|Year : 2021 | Volume
| Issue : 1 | Page : 13-19
Response to neoadjuvant chemotherapy in locally advanced breast cancers in association with different clinicopathological parameters
Barasha Sarma Bharadwaj1, Neelakshi Mahanta2, Bibhash Chandra Goswami3, Kanakeshwar Bhuyan4
1 Department of Oncopathology, State Cancer Institute, Guwahati, Assam, India
2 Department of Medical Oncology, State Cancer Institute, Guwahati, Assam, India
3 Department of Radiation Oncology, State Cancer Institute, Guwahati, Assam, India
4 Department of Surgical Oncology, State Cancer Institute, Guwahati, Assam, India
|Date of Submission||28-May-2020|
|Date of Decision||12-Oct-2020|
|Date of Acceptance||23-Feb-2021|
|Date of Web Publication||14-Apr-2021|
Department of Medical Oncology, State Cancer Institute, Bhangagarh, Guwahati, Assam
Source of Support: None, Conflict of Interest: None
Introduction: Breast cancer being a multifactorial disorder outcome depends on various clinicopathological and molecular factors. Neoadjuvant chemotherapy (NACT) is increasingly used before surgery to obtain pathological complete response (pCR) as it is associated with increase event-free survival and overall survival. Aim: The aim of this study is to evaluate the response to NACT in locally advanced breast cancer (LABC) in association with various clinicopathological factors in a tertiary care setting. Materials and Methods: LABC patients (clinical Stage IIB and III) who underwent either modified radical mastectomy or breast conservative surgery after NACT treatment in a 1-year period were retrospectively reviewed for the clinical and pathological response. Effect of clinicopathological and molecular factors on treatment response were evaluated. pCR was evaluated on final histopathology. Results: Fifty LABC patients fulfilled the study criteria and were reviewed. pCR was present in 6 (12%) cases. All the pCR cases were invasive ductal carcinoma. A statistically significant association between the presence of tumor necrosis in initial biopsy and pCR to NACT was observed (P = 0.024) with a high negative predictive value of 94%. All the 11 patients (100%) with positive lymphovascular emboli (LVE) on initial biopsy did not show pCR. Four out of 6 pCR cases had preclinical tumor size ≤5 cm. Ductal carcinoma in situ (DCIS) was present in 15 cases and only 1 pCR patient had the presence of DCIS. Conclusion: Preclinical tumor size, histopathological tumor type, DCIS, and presence of tumor necrosis and LVE on initial core biopsy are some of the notable factors for pCR among LABC patients who received NACT.
Keywords: Breast cancer, hormonal receptor, neoadjuvant chemotherapy, pathological complete response
|How to cite this article:|
Bharadwaj BS, Mahanta N, Goswami BC, Bhuyan K. Response to neoadjuvant chemotherapy in locally advanced breast cancers in association with different clinicopathological parameters. Oncol J India 2021;5:13-9
|How to cite this URL:|
Bharadwaj BS, Mahanta N, Goswami BC, Bhuyan K. Response to neoadjuvant chemotherapy in locally advanced breast cancers in association with different clinicopathological parameters. Oncol J India [serial online] 2021 [cited 2021 May 16];5:13-9. Available from: https://www.ojionline.org/text.asp?2021/5/1/13/313665
| Introduction|| |
Breast cancer is the most common and leading cause of cancer death among women worldwide. According to Globocan 2018 estimated new cases of breast cancer worldwide is 2,088,849 (11.6%), which accounts for almost 1 in 4 cases of cancer among women. Estimated number deaths is 626,679 (6.6%). The number of new cases of breast cancer in India according to Globocan 2018 is 162,468 (14%), estimated number of deaths is 87,090 (11.1%). The rate of incidence of breast cancer in India exceeds the incidence of cervical cancer today and it has become the leading cause of mortality in urban areas.
Breast cancer is a multifactorial disorder. The long-term outcome depends on various clinicopathological factors. The 8th ed.ition of AJCC has incorporated various biomarker evaluations besides regular TNM staging. Important biomarkers include estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and multigene assays. Biomarker evaluation has prognostic significance and also treatment impact.
Breast cancer was initially treated with chemotherapy as adjuvant setting, later on use of neoadjuvant chemotherapy (NACT) became a practice especially in locally advanced breast cancers (LABC) in order to obtain pathological complete response (pCR). Various trials on NACT have clearly defined pCR as a favorable prognostic factor in especially in triple-negative breast cancer (TNBC) and HER2 overexpressed tumors. In a neoadjuvant setting, additional benefits have been described by use of targeted approach like HER2 blockers along with chemotherapeutic drugs in HER2 positive tumors., Vasudevan et al. concluded in their study that histopathological examination of the surgical specimen is the gold standard for assessing the tumor response in post NACT cases. Díaz-Casas et al. studied 414 breast cancer cases, showed a clear relationship between pathological response after NACT and molecular subtypes of breast cancer. Event-free survival and overall survival (OS) were higher in patients achieving pCR after NACT and were statistically significant in TNBCs. Fayanju et al. conducted a review of breast cancer cases in the National Cancer Data Base (NCDB), they show that pCR was associated with improved OS and the relationship of OS with molecular subtypes of breast cancer.
The use of NACT can downstage the tumor, decrease the tumor size effectively which makes the tumor operable, and in many cases breast conservative surgery becomes feasible for better cosmetic results.
Therefore, the objective of this study is to evaluate the response to NACT in LABC patients with respect to various clinicopathological as well molecular factors in a tertiary care setting.
| Materials and Methods|| |
The present retrospective study included biopsy-proven LABC patients who received NACT followed by surgery from January 2018 to December 2019. Institution ethics committee approval had been obtained (via letter number: SCI/ECR/2020/07) for the study. Clinical stage IIB and III cases of breast cancer are included in the study and AJCC 8th edition was used for staging of breast cancer patients.
Previously treated breast cancer patients and those with distant metastasis were excluded. Age and sex of the patient, family history of breast carcinoma, tumor size, histological type, tumor grade, TNM staging, NACT regimen, and other relevant clinicopathological, radiological data were recorded in the structured proforma. Grading was done on the biopsy specimens by Nottingham histological grading system or modified Bloom Richardson grading system. Initial biopsy specimens were also evaluated for the presence of tumor necrosis and lymphovascular emboli (LVE). Clinical node-positive cases were identified by imaging studies, clinical examination, and/or pathologic diagnosis of fine-needle aspiration cytology or biopsy.
Chemotherapeutic regimens were considered according to biomarker expression. ER, PR, and HER2 were evaluated by immunohistochemistry (IHC) and HER2 equivocal findings on IHC were further evaluated by fluorescent in situ hybridization. TNBC patients are ER, PR negative, and lack overexpression of HER2.
NACT were categorized into three groups based on chemotherapy regimens: Group I (anthracyclin with taxane) was given as 4 cycles of AC regimen followed by 4 cycles of taxane at 3-weekly intervals. Whereas, Group II (anthracyclin without taxane) was given as 4 cycles of AC regimen at 3-weekly intervals without taxane. Group III (Herceptin-based therapy) was given either as TCH regimen for 6 cycles at 3-weekly intervals. AC regimen consisted of adriamycin 60 mg/m2 on day 1 and cyclophosphamide 600 mg/m2 on day 1 in each cycle. Taxane was given was paclitaxel 175 mg/m2 body surface area on day 1 of each cycle. TCH regimen consisted of docetaxel 50 mg/m2, carboplatin area under the curve 5, and herceptin). Herceptin dose was 8 mg/kg body weight in the first cycle, then 6 mg/m2 in subsequent cycles.
Initial tumor size and axillary lymph node size were recorded in all cases. Clinical response to chemotherapy was determined by using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1. Initial tumor size was compared to tumor size after chemotherapy with the help of clinical assessment and radiological imaging. As per the RECIST criteria: Clinical complete response (cCR) is the disappearance of all lesions; clinical partial response (cPR) is the reduction of at least 30% in the diameters of lesions; clinical progressive disease (cPD) is the increase of at least 20% in the diameter of the lesions, and clinical stable disease (cSD) is the presence of lesions with neither sufficient shrinkage to qualify as cPR nor sufficient increase to qualify as cPD. Clinical overall response is the sum of complete response (cCR) and partial response (cPR).
Treatment response was evaluated by histopathological examination of post-NACT specimen. pCR cases were segregated from nonresponders. In case of complete response cases area of fibrosis was noted in the tumor bed in the form of a whitish thickened area. The whole tumor bed was processed to see any residual tumor. pCR was defined as the absence of residual invasive carcinoma in the breast or lymph nodes. Residual in situ component was included under pCR., Histological type, grade, presence of ductal carcinoma in situ (DCIS), and lymphovascular invasion (LVI) were noted.
Statistical analysis was done using IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. IBM Corp. India software. Results were obtained by Chi-square calculation and were considered statistically significant when P < 0.05.
| Results|| |
A total of 50 cases of LABC received NACT followed by undergoing surgery. All the breast cancer cases were female and the mean age of presentation was 46.24 years within the range of 26–70 years. The details of demographic and clinicopathological characteristics along with receptor status are mentioned in [Table 1]. Tumor size was varied from 2 cm to 11 cm at the time of presentation with the mean size of 5.6 cm. Lymph node involvement was found in 39 cases (78%). Forty-eight cases (96%) were of invasive ductal carcinoma (IDC) histology, rest were invasive lobular carcinoma (ILC) and carcinosarcoma 1 case each. Hormonal receptor (ER, PR) positive, HER2 positive, and TNBC were seen in 25 (50%), 22 (44%), and 11 (22%) of patients, respectively. In initial core biopsy, tumor necrosis and LVE were present in 14 cases (28%) and 11 cases (22%), respectively.
After completion of NACT courses, the clinical response based on RECIST criteria revealed cCR in 17 patients (34%), cPR in 20 patients (40%), cSD in 9 patients (18%), and cPD in 4 patients (8%). The overall clinical response was seen in 37 patients (includes cCR and cPR). There was a higher trend of overall clinical response among patients of younger age group ≤50 years (P = 0.148) and those with TNBC (P = 0.054) Whereas, tumor size, histological grading, ER/PR status, and HER2 status had no association with overall clinical response [Table 2].
|Table 2: Clinical and demographic factors associated with clinical response to neoadjuvant chemotherapy|
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The pathological findings of the resected specimens after surgery are mentioned in [Table 3]. pCR was attended in 6 (12%) out of 50 cases. There was no change in histological grading of tumor on postoperative specimen over initial core biopsy. DCIS was seen in initial core biopsy in 15 out of 50 patients.
The association of demographic, clinical, and pathological factors for pCR versus no pCR is evaluated in [Table 4] and [Table 5]. We found a trend of more pCR among patients with tumor size ≤5 cm versus size >5 cm (P = 0.151). All the pCR cases were IDC in histology and 1 case each of ILC and carcinosarcoma did not show pCR (P = 0.083). All the patients with LVE positive on initial core biopsy (n = 11) did not show pCR, although statistically not significant (P = 0.109). DCIS negative cases had a trend of higher chance of pCR than that of positive cases (P = 0.162). The factors such as age, clinical lymph node, histological grade of tumors, molecular biomarkers (hormone receptor, HER2, and TNBC status), and different NACT regimens had no association with pCR achievement (P > 0.05). However, there was a trend of higher pCR achievement among ER/PR negative patients (P = 0.157).
|Table 4: The association of clinical and demographic factors with pathological complete response|
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|Table 5: The association of pathological factors with pathological complete response|
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Tumor necrosis on initial biopsy was seen in 14 out of 50 patients. Four out of 6 patients (66.7%) who achieved pCR had tumor necrosis on initial core biopsy. A statistically significant association was observed between tumor necrosis in the initial biopsy and pCR to NACT (P = 0.024). The presence of tumor necrosis in the core biopsy had a sensitivity of 67% and specificity of 77% in predicting pCR. The negative predictive value (NPV) was found very high (94%), although, the positive predictive value (PPV) was found low (29%), therefore the absence of tumor necrosis was found highly predictive of pathological nonresponders [Table 6].
|Table 6: Evaluation of tumor necrosis in core biopsy as a predictive factor for pathological complete response|
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LVE on initial core biopsy was present in 11 cases (22%). A high specificity (89%) was observed however sensitivity was low (29%) but it has high PPV (82%) to predict axillary node metastasis. None of these 11 cases having LVE in the initial biopsy achieved pCR, which represents a poor prognostic parameter in core biopsy. Although, P value (0.109) was not found statistically significant [Table 7].
|Table 7: Evaluation of lymphovascular emboli in core biopsy as a predictive factor for axillary lymph node metastasis|
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| Discussion|| |
pCR has been defined as the ultimate goal to achieve after NACT in breast cancers, which is associated with increase DFS and OS as concluded in many studies.,,, Therefore, we tried to evaluate various clinicopathological factors that are associated with pathological treatment response in LABC cases which receive NACT.
It was a single-institution study done in a tertiary cancer care setting in a period of 1 year. In this study of 50 LABC patients, the mean age of presentation was 46.24 years which was supported by other studies. Several studies on LABC patients revealed similar findings Study on LABC patients by Patel et al. found the median age of presentation being 45.5 years and by Vasudevan et al. found the mean age of presentation being 50.58 years. Lymph node involvement is common in LABC patients than early-stage breast cancer patients. We found lymph node involvement in 78% of LABC patients. It was supported by other studies. Díaz-Casas et al. in a study on LABC patients found lymph node involvement 91.3% of cases. An Indian study conducted by Saxena et al. on breast cancer patients irrespective of stage found lymph node positivity of 80.2% of cases. According to the type of histopathology, IDC is the most common histology and we found similar findings (96% of IDC)., Majority of LABC patients had higher grade of histological differentiation (grade-2 or-3). All the LABC cases had either grade II (n = 23) or grade III (n = 27) histological differentiation. Similarly, Díaz-Casas et al. showed 53.1% and 42.0% of LABC patients were grade 2 and grade 3, respectively. According to molecular biomarkers, we found 50% of cases as hormonal receptor (ER, PR) positive, 44% as HER2 positive, and 22% as TNBC.
In the present study, pCR was attended in 12% of LABC patients (6 out of 50 cases) after NACT treatment. A review on breast cancer patients as per NCDB between 2010 and 2014 showed breast plus axilla pCR in 6,370 number (19.2%) of patients. A study conducted by Díaz-Casas et al. and Patel et al. showed an overall pCR rate of 15.2% (63 out of 414 cases) and 14% (7 out of 50 cases), respectively.
Only IDC cases showed pCR whereas ILC and carcinosarcoma did not show pCR. similar to a study conducted by Vasudevan et al. and Patel et al. Hence, the histological type can be evaluated further as a probable predictive factor for achieving pCR. We found no association between pCR and tumor grade. It was observed that most of the tumors that achieve pCR were of smaller pretreatment clinical tumor size (<5 cm) although statistically insignificant, and our data were well correlated with other international studies., Estevez and Gradishar concluded that smaller tumor size is a marker for good outcome. Similarly, Jang et al. showed that the lower the clinical T stage better the chance of treatment response. Tumor grade has not been described as an independent prognostic factor in achieving pCR after NACT., Downgrading of tumor was not observed after NACT, similar to a study conducted by Patel et al. LVE has been described as a poor prognostic factor for achieving pCR in many studies. Patel et al. found no pCR in the final histopathology of 13 out of 47 core biopsies (28%) with LVE. Vasudevan et al. found no LVI in any LABC case which showed pCR to NACT treatment and was found to be as a statistically significant (P = 0.015). Our study also showed similar comparable results; all the 11 cases with LVE positive on initial core biopsy did not show pCR, although statistical significance result could not be established due to small sample size.
We found a trend of better overall clinical response for TNBC patients after NACT treatment (P = 0.054). We found no association between molecular biomarkers (hormonal receptor positivity, HER2 neu positivity, and TNBC cases) and pCR after NACT treatment. Although, pCR achievement in TNBC was 18.18%, whereas it was 8% for hormone receptor-positive and 9.10% for HER2 positive cases but small sample size could not find a strong association. Ring et al. showed pCR of 8.1% in ER-positive tumors and Díaz-Casas et al. with a pCR rate of 23.2% for TNBCs patients which is comparable to our study. Fayanju et al. found overall pCR rate of 26.5% in TNBC patients. In our study, HER2 positive tumors achieving pCR was less (9.10%) compared to other studies inspite of the use of targeted regimens which might indicate poor prognostic behavior., pCR in TNBCs predicts the survival and clinical outcome. It is a well-known fact that TNBCs and BRCA-1 mutated tumors share histopathological similarity and also TNBCs are found to be associated with a mutation in the germline BRCA-1 gene, which responds well to specific targeted therapy. There are few studies describing additional benefits of platinum-based therapies along with the use of routine taxane.
In our study, the presence of DCIS was found to be resistant to chemotherapy as DCIS negative cases had a trend of higher chance of pCR than that of positive cases (P = 0.162). Moreover, our data were supported by a study done by Vasudevan et al. where DCIS was present only in 2 cases with pCR (15.4%) suggesting that the presence of DCIS is resistant to chemotherapy. We found a strong association of the presence of tumor necrosis in initial core biopsy with pCR achievement (P = 0.024) and a high NPV of 94%. Hence, we concluded that tumor necrosis on initial biopsy is to be as an important predicting factor for pCR to NACT. An Indian study by Patel et al. observed similar results (P = 0.035). The presence of LVE in initial biopsy can be considered to be a poor prognostic factor as we observed that none of these cases had pCR. We found that the presence of LVE in the initial biopsy had a high specificity (89%) and a high PPV (82%) in predicting axillary node metastasis. Moreover, Patel et al. found similar results on LVE over predicting axillary node metastasis. Therefore, evaluation of some of the parameters like LVE and necrosis in the initial core biopsy is of significant predictive value.
The small sample size is the major limitation of the present study and moreover, our study is retrospective in nature. Therefore, a larger number of cases are needed to evaluate various factors associated with treatment response in post NACT cases of LABC cases.
| Conclusion|| |
The histopathological study is the gold standard to evaluate the treatment response in post NACT cases. The presence of tumor necrosis on initial core biopsy is strongly associated with pCR achievement with a very high NPV suggesting the absence of tumor necrosis was found highly predictive of pathological nonresponders. The presence of DCIS and LVE is resistant to chemotherapy. The prediction of details clinicopathological factors including molecular biomarkers as significant prognostic parameters needs further larger prospective studies.
Acknowledged Mr. Bhaskarjyoti Talukdar, MSC in statistics, project technical officer for helping us in the statistical analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol 2017;13:289-95.
Fayanju OM, Ren Y, Thomas SM, Greenup RA, Plichta JK, Rosenberger LH, et al
. The clinical significance of breast-only and node-only pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT): A review of 20,000 breast cancer patients in the National Cancer Data Base (NCDB). Ann Surg 2018;268:591-601.
Subbiah S, Gopu G, Senthilkumar P, Muniasamy P. Molecular subtypes as a predictor of response to neoadjuvant chemotherapy in breast cancer patients. Indian J Cancer 2017;54:652-7.
] [Full text]
McFarland DC, Naikan J, Rozenblit M, Mandeli J, Bleiweiss I, Tiersten A. Changes in pathological complete response rates after neoadjuvant chemotherapy for breast carcinoma over five years. J Oncol 2016;2016:4324863.
Vasudevan D, Jayalakshmy PS, Kumar S, Mathew S. Assessment of pathological response of breast carcinoma in modified radical mastectomy specimens after neoadjuvant chemotherapy. Int J Breast Cancer 2015;2015:536145.
Díaz-Casas SE, Castilla-Tarra JA, Pena-Torres E, Orozco-Ospino M, Mendoza-Diaz S, Nuñez-Lemus M, et al
. Pathological response to neoadjuvant chemotherapy and the molecular classification of locally advanced breast cancer in a Latin American Cohort. Oncologist 2019;24:e1360-70.
von Minckwitz G, Martin M. Neoadjuvant treatment for triple-negative breast cancer (TNBC). Ann Oncol 2012;23 Suppl 6:vi35-9.
Hennessy BT, Hortobagyi GN, Rouzier R, Kuerer H, Sneige N, Buzdar AU, et al
. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 2005;23:9304-11.
Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al
. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 1998;16:2672-85.
Patel T, Gupta A, Shah M. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy. J Cancer Res Ther 2013;9:245-9.
Saxena S, Rekhi B, Bansal A, Bagga A, Chintamani , Murthy NS. Clinico-morphological patterns of breast cancer including family history in a New Delhi hospital, India – A cross-sectional study. World J Surg Oncol 2005;3:67.
Estévez LG, Gradishar WJ. Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer. Clin Cancer Res 2004;10:3249-61.
Jang CE, Kim JR. Prognostic factor in patient with locally advanced breast cancer treated with neoadjuvanttaxane – Anthracycline combination chemotherapy. Korean J Clin Oncol 2015;11:106-13.
Ring AE, Smith IE, Ashley S, Fulford LG, Lakhani SR. Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer. Br J Cancer 2004;91:2012-7.
Connor CS, Tawfik OW, Joyce AJ, Davis MK, Mayo MS, Jewell WR. A comparison of prognostic tumor markers obtained on image-guided breast biopsies and final surgical specimens. Am J Surg 2002;184:322-4.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]