Abstract
Background/Aim: Neoadjuvant chemotherapy (NAC) for breast cancer (BC) is the gold standard treatment for locally advanced tumors (LABC) that aims at achieving a complete pathological response (pCR). Studies have been conducted to evaluate and identify te concordance between radiological, histopathological and biological variables of BC and final response to therapy, verified by definitive histological examination after surgery. Patients and Methods: Ninety-five BC patients were examined and subjected to NAC. Immunohistochemical markers including oestrogen-receptor (ER), progesterone-receptor (PR), Ki67 index, and human epidermal growth factor receptor 2 (HER2) score were examined before and after neoadjuvant treatment. Results: Younger age and a significant decrease in ER expression were associated with better prognosis. Triple Negative (TN) and Her2-type breast cancers benefited most from neoadjuvant chemotherapy with higher frequency of pCR. Conclusion: HER2-type and TN BC are correlated with best response to NAC. A statistically significant correlation between radiological images and definitive histological examination was not observed.
- Breast cancer
- neoadjuvant chemotherapy
- complete pathological response
- MRI accuracy
- histological examination
Neoadjuvant chemotherapy (NAC) is now considered the gold standard treatment for advanced breast cancer (BC) (1) and inflammatory carcinoma (2) to reduce the extent of subsequent surgical treatment (3, 4). Up to 40% of patients undergoing NAC were able to benefit from conservative treatments with oncoplastic techniques through radio-guided localization lesion and peripheral nerve block (5-8), due to downsizing and downstaging yielded by NAC. Important aspects in the use of NAC concern the early introduction of systemic therapy and the in vivo assessment of tumor response (9). Randomized studies have not actually shown a clear increase in the overall survival of patients following neoadjuvant therapy, therefore the pre-operative and post-operative systemic strategy appear to be equivalent (10-15). Patients with total absence of BC after NAC, namely pathological complete response (pCR), demonstrate an advantage in overall survival (OS) and events-free survival (EFS) as recently confirmed by a metanalysis study presented at the San Antonio Breast Cancer Symposium in 2018 (16-18), where Spring et al. showed that patients who obtained a pCR had reduced relapse probability of 69% than their counterparts with residual disease [HR=0.31, 95% probability intervals (PI)=0, 24-39] (16). The importance of NAC has been suggested by oncological clinical studies; in fact, pCR rate is routinely used as a surrogate outcome related to OS and EFS in new drug development in biological and immunological therapy (19, 20). Furthermore, different gains of OS and EFS after pCR seem to correlate to different BC subtypes (21). However, only a small percentage of patients obtain a pCR and a statistically significant gain on disease-free survival (DFS) and/or OS.
Recent studies have indicated that predictive molecular biomarkers may optimize the selection of effective therapies in NAC candidate patients, thus reducing costs and side effects in BC and oncology treatments in general (22-25).
The present study aimed to evaluate and identify a concordance between radiological, histopathological and biological variables of the neoplasia, assessed before and after neoadjuvant chemotherapy treatment, and the final response to therapy, verified by definitive histological examination after surgery. Consequently, having established a correlation between them, these characteristics could be used to define a more personalized therapeutic strategy for the patient by selecting specific cases that would yield the benefit of less invasive surgical treatments, such as conservative surgical procedures (24, 26-29) (quadrantectomy or glandular resection) or oncoplastic surgery (6, 30, 31).
Patients and Methods
Our retrospective monocentric study examined ninety-five patients, from 2005 to 2019, having mammary neoplasia as a first diagnosis, undergoing neoadjuvant chemotherapy and, subsequently, surgery at the Tor Vergata Hospital in Rome. All patients were evaluated by a multidisciplinary team composed of an oncoplastic breast surgeon, a radiologist, an anatomopathologist, an oncologist, a radiotherapist and a specialized nurse.
All patients underwent magnetic resonance imaging (MRI) with a contrast medium and a biopsy using a mammotome or tru-cut method to determine the histology and biological structure of the tumor. In particular, hormonal receptor status of ER and PR, Ki67 and HER2 overexpression were evaluated. On the basis of the immunohistochemical characteristics, the tumors were subsequently classified into luminal and non-luminal categories. Additional eligibility criteria included a Performance Status assessed on an ECOG scale of 0/1, haemoglobin levels >12g/dl, white blood cells >4.0×109/l and platelets >100×109/l. All patients had also adequate renal, hepatic and cardiac function indicated by an Ejection Fraction (FE) >50%.
For the clinical evaluation of chemotherapy response, a mammary MRI was performed during and at the end of the treatment; a physical examination was also performed on the same day of the chemotherapy session. At the end of the neoadjuvant therapy, the patients underwent surgery and, subsequently, where necessary, adjuvant radiotherapy treatment. At the time of diagnosis, the patients tested had an average age of 51.9 years. The general admission criteria were successful neo-adjuvant chemotherapy, surgical treatment, and subsequent follow-up at the departments of General Surgery C, Medical Oncology, Pathological Anatomy, and Radiology at the Tor Vergata hospital.
The entire patient population was divided into two groups: the first consisting of seventy patients, who had a residual tumor or progression of the disease and did not reach the complete pathological response; the second consisting of twenty-five women who achieved pCR, confirmed by definitive histology indicating the absence of neoplasia.
At the end of the last chemotherapy cycle, all patients underwent mastectomy or quadrantectomy as deemed required on the basis of the last MRI. The choice of the surgical procedure was made during a multidisciplinary meeting, and was based on patient's preference, scientific evidence at the time of diagnosis, and the therapeutic program.
If possible, an oncoplastic conservative surgical approach was adopted on all patients following neoadjuvant chemotherapy, as required on the basis of the extemporaneous, definitive, and radical histological examination (no Ink on Tumor).
In the case of non-palpable neoplasia susceptible to conservative surgical treatment, the localization of the lesion was achieved by wire-guided localization or radio-guided occult lesion localization according to the surgeon's preference (8, 32). Either ultrasound or mammography were used for guidance in performing the surgical procedure based on the specific clinical case and preference of the breast radiologist. If the preoperative examinations indicated the presence of microcalcifications, specimen mammography was used to verify the radicality of the surgical procedure carried out.
Furthermore, the oncological radicality was assessed by studying the margins by extemporaneous histological examination using haematoxylin-eosin staining.
Patients diagnosed with infiltrating or micro-infiltrating neoplasia underwent sentinel node biopsy or axillary dissection, depending on the patient's clinical characteristics, the clinical stage of the regional lymph nodes (cN), the clinical stage of the tumor (cT) and other clinical-instrumental parameters.
The diagnosis of infiltrating carcinoma was carried out by micro-histological biopsy (VAB or Mammotome procedure), eco-guided diagnostic needle biopsy, performed on small portions of tissue taken from a nodule or a suspected area.
Localisation of the sentinel lymph node, where necessary, was performed through Segmental Lymphatic Scintigraphy using 99mTc Albumin nanocolloid by Gamma Detection System (33).
Statistical analysis. Patients and tumor characteristics were analysed by Student's t-test for quantitative variables and the Pearson Chi-square test for qualitative or categorical variables. In the case of statistically significant values, the odds ratio (OR) was calculated based on the contingency tables (Chi square test), to evaluate the strength of the statistical association between the variables considered.
Statistical analysis was performed using SPSS Software (IBM SPSS V.20, Chicago, IL, USA).
Results
Age at diagnosis. Considering the two populations examined, statistically significant differences emerged regarding the average age at the time of diagnosis (p=0.018), which demonstrated a gap of about 5 years among those who obtained pCR (47.96 years), compared to the second group of patients who instead had no pCR (53.39 years) (34).
Immunohistochemistry. The immunohistochemical histological examination showed significant correlations with the achievement of pCR. The mean expression value of the oestrogen receptor (ER) was much lower among the pCR+ patients compared to pCR−: 63% vs. 46.84% (p=0.031), respectively (35) (Table I).
Immunophenotype. Taking into consideration each different tumour subtype, it was found that patients with biological features of Luminal B - represent the highest percentage in both the total number of patients, 41 out of 95 (43.1%), and those with pCR, which were 11 out of 25 (44%) (p=0.043) (Table II). It is also encouraging that the analysis concerning the HER2 Type and the TN BC confirmed the data presented in the literature, which indicate that these two subtypes benefit most from NAC with a remarkable sensitivity compared to the others (34, 36) (Table II). Although the HER2 Type represents a small percentage of patients studied, i.e. 5 (5.2% of the total), 4 of these achieved pCR (80% of the total HER2 Type, 16% of the total cases with pCR). For the TN group, 3 of the 8 cases obtained pCR (37% of the total with TNBC, and 12% of the total cases with pCR) (Table II).
Expression of ER, PR and Ki-67 in tumors in pCR+ and pCR−.
Subdivision of the sample according to the immunological subtype in pCR+ and pCR− groups.
Subsequently, the sample was subdivided in luminal (Lum) and non-luminal (NLum) to highlight the different response to NAC based on the positivity or not of hormone receptors.
Eighty-two patients belonged to the Lum group (86.3%), while 13 to the NLum group (13.6%) (Table III). Of great importance are the data showing that among the Nlum, 7 patients obtained pCR after surgery, which is more than half of the patients of this group (Table III).
Index cT. A greater frequency of cT2 (neoplasia with a size between 2 cm and 5 cm) was found in this sample corresponding to 52.6%; this group also includes the highest percentage of patients, 16 out of 25 (64%), who then obtained pCR.
Subdivision of patients according to the Lum and Nlum groups.
Histological subdivision in the pCR+ and pCR−.
By calculating the dimensions of the larger diameter at the time of diagnosis, no statistically significant value was reached regarding the correlation between the initial dimensions of the neoplasia and the final pCR. The pCR+ group had an average diameter of 38.63 mm while that of the pCR− group was 39.95 mm.
Histology. The comparison between the initial histological examination and pCR did not yield any statistical significance (Table IV).
RECIST criteria. Complete response was found in only 14 patients, in which remission of the disease was no longer visible through MRI with contrast medium. Of these, 5 obtained to pCR, while 9 still had residual tumor. Conversely, 57 of the total number of patients belonged to the partial response (PR) group, characterized by a considerable reduction of disease (>30%), but not its complete disappearance on MRI. Of these 57 patients, 17 obtained pCR in the definitive histological examination, while 40 did not reach pCR (Table V).
EFS and OS. Given an average follow-up period of 5.3 years, we highlighted how the achievement of pCR has been an endpoint of primary importance because it was associated with a higher percentage of EFS (37) compared to those who did not reach EFS 76.7% vs. 72.8% (Table VI).
The same result was also observed in the OS analysis, in which the percentage was always higher in the pCR+ population (37), 96.1% against 88.4% compared to pCR−, which still presented with neoplasia in the final histological examination after surgery (Table VI). Analysis of EFS and OS scores based on the Lum and NLum subdivision of mammary carcinomas demonstrated that in luminal subjects the percentages of EFS and OS did not differ significantly with respect to pCR achievement, i.e. EFS 72% vs. 75%; OS 94% vs. 90% (Table VI). The NLum group presented a different situation: the percentages of EFS and OS with respect to pCR were significantly higher; 86% vs. 50% and 100% vs. 66%, respectively.
Discussion
Our study demonstrated that age can be a predictor of response to therapy because the average age of patients who underwent pCR was 5 years smaller than those who had residual neoplasia still visible upon the final histological examination. Literature also shows that the age at onset of neoplasia constitutes an unfavourable prognostic factor (34). The ER expression is another factor which was analysed. A lower ER value was statistically associated with a better response to chemotherapy (35). HER2 Type and TN neoplasms benefit most from NAC with a clearly higher frequency of pCR (34, 38). The HER2 types were the subtypes with the highest pCR rates of 80%. There were also significant differences between Lum and NLum subjects in their response to NAC: pCR was reached in 21% of Lum patients and 53% of NLum patients. Data, therefore, confirmed that the absolute indications for women with breast cancer are over-expression of HER2, high Ki67 score, and negative hormone receptors. Our study did not yield a statistically valid predictive value that could correlate the complete response, on the basis of an MRI performed at the end of chemotherapy, and the pCR. Therefore, histological examination of the biopsies' sample at the end of NAC is essential before subsequent surgical treatment. In our opinion, either molecular or nuclear dedicated breast imaging could improve the sensibility and complete surgical resection of any residual tumors (39-41). Additionally, EFS and OS indices have been calculated and proven to be greater, as also reported in literature, in those patients who obtained pCR.
In conclusion, it would be plausible to underscore that tumors belonging to the HER2 Type class and the TN BC are those most sensitive and with the best response to NAC, with statistically higher pCR rates than luminal. A statistically significant agreement between radiological images and definitive histological examination was not observed. In fact, no evidence was found from our study that would allow an association to be made between the disappearance of tumors in preoperative MRI and subsequent pCR. The results obtained from the follow-up of the patients confirmed that a higher percentage of patients reached pCR with respect to both EFS and OS.
Subdivision according to RECIST criteria of pCR+ and pCR− groups.
Events Free Survival and Overall survival values in the pCR+ and pCR− groups.
Subdivision of pCR+ and pCR− groups into Lum and NLum for the evaluation of EFS Ed OS.
Acknowledgements
The study was in part supported by a grant from the Italian Ministry of Health.
Footnotes
Authors' Contributions
Study conception and design: Buonomo Oreste Claudio, Grasso Andrea; Acquisition of data: Materazzo Marco, Chiara Adriana Pistolese; Analysis of data: Ilaria Portarena, Lucia Anemona; Interpretation of data: Buonomo Oreste Claudio; Drafting of article: Materazzo Marco, Gianluca Vanni, Andrea Grasso; Critical revision: Rosaria Meucci, Camilla Deiana, Ljuba Morando.
Conflicts of Interest
The Authors declare no conflicts of interest in regard to this study.
- Received November 29, 2019.
- Revision received December 4, 2019.
- Accepted December 6, 2019.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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