ breast cancer, this study exist several limitations. In particular, this was a retrospective study and involved a limited number of patients. The nomogram has not been validated using a large, independent, external or prospective cohort. In addition, doppler ultrasound was used to evaluate the tumor size, which has great subjectivity. Adding more sample and parameters will improve this nomogram, nevertheless, the C-index of 0.809 suggests a sufficient level of accuracy.
In conclusion, NACT is generally used in the treatment of breast cancer, while the patients with ER+ breast cancer who are relatively insensitive to NACT. Recognizing the outcome of the patients after NACT is an important element for determining the treatment plan. This study established a prediction model for achieving pCR in ER+ breast cancer patients after NACT, and screened out the patients with high sensitivity to chemotherapy. It will plays an important role in the formulation of the best treatment plan.